Rapid progression of Graves' ophthalmopathy despite the administration of thiamazole.

A 42-year-old female with body weight loss, finger tremors and ocular discomfort was diagnosed with Graves' disease complicated with ophthalmopathy. Thiamazole therapy rapidly improved her hyperthyroidism. However, she was admitted to our hospital because her eye symptoms acutely deteriorated over a period of two weeks. She had ocular immotility, exposure keratitis, conjunctival edema, severe proptosis and visual impairment with a high titer of serum thyroid-stimulating antibody (TSAb). Methylprednisolone pulse therapy at a dose of 500 mg/day improved her eye symptoms. Although the mechanism of the progression of Graves' ophthalmopathy has not yet been elucidated, special attention should be paid to the occurrence of ophthalmopathy even after the initiation of thiamazole therapy.

Functional interaction of bone morphogenetic protein and growth hormone releasing peptide in adrenocorticotropin regulation by corticotrope cells.

Mechanisms by which GHRP stimulates ACTH release in corticotrope cells were investigated using mouse corticotrope AtT20 cells by focusing on the biological activity of BMP-4. GHRP-2 increased ACTH and cAMP secretion by AtT20 cells; however, its effects were less potent than the effects of CRH. BMP-4 suppressed basal ACTH production and POMC transcription, and the inhibition of endogenous BMP receptor signaling led to an increase in ACTH production. Of note, BMP-4 suppressed ACTH production and POMC-promoter activity induced by CRH more efficaciously than that induced by GHRP-2. BMP-4 had no significant effect on cAMP synthesis induced by CRH or GHRP-2. Stimulation with CRH, but not GHRP-2, activated ERK1/2, p38, SAPK/JNK and Akt phosphorylation, in which CRH-induced phosphorylation of ERK and p38 was suppressed by BMP-4. GHRP-2-induced ACTH secretion was not affected by inhibitors of ERK, p38 and Akt pathways, which effectively suppressed CRH-induced ACTH release. Blockage of the cAMP-PKA pathway reversed CRH- as well as GHRP-2-induced ACTH secretion. Furthermore, the inhibition of ERK and p38 significantly reduced cAMP synthesis induced by CRH but not by GHRP-2. Thus, CRH activates ACTH production through ERK and p38 pathways in addition to the cAMP-PKA pathway, which is also activated downstream of MAPK. On the other hand, GHRP-2-induced ACTH production was predominantly linked to the cAMP-PKA pathway. Moreover, CRH and GHRP-2 upregulated BMP receptor signaling, while BMP-4, CRH and GHRP-2 had no significant effect on the expression level of GHSR. In addition, GHRP-2 suppressed the expression of Smad7, which is an inhibitor of the BMP-Smad1/5/8 pathway. Collectively, the results revealed a functional interaction between GHRP-2 and BMP signaling, in which endogenous BMP may act as an autoregulatory system in controlling ACTH production.

Relationship between impacts attributed to malocclusion and psychological stress in young Japanese adults.

Identifying risk factors is important to prevent a wide range of health-damaging behaviours and to improve the quality of life of young people. The aim of this study was to investigate the relationship between impacts on daily performance attributed to malocclusion and psychological stress in healthy young Japanese adults. Medical and oral health data were collected during a cross-sectional examination conducted by the Health Service Center of Okayama University. Systemically healthy non-smoking students aged 18 and 19 years (n = 641; 329 males and 312 females) were included. Malocclusion was defined using a modified version of the Index of Orthodontic Treatment Need (IOTN). The impacts on daily performance attributed to malocclusion and psychological stress were assessed using self-reported questionnaires, the condition-specific oral impacts on daily performances (CS-OIDP), and the Hopkins Symptoms Checklist. Mann-Whitney U- and chi-square tests and structural equation modelling (SEM) were used for statistical analysis. Forty per cent of subjects had a malocclusion (n = 255). Subjects with impacts on daily performance had a significantly higher prevalence of malocclusion than those without impacts (P < 0.001). SEM showed that psychological stress, especially interpersonal sensitivity and depression, was significantly correlated with CS-OIDP and malocclusion. Negative impacts on daily performance attributed to malocclusion may contribute to psychological stress in young Japanese adults.

Sex differences in gingivitis relate to interaction of oral health behaviors in young people.

BACKGROUND: Although many epidemiologic surveys have shown that gingivitis is more prevalent in males than in females, few studies have clearly explained what causes this difference. The objective of the present study is to explain the sex difference in gingivitis based on the interaction between oral health behaviors and related factors, such as knowledge, attitude, and lifestyle, in young people. METHODS: The study was comprised of 838 subjects (440 males and 398 females), aged 18 and 19 years. Gingivitis was assessed by the percentage of bleeding on probing (%BOP). Additional information was collected regarding oral hygiene status, oral health behaviors, and related factors. Structural equation modeling was used to test pathways from these factors to %BOP. Multiple-group modeling was also conducted to test for sex differences. RESULTS: Females had greater knowledge, a more positive attitude, a healthier lifestyle, and higher level of oral health behaviors than males. There were significant differences in the paths (i.e., from lifestyle, knowledge, and attitude to %BOP) through oral health behaviors and oral health status. CONCLUSIONS: Sex-based differences in gingivitis in young people can be explained by oral health behaviors and hygiene status, which are influenced by lifestyle, knowledge, and attitude. To prevent gingivitis, different approaches to males and females may be useful.

Activities of bone morphogenetic proteins in prolactin regulation by somatostatin analogs in rat pituitary GH3 cells.

Involvement of the pituitary BMP system in the modulation of prolactin (PRL) secretion regulated by somatostatin analogs, including octreotide (OCT) and pasireotide (SOM230), and a dopamine agonist, bromocriptine (BRC), was examined in GH3 cells. GH3 cells are rat pituitary somato-lactotrope tumor cells that express somatostatin receptors (SSTRs) and BMP system molecules including BMP-4 and -6. Treatment with BMP-4 and -6 increased PRL and cAMP secretion by GH3 cells. The BMP-4 effects were neutralized by adding a BMP-binding protein Noggin. These findings suggest the activity of endogenous BMPs in augmenting PRL secretion by GH3 cells. BRC and SOM230 reduced PRL secretion, but OCT failed to reduce the PRL level. In GH3 cells activated by forskolin, BRC suppressed forskolin-induced PRL secretion with reduction in cAMP levels. OCT did not affect forskolin-induced PRL level, while SOM230 reduced PRL secretion and PRL mRNA expression induced by forskolin. BMP-4 treatment enhanced the reducing effect of SOM230 on forskolin-induced PRL level while BMP-4 did not affect the effects of OCT or BRC. Noggin treatment had no significant effect on the BRC actions reducing PRL levels by GH3 cells. However, in the presence of Noggin, OCT elicited an inhibitory effect on forskolin-induced PRL secretion and PRL mRNA expression, whereas the SOM230 effect on PRL reduction was in turn impaired. It was further found that BMP-4 and -6 suppressed SSTR-2 but increased SSTR-5 mRNA expression of GH3 cells. These findings indicate that Noggin rescues SSTR-2 but downregulates SSTR-5 by neutralizing endogenous BMP actions, leading to an increase in OCT sensitivity and a decrease in SOM230 sensitivity of GH3 cells. In addition, BMP signaling was facilitated in GH3 cells treated with forskolin. Collectively, these findings suggest that BMPs elicit differential actions in the regulation of PRL release dependent on cellular cAMP-PKA activity. BMPs may play a key role in the modulation of SSTR sensitivity of somato-lactotrope cells in an autocrine/paracrine manner.

A novel antagonistic effect of the bone morphogenetic protein system on prolactin actions in regulating steroidogenesis by granulosa cells.

To investigate the mechanism by which prolactin (PRL) regulates follicular steroidogenesis in the ovary, we examined the functional roles of PRL in steroidogenesis using rat oocyte/granulosa cell coculture and focusing on the bone morphogenetic protein (BMP) system. The expression of long and short forms of PRL receptor (PRLR) were detected in both oocytes and granulosa cells, and PRL effectively up-regulated PRLR expression in granulosa cells in the presence of FSH. PRL suppressed FSH-induced estradiol production and increased FSH-induced progesterone production in granulosa cells. The PRL effects on FSH-induced progesterone were blocked by coculture with oocytes, implying roles of oocyte-derived factors in suppression of progesterone production in PRL-exposed granulosa cells. In accordance with the data for steroids, FSH-induced aromatase expression was suppressed by PRL, whereas FSH-induced steroidogenic acute regulatory protein, P450scc (P450 side-chain cleavage enzyme), and 3ß-hydroxysteroid dehydrogenase type 2 levels were amplified by PRL. However, forskolin- and N(6),O(2)-dibutyryl cAMP-induced steroid levels and FSH- and forskolin-induced cAMP were not affected by PRL, suggesting that PRL action on FSH-induced steroidogenesis was not due to cAMP-protein kinase A regulation. Treatment with a BMP-binding protein, noggin, facilitated PRL-induced estradiol reduction, and noggin increased PRL-induced progesterone production in FSH-treated granulosa cells cocultured with oocytes, suggesting that endogenous BMPs reduce progesterone but increase estradiol when exposed to high concentrations of PRL. PRL increased the expression of BMP ligands in oocyte/granulosa cell coculture and augmented BMP-induced phosphorylated mothers against decapentaplegic 1/5/8 signaling by reducing inhibitory phosphorylated mothers against decapentaplegic 6 expression through the Janus kinase/signal transducer and activator of transcription (STAT) pathway. In addition to STAT activation, PRL enhanced FSH-induced MAPK phosphorylation in granulosa cells, in which ERK activation was preferentially involved in suppression of FSH-induced estradiol. Furthermore, noggin treatment enhanced PRLR signaling including MAPK and STAT. Considering that BMPs suppressed PRLR in granulosa cells, it is likely that the BMP system in growing follicles plays a key role in antagonizing PRLR signaling actions in the ovary exposed to high concentrations of PRL.

Effects of bone morphogenetic protein (BMP) on adrenocorticotropin production by pituitary corticotrope cells: involvement of up-regulation of BMP receptor signaling by somatostatin analogs.

The mechanism by which somatostatin analogs suppress ACTH production by corticotropinomas has yet to be fully elucidated. We here studied the effects of somatostatin analogs on ACTH secretion using mouse corticotrope AtT20 cells focusing on the biological activity of bone morphogenetic proteins (BMPs). BMP ligands, receptors and Smads, and somatostatin receptors (SSTRs)-2, -3, and -5 were expressed in AtT20 cells. BMP-2, -4, -6, and -7 decreased basal ACTH production with BMP-4 effects being the most prominent. BMP-4 also inhibited CRH-induced ACTH production and proopiomelanocortin (POMC) transcription. However, the decrease in CRH-induced cAMP accumulation caused by BMP-4 was not sufficient to completely account for BMP-4 actions, indicating that ACTH suppression by BMPs was not directly linked to cAMP inhibition. CRH-activated ERK1/ERK2, p38-MAPK, stress-activated protein kinase/c-Jun NH(2)-terminal kinase, protein kinase C, and Akt pathways and CRH-induced ACTH synthesis was significantly decreased in the presence of U0126 or SB203580. Because BMPs attenuated CRH-induced ERK and p38 phosphorylation, it was suggested that BMP-4 suppresses ACTH production by inhibiting CRH-induced ERK and p38 phosphorylation. Somatostatin analogs octreotide and pasireotide (SOM230) significantly suppressed CRH-induced ACTH and cAMP production in AtT20 cells and reduced ERK and p38 phosphorylation. Notably, CRH-induced ACTH production was enhanced in the presence of noggin, a BMP-binding protein. The inhibitory effects of octreotide and SOM230 on CRH-induced ACTH production were also attenuated by noggin, implying that the endogenous BMP system plays a key role in inhibiting CRH-induced ACTH production by AtT20 cells. The findings that OCT and SOM230 up-regulated BMP-Smad1/Smad5/Smad8 signaling and ALK-3 and BMPRII and down-regulated inhibitory Smad6/7 establish that the activation of endogenous BMP system is functionally involved in the mechanism by which somatostatin analogs suppress CRH-induced ACTH production.

Regulation of GNRH production by estrogen and bone morphogenetic proteins in GT1-7 hypothalamic cells.

Recent studies have shown that bone morphogenetic proteins (BMPs) are important regulators in the pituitary-gonadal endocrine axis. We here investigated the effects of BMPs on GNRH production controlled by estrogen using murine GT1-7 hypothalamic neuron cells. GT1-7 cells expressed estrogen receptor alpha (ERalpha; ESR1 as listed in MGI Database), ERbeta (ESR2 as listed in MGI Database), BMP receptors, SMADs, and a binding protein follistatin. Treatment with BMP2 and BMP4 had no effect on Gnrh mRNA expression; however, BMP6 and BMP7 significantly increased Gnrh mRNA expression as well as GnRH production by GT1-7 cells. Notably, the reduction of Gnrh expression caused by estradiol (E(2)) was restored by cotreatment with BMP2 and BMP4, whereas it was not affected by BMP6 or BMP7. E(2) activated extracellular signal-regulated kinase (ERK) 1/2 and stress-activated protein kinase/c-Jun NH(2)-terminal kinase (SAPK/JNK) signaling but did not activate p38-mitogen-activated protein kinase (MAPK) signaling in GT1-7 cells. Inhibition of ERK1/ERK2 reversed the inhibitory effect of estrogen on Gnrh expression, whereas SAPK/JNK inhibition did not affect the E(2) actions. Expression levels of Eralpha and Erbeta were reduced by BMP2 and BMP4, but were increased by BMP6 and BMP7. Treatment with an ER antagonist inhibited the E(2) effects on Gnrh suppression including reduction of E(2)-induced ERK phosphorylation, suggesting the involvement of genomic ER actions in Gnrh suppression. BMP2 and BMP4 also suppressed estrogen-induced phosphorylation of ERK1/ERK2 and SAPK/JNK signaling, suggesting that BMP2 and BMP4 downregulate estrogen effects by attenuating ER-MAPK signaling. Considering that BMP6 and BMP7 increased the expression of alpha1E-subunit of R-type calcium channel (Cacna1e), which is critical for GNRH secretion, it is possible that BMP6 and BMP7 directly stimulate GNRH release by GT1-7 cells. Collectively, a newly uncovered interaction of BMPs and ER may be involved in controlling hypothalamic GNRH production and secretion via an autocrine/paracrine mechanism.

Enhancement of aldosterone-induced catecholamine production by bone morphogenetic protein-4 through activating Rho and SAPK/JNK pathway in adrenomedullar cells.

Here we investigated the effects of mineralocorticoid in the regulation of catecholamine biosynthesis using rat pheochromocytoma PC12 cells. Expression of mineralocorticoid receptor (MR) was confirmed in undifferentiated PC12 cells. Aldosterone stimulated dopamine production by PC12 cells without any increase in cAMP activity. Aldosterone-induced dopamine accumulation was enhanced in accordance with the increase in the rate-limiting enzyme tyrosine hydroxylase (TH). Blocking MR with eplerenone suppressed aldosterone-induced increases of TH mRNA and dopamine production. A glucocorticoid receptor (GR) antagonist, RU-486, attenuated dexamethasone- but not aldosterone-induced TH expression. Cycloheximide reduced both aldosterone- and dexamethasone-induced TH mRNA. A SAPK/JNK inhibitor, SP600125, suppressed aldosterone-induced TH mRNA expression; however, the aldosterone-induced TH expression was not affected by inhibition of ERK1/2, p38-MAPK, Rho-kinase, PI 3-kinase, and PKC. It was of note that cotreatment with eplerenone and SP600125 restored aldosterone-induced TH mRNA expression to basal levels. To investigate the involvement of bone morphogenetic protein (BMP) actions in aldosterone-induced catecholamine production, we examined the effects of BMP-4 and BMP-7, which are expressed in the adrenal medulla, on catecholamine biosynthesis. BMP-4 preferentially enhanced aldosterone-induced TH mRNA and dopamine production, although BMP-4 alone did not affect TH expression. The BMP-4 enhancement of aldosterone-induced TH expression was not observed in cells treated with eplerenone. BMP-4 did not affect MR expression of PC12 cells; however, it did enhance aldosterone-induced SAPK/JNK phosphorylation. Inhibition of SAPK/JNK or Rho suppressed BMP-4 enhancement of aldosterone-induced TH expression. Collectively, our findings demonstrate that aldosterone stimulates catecholamine biosynthesis in adrenomedullar cells via MR through genomic action and partly through nongenomic action by Rho-SAPK/JNK signaling, the latter of which is facilitated by BMP-4. A functional link between MR actions and endogenous BMP may be involved in the catecholamine production.

Effects of growth hormone reduction in a patient with polycystic ovary syndrome complicated with acromegaly.

We report a rare case of polycystic ovary syndrome (PCOS) complicated with acromegaly due to a growth hormone (GH)-producing pituitary adenoma. Complete removal of the pituitary adenoma successfully reduced circulating levels of GH and insulin-like growth factor (IGF)-1, which, in turn, resulted in the amelioration of gonadal dysfunction, hyperandrogenism, lutenizing hormone hypersecretion, and severe insulin resistance. This clinical complication suggests that activation of systemic GH-IGF-1 axis is potentially involved in the development of PCOS.

Bone morphogenetic protein 6 (BMP6) and BMP7 inhibit estrogen-induced proliferation of breast cancer cells by suppressing p38 mitogen-activated protein kinase activation.

Estrogen is involved in the development and progression of breast cancer. Here, we investigated the effects of bone morphogenetic proteins (BMPs) on breast cancer cell proliferation caused by estrogen using human breast cancer MCF-7 cells. MCF-7 cells express estrogen receptors (ESR1 and ESR2), BMP receptors, and SMAD signaling molecules. Estradiol and membrane-impermeable estradiol stimulated MCF-7 cell proliferation. Estradiol also reduced mRNA levels of ESR1, aromatase, and steroid sulfatase. Treatment with BMPs and activin had no effects on MCF-7 cell proliferation. However, BMP2, BMP4, BMP6, BMP7, and activin suppressed estradiol-induced cell mitosis, with the effects of BMP6, BMP7, and activin being more prominent than those of BMP2 and BMP4. Activin decreased ESR1 mRNA expression, while BMP6 and BMP7 impaired steroid sulfatase expression in MCF-7 cells. Interestingly, SMAD1,5,8 activation elicited by BMP6 and BMP7, but not by BMP2 and BMP4, was preserved even under the exposure of a high concentration of estradiol. The difference of BMP responsiveness was likely due to the differential modulation of BMP receptor expression induced by estradiol. In this regard, estradiol decreased the expression levels of BMPR1A, BMPR1B, ACVR2A, and ACVR2B but did not affect ACVR1 and BMPRII, leading to the sustained effects of BMP6 and BMP7 in estrogen-treated MCF-7 cells. Estradiol rapidly activated MAPK phosphorylation including extracellular signal-regulated kinase 1/2, p38, and stress-activated protein kinase/c-Jun NH2-terminal kinase pathways and BMP6, BMP7, and activin preferentially inhibited estradiol-induced p38 phosphorylation. SB203580, a selective p38 MAPK inhibitor effectively suppressed estradiol-induced cell mitosis, suggesting that p38 MAPK plays a key role in estrogen-sensitive breast cancer cell proliferation. Thus, a novel interrelationship between estrogen and the breast cancer BMP system was uncovered, in which inhibitory effects of BMP6 and BMP7 on p38 signaling and steroid sulfatase expression were functionally involved in the suppression of estrogen-induced mitosis of breast cancer cells.

Involvement of bone morphogenetic protein-4 in GH regulation by octreotide and bromocriptine in rat pituitary GH3 cells.

Here we investigated roles of the pituitary bone morphogenetic protein (BMP) system in modulating GH production regulated by a somatostatin analog, octreotide (OCT) and a dopamine agonist, bromocriptine (BRC) in rat pituitary somatolactotrope tumor GH3 cells. The GH3 cells were found to express BMP ligands, including BMP-4 and BMP-6; BMP type-1 and type-2 receptors (except the type-1 receptor, activin receptor-like kinase (ALK)-6); and Smad signaling molecules. Forskolin stimulated GH production in accordance with cAMP synthesis. BRC, but not OCT, suppressed forskolin-induced cAMP synthesis by GH3 cells. Individual treatment with OCT and BRC reduced forskolin-induced GH secretion. A low concentration (0.1 microM) of OCT in combination with BRC (1-100 microM) exhibited additive effects on reducing GH and cAMP production induced by forskolin. However, a high concentration (10 microM) of OCT in combination with BRC failed to suppress GH and cAMP production. BMP-4 specifically enhanced GH secretion and cAMP production induced by forskolin in GH3 cells. BRC, but not OCT, inhibited BMP-4-induced activation of Smad1,5,8 phosphorylation and Id-1 transcription and decreased ALK-3 expression. Of note, in the presence of a high concentration of OCT, the BRC effects suppressing BMP-4-Smad1,5,8 signaling were significantly impaired. In the presence of BMP-4, a high concentration of OCT also attenuated the BRC effects suppressing forskolin-induced GH and cAMP production. Collectively, a high concentration of OCT interferes with BRC effects by reducing cAMP production and suppressing BMP-4 signaling in GH3 cells. These findings may explain the mechanism of resistance of GH reduction to a combination therapy with OCT and BRC for GH-producing pituitary adenomas.

Aldosterone breakthrough caused by chronic blockage of angiotensin II type 1 receptors in human adrenocortical cells: possible involvement of bone morphogenetic protein-6 actions.

Circulating aldosterone concentrations occasionally increase after initial suppression with angiotensin II (Ang II) converting enzyme inhibitors or Ang II type 1 receptor blockers (ARBs), a phenomenon referred to as aldosterone breakthrough. However, the underlying mechanism causing the aldosterone breakthrough remains unknown. Here we investigated whether aldosterone breakthrough occurs in human adrenocortical H295R cells in vitro. We recently reported that bone morphogenetic protein (BMP)-6, which is expressed in adrenocortical cells, enhances Ang II- but not potassium-induced aldosterone production in human adrenocortical cells. Accordingly, we examined the roles of BMP-6 in aldosterone breakthrough induced by long-term treatment with ARB. Ang II stimulated aldosterone production by adrenocortical cells. This Ang II stimulation was blocked by an ARB, candesartan. Interestingly, the candesartan effects on Ang II-induced aldosterone synthesis and CYP11B2 expression were attenuated in a course of candesartan treatment for 15 d. The impairment of candesartan effects on Ang II-induced aldosterone production was also observed in Ang II- or candesartan-pretreated cells. Levels of Ang II type 1 receptor mRNA were not changed by chronic candesartan treatment. However, BMP-6 enhancement of Ang II-induced ERK1/2 signaling was resistant to candesartan. The BMP-6-induced Smad1, -5, and -8 phosphorylation, and BRE-Luc activity was augmented in the presence of Ang II and candesartan in the chronic phase. Chronic Ang II exposure decreased cellular expression levels of BMP-6 and its receptors activin receptor-like kinase-2 and activin type II receptor mRNAs. Cotreatment with candesartan reversed the inhibitory effects of Ang II on the expression levels of these mRNAs. The breakthrough phenomenon was attenuated by neutralization of endogenous BMP-6 and activin receptor-like kinase-2. Collectively, these data suggest that changes in BMP-6 availability and response may be involved in the occurrence of cellular escape from aldosterone suppression under chronic treatment with ARB.

A rare tumor in the adrenal region: neuron-specific enolase (NSE)-producing leiomyosarcoma in an elderly hypertensive patient.

A 73-year-old Japanese woman was referred for examination of right flank pain and progressive hypertension. Abdominal CT incidentally detected a right adrenal mass 8 cm in size. The tumor exhibited isodensity by CT and contained high-intense lesion by T2-weighted MRI. Scintigraphy with (131) I-metaiodobenzylguanidine and (131) I-adosterol showed no abnormal uptake by whole body scan. Positron emission tomography scan with (18) F-2-fluoro-D-deoxyglucose demonstrated an exclusive uptake in the right adrenal mass. Adrenocortical hormone levels and catecholamine secretion were within normal range; however, the level of serum neuron-specific enolase (NSE) was found to be markedly high. After controlling systemic blood pressure with an alpha1-blocker, the right adrenal tumor was surgically removed, along with the right kidney and inferior vena cava which adhered to it. The tumor was pathologically proven to be leiomyosarcoma, which was immunohistochemically positive with alpha-smooth muscle actin and negative with CD57, S-100 and c-kit proteins. Notably, NSE protein was massively expressed in the resected tumor. After surgery blood pressure was controlled with regular medication and serum NSE levels have since normalized. The possibility of leiomyosarcoma should be kept in mind in adrenal incidentalomas with rapid growth and atypical radiological images. Our findings suggest that circulating NSE levels may be clinically useful for early detection of recurrence.

Gastric diverticulum simulating left adrenal incidentaloma in a hypertensive patient.

A 46-year-old Japanese male with hypertension was referred for examination of left adrenal tumor incidentally detected by computed tomography (CT) scan. The patient had a 4-month history of hypertension. Abdominal CT demonstrated a low-density mass 2.5 cm in diameter in the left adrenal region that was observed as a high-intense lesion with T2-weighted magnetic resonance imaging. (131) I-adosterol scintigraphy showed normal uptake of bilateral adrenals. The adrenocortical hormone levels were within normal ranges; however, urinary noradrenaline excretion was slightly elevated, likely due to concurrent sleep apnea syndrome. Based on the observation of a very tiny bubble in the ventral portion of the adrenal mass by careful review of CT images examined at a previous hospital, a restudy of abdominal CT with oral contrast was performed. In this restudy abdominal CT we observed positive enhancement of the left adrenal mass, indicating that the adrenal mass was a diverticulum derived from posterior gastric fornix. The present case study reinforces that preoperative differentiation from mimic adrenal tumors is necessary in cases of cystic adrenal mass in the left adrenal region.

Whole blood interferon-gamma assay for baseline tuberculosis screening among Japanese healthcare students.

BACKGROUND: The whole blood interferon-gamma assay (QuantiFERON-TB-2G; QFT) has not been fully evaluated as a baseline tuberculosis screening test in Japanese healthcare students commencing clinical contact. The aim of this study was to compare the results from the QFT with those from the tuberculin skin test (TST) in a population deemed to be at a low risk for infection with Mycobacterium tuberculosis. METHODOLOGY/PRINCIPAL FINDINGS: Healthcare students recruited at Okayama University received both the TST and the QFT to assess the level of agreement between these two tests. The interleukin-10 levels before and after exposure to M tuberculosis-specific antigens (early-secreted antigenic target 6-kDa protein [ESAT-6] and culture filtrate protein 10 [CFP-10]) were also measured. Of the 536 healthcare students, most of whom had been vaccinated with bacillus-Calmette-Guérin (BCG), 207 (56%) were enrolled in this study. The agreement between the QFT and the TST results was poor, with positive result rates of 1.4% vs. 27.5%, respectively. A multivariate analysis also revealed that the induration diameter of the TST was not affected by the interferon-gamma concentration after exposure to either of the antigens but was influenced by the number of BCG needle scars (p = 0.046). The whole blood interleukin-10 assay revealed that after antigen exposure, the median increases in interleukin-10 concentration was higher in the subgroup with the small increase in interferon-gamma concentration than in the subgroup with the large increase in interferon-gamma concentration (0.3 vs. 0 pg/mL; p = 0.004). CONCLUSIONS/SIGNIFICANCE: As a baseline screening test for low-risk Japanese healthcare students at their course entry, QFT yielded quite discordant results, compared with the TST, probably because of the low specificity of the TST results in the BCG-vaccinated population. We also found, for the first time, that the change in the interleukin-10 level after exposure to specific antigens was inversely associated with that in the interferon-gamma level in a low-risk population.

Primary aldosteronism caused by a unilateral adrenal adenoma accompanied by autonomous cortisol secretion.

A 35-year-old Japanese woman was referred for further examination of persistent hypertension with hypokalemia. Her serum aldosterone levels were high and her plasma renin activity markedly suppressed. Radiological examinations revealed the presence of a 3-cm diameter left adrenal tumor. (131)I-adosterol was specifically accumulated in the left adrenal tumor, whereas the accumulation in the right adrenal was completely suppressed. Low-dose dexamethasone failed to suppress cortisol secretion although the serum cortisol levels were within the normal range. Urinary excretion of 17-hydroxycorticosteroids but not 17-ketosteroids was increased. Levels of plasma adrenocorticotropin (ACTH) and serum dehydroepiandrosterone sulfate (DHEAS) were decreased. Upon diagnosis of left aldosteronoma with autonomous secretion of cortisol, left adrenalectomy was performed by laparoscopy. In the resected adenoma tissues, clear cells expressed P450c17 protein and the ratio of CYP17/CYP11B2 mRNA evaluated by quantitative real-time polymerase chain reaction (PCR) was apparently higher than that of typical aldosteronomas. Based on the corticotropin-releasing hormone (CRH) loading tests, the contra-lateral adrenal functions were restored 3 months after surgery. These results indicate that evaluation for autonomy of cortisol secretion and contra-lateral adrenal function is clinically important to avoid the risk of adrenal failure after surgery for primary aldosteronism.

Effects of peroxisome proliferator-activated receptor activation on gonadotropin transcription and cell mitosis induced by bone morphogenetic proteins in mouse gonadotrope LbetaT2 cells.

Involvement of peroxisome proliferator-activated receptor-gamma (PPAR-gamma ) activation and bone morphogenetic protein (BMP) signaling in regulating cell proliferation and hormonal production of pituitary tumors has been reported, although the underlying mechanism remains poorly understood. Here, we investigated regulatory roles of PPARalpha and PPARgamma in gonadotropin transcription and cell mitosis modulated by pituitary activin/BMP systems using a mouse gonadotropinoma cell line Lbeta T2, which expresses activin/BMP receptors, transcription factor Smads, PPARalpha , and PPARgamma . In Lbeta T2 cells, BMP signaling shown by Smad1/5/8 phosphorylation and Id-1 transcription was readily activated by BMPs. A PPARgamma agonist, pioglitazone significantly reduced BMP-induced DNA synthesis by Lbeta T2; whereas the PPARalpha agonist, fenofibric acid, did not. In accordance with the effects on cell mitosis, pioglitazone but not fenofibric acid significantly decreased BMP-induced Id-1-Luc activation. Neither fenofibric acid nor pioglitazone affected activin signaling detected by (CAGA)9-Luc activity. Both PPARalpha and PPARgamma ligands directly suppressed transcriptional activities of FSHbeta , LHbeta , and GnRHR. Activation of PPARalpha and PPARgamma increased mRNA levels of follistatin, but did not affect the expression of follistatin-related gene. Thus, PPAR agonists not only directly suppress gonadotropin transcription and BMP signaling, but also inhibit the biological actions of activins which facilitate gonadotropin transcription through upregulating follistatin expression. In addition, pioglitazone increased BMP ligands mRNA, but decreased activin-beta B mRNA in Lbeta T2 cells. Collectively, PPAR activation differentially regulates gonadotrope cell proliferation and gonadotropin transcription in a ligand-dependent manner.

An elderly patient with sarcoidosis manifesting panhypopituitarism with central diabetes insipidus.

We here report a 77-year-old Japanese male who suffered general fatigue with progressive thirst and polyuria. Central diabetes insipidus was diagnosed by depletion of vasopressin secretion in response to increases in serum osmolality. Secretory responses of anterior pituitary hormones including adrenocorticotropin, thyrotropin, gonadotropins and growth hormone were severely impaired. Diffuse swelling of the infundibulum as well as lack of T1-hyperintense signal in the posterior lobe was noted by pituitary magnetic resonance imaging. The presence of bilateral hilar lymphadenopathy and increased CD4/CD8 ratio in bronchoalveolar lavage fluid was diagnostic for lung sarcoidosis. Physiological doses of corticosteroid and thyroid hormone were administered in addition to desmopressin supplementation. Complete regression of the neurohypophysial swelling was notable two years after corticosteroid replacement. Diffuse damage of anterior pituitary combined with hypothalamic involvement leading to central diabetes insipidus is a rare manifestation in such elderly patients with neurosarcoidosis.