Recent discoveries that Rab27a/b and their multiple effectors are involved in the regulated exocytosis of lysosome-related organelles and secretory granules have generated numerous related studies. However, not all of these studies have yielded physiologically relevant data because they were not all performed under physiological conditions. For example, "in vivo interactions" have been claimed without examination of the endogenous complex. In some studies, the only proof of interaction was between exogenously expressed proteins in cultured cells where these proteins are not normally expressed. Because regulated exocytic pathways contain highly differentiated secretory organelles, it is important to analyze the molecular interaction in cells harboring these organelles and the associated molecules. Furthermore, previous overexpression experiments to examine the effect on secretion often failed to compare the level of the exogenous protein with that of the endogenous one. Similarly, some knockdown experiments using small-interfering RNAs have only shown downregulation of the exogenously expressed protein, and not of the endogenous one. Many of the conflicting findings in previous studies may be attributable to these shortcomings. The present study summarizes our knowledge about the roles of Rab27 effectors in regulated exocytic pathways based on physiologically relevant data.

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Insulin is a critical hormone in the regulation of blood glucose levels. It is produced exclusively by pancreatic islet β-cells. β-cell-enriched transcription factors, such as Pdx1 and Beta2, have dual roles in the activation of the insulin gene promoter establishing β-cell-specific insulin expression, and in the regulation of β-cell differentiation. It was shown that MafA, a β-cell-specific member of the Maf family of transcription factors, binds to the conserved C1/RIPE3b element of the insulin promoter. The Maf family proteins regulate tissue-specific gene expression and cell differentiation in a wide variety of tissues. MafA acts synergistically with Pdx1 and Beta2 to activate the insulin gene promoter, and mice with a targeted deletion of mafA develop age-dependent diabetes. MafA also regulates genes involved in β-cell function such as Glucose transporter 2, Glucagons-like peptide 1 receptor, and Prohormone convertase 1/3. The abundance of MafA in β-cells is regulated at both the transcriptional and post-translational levels by glucose and oxidative stress. This review summarizes recent progress in determining the functions and roles of MafA in the regulation of insulin gene transcription in β-cells.

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Endometrial carcinoma is one of the most common female pelvic malignancies. It is well known that uterine endometrial cell proliferation is under the control of both estrogen and progesterone. In this review, results of the recent studies on the biosynthesis and action of estrogen and progestin in normal endometrium and its disorders will be summarized and the new aspects of hormonal therapies in the patients with endometrial carcinoma will be discussed including its future prospectives. We reported that the enzymes responsible for intratumoral estrogen metabolism and biosynthesis are markedly different between human breast and endometrial carcinoma, although both of them are considered "estrogen-dependent malignancies". In addition, the biological significance of Progesterone receptor (PR) isoforms is considered to differ between endometrial and breast carcinomas. Clinical data concerning Hormone replacement therapy (HRT) and estrogen-dependent cancer risk also support these findings. These basic and clinical findings help to understand the biology and provide the new knowledge for prevention, diagnosis and treatment of human endomerial carcinoma. Specific endocrine treatment of endometrial carcinoma should be explored in future, although aromatase inhibitors are the most effective endocrine treatments of estrogen-responsive breast carcinoma. Retinoid, metabolities of vitamin A, and synthetic peroxisome proliferator-activated receptor (PPAR) γ ligands, which have been used for the treatment of insulin resistance in type II diabetes mellitus, may be the important candidates as drugs not only for prevention but also for possible endocrine treatment of endometrial carcinoma.

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Pituitary apoplexy (PA), which is one of the most serious life-threatening complications of pituitary adenoma, is characterized by abrupt onset of headache, nausea, vomiting, visual disturbances and oculomotor paresis. Combination of oculomotor cranial nerve paralysis with normal visual fields is very rare in PA. We report a 60-year-old acromegalic man presented with panhypopituitarism and bilateral total opthalmoplegia without a visual field defect. At initial evaluation his clinical findings were compatible with adrenal crisis and eye examination revealed total opthalmoplegia, bilateral ptosis and normal vision. MRI showed a large heterogeneous mass in the pituitary fossa. Although clinical findings due to adrenal crisis improved after glucocorticoid therapy there was no improvement in opthalmoplegia and ptosis. The patient underwent transsphenoidal excision of the pituitary mass. Histological examination revealed an adenoma with large areas of hemorrhagic infarction and most of the cells were positive for GH in immunohistochemical analysis. Although opthalmoplegia was severe at presentation, total recovery was achieved 3 months after transsphenoidal surgery. Therefore the presented case clearly demonstrates that opthalmoplegia without a visual field defect due to PA has a good prognosis and early diagnosis and treatment including surgical decompression are crucially important.

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Since accumulation and interaction of immune cells including T cells and monocytes/macrophages are involved in the processes of atherosclerosis, atherosclerosis is currently understood as an inflammatory disorder. Entrapment of extracellular matrices components such as hyaluronan by monocytes and macrophages, as well as uptake of oxidized low-density lipoprotein (ox-LDL) by these cells, plays a central role in foam cell formation and the pathogenesis of atherosclerosis. We investigated the role of CD44, the principal receptor for hyaluronic acid, and ox-LDL in scavenger receptor expression on resting monocytes prepared by counterflow centrifugal elutriation from the endothelium. Our results showed that the low-molecular weight (6.9 kDa) form of hyaluronan increased the expression of CD36 scavenger receptor; the incorporation of ¹²⁵ I-labeled ox-LDL, and the transendothelial migration of monocytes, which were mediated at least in part via tyrosine kinase and the PKC pathway. Our results imply that low molecular weight hyaluronan produced in large amounts in atherosclerotic lesions induces differentiation of circulating monocytes to macrophages/foam cells and enhances the progression of atherosclerosis via the PKC pathway. Furthermore, low molecular weight hyaluronan also amplifies the migration of monocytes into inflamed atherosclerotic plaques. Thus, we propose that engagement of CD44 with low molecular weight hyaluronan is centrally involved in the inflammatory pathogenesis of athelosclerotic plaques through migration of monocytes and foamed macrophage differentiation.

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Metabolic syndrome has been revealed to be a major risk factor for cardiovascular disease (CVD) and early mortality in non-diabetic and diabetic patients. In 2005, the International Diabetes Federation (IDF) and the Examination Committee of Criteria for Diagnosis of Metabolic Syndrome in Japan published new definitions of metabolic syndrome in which central obesity was an indispensable factor. However, the significance of this new definition to CVD in type 2 diabetes has not yet been clarified. A cross-sectional study was conducted with 294 Japanese type 2 diabetic patients without known cardiovascular disease to evaluate the association between metabolic syndrome defined by this new definition and carotid atherosclerosis, and the significance of central obesity for the prediction of the development of carotid atherosclerosis. In a multivariate regression analysis, metabolic syndrome but not central obesity was significantly associated with carotid intima-media thickness (IMT) independent of known cardiovascular risk factors (p<0.05). In addition, whereas carotid IMT was significantly increased according to the increase in the number of components of metabolic syndrome, it was not significantly different between the groups with the same number of components of metabolic syndrome with or without central obesity. These findings suggest that the prediction of the development of carotid atherosclerosis in Japanese type 2 diabetic patients could be improved by the assessment of aggregation of components of metabolic syndrome rather than with or without metabolic syndrome by this new definition.

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The present study characterized the different hormonal responses to stress in the endocrine milieu with different circulating levels of prolactin (PRL) and examined the direct effects of PRL on adrenal steroidogenic responses to adrenocorticotropic hormone (ACTH) using experimentally induced hyperprolactinemia and hypoprolactinemia male rat models. Hyperprolactinemia was induced by transplantation of two adult female rat anterior pituitary glands under the kidney capsule for 2 weeks, and hypoprolactinemia was induced by daily subcutaneous injection of 2-Bromo-alpha-Ergocryptine (CB-154) for 2 weeks. Under stress conditions, the peak levels of ACTH were significantly higher in hypoprolactinemia than normal rats. Meanwhile, the peak levels of corticosterone and progesterone were significantly higher in hyperprolactinemia than in normal and hypoprolactinemia stressed rats. Results of in vitro experiments showed that adrenocortical cells in hyperprolactinemia exhibited higher basal levels of corticosterone and progesterone rats than normal and hypoprolactinemia rats. The stimulatory effect of ACTH on corticosterone and progesterone release was higher in hyperprolactinemia than hypoprolactinemia rats. In addition, PRL increased the stimulatory effect of ACTH-induced corticosterone secretion in all rat models. These results suggest that hypoprolactinemia and hyperprolactinemia rats exhibit marked differences in the response of their hypothalamic-pituitary-adrenal (HPA) axis during acute restrain stress. Additionally, these studies emphasize that the adrenal cortex might be more sensitive to ACTH stimulation in endocrine milieu with high levels of PRL resulting in high corticosterone and progesterone release.

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In most trials, at least 30-60% of patients with Graves' disease treated with antithyroid drugs relapse within 2 years after therapy withdrawal. At present, there are no prognostic parameters available early in treatment to indicate patients likely to achieve long-term remission. Because thyrotropin receptor autoantibodies (TRAb) are specific for Graves' disease, we evaluated the ability of their levels and of their rate of change to predict long-term prognosis. In our study 216 consecutive patients with newly diagnosed Graves' disease started a therapy with methimazole. Patients were treated until they achieved euthyroidism and TRAb were measured at 6-month intervals throughout a follow up of 120 months. Our study demonstrated that at the onset of hyperthyroidism patients' age, sex, fT4 levels and goiter size had no prognostic value in predicting long-term prognosis (respectively p = 0.79; p = 0.98; p = 0.83; p = 0.89). On the contrary, at the time of diagnosis TRAb titer was a good predictor of the final outcome (p<0.001); a titer equal to (or) more than 46.5 UI/L could identify patients who had never achieved long-term remission with a sensitivity of 52% and a specificity of 78%. Also fall rate of TRAb at 6 months of follow up and after therapy withdrawal were useful to predict the final outcome (p<0.001). At 6 months of follow up the time of therapy withdrawal, a decrease of TRAb lower than 52.3% or even its increase could identify patients who had never achieved permanent remission with a sensitivity of 55% and a specificity of 79.1%. No single parameter among TRAb, satisfactory identified a sub-set of patients who achieved long remission. Accordingly to our data, the best result in predicting long term remission is probably given by the presence of at least one of the two features evaluated at 6 months (TRAb titer and/or percentage of TRAb fall rate), with a sensitivity of 63% and specificity of 88%. TRAb titers evaluated both at the onset of hyperthyroidism that at 6 months of therapy or their rate of fall at 6 months and at ATD withdrawal are predictors of outcome. However, the presence of at least one, between titers of TRAb or their rate of fall at six months, resulted to be the best predictor of remission with the higher sensitivity and specificity.

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The present study demonstrated genetic analysis of human leukocyte antigen (HLA) in a familial Graves' disease linked to autoimmune mechanism. The proband was a 17 year-old female. At 15 years, Graves' disease was diagnosed with serum TSH was <0.015 IU/ml; free T₃, 13.6 pg/ml; free T₄, 4.51 ng/dl; and TSH receptor antibody (TRAb), 94.1%. She had two brothers (19 and 13 years-old), who manifested Graves' disease at 18 and 13 years, respectively. They also had elevated TRAb as high as 48.4 and 49.1%, respectively. There was a strong family history of Graves' disease in their maternal pedigree. Namely, their two aunts and a cousin had Graves' disease, and their onset ages of Graves' disease were also during their teen-age years. However, there was no patient with Graves' disease in the paternal pedigree. We checked HLA-DRB and -DQB haplotype in the members of maternal pedigree and proband's father. The members of maternal pedigree including both affected and unaffected Graves' disease had haplotypes of DRB1*150101 and DQB1*0602, except for the cousin who had DRB1*140301 and DQB1*030101. The haplotypes of DRB1*150101 and DQB1*0602 were different from susceptible HLA types in Japanese childhood onset Graves' disease. However, two cases of Graves' disease also had HLA types of DRB1*40501 and DQB1*0401, in addition to the haplotypes of DRB1*150101 and DQB1*0602. There was no other autoimmune disease including type 1 diabetes mellitus in their family. The present findings indicated that familial Graves' disease was found mainly in the maternal females and become overt during their teen-age years. They had new HLA haplotypes distinct from those susceptibly in Japanese Graves' patients. Further study will be necessary to analyze the mutant locus of DNA to elucidate pathogenesis of familial Graves' disease.

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Resistance to thyroid hormone (RTH) is a dominantly inherited syndrome of variable tissue hyporesponsiveness to thyroid hormone (TH). Its characteristics are a high level of TH and inappropriate lack of TSH suppression. RTH is mainly categorized as generalized RTH (GRTH), pituitary RTH (PRTH), and peripheral tissue RTH (PTRTH). Untreated subjects with GRTH usually achieve a normal metabolic state. We describe a 21-year-old Japanese woman with GRTH and coincidental chronic thyroiditis. Physical examination revealed palpable goiter, congenital alopecia on top of the head, and short stature. She showed elevated levels of free triiodothyronine (FT3) and free thyroxine (FT4), and an inappropriately normal level of TSH. Anti-thyroglobulin and anti-thyroid peroxidase antibodies were positive. A TRH stimulation test showed a normal TSH response. The patient received the standardized diagnostic protocol, administration of incremental doses of liothyronine (L-T3). The peak TSH level after the TRH stimulation test gradually decreased. The patient showed low sensitivity to TH in terms of bone metabolism, protein catabolism, lipid metabolism, and urine magnesium metabolism. Sequence analysis of the TR β gene was performed with informed consent, and this revealed a novel heterozygous mutation at codon 347 resulting in a GGG (glycine) to GCG (alanine) substitution (G347A). The patient was diagnosed as having GRTH with chronic thyroiditis, and carrying a novel mutation, G347A, of the TR β gene.

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In secretory cells, osmotic swelling of secretory granules is proposed to be an intermediate step in exocytic fusion of the granules with the plasma membrane. For osmotic swelling of the granule, a H ⁺ gradient generated by vacuolar-type H ⁺ -ATPase (V-ATPase) may be a driving force for accumulation of K ⁺ via its exchange with H ⁺ , concurrent with accumulation of Cl ^- and H₂O. Here, we investigated whether a similar chemiosmotic mechanism is involved in the insulin-stimulated recruitment of GLUT4 to the plasma membrane in 3T3-F442A adipocytes. Incubating cells in a hypo-osmotic medium significantly increased 2-deoxy glucose (2-DG) uptake and the plasma membrane GLUT4 content (possibly via induction of osmotic swelling of GLUT4-containing vesicles (G4V)) and also potentiated the insulin-stimulated 2-DG uptake. Promotion of the G4V membrane ionic permeability using nigericin, an electroneutral K ⁺ /H ⁺ exchange ionophore, increased 2-DG uptake and the plasma membrane GLUT4 content. However, co-treatment with nigericin and insulin did not show an additive effect. Bafilomycin A₁, a diagnostically specific inhibitor of V-ATPase, inhibited insulin- and nigericin-stimulated 2-DG uptake. Immunoadsorption plus immunoblotting demonstrated that GLUT4 and V-ATPase co-localize in the same intracellular membranes. Together, these results indicate that V-ATPases in the G4V membrane may play an important role in the insulin-stimulated exocytic fusion of G4V with the plasma membrane via its participation in osmotic swelling of the vesicle.

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It has been suggested that metabolic syndrome (MetS) overlaps prediabetes and type 2 diabetes and that it is not necessary to consider it as a separate clinical entity. In the present study, patients with normoglycemia and dysglycemia were compared in terms of MetS frequency and MetS criteria characteristics, in order to test the appropriateness of considering MetS as a condition independent of prediabetes and type 2 diabetes. A total of 1222 (801 females, 401 males, mean age: 51.50 11.73 y) consecutive patients attending Internal Medicine outpatient clinics were included. Cases were assigned into two groups: patients with normoglycemia (fasting plasma glucose <100 mg/dl, n = 555) or dysglycemia (fasting plasma glucose ≥100 mg/dl and/or receiving antidiabetic treatment, n = 667). Groups were compared in terms of MetS frequency and MetS criteria characteristics. A 2-hour oral glucose tolerance test was administered to the normoglycemia group. In addition, patients with MetS were assigned into two groups: patients with normoglycemia and dysglycemia. These two groups were also compared in terms of MetS criteria characteristics. Adult Treatment Panel III criteria were used for the diagnosis of MetS. The overall frequency of MetS was 52.2%. MetS was found in 72.7% of patients with dysglycemia and 27.6% of patients with normoglycemia (p = 0.001). Mean systolic and diastolic blood pressure, waist circumference and triglyceride levels were similar between normoglycemic and dysglycemic MetS patients (p>0.05). Impaired glucose tolerance was higher among normoglycemic MetS patients compared to normoglycemic patients without MetS (13.7% vs. 6.5%, p = 0.006). In conclusion, although MetS is a well known risk factor for type 2 diabetes, our results support that it is a separate entity independent of prediabetes and type 2 diabetes mellitus.

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Ascites caused by hypothyroidism is rare and the pathogenesis is unclear. Several reports have presented cases of progressive ascites with hypothyroidism and elevated tumor markers. We report a 31-year-old female case with massive ascites and elevated serum CA 125 concentrations. The patient had no typical feature of hypothyroidism except an accumulation of ascitic fluid which showed elevated total protein concentration and a high serum-ascites albumin gradient (SAAG). There was no finding of malignancy. Following thyroid hormone replacement, the ascites was completely resolved accompanied by reduced concentrations of serum CA125. In general, primary hypothyroidism with ascites presents with coexisting massive pericardial or pleural effusion. The massive ascites and increased serum CA125 concentrations may have led us to make the incorrect diagnosis of ovarian malignancy. The evaluation of thyroid function is useful to determine the pathology of high-protein ascites or elevated tumor markers, and ascites may be treatable by thyroid replacement therapy.

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Maturity-onset diabetes of the young type 5 (MODY5) is caused by mutation of hepatocyte nuclear factor 1β (HNF1 β) (TCF2) gene, resulting in a wide range of phenotypes including diabetes and renal abnormalities, but little is known about the pathogenesis of the clinical spectrum. We describe a 27-year-old Japanese male with the MODY phenotype including an atrophic kidney and multiple renal cysts. Genetic analysis revealed the patient to be heterozygous for a nonsense mutation in codon 276 of the HNF1β gene (CGA or Arginine to TGA or stop codon; R276X). To clarify the pathophysiological relevance of this mutation, we conducted an in vitro study monitoring human C-peptide secretion after transfecting both the HNF1β mutant cDNA and preproinsulin cDNA into a murine β cell line, MIN6. Functional studies of the transformed MIN6 cells indicated that expression of the R276X caused a significant decrease in glucose-stimulated insulin secretion but no change in either KCl-stimulated or basal insulin secretion. These results suggest that the R276X functions in a negative manner in regard to metabolic responses of insulin secretion in β cells. Analysis with light and electron microscopy on biopsied kidney specimens suggested that the origin of the cysts might be glomeruli but the primary lesion could be tubules.

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An eighty-year-old man who had complained of skin pigmentation and weight loss was referred to our hospital. Upon physical examination, marked hyperpigmentation was found on the whole body including oral mucosa, tongue and fingernails. Endocrinological findings showed increased ACTH (126 pg/ml) and normal serum cortisol (15.4 μg/dl). First, we used a 250 μg cosyntropin stimulation test which is valid to diagnose Addison's disease, resulting in an adequate cortisol response. Second, we performed 1 μg cosyntropin stimulation test, and the cortisol response was blunted. Since the diagnosis of Addison's disease was fairly certain, he was treated with hydrocortisone 15 mg/day, and improvement of his skin pigmentation and an increase in body weight were observed. To our knowledge, this is the first report that 1 μg cosyntropin stimulation test was helpful to make diagnosis as having Addison's disease rather than the 250 μg cosyntropin stimulation test, although it is established that the 1 μg cosyntropin stimulation test is useful in secondary or relative adrenal insufficiency.

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To examine whether benidipine hydrochloride, one of the calcium channel blockers, up-regulate uncoupling protein 3 (UCP3) expression in two skeletal muscles (gastrocnemius and soleus) in rats. Wistar rats were treated orally with benidipine hydrochloride at 4 mg/kg for 7 days. Blood pressure was measured after 4 days. At the end of experiments, the rats were weighed, and brown adipose tissue (BAT) and skeletal muscles (gastrocnemius and soleus muscles) were removed. The mRNA levels of uncoupling protein 1 (UCP1) and UCP3 were measured using the real-time quantitative reverse transcription-polymerase chain reaction method. Benidipine reduced body weight and also had a hypotensive effect. In rats treated with benidipine, UCP1 mRNA levels were significantly increased 1.4-fold in BAT, and UCP3 mRNA levels in BAT and gastrocnemius muscle were significantly increased 1.7 and 3.0-fold, respectively, compared with the control rats. There was no difference in UCP3 mRNA levels in soleus muscle between the two groups. We concluded that benidipine up-regulates not only UCP1 gene expression in BAT but also UCP3 gene expression in BAT and gastrocnemius muscle, which may contribute to thermogenesis in rats.

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Silent corticotroph adenoma (SCA) is defined as an ACTH-producing pituitary tumor not associated with clinical and endocrine feartures of Cushing's syndrome, but its underlying molecular mechanism(s) remains unknown thus far. We tested the hypothesis that reduced expression of prohormone convertase (PC) 1/3 responsible for proteolytic processing of proopiomelanocortin (POMC) in SCA may lead to production of unprocessed, biologically inactive POMC and/or precursor of ACTH. Among 30 non-functioning pituitary macroadenomas (NFA) examined, we found 6 SCAs by immunohistochemical study using anti-ACTH antibody. Preoperative endocrine and diagnostic image tests did not reveal any differences between SCA and the remaining NFA except for the higher recurrence rate of SCA. While steady-state PC1/3 mRNA levels determined by RT-PCR were almost comparable between SCAs and NFAs, immunohistochemical study showed negative immunostaining for PC1/3 in all 6 SCAs. Our data suggest that defective PC1/3 expression may lead to preferential production of unprocessed, biologically inactive ACTH variants in SCA.

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Transcription factor GATA-6 has been demonstrated to be expressed in the human fetal and adult adrenal cortex and has been postulated to play an important role in adrenal steroid biosynthesis. However, the status for GATA-6 expression has not been examined in detail especially in relation to adrenal development and aging. Therefore, in this study, we analyzed GATA-6 expression in 11 human fetal adrenals and 19 adrenal glands after birth using immunohistochemistry. In the fetal adrenals, the status of GATA-6 immunoreactivity in the definitive zone was significantly and directly correlated with ages of development (P<0.05) but in the fetal zone was significantly and inversely correlated with ages of development (P<0.05). After birth, GATA-6 was more abundant in the zona fasciculata compared to other zones (P<0.05) but was not related to aging of the subject. These results suggest that GATA-6 expression is involved in the regulation of corticosteroid production in both the human fetal and adult adrenals, and the changes of intra-adrenal GATA-6 expression in the human fetal adrenal plays important roles in developmental changes of both the definitive and fetal zones.

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To examine the effect of muscle strength on insulin resistance, we investigated the association between quantitative lower-extremity muscle strength and insulin resistance index as evaluated by homeostasis model assessment (HOMA-IR) in patients with type 2 diabetes (20 men and 20 women, mean age SD: 53.3 12.7 years). By simple linear regression analyses, the knee extension force normalized for body weight (%KEF) was found to be significantly correlated with HOMA-IR in both male (r = -0.510, P<0.05) and female patients (r = -0.462, P<0.05). Stepwise regression analysis also showed that %KEF was an independent determinant of HOMA-IR (β = -0.331, F = 5.400, P<0.005), as was BMI (β = 0.409, F = 8.260, P<0.05). Our data suggest that lower-extremity muscle strength is independently associated with insulin resistance, which seems to be consistent with previous reports that resistance training improves glycemic control in type 2 diabetic patients. Further studies based on a larger study population will be required to confirm this possibility.

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Toxic thyroid adenoma presenting as hypokalemic periodic paralysis is extraordinarily rare. We describe a 26-year-old Japanese man who suffered from acute and painful muscle weakness of extremity in the morning. Physical examination showed a left anterior neck mass and laboratory tests revealed hypokalemia during his paralysis, and thyrotoxicosis. Neck sonogram showed a solitary nodule in the left lobe of the thyroid. Thyroid scintigraphy revealed a hot nodule of the tumor region with suppressed uptake in the other thyroid area. The tumor was surgically removed and his paralytic attack ceased. No somatic mutation of TSH receptor was found in his thyroid adenoma and no known genetic mutations of ionic channel genes, such as calcium (CACN1S), sodium (SCN4A) and potassium (KCNE3), were found. Although thyrotoxic periodic paralysis is usually accompanied with Graves' disease, thyrotoxicosis of other conditions including Plummer's disease should be considered.

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Anti-hypertensive agents with antioxidative effects are potentially useful for diabetic patients with hypertension to prevent the onset and progression of their complication. While dihydropyridine-type calcium antagonists are among the frequently used anti-hypertensive drugs, azelnidipine, a novel calcium antagonist, has been reported to have a unique anti-oxidative effect in vitro and in animals. In this study, we measured lipid hydroperoxides in human sample using diphenyl-1-pyrenylphosphine for the first time, and used the value of lipid hydroperoxides as an index of oxidative stress. Then, we compared the antioxidative properties of azelnidipine and amlodipine, a frequently used calcium antagonist in hypertensive diabetic patients. Administration of vitamin C and E for 8 weeks significantly reduced lipid hydroperoxides in erythrocyte membrane in normal subjects. In hypertensive diabetic patients, azelnidipine treatment for 12 weeks induced a more significant fall in erythrocyte lipid hydroperoxide level than amlodipine, though blood pressure during each treatment was comparable. Our data confirm the usefulness of lipid hydroperoxides in erythrocyte membrane as a marker of oxidative stress in vivo, and indicate that azelnidipine has a unique antioxidative property in human.

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We experienced a case of fetal goitrous hypothyroidism in an infant delivered by a 33-year-old woman receiving 300 mg/day of propylthiouracil (PTU) for hyperthyroidism due to Graves' disease. A large fetal goiter (maximum diameter, 60 mm) was detected by magnetic resonance imaging (MRI) at 36 weeks of gestation. Initial fetal blood sampling revealed hypothyroidism with a serum thyroid-stimulating hormone (TSH) of 99 μIU/mL, free triiodothyronine (T₃) of 1.97 pg/mL, and free thyroxine (T₄) of 0.29 ng/dL. Consequently, a diagnosis of fetal goitrous hypothyroidism due to transplacental passage of maternal PTU was made. To reduce the risk of perinatal complications, 300 μg of levothyroxine sodium (L-T₄) was administered into the maternal amniotic fluid twice between 37 and 38 weeks of gestation. Subsequent fetal MRI showed that the size of goiter had decreased. At 38 weeks and 5 days of gestation, a 3042-g male infant was born by cesarean section. There were no severe complications at delivery, although mild tachypnea was observed and the infant's thyroid gland was slightly enlarged. He was treated with L-T₄ for two weeks. At present, his growth and neurological development are normal. This case indicates that intrauterine therapy by the intraamniotic administration of L-T₄ can be effective in treating fetal goitrous hypothyroidism even during late gestation.

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A 66-year-old woman with type C hepatitis had been treated for hepatocellular carcinoma (HCC) with transcatheter arterial embolization and radiofrequency ablation. Liver function worsened gradually to decompensated liver cirrhosis. She had recurrence of HCC and was later admitted to Juntendo University Hospital for living-donor liver transplantation. Although blood glucose was high, she had never been diagnosed with diabetes mellitus. No diabetes-related complications were detected at that time. We started treatment with multiple insulin injections. There is a unique time called the anhepatic phase during liver transplantation during which the liver does not exist in the body. Recent reports show that it is not necessary to administer glucose for patients with normal glucose tolerance during the anhepatic phase since plasma glucose could be maintained at normoglycemia to hyperglycemia (100-150 mg/dl). In our patient, plasma glucose concentration was rather high during the anhepatic phase without glucose administration. We analyzed the levels of blood glucose, insulin and various other hormones during the anhepatic phase. This could be the first report on glucose homeostasis during the anhepatic phase in a diabetic patient.

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Macroprolactinemia was recognized more than a decade ago as a cause of hyperprolactinemia and the prevalence of macroprolactinemia is thought to be 10%-26% of patients with hyperprolactinemia. However, there are few published reports about macroprolactinemia in childhood. We report a 7-year-and-1-month-old girl with hyperprolactinemia due to macroprolactinemia with the complication of transient idiopathic central precocious puberty (ICPP). At the age of 6 years and 9 months, she was diagnosed with ICPP at another clinic, on the basis of isolated mammary development and increased height velocity with slightly advanced bone age. At that time, the unexpected finding of high PRL level was also observed. Four months later, she was referred to our clinic for persistently high PRL level. At this time, other endocrinological data showed prepubertal stage and we demonstrated macroprolactinemia and the presence of anti-PRL autoantibody. After other causes of hyperprolactinemia such as prolactinoma and stress were ruled out, we finally diagnosed her with hyperprolactinemia due to macroprolactinemia. Because most patients with macroprolactinemia are symptom-free despite hyperprolactinemia and drug therapy would not be indicated, macroprolactinemia should be suspected even in children to avoid unnecessary examinations and treatments.

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