Search

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

Gestational diabetes mellitus (GDM) is known to be a significant risk factor for the future development of type 2 diabetes. Here, we investigated whether a precise evaluation of β- and α-cell functions helps to identify women at high risk of developing glucose intolerance after GDM. Fifty-six women with GDM underwent a 75-g oral glucose tolerance test (OGTT) at early (6-12 weeks) postpartum. We measured their concentrations of glucose, insulin, proinsulin and glucagon at fasting and 30, 60 and 120 min. At 1-year post-delivery, we classified the women into a normal glucose tolerance (NGT) group or an impaired glucose tolerance (IGT)/diabetes mellitus (DM) group. Forty-three of the 56 women completed the study. At 1-year post-delivery, 17 women had developed IGT/DM and 26 women showed NGT. In the early-postpartum OGTTs, the IGT/DM group showed a lower insulinogenic index, a less glucagon suppression evaluated by the change from fasting to 30 min (ΔGlucagon 30 min), and a higher glucagon-to-insulin ratio at 30 min compared to the NGT group. There were no significant between-group differences in proinsulin levels or proinsulin-to-insulin ratios. Insulinogenic index0.6 and ΔGlucagon 30 min0 pg/mL were identified as predictors for the development of IGT/DM after GDM, independent of age, body mass index, and lactation intensity. These results suggest that the bihormonal disorder of insulin and glucagon causes the postpartum development of glucose intolerance. The measurement of plasma insulin and glucagon during the initial OGTT at early postpartum period can help to make optimal decisions regarding the postpartum management of women with GDM.

Thyroid tumors are the most common types of endocrine malignancies and are commonly treated with radioactive iodine (RAI) to destroy remaining cancer cells following surgical intervention. We previously reported that the expression levels of double-stranded DNA-dependent protein kinase catalytic subunit (DNA-PKcs), which plays a key role in non-homologous end joining, are correlated with the radiosensitivity of cancer cells. Specifically, cells expressing high levels of DNA-PKcs exhibited radiation resistance, whereas cells expressing low levels were sensitive to radiation treatment. In this study, we observed full-length native DNA-PKcs (460 kDa) in radiation-resistant FRO and KTC-2 cells through western blot analysis using an antibody against the C-terminus of DNA-PKcs. In contrast, cleaved DNA-PKcs (175 kDa) were observed in radiation-sensitive TPC-1 and KTC-1 cells. Almost equal amounts of DNA-PKcs were observed in moderately radiation-sensitive WRO cells. We also describe a simple method for the prediction of radiation therapy efficacy in individual cases of thyroid cancers based on staining for DNA-PKcs in human cancer cell lines. Immunofluorescent staining showed that native DNA-PKcs was localized largely in the cytoplasm and only rarely localized in the nuclei of radiation-resistant thyroid cancer cells, whereas in radiation-sensitive cancer cells a 175-kDa cleaved C-terminal fragment of DNA-PKcs was localized mainly inside the nuclei. Therefore, DNA-PKcs moved to the nucleus after γ-ray irradiation. Our results suggest a new method for classifying human thyroid tumors based on their cellular distribution patterns of DNA-PKcs in combination with their radiosensitivity., Journal of radiation research, 61(4), pp.511-516; 2020

A 65-year-old Japanese woman with an intrapericardial tumor and neck tumor was admitted to our hospital. Intrapericardial tumor had not been resected because of massive bleeding from the hypervascular tumor and its invasion into the pericardium, ascending aorta, and pulmonary artery. The neck tumor had been successfully resected, and paraganglioma was pathologically diagnosed. Abnormal accumulation in the intrapericardial tumor was seen with (123)I-metaiodobenzylguanidine scintigraphy. Moreover, gene mutation of succinate dehydrogenase type D was found. Finally, paraganglioma of the carotid body and intrapericardium was diagnosed.

Aims/Introduction The role of glucagon abnormality has recently been reported in type 2 diabetes; however, its role in gestational diabetes mellitus (GDM) is still unknown. The glucose intolerance in GDM is heterogeneous, and not all patients require insulin treatment during pregnancy. Here, we investigated whether glucagon abnormality is associated with the requirement for insulin treatment during pregnancy. Materials and Methods A total of 49 pregnant women diagnosed with GDM were enrolled. They underwent a 75‐g oral glucose tolerance test during mid‐gestation, and we measured their plasma glucagon levels (by a new sandwich enzyme‐linked immunosorbent assay) at fasting (0 min), and at 30, 60 and 120 min after glucose load in addition to the levels of plasma glucose and serum insulin. All participants underwent another oral glucose tolerance test at postpartum. Results Of the 49 patients, 15 required insulin treatment (Insulin group) and 34 were treated with diet therapy alone until delivery (Diet group). The early‐phase glucagon secretion after glucose load, as determined by the changes in glucagon from the baseline to 30 min, was paradoxically augmented during mid‐gestation in the Insulin group, but not in the Diet group. The impaired glucagon suppression during mid‐gestation in the Insulin group was not associated with insulin secretory/sensitivity indexes studied, and was ameliorated postpartum, although the plasma glucose levels remained higher in the Insulin group versus the Diet group. Conclusions Impaired early‐phase suppression of glucagon could be associated with the requirement for insulin treatment during pregnancy in patients with GDM., We evaluated the glucagon responses to oral glucose load in patients with gestational diabetes mellitus using a new sandwich enzyme‐linked immunosorbent assay. We investigated whether the glucagon abnormality is associated with the requirement for insulin treatment during pregnancy.

Differentiated thyroid carcinomas (DTC) are the most frequent malignancies of the endocrine system in 2015 in Japan. The purpose of this study is to estimate clearance rate of Iodine-131 from thyroid cancer patients based on individual patient’s characteristics. Materials and methods: We conducted retrospective study including 87 cases with DTC who had received RAI from June 2016 till July 2018. Patients who had complete information on primary tumor size (PTS) as mentioned in their histopathology reports, TNM staging, serum TSH (uIU/ml), free-T3 (pg/mL), free-T4 (ng/dL), thyroglobulin level (Tg) (ng/ml) (one month before, on the day of the treatment, and one month after receiving RAI), anti-Tg antibodies (IU/mL), dose of Levothyroxine (before and after RAI), as well as renal function (creatinine, BUN, eGFR), exposure rate (µSv/h) and taken dose (mCi) were included in our study. Results: Univariate analysis showed significant associations of effective half-life with several factors (gender, body height, body weight, eGFR, size of tumor, dose of Levothyroxine, free-T3 one month after receiving RAI). Conclusion: Effective management of these factors could help the doctors to optimize the occupancy of isolated rooms with higher output, but also reduce the operational cost of the hospital and improving the comfort to patients.

Aims/Introduction Controlling postprandial glucose levels in patients with type 1 diabetes is challenging even under the adequate treatment of insulin injection. Recent studies showed that dysregulated glucagon secretion exacerbates hyperglycemia in type 2 diabetes patients, but little is known in type 1 diabetes patients. We investigated whether the glucagon response to a meal ingestion could influence the postprandial glucose excursion in patients with type 1 diabetes. Materials and Methods We enrolled 34 patients with type 1 diabetes and 23 patients with type 2 diabetes as controls. All patients underwent a liquid mixed meal tolerance test. We measured levels of plasma glucose, C‐peptide and glucagon at fasting (0 min), and 30, 60 and 120 min after meal ingestion. All type 1 diabetes patients received their usual basal insulin and two‐thirds of the necessary dose of the premeal bolus insulin. Results The levels of plasma glucagon were elevated and peaked 30 min after the mixed meal ingestion in both type 1 diabetes and type 2 diabetes patients. The glucagon increments from fasting to each time point (30, 60 and 120 min) in type 1 diabetes patients were comparable to those in type 2 diabetes patients. Among the type 1 diabetes patients, the glucagon response showed no differences between the subgroups based on diabetes duration (, We investigated the glucagon response to mixed‐meal in type 1 diabetes. Hyperglucagonemia after mixed‐meal ingestion was associated with early‐postprandial glucose excursions.

As a rare condition characterized by inflammation of the pituitary gland, hypophysitis usually results in hypopituitarism and pituitary enlargement. The most critical outcome of hypopituitarism is caused by secondary adrenal insufficiency. Glucocorticoid deficiency is a life-threatening condition, and patients who develop this deficiency require prompt diagnosis and treatment. However, a delayed diagnosis of hypopituitarism may occur due to its non-specific clinical manifestations. A common presenting sign of glucocorticoid deficiency is hypoglycemia. The amelioration of hyperglycemia has been observed in diabetic patients with adrenal insufficiency. We report the case of a 70-year-old Japanese woman who had suffered from fatigue and anorexia for several months; she was admitted based on refractory hyponatremia (sodium 125-128 mEq/L) and hypoglycemia (glucose 58-75 mg/dL). Laboratory findings and magnetic resonance imaging findings led to the diagnosis of panhypopituitarism caused by autoimmune hypophysitis. After receiving 10 mg/day of hydrocortisone, the patient developed severe hyperglycemia (glucose >500 mg/dL). Undetectable C-peptide levels and positive results of both insulinoma-associated antigen-2 antibodies and insulin autoantibodies indicated that she had experienced a recent onset of type 1 diabetes. The pathophysiological process indicated that overt hyperglycemia could be masked by the deficient action of glucocorticoids even in a diabetic patient with endogenous insulin deficiency. This uncommon case reinforces the importance of the prompt diagnosis and treatment of hypopituitarism. Clinicians should remain aware of the possibility of hidden diabetes when treating hypoglycemia in patients with adrenal insufficiency.

BACKGROUND: New-onset diabetes mellitus (DM) often develops after partial pancreatectomy. Little is known regarding how soon patients develop glucose intolerance after partial pancreatectomy. We investigated the incidence of and factors contributing to the development of glucose intolerance during hospitalization after partial pancreatectomy. PATIENTS AND METHODS: We retrospectively analyzed the cases of 38 patients with normal glucose tolerance pre-surgery who underwent a partial pancreatectomy (pancreaticoduodenectomy, n = 23; distal pancreatectomy, n = 15). The patients’ glucose tolerance and insulin secretory/sensitivity values were determined by a normal meal tolerance test (NMTT) within 2 months post-surgery during their hospitalization. RESULTS: The post-surgery NMTT values revealed that 11 (28.9%) patients developed new-onset impaired glucose tolerance (the IGT group); the other 27 (71.1%) patients maintained normal glucose tolerance (the NGT group). The pre-operative hemoglobin A1c (HbA1c) levels were significantly higher in the IGT group (5.84%) versus the NGT group (5.58%, p = 0.034). There were no significant between-group differences in age, sex ratio, body mass index, the ratio of operative procedure (either pancreaticoduodenectomy or distal pancreatectomy), or post-operative insulin secretory values including the fasting/postprandial C-peptide index. The IGT group showed significantly higher insulin resistance assessed by the homeostasis model assessment of insulin resistance (HOMA-IR) versus the NGT group (1.52 ± 0.67 vs. 0.65 ± 0.42, p

Objective: Patients with Graves disease (GD) tend to gain weight after treatment, but it remains unknown if weight gain is associated with an increase in the visceral and/or subcutaneous f...

Aims: To evaluate the glycaemic control of combination therapy with basal insulin and liraglutide, and to explore the factors predictive of efficacy in patients with type 2 diabetes when switched from longstanding basal-bolus insulin therapy. Methods: We studied 41 patients who switched from basal-bolus insulin therapy of more than 3 years to basal insulin/liraglutide combination therapy. Glycaemic control was evaluated at 6 months after switching therapy and used to subdivide the patients into good-responders (HbA1c, Diabetes Research and Clinical Practice, 144, pp.161-170; 2018

A 27-year-old woman with a history of gestational diabetes mellitus (GDM) developed type 1 diabetes mellitus (T1D) in the early postpartum period. Women with a history of GDM are at an increased risk of developing T1D, which is rarer than type 2 diabetes mellitus. A postpartum follow-up 75-g oral glucose tolerance test and the measurement of glutamic acid decarboxylase autoantibodies aided in the early detection of T1D in this patient. Careful attention should be paid to women with a history of GDM who exhibit clinical features suggestive of future development of T1D.

Cerebrotendinous xanthomatosis (CTX) is a rare, autosomal recessive, inborn disruption in bile acid synthesis characterized by severe systemic xanthomas, cataracts and neurological injuries occurring before adolescence without elevation of the serum cholesterol or triglyceride levels. CTX is caused by a deficiency of the mitochondrial enzyme sterol 27-hydroxylase, which is encoded by the CYP27A1 gene. We herein report a 50-year-old Japanese woman with late-onset CTX who had no relevant symptoms before the development of bilateral Achilles tendon xanthomas in middle age. A genetic analysis revealed a compound heterozygous mutation in the CYP27A1 gene with a previously known missense mutation (NM_000784.3:c.1421 G>A) and a novel frame shift mutation of NM_000784.3:c.1342_1343insCACC.

It has been reported that glucose responses during the oral glucose tolerance test differ between healthy women and men. However, it remains unknown what factors contribute to these differences between the sexes. The present study analyzed the insulin and glucagon responses during the oral glucose tolerance test in 25 female and 38 male healthy young adults aged 22–30 years. The plasma glucose levels at 120 min were significantly higher in women than men. Insulin secretion was significantly greater at 30, 90 and 120 min from baseline in women than men. Glucagon suppression was greater at 30 and 120 min from baseline in men than women when determined by a sandwich enzyme‐linked immunosorbent assay glucagon kit. These results suggest that the differences in glucose responses during the oral glucose tolerance test are mediated by the difference between the sexes in bi‐hormonal responses in healthy individuals.

Aims Sodium-glucose cotransporter 2 inhibitors (SGLT2i) cause substantially less weight loss than would be expected based on their caloric deficits, probably due to enhanced appetite regulation known as “compensatory hyperphagia,” which occurs to offset the negative energy balance caused by increased glycosuria. We examined whether any specific nutrients contributed to the compensatory hyperphagia in diabetic patients taking SGLT2i. Methods Sixteen patients with type 2 diabetes were newly administered dapagliflozin 5 mg daily as the experimental SGLT2i group. Sixteen age-, sex- and BMI-matched type 2 diabetes patients not receiving dapagliflozin served as controls. A brief-type self-administered diet history questionnaire (BDHQ) was undertaken just before and 3 months after study initiation to evaluate changes of energy and nutrient intakes in each group. Results At 3 months, daily intakes of total calories and the proportions of the three major nutrients were not significantly increased in either group. However, daily sucrose intake was significantly increased after treatment versus the baseline value in the SGLT2i group (p =.003), but not in controls. The calculated intakes of all other nutrients were not significantly changed in either group. Conclusions Dapagliflozin treatment specifically increased sucrose intake, which might be an ideal target for nutritional approaches to attenuate compensatory hyperphagia., Diabetes Research and Clinical Practice, 135, pp.178-184; 2018

A 46-year-old woman with a history of Graves' disease presented with the chief complaints of appetite loss, weight loss, fatigue, nausea, and sweating. She was diagnosed with diabetic ketoacidosis (DKA), thyroid storm, and influenza A. She was treated with an intravenous insulin drip, intravenous fluid therapy, intravenous hydrocortisone, oral potassium iodine, and oral methimazole. As methimazole-induced neutropenia was suspected, the patient underwent thyroidectomy. It is important to maintain awareness that thyroid storm and DKA can coexist. Furthermore, even patients who have relatively preserved insulin secretion can develop DKA if thyroid storm and infection develop simultaneously.

Objective: Synovitis, acne, pustulosis, hyperostosis, osteitis (SAPHO) syndrome is a rare, chronic, relapsing inflammatory osteoarticular disorder with dermatologic manifestations. SAPHO syndrome can be a rare cause of atypical symptoms including neurologic defects. We report a case with SAPHO syndrome with the endocrinologic defects most likely associated with SAPHO syndrome.Methods: Case report and review of the literature.Results: A 61-year-old Japanese female with SAPHO syndrome presented with polyuria and polydipsia. Pituitary magnetic resonance imaging (MRI) with gadolinium enhancement showed an enlarged infundibulum and pituitary with ring-enhancing masses located at the posterior pituitary and upper infundibulum. Extensive diagnostic workup excluded local and systemic infection, brain metastasis, and various secondary hypophysitis as the cause of the infundibular and pituitary lesions. There were spontaneous improvements in the MRI findings taken 4 months after her initial presentation. The patient underwent a biopsy of the anterior pituitary, which showed a sterile lymphocytic infiltration.Conclusion: There are rare cases of SAPHO syndrome patients in which transient neurologic symptoms associated with the self-limiting ring-enhancing lesions consisting of a sterile and nonspecific inflammation are described. Since cystic formation in the infundibulum caused by idiopathic lymphocytic hypophysitis has not been reported, to the best of our knowledge, we concluded that the endocrinologic defects in our patient were most likely associated with SAPHO syndrome. Thus, SAPHO syndrome should be considered as one of the causes not only for ring-enhancing lesions in the brain but also for secondary hypophysitis, especially in patients with dermatologic and osteoarticular manifestations.

Aims: The prevalence of gestational diabetes mellitus (GDM) has recently increased all over the world. It is hard to predict insulin need during pregnancy even if the insulin secretory capacity is evaluated when studying 75-g OGTT to screen for GDM. The role of glucagon abnormality has remarked in pathogenesis of type 2 diabetes, however, still unknown in GDM. This study was aimed to evaluate glucagon responses in GDM and to investigate whether measurement of glucagon is useful to anticipate insulin need during pregnancy. Methods: Forty-nine women diagnosed with GDM based on IADPSG criteria were enrolled into the study and re-studied OGTT during mid-gestation to evaluate glucagon responses. Plasma glucagon levels were measured before and 30, 60, 120 min after glucose load using a sandwich ELISA kit. Insulin treatment was initiated when either a fasting glucose >95 mg/dL or postprandial 2-h glucose >120 mg/dL continues for more than a week after starting diet therapy. Results: Of 49 patients, fifteen were required insulin (defined as GDM/Insulin) and 34 could be treated with diet therapy alone until delivery (defined as GDM/Diet). GDM/Insulin was started insulin treatment at 29.6±3.6 weeks of gestation and the maximum insulin dose was 39.0±24.8 units/day. There were no significant differences in maternal age, pre-gravid BMI and insulin secretory responses during OGTT between the groups. Although fasting glucagon levels were not different between the groups, paradoxical increases in early-phase glucagon secretion after glucose load were observed in GDM/Insulin but not in GDM/Diet. The changes in glucagon levels (pg/mL) from 0 min to 30 min were significantly different between the groups (1.3±8.1 in GDM/Insulin vs. -4.2±4.0 in GDM/Diet, p Conclusions: Impaired early-phase glucagon suppression might be useful to predict for insulin need during pregnancy in GDM. Disclosure I. Horie: None. A. Haraguchi: None. N. Abiru: None. A. Kawakami: None.

Background Patients with central diabetes insipidus (CDI) are known to lose weight because their polydipsia interferes with their nutritional intake. We retrospectively examined weight changes in CDI patients when they switched from nasal to oral desmopressin. Methods Twenty-three patients with CDI were included. Weight change was defined as an increase or decrease of more than 3 kg or 3% body weight. As factors contributing to the weight change, we studied the patients' clinical characteristics and quality of life (QOL) scores as determined by our original questionnaire. Results Five patients showed a weight loss of 5.9 kg (2.4-9.0 kg), and two patients showed weight gain, while 16 out of 23 patients were weight neutral. When the patients with weight gain and weight neutral were analyzed together, the mean weight change was +0.3 kg (-0.5 to +1.1 kg). All the patients who lost weight had a Body Mass Index ≥22 kg/m2 (38% vs. 0%, P=0.027) and higher frequencies of abnormally high serum levels of AST (40% vs. 0%, P=0.005). The sum of the QOL scores was similar between the two groups, but higher in patients who lost weight after switching to oral desmopressin (43.3±2.7) than in those who did not (38.2±5.0, P=0.01). Conclusions Switching the treatment from nasal to oral desmopressin may cause weight loss in patients with CDI who seemed to have polydipsia-associated weight gain.

Background: Mitochondrial diabetes mellitus (MDM) is characterized by maternal inheritance, progressive neurosensory deafness, insulin secretory disorder, and progressive microvascular complications. Mitochondria are critical organelles that provide energy in the form of adenosine triphosphate (ATP). An impairment of ATP production in pancreatic β cells is regarded as the main cause of the insulin secretory disorder in patients with MDM, and these patients require insulin replacement therapy early after the diagnosis. The amino acid 5-aminolevulinic acid (5-ALA), a precursor of heme metabolites, is a non-proteinogenic δ amino acid synthesized in mitochondria. An addition of ferrous iron to 5-ALA enhances heme biosynthesis and increases ATP production through an upregulation of the respiratory complex. Several studies have reported that the administration of 5-ALA and ferrous iron to existing treatment improved the glycemic control in both patients with prediabetes and those with type 2 diabetes mellitus. The additional administration of 5-ALA and ferrous iron to MDM patients on insulin therapy may improve their insulin secretory capacity and glycemic control by improving their mitochondrial function. The findings of this study are expected to provide new treatment options for MDM and improve the patients’ glycemic control and prognosis. Methods/design: This study is a single-arm, open-label pilot intervention study using clinical endpoints to investigate the effects of treatment with 5-ALA plus sodium ferrous citrate (SFC) to patients with MDM on their glucose tolerance. A total of 5 patients with MDM will be administered 5-ALA/SFC (200 mg/d) for 24 weeks. We will perform a 75-g oral glucose tolerance test before and at 24 weeks after the start of this 5-ALA/SFC treatment to evaluate glucose-dependent insulin responses. Discussion: To the best of our knowledge, this study will be the first assessment of the effects of 5-ALA/SFC in patients with MDM. This study will obtain an evidence regarding the effectiveness and safety of 5-ALA/SFC for patients with MDM. Trial registration: This study was registered with the University Hospital Medical Information Network (UMIN000040581) on July 1, 2020 and with the Japan Registry of Clinical Trials (jRCTs071200025) on August 3, 2020., Medicine, 100(10), pp. e25100; 2021

BACKGROUND: Older patients with type 2 diabetes mellitus (T2DM) have an increased risk of bone fracture independent of their bone mineral density (BMD), which is explained mainly by the deteriorated bone quality in T2DM compared to that in non-diabetic adults. Sodium-glucose co-transporter (SGLT) 2 inhibitors have been studied in several trials in T2DM, and the Canagliflozin Cardiovascular Assessment Study showed an increased fracture risk related to treatment with the SGLT2 inhibitor canagliflozin, although no evidence of increased fracture risk with treatment with other SGLT2 inhibitors has been reported. The mechanism of the difference in the fracture risk between the SGLT2 inhibitors is unknown, but the differences among the SGLT2 inhibitors in the selectivity of SGLT2 against SGLT1 may affect bone metabolism, since among the SGLT2 inhibitors the selectivity of canagliflozin is lowest. We will investigate whether the SGLT2 inhibitor luseogliflozin, which has the higher SGLT2 selectivity, affects bone metabolism by using high-resolution, peripheral quantitative computed tomography (HR-pQCT) which provides direct in vivo morphometric information about the bone microarchitecture. METHODS/DESIGN: This is a single-center, randomized, open-label, active-controlled, parallel pilot trial. Eligible participants are older (age???60?years) individuals with T2DM with HbA1c levels at 7.0-8.9%. A total of 24 participants will be allocated to either the luseogliflozin group (taking luseogliflozin) or the control group (taking metformin) in a 1:1 ratio to compare the groups' changes in bone microarchitecture of the radius and tibia which are analyzed by HR-pQCT before and at 48?weeks after the administration of each medication. The laboratory data associated with glycemic control and bone metabolism will be collected every 12?weeks during the study. Recruitment began in June 2019. DISCUSSION: The reason that we use metformin as an active control is to avoid yielding differences in glycemic control between the luseogliflozin and control groups. Besides, metformin is considered to have a neutral effect on bone. This trial should reveal the effect of luseogliflozin on bone metabolism in older patients with T2DM. TRIAL REGISTRATION:The study was registered with the University Hospital Medical Information Network (UMIN000036202) on 1 April 2019 and with the Japan Registry of Clinicla Trials (jRCTs071180061) on 14 March 2019., Trials, 21(1), art.no.379; 2020

We examined the baseline pulmonary resistance (RLung), baseline dynamic lung compliance (Cdyn), cytokine inductions, and histological alterations in rats exposed to nitrous acid (HONO) with secondary products of nitrogen dioxide (NO

Aims/hypothesis: Interferon regulatory factor (IRF)4 plays a critical role in lymphoid development and the regulation of immune responses. Genetic deletion of IRF4 has been shown to suppress autoimmune disease in several mouse models, but its role in autoimmune diabetes in NOD mice remains unknown. Methods: To address the role of IRF4 in the pathogenesis of autoimmune diabetes in NOD mice, we generated IRF4-knockout NOD mice and investigated the impact of the genetic deletion of IRF4 on diabetes, insulitis and insulin autoantibody; the effector function of T cells in vivo and in vitro; and the proportion of dendritic cell subsets. Results: Heterozygous IRF4-deficient NOD mice maintained the number and phenotype of T cells at levels similar to NOD mice. However, diabetes and autoantibody production were completely suppressed in both heterozygous and homozygous IRF4-deficient NOD mice. The level of insulitis was strongly suppressed in both heterozygous and homozygous IRF4-deficient mice, with minimal insulitis observed in heterozygous mice. An adoptive transfer study revealed that IRF4 deficiency conferred disease resistance in a gene-dose-dependent manner in recipient NOD/severe combined immunodeficiency mice. Furthermore, the proportion of migratory dendritic cells in lymph nodes was reduced in heterozygous and homozygous IRF4-deficient NOD mice in an IRF4 dose-dependent manner. These results suggest that the levels of IRF4 in T cells and dendritic cells are important for the pathogenesis of diabetes in NOD mice. Conclusions/interpretation: Haploinsufficiency of IRF4 halted disease development in NOD mice. Our findings suggest that an IRF4-targeted strategy might be useful for modulating autoimmunity in type 1 diabetes., Diabetologia, 58(11), pp.2606-2614; 2015

Central diabetes insipidus (CDI) is characterized by polyuria and polydipsia due to a deficiency of vasopressin. Currently, the treatment goal for CDI is improvement of quality of life (QOL) by desmopressin (DDAVP) without developing hyponatremia. However, there is no reliable measure for QOL in CDI patients. We evaluate our original questionnaire for QOL, consisting of 12 questions focusing on polyuria, polydipsia, and DDAVP treatment, in CDI patients who underwent a switch from nasal spray to oral disintegrating tablets of DDAVP. Twenty-five CDI patients under nasal DDAVP treatment, six with newly developed CDI, and 18 healthy individuals without known polyuric/polydipsic disorders as control subjects were enrolled. QOL scores were determined by our questionnaire at the enrollment and 3 months after the start of oral DDAVP treatment and were examined by the Wilcoxon signed-rank test. Eleven questions detected improvement in QOL. The sum of the QOL scores of the eleven questions increased from 29.2 ± 5.6 under nasal to 36.8 ± 4.5 under oral DDAVP (p < 0.001). There were no clinically relevant changes in serum levels of Na. After eliminating two questions about DDAVP treatment, the sum of QOL scores was 15.3 ± 6.5 in untreated CDI patients, 24.4 ± 5.2 in those with nasal treatment, 28.9 ± 4.9 in those with oral DDAVP, and 29.5 ± 3.6 in healthy controls. The difference among groups was significant (p < 0.05 in Steel-Dwass test) except between patients treated with oral DDAVP and healthy controls. Our questionnaire can be used to accurately assess QOL in CDI patients.

Thyroid storm is a rare and life-threatening complication of thyrotoxicosis that requires prompt treatment. Thyroid storm is also known to be associated with precipitating events. The simultaneous treatment of thyroid storm and its precipitant, when they are recognized, in a patient is recommended; otherwise such disorders, including thyroid storm, can exacerbate each other. Here we report the case of a thyroid storm patient (a 55-year-old Japanese male) complicated with a perforated duodenal ulcer. The patient was successfully treated with intensive treatment for thyroid storm and a prompt operation. Although it is believed that peptic ulcer rarely coexists with hyperthyroidism, among patients with thyroid storm, perforation of a peptic ulcer has been reported as one of the causes of fatal outcome. We determined that surgical intervention was required in this patient, reported despite ongoing severe thyrotoxicosis, and reported herein a successful outcome.

T helper type (Th) 17 cells have been shown to play important roles in mouse models of several autoimmune diseases that have been classified as Th1 diseases. In the NOD mouse, the relevance of Th1 and Th17 is controversial, because single-cytokine-deficient NOD mice develop diabetes similarly to wild-type NOD mice.We studied the impact of IL-17/IFN-γ receptor double deficiency in NOD mice on the development of insulitis/diabetes compared with IL-17 single-deficient mice and wild-type mice by monitoring diabetes-related phenotypes. The lymphocyte phenotypes were determined by flow cytometric analysis.IL-17 single-deficient NOD mice showed delayed onset of diabetes and reduced severity of insulitis, but the cumulative incidence of longstanding diabetes in the IL-17-deficient mice was similar to that in wild-type mice. The IL-17/IFN-γ receptor double-deficient NOD mice showed an apparent decline in longstanding diabetes onset, but not in insulitis compared with that in the IL-17 single-deficient mice. We also found that double-deficient NOD mice had a severe lymphopenic phenotype and preferential increase in regulatory T cells among CD4(+) T cells compared with the IL-17 single-deficient mice and wild-type NOD mice. An adoptive transfer study with CD4(+)CD25(-) T cells from young non-diabetic IL-17 single-deficient NOD mice, but not those from older mice, showed significantly delayed disease onset in immune-deficient hosts compared with the corresponding wild-type mice.These results indicate that IL-17/Th17 participates in the development of insulitis and that both IL-17 and IFN-γ signalling may synergistically contribute to the development of diabetes in NOD mice.

The Na+/Ca2+ exchanger (NCX), an ion-transporter located in the plasma membrane of neuronal cells, contributes to intracellular Ca2+ homeostasis. Within the brain, three isoforms (NCX1, NCX2, and NCX3) are widely distributed. However, it is not clear to what extent these isoforms are involved in ischemic brain damage in mammals. We therefore used genetically altered mice and isoform-selective NCX inhibitors in a model of transient focal ischemia to investigate the role of each NCX isoform in ischemic brain damage. NCX isoform-mutant mice (NCX1+/−, NCX2+/−, and NCX3+/−) and wild-type mice were subjected to 90 min of middle cerebral artery occlusion (MCAO) followed by 24 h of reperfusion. One of three NCX inhibitors [SN-6, KB-R7943, or SEA0400 (3 or 10 mg kg−1, i.p.)] was administered to ddY mice at 30 min before more prolonged (4-h) MCAO followed by 24 h of reperfusion. After transient MCAO reperfusion, the cerebral infarcts in NCX1+/− mice, but not those in NCX2+/− or NCX3+/− mice, were significantly smaller than those in wild-type mice. SN-6 and SEA0400, which are more selective for the NCX1 isoform, significantly reduced the infarct volume at 10 mg/kg. In contrast, KB-R7943, which is more selective for NCX3, did not. These results suggest that the NCX1 isoform may act preferentially (vs. the NCX2 and NCX3 isoforms) to exacerbate the cerebral damage caused by ischemic insult in mice, and that NCX1-selective inhibitors warrant investigation as a potential therapeutic agents for stroke.

A low-carbohydrate diet is effective to improve hyperglycemia via insulin-independent actions. We report here that a low-carbohydrate diet combined with an SGLT2 inhibitor was effective and safe to treat refractory hyperglycemia in the perioperative period in a type 2 diabetes patient complicated with a high titer of insulin antibodies.

Glycogenic hepatopathy (GH) has been reported as a very rare and under recognized complication in long-standing poorly controlled type 1 diabetes (T1D) patients. GH is characterized by transient elevation of liver transaminase and hepatomegaly caused by reversible and excessive glycogen accumulation in hepatocytes. It has been reported that GH is indistinguishable from non-alcoholic fatty liver disease, which is more commonly seen in diabetic patients, even after a history is taken and a physical examination or imaging studies have been performed. GH can only be diagnosed by liver biopsy. We here demonstrate a 21-year-old male patient with new-onset fulminant T1D complicated with diabetic ketoacidosis who subsequently developed GH just after the initiation of insulin treatment. The marked liver dysfunction (serum levels of aspartate aminotransferase 769 IU/L and alanine aminotransferase 1348 IU/L) and hepatomegaly improved spontaneously via glycemic control without any specific treatments thereafter. Moreover, the insulin requirement dramatically decreased from 168 to 80 units per day as GH improved, suggesting a potential role of GH in insulin resistance. GH was diagnosed based on the histological findings of the liver in our case, but we were able to predict GH before the biopsy based on the findings in the gradient-dual-echo magnetic resonance imaging sequence combined with ultrasound and/or computed tomography examinations of the liver.

MUC1 is a type I transmembrane glycoprotein aberrantly overexpressed in various cancer cells. High expression of MUC1 is closely associated with cancer progression and metastasis, leading to poor prognosis. We previously reported that MUC1 is internalized by the binding of the anti-MUC1 antibody, from the cell surface to the intracellular region via the macropinocytotic pathway. Since MUC1 is closely associated with ErbBs, such as EGF receptor (EGFR) in cancer cells, we examined the effect of the anti-MUC1 antibody on EGFR trafficking. Our results show that: (1) anti-MUC1 antibody GP1.4, but not another anti-MUC1 antibody C595, triggered the internalization of EGFR in pancreatic cancer cells; (2) internalization of EGFR by GP1.4 resulted in the inhibition of ERK phosphorylation by EGF stimulation, in a MUC1 dependent manner; (3) inhibition of ERK phosphorylation by GP1.4 resulted in the suppression of proliferation and migration of pancreatic cancer cells. We conclude that the internalization of EGFR by anti-MUC1 antibody GP1.4 inhibits the progression of cancer cells via the inhibition of EGFR signaling.

T helper type 17 (Th17) cells, a newly identified effector T-cell subset, have recently been shown to play a role in numerous autoimmune diseases, including iodine-induced autoimmune thyroiditis in non-obese diabetic (NOD)-H2(h4) mice, which had previously been thought Th1-dominant. We here studied the role of Th17 in Graves' hyperthyroidism, another thyroid-specific autoimmune disease, in a mouse model. Two genetically distinct BALB/c and NOD-H2(h4) strains with intact or disrupted IL-17 genes (IL-17(+/+) or IL-17(-/-)) were immunized with adenovirus (Ad) expressing the thyrotropin receptor (TSHR) A-subunit (Ad-TSHR289). Both IL-17(+/+) and IL-17(-/-) mice developed anti-TSHR antibodies and hyperthyroidism at equally high frequencies on the BALB/c genetic background. In contrast, some IL-17(+/+), but none of IL-17(-/-), mice became hyperthyroid on the NOD-H2(h4) genetic background, indicating the crucial role of IL-17 for development of Graves' hyperthyroidism in non-susceptible NOD-H2(h4), but not in susceptible BALB/c mice. In the T-cell recall assay, splenocytes and lymphocytes from the draining lymph nodes from either mouse strains, irrespective of IL-17 gene status, produced IFN-γ and IL-10 but not other cytokines including IL-17 in response to TSHR antigen. Thus, the functional significance of Th17 may not necessarily be predictable from cytokine expression patterns in splenocytes or inflammatory lesions. In conclusion, this is, to our knowledge, the first report showing that the role of Th17 cells for the pathogenesis of a certain autoimmune disease depends on the mouse genetic backgrounds., Autoimmunity, 44(2), pp.159-165; 2011

Circulating anti-islet autoantibodies in sera are used as a predictive marker for type 1 diabetes (T1D). We here report two Japanese patients with autoimmune thyroid disease complicated with T1D in whom the time course of anti-islet autoantibodies were observed before the clinical onset of diabetes. Case 1: A woman who had developed Graves' disease at age 25 was diagnosed with type 2 diabetes at age 31; six months later, insulin therapy was started. At age 36 she was diagnosed with T1D due to glutamic acid decarboxylase 65 autoantibodies (GAD65Ab)-positive status and decreased C-peptide levels. With stored sera we retrospectively followed her anti-islet autoantibodies. GAD65Ab, zinc transporter 8 autoantibodies (ZnT8Ab) and insulin autoantibodies (IAA) were found to be positive at age 25. IAA soon turned negative, but GAD65Ab and ZnT8Ab remained positive with high levels. Insulinoma-associated antigen-2 autoantibodies (IA-2Ab) emerged 2 years before the initiation of insulin therapy. She has T1D-susceptible HLA-DRB1-DQB1 haplotypes, (*)0405- (*)0401/(*)0802-(*)0302. Case 2: A 49-year-old woman with hypothyroidism due to 19 years' history of atrophic thyroiditis noticed marked thirst, polyuria and weight loss. On admission she was diagnosed as T1D due to GAD65Ab-positive findings and poor C-peptide response to i.v. glucagon. Retrospective serology revealed the emergence of GAD65Ab and IAA just after the clinical onset. IA-2Ab and ZnT8Ab never developed. She has T1D-susceptible and -resistant HLADRB1- DQB1 haplotypes, (*)0901-(*)0303/(*)1502-(*)0601. The autoantibody profile and the mode of diabetes onset in the two cases were remarkably different. These cases imply that anti-islet autoantibodies do not always precede the onset of T1D.

Patients with unresectable parathyroid carcinoma develop severe hypercalcemia, bone fractures and renal failure, and become unresponsive to conventional treatments. It has been shown that successful induction of anti-parathyroid hormone (PTH) antibodies, using PTH peptide fragments for immunisation, normalized serum levels of calcium as well as improved clinical symptoms. Here, we report our experience of PTH immunization in a Japanese female suffering from refractory hypercalcemia and renal failure caused by unresectable metastatic parathyroid carcinoma. Upon immunization, there were apparent clinical responses including reduction of serum levels of Ca along with anti-PTH antibodies induction. Therefore, we concluded that PTH immunization was an effective treatment against hypercalcemia caused by metastatic parathyroid carcinomas that are unresponsive to conventional treatments.

T helper type 1(Th1)/Th2 paradigm has been expanded by discovery of a novel effector T cell (T(eff)) subset, Th17 cells, which produce a proinflammatory cytokine IL-17. Th17 cells have recently been shown to play a major role in numerous autoimmune diseases that had previously been thought to be Th1-dominant diseases. We here studied the significance of Th17 cells in iodine-induced autoimmune thyroiditis in nonobese diabetic-H2(h4) mice, a mouse model of Hashimoto's thyroiditis in humans, which spontaneously develop antithyroglobulin autoantibodies and intrathyroidal lymphocyte infiltration when supplied with iodine in the drinking water. We observed increased numbers of Th1 and Th17 cells in spleen and accumulation of both types of T(eff) in the thyroid glands of iodine-fed wild-type mice, indicating that Th17 cells as well as Th1 cells constitute thyroid lesions. Furthermore, the incidence and severity of intrathyroidal lymphocyte infiltration, and the titers of antithyroglobulin autoantibodies were markedly reduced in iodine-treated IL-17(-/-) mice as compared with wild-type mice. Of interest, IL-17(+/-) mice showed an intermediate phenotype. Therefore, the present study, together with a previous report demonstrating the importance of Th1, not Th2, immune response for developing thyroiditis using mice deficient for interferon-gamma or IL-4, clearly indicates that both Th1 and Th17 cells are critical T(eff) subsets for the pathogenesis of spontaneous autoimmune thyroiditis in nonobese diabetic-H2(h4) mice., Endocrinology, 150(11), pp.5135-5142; 2009

NOD-H2(h4) mice, which express I-A(k) on the NOD background, spontaneously develop autoimmune thyroiditis, a model of Hashimoto thyroiditis in humans, by adding iodide in the drinking water. Parental NOD mice have previously been shown to have intrinsic numerical abnormalities in peripheral lymphocytes and lymphocyte subpopulations such as CD4(+)CD25(+) naturally occurring regulatory T cells (Treg). Therefore we first investigated whether the similar abnormalities exist in NOD-H2(h4) mice. We observed that, compared with other non-autoimmune disease prone BALB/c and C57BL/6 mice, NOD-H2(h4) mice have lower numbers of splenocytes, CD3(+)T, CD4(+)T and CD8(+)T cells but the ratios of Treg to CD4(+)T cells were comparable. Increasing the numbers of peripheral lymphocytes by Complete Freund's Adjuvant immunization or splenocyte transfer did not affect development of thyroiditis, indicating that lymphopenia does not play a critical role in the pathogenesis of thyroiditis. We next examined the significance of Treg by depleting this lymphocyte subset with anti-CD25 antibody. Treg depletion, performed 4days before the administration of NaI water for 8 weeks, significantly exacerbated thyroiditis (p

Hyponatremia is observed in hypothyroidism, but it is not known if hypo- or hyperkalemia is associated with hypothyroidism. To study these questions, we determined serum potassium (K(+)) levels in thyroidectomized patients undergoing levothyroxine withdrawal before radioactive iodine (RAI) therapy for thyroid carcinoma.We retrospectively studied the records of 108 patients who had undergone total thyroidectomy for thyroid carcinoma followed by levothyroxine withdrawal and then ablation with RAI at Nagasaki University Hospital from 2009-2013. Blood samples were analyzed for serum K(+) concentrations when patients were euthyroid just before levothyroxine withdrawal and hypothyroid 21 days after levothyroxine withdrawal. We determined the proportion of patients who developed hyperkalemia (K(+) ≥5 mEq/L) and hypokalemia (K(+) ≤3.5 mEq/L).Five (4.6%) patients developed hyperkalemia and 2 (1.9%) patients developed hypokalemia after levothyroxine withdrawal. The mean serum K(+) level after levothyroxine withdrawal was significantly higher than before levothyroxine withdrawal (4.23 ± 0.50 mEq/L vs. 4.09 ± 0.34 mEq/L; P.001). After levothyroxine withdrawal, serum K(+) values were significantly correlated with age, serum sodium and creatinine levels, and the estimated glomerular filtration rate but not with serum free thyroxine or thyroid-stimulating hormone concentrations. The finding of an elevated serum K(+) of0.5 mEq/L after levothyroxine withdrawal was more prevalent with age60 years (odds ratio [OR], 4.66; P = .026) and with the use of angiotensin-II receptor blockers or angiotensin-converting enzyme inhibitors (OR, 3.53; P = .033) in a multivariate analysis.Hyperkalemia develops in a small percentage of hypothyroid patients after thyroid hormone withdrawal, especially in patients over 60 years of age who are using antihypertensive agents that inhibit the reninangiotensin-aldosterone system.

The Na(+)/Ca(2+) exchanger (NCX) is a bidirectional transporter that is controlled by membrane potential and transmembrane gradients of Na(+) and Ca(2+). Although two isoforms of NCX1 and NCX2 are coexpressed on the basolateral membrane of the distal nephron, the functional significance of these isoforms is not entirely clear. Therefore, we used NCX1- and NCX2-heterozygote knockout mice (KO) and their double KO, as well as isoform-selective NCX inhibitors, to determine the roles of NCX isoforms in urine formation and electrolyte excretion in mice. NCX inhibitors, particularly NCX2-sensitive inhibitors, caused a dose-dependent natriuresis and in a higher dose, moreover, hypercalciuria. Consistently, NCX1-KO possessed normal renal function similar to wild-type mice (WT), whereas NCX2-KO and double KO exhibited moderate natriuresis and hypercalciuria. Notably, renal responses to YM-244769 were equivalently observed in NCX1-KO and WT, but disappeared in NCX2-KO and double KO. Thus, functional inhibition of NCX2 initially causes natriuresis, and further inhibition of NCX2 produces hypercalciuria, suggesting that the functional significance of NCX2 lies in Na(+) and Ca(2+) reabsorption of the kidney.

Objective To describe the challenging case of a 59-year-old male with a deoxycorticosterone (DOC)-producing adrenal adenoma concomitant with an aldosterone-producing microadenoma. Methods We measured the patient’s aldosterone and progesterone levels during adrenal venous sampling (AVS). The steroidogenic enzyme expression was studied with in situ hybridization (ISH). Steroids profiles were determined in the peripheral serum obtained before and after the operation, as well as in the main adrenal tumor. Results The patient was diagnosed with primary aldosteronism (PA) based on typical clinical findings. He had an adrenal tumor located at the lower pole of the left adrenal gland. The aldosterone concentration in the adrenal vein proximal to the adrenal tumor was higher than that of the ipsilateral adrenal vein distal to the tumor during the AVS. Progesterone was only elevated in the adrenal vein proximal to the tumor, suggesting that the tumor produced steroids other than aldosterone. The postoperative findings revealed that the main tumor was accompanied by 2 microadenomas. The main adrenal tumor was diagnosed as a DOC-producing adenoma, and one of the microadenomas was diagnosed as aldosterone-producing based on the ISH and the determination of the steroid profiles. Conclusions Concomitant PA masked the key findings of a DOC-producing tumor; the suppression of aldosterone in this patient. Multiple sampling in the adrenal vein considering the location of the adrenal tumor provided a clue to the diagnosis. Progesterone measurement during AVS is easy and may be useful in diagnosing rare adrenal tumors that produce intermediate products in adrenal steroid biosynthesis. (Endocr Pract. 2014;20:e171-e175)

Among women with gestational diabetes mellitus (GDM), the aggravation of glucose intolerance during gestation differs substantially. We retrospectively investigated whether the glucose intolerance of women diagnosed with GDM during early gestation (i.e., early-onset GDM) improved in the mid-gestation under appropriate nutrition therapy.We conducted a longitudinal analysis of glucose tolerance derived from 75-g oral glucose tolerance test (OGTT) in 41 Japanese women with early-onset GDM defined by International Association of Diabetes and Pregnancy Study Group criteria during early gestation (20 weeks). Glucose tolerance was also evaluated in mid-gestation (24-32 weeks) and postpartum. Insulin sensitivity, insulin secretion, and β-cell function were assessed at each period.The glucose tolerance in 18 of the 41 early-onset GDM patients normalized during mid-gestation with appropriate nutrition therapy, defined as GDM→NGT. These women did not require insulin therapy during their pregnancies, whereas 39.1% of women who retained GDM in mid-gestation (defined as GDM→GDM) required insulin therapy. The frequency of the postpartum development of type 2 diabetes or impaired glucose tolerance was significantly lower (5.6% vs. 39.1% in GDM→NGT vs. GDM→GDM, p=0.03). Primiparity was determined as a predictive factor whether or not glucose intolerance was improved by nutrition therapy, but results of plasma glucose levels from OGTT at early gestation were not, in a multivariate logistic regression analysis.Appropriate nutrition therapy for women with early-onset GDM seemed effective to improve glucose tolerance during pregnancy. OGTT retesting during their mid-gestation seemed effective for predicting the appropriate treatment after the second trimester.

Summary Major histocompatibility complex (MHC) class I-restricted T cell epitopes are generated mainly by the immunoproteasome in antigen-presenting cells. Therefore, inhibition of activity of this proteolytic complex molecule is thought to be a potential treatment for cell-mediated autoimmune diseases. We therefore studied the efficacy of an immunoproteasome inhibitor, ONX 0914 (formerly PR-957), for the treatment of autoimmune thyroid diseases, including cell-mediated Hashimoto's thyroiditis and autoantibody-mediated Graves' hyperthyroidism using mouse models. Our data show that ONX 0914 was effective prophylactically and therapeutically at suppressing the degree of intrathyroidal lymphocyte infiltration and, to a lesser degree, the titres of anti-thyroglobulin autoantibodies in non-obese diabetic (NOD)-H2h4 mice, an iodine-induced autoimmune thyroiditis model. It also inhibited differentiation of T cells to T helper type 1 (Th1) and Th17 cells, effector T cell subsets critical for development of thyroiditis in this mouse strain. In contrast, its effect on the Graves' model was negligible. Although ONX 0914 exerts its immune-suppressive effect through not only suppression of immune proteasome but also other mechanism(s), such as inhibition of T cell differentiation, the present results suggest that the immunoproteasome is a novel drug target in treatment of Hashimoto's thyroiditis in particular and cell-mediated autoimmune diseases in general.

Objective: Type 1 diabetes (T1D) iscommonlyassociated withautoimmunethyroid disease (AITD),and the occurrence of both T1D and AITD in a patient is defined as autoimmune polyglandular syndrome type 3 variant (APS3v). We aimed to clarify the differences in the clinical and genetic characteristics of APS3v patients and T1D patients without AITD [T1D/AITD(-)] in the Japanese population. Design/Patients: Our subjects were 54 APS3v patients and 143 T1D/AITD(-) patients who were consecutively diagnosed at Nagasaki University Hospital from 1983 to the present. Results: A remarkable female predominance, a slow and older age onset of T1D, and a higher prevalence of glutamic acid decarboxylase autoantibodies were observed in APS3v patients compared to T1D/AITD(-) patients. The older onset age of T1D in APS3v patients was associated with a higher proportion of slow-onset T1D. Among the two major susceptible human leukocyte antigen (HLA) class II haplotypes in Japanese T1D, DRB1*0405- DQB1*0401, but not DRB1*0901-DQB1*0303, was associated with APS3v patients. Furthermore, DRB1*0803-DQB1*0601 was not protective in patients with APS3v. The frequencies of the GG genotype in +49G>A and +6230G>A polymorphism in the CTLA4 gene were significantly higher in T1D/AITD(-) patients, but not in APS3v patients, compared to control subjects. Conclusions: In conclusion, we found notable differences in the clinical and genetic characteristics of APS3v patients and T1D/AITD(-) patients in the Japanese population, and the differences in the clinical characteristics between the two groups may reflect distinct genetic backgrounds including the HLA DRB1-DQB1 haplotypes and CTLA4 gene polymorphisms., Journal of Clinical Endocrinology & Metabolism, 97(6), pp.E1043-E1050; 2012

Pituitary carcinoma is a rare malignancy and is difficult to manage. Pituitary carcinomas commonly produce either PRL or ACTH, but some do not produce pituitary hormones. The alkylating reagent temozolomide (TMZ) was recently shown to be effective as a treatment for pituitary carcinoma. Most of the published reports of TMZ use in pituitary carcinoma cases were against hormone-producing carcinomas. Only a few patients with a nonfunctioning pituitary carcinoma treated with TMZ have been reported. Here we describe our treatment of a patient with nonfunctioning pituitary carcinoma and a background of multiple endocrine neoplasia type 1. The pituitary carcinoma was accompanied by meningeal dissemination with cerebral and L1 spinal bone metastasis. The patient received continuous dosing of TMZ along with external radiation, followed by standard dosing of TMZ. There was an apparent antitumor response seen in MRI. MGMT, an enzyme antagonized by TMZ, was negative in the tumor. The therapeutic efficacy of TMZ and dosing schedules of TMZ in pituitary carcinoma are discussed.

A medullary thyroid carcinoma is a malignant tumor derived from the C-cells of the thyroid. Despite their distinct embryological origin, medullary thyroid carcinomas are exceptionally accompanied by a tumor derived from the follicular cells; this is defined as mixed medullary and follicular cell carcinoma. There have been controversies regarding the origin of this rare mixed thyroid carcinoma questioning whether or not a mixed carcinoma originates from a common cancer stem cell. We present a case of mixed medullary and follicular cell carcinoma in which two thyroid carcinomas were found intermingled in the thyroid as well as in the metastatic cervical lymph nodes. We examined the tumor by immunostaining with thyroglobulin, calcitonin, and thyroid transcription factor-1, and also reviewed the literature and discuss the origin of this rare mixed thyroid carcinoma., Internal Medicine, 50(12), pp.1313-1316; 2011

Propylthiouracil (PTU) is known to induce myeloperoxidase antineutrophil cytoplasmic antibodies (MPO-ANCA) in patients with Graves disease (GD). Previously, we showed that serum MPO-ANCA were frequently seen in patients with GD treated with PTU. In this study, we analyzed 13 patients with positive MPO-ANCA examining a long-term clinical consequence of these patients as well as antibody titers during 5.6 +/- 3.0 years. PTU therapy was continued in 8 patients and discontinued in 5 patients. Antibody titers decreased in 7 of 8 patients who discontinued PTU therapy but remained positive in 5 patients 5 years after PTU withdrawal. The initial MPO-ANCA levels were significantly higher in those antibody titers remained positive for longer than 5 years (n=5) than in those titers turned to be negative within 5 years after PTU withdrawal (n=3) (203 +/- 256 EU and 22 +/- 2 EU, respectively, P=0.04), but there were no significant differences in age, gender, duration of PTU therapy or dosage of PTU. Among 5 patients who continued PTU therapy, 2 patients with initially low MPO-ANCA titers turned to having negative antibody. No patients had new symptoms or signs of vasculitis throughout the follow-up periods. The long-term follow-up study suggests that higher MPO-ANCA levels remain positive for years after PTU withdrawal but are rarely associated with vasculitis.