Periodontal diseases assessed by average bone resorption are associated with microvascular complications in patients with type 2 diabetes.

Periodontal disease often develops in patients with diabetes, and further exacerbated with diabetic complications. It would be clinically important to clarify the relationship between diabetic microvascular diseases and periodontal disease. This study aimed to evaluate the association between periodontal disease and diabetic complications in patients with type 2 diabetes with poor glycemic control. A total of 447 patients with type 2 diabetes hospitalized at Rakuwakai Otowa Hospital, Japan, were initially recruited in this study. After excluding 134 patients who lacked clinical data or were edentulous, 312 were included in our study. The severity of periodontal disease was evaluated based on the average bone resorption rate. Patients with diabetic nephropathy developed severe periodontal disease (multivariate-adjusted odds ratio, 3.00 [95% CI 1.41-5.19]). Diabetic neuropathy was positively associated with the severity of periodontal disease; the multivariate-adjusted odds ratio (95% CI) was 1.62 (0.87‒2.99) for moderate and 4.26 (2.21‒8.20) for severe periodontal disease. In contrast, diabetic retinopathy was linked with moderate periodontal disease (multivariate-adjusted odds ratio 2.23 [95% CI 1.10-4.10]), but not with severe conditions (multivariate-adjusted odds ratio 0.92 [95% CI 0.67-3.07]). In conclusion, periodontal disease, evaluated by average bone resorption rate, was associated with diabetic nephropathy and neuropathy. Supplementary Information: The online version contains supplementary material available at 10.1007/s13340-022-00591-0.

Regulation of type 1 iodothyronine deiodinase by LXRα.

The iodothyronine deiodinases are selenoenzymes that regulate the activity of thyroid hormone via specific inner- or outer-ring deiodination. In humans, type 1 deiodinase (D1) is highly expressed in the liver, but the mechanism by which its gene expression is regulated remains to be elucidated. Liver X receptor α (LXRα), a transcription factor of the nuclear receptor superfamily, is highly expressed in the liver, where it functions as a sensor for excess intracellular oxysterols. LXRα interacts with other nuclear receptors on promoters of genes that contain a binding core sequence for nuclear receptors. In addition, it is reported that the promoter of the gene encoding human D1 (hDIO1) contains the core sequence for one of nuclear receptors, thyroid hormone receptor (TR). We investigated the involvement of LXRα in the regulation of hDIO1, in the liver. We performed hDIO1 promoter-reporter assays using a synthetic LXR agonist, T0901317, and compared promoter activity between a human liver carcinoma cell line, HepG2, and a clone of human embryonic kidney cells, TSA201. We defined the region between nucleotides -131 and -114, especially nucleotides -126 and -125, of the hDIO1 promoter as critical for basal and LXRα-mediated specific transcriptional activation in HepG2 cells. An increase in hDIO1 expression was observed in LXRα-stimulated cells, but absent in cycloheximide-treated cells, indicating that new protein synthesis is required for LXRα-mediated regulation of hDIO1. On the other hand, electrophoretic mobility shift assays revealed that LXRα and RXRα bound to the hDIO1 promoter. We also demonstrated that LXRα and TRß compete with each other on this specific region of the promoter. In conclusion, our results indicated that LXRα plays a specific and important role in activation of TH by regulating D1, and that LXRα binds to and regulates the hDIO1 promoter, competing with TRß on specific sequences within the promoter.

Overall safety and efficacy of high-dose and low-dose intravenous glucocorticoid therapy in patients with moderate-to-severe active Graves' ophthalmopathy.

The objective of this study was to compare the safety and efficacy of high-dose and low-dose intravenous (iv) glucocorticoid (GC) therapy in patients with Graves' ophthalmopathy (GO) and to investigate which factors may help determine appropriate iv GC doses. The medical records of 43 patients who received different doses of iv GCs for GO were retrospectively reviewed. Twenty patients received high-dose iv GCs (HD group, cumulative dose 9.0-12.0 g) and 18 received low-dose iv GCs (LD group, cumulative dose 4.5 g). Five patients with previous treatment for GO were excluded. Changes in ophthalmic parameters after treatment and frequencies of adverse effects due to GCs of the 2 groups were compared. We also reviewed the incidence of GO progression and hepatic dysfunction after patients were discharged. We evaluated correlations among pretreatment (before treatment) ophthalmic parameters and investigated useful predictive factors for determining iv GC doses. There were no significant differences in ophthalmic parameters reflecting treatment efficacy or overall safety between the groups. Among baseline ophthalmic parameters, corrected signal intensity ratio (cSIR) correlated well with magnetic resonance imaging findings and were more strongly associated with changes in ophthalmic parameters after treatment in the HD group than in the LD group, indicating that pretreatment cSIR might be useful for determining iv GC doses. In conclusion, there were no significant differences in overall safety and efficacy between high-dose and low-dose iv GC therapy in patients with active GO. Further randomized clinical trials with longer observation periods are required to establish the optimal treatment regimen of GO.

Brain-specific natriuretic peptide receptor-B deletion attenuates high-fat diet-induced visceral and hepatic lipid deposition in mice.

C-type natriuretic peptide (CNP) and its receptor, natriuretic peptide receptor-B (NPR-B), are abundantly distributed in the hypothalamus. To explore the role of central CNP/NPR-B signaling in energy regulation, we generated mice with brain-specific NPR-B deletion (BND mice) by crossing Nestin-Cre transgenic mice and mice with a loxP-flanked NPR-B locus. Brain-specific NPR-B deletion prevented body weight gain induced by a high-fat diet (HFD), and the mesenteric fat and liver weights were significantly decreased in BND mice fed an HFD. The decreased liver weight in BND mice was attributed to decreased lipid accumulation in the liver, which was confirmed by histologic findings and lipid content. Gene expression analysis revealed a significant decrease in the mRNA expression levels of CD36, Fsp27, and Mogat1 in the liver of BND mice, and uncoupling protein 2 mRNA expression was significantly lower in the mesenteric fat of BND mice fed an HFD than in that of control mice. This difference was not observed in the epididymal or subcutaneous fat. Although previous studies reported that CNP/NPR-B signaling inhibits SNS activity in rodents, SNS is unlikely to be the underlying mechanism of the metabolic phenotype observed in BND mice. Taken together, CNP/NPR-B signaling in the brain could be a central factor that regulates visceral lipid accumulation and hepatic steatosis under HFD conditions. Further analyses of the precise mechanisms will enhance our understanding of the contribution of the CNP/NPR-B system to energy regulation.

Isolation of mesenchymal stromal/stem cells from small-volume umbilical cord blood units that do not qualify for the banking system.

The clinical application of mesenchymal stromal/stem cells (MSCs) has been extensively explored. In this study, we examined the availability of freshly donated umbilical cord blood (UCB) units that do not qualify for the Japanese banking system for transplantation because of their small volume as a source of MSCs. Forty-five UCB units were used. The median volume of each UCB unit and number of nucleated cells per unit were 40 mL and 5.39 × 10(8), respectively. MSCs were successfully isolated from 18 of 45 units (40 %). The MSC isolation rate was not affected by cell processing method or the interval between delivery and cell processing. The volume of the UCB unit and the mononuclear cell count were predictive factors of the MSC isolation rate. MSCs were effectively isolated by selecting UCB units with a volume of ≥54 mL and containing ≥1.28 × 10(8) mononuclear cells, yielding a MSC isolation rate of >70 %. UCB-derived MSCs were similar to bone marrow-derived MSCs in terms of their morphology, surface marker expression, and differentiation potential, apart from adipogenesis. Our data indicate that UCB units that are currently discarded due to inadequate volume should be reconsidered as a source of MSCs using the well-established UCB banking system.

The Local CNP/GC-B system in growth plate is responsible for physiological endochondral bone growth.

Recent studies revealed C-type natriuretic peptide (CNP) and its receptor, guanylyl cyclase-B (GC-B) are potent stimulators of endochondral bone growth. As they exist ubiquitously in body, we investigated the physiological role of the local CNP/GC-B in the growth plate on bone growth using cartilage-specific knockout mice. Bones were severely shorter in cartilage-specific CNP or GC-B knockout mice and the extent was almost the same as that in respective systemic knockout mice. Cartilage-specific GC-B knockout mice were shorter than cartilage-specific CNP knockout mice. Hypertrophic chondrocyte layer of the growth plate was drastically reduced and proliferative chondrocyte layer, along with the proliferation of chondrocytes there, was moderately reduced in either cartilage-specific knockout mice. The survival rate of cartilage-specific CNP knockout mice was comparable to that of systemic CNP knockout mice. The local CNP/GC-B system in growth plate is responsible for physiological endochondral bone growth and might further affect mortality via unknown mechanisms.

Increased Bone Turnover and Possible Accelerated Fracture Healing in a Murine Model With an Increased Circulating C-Type Natriuretic Peptide.

Recent studies have revealed that C-type natriuretic peptide (CNP) is a potent stimulator of endochondral bone growth. Nevertheless, the effect of CNP on bone turnover has not yet been well studied. To elucidate this issue, we investigated the bone phenotype of a mouse model with elevated plasma CNP concentrations (SAP-CNP-Tg mice) in the present study. Microcomputed tomography (CT) analysis revealed less bone in femurs, but not in lumber vertebrae, of young adult SAP-CNP-Tg mice than that of wild-type mice. Bone histomorphometry of the tibiae from 8-week-old SAP-CNP-Tg mice showed enhanced osteoblastic and osteoclastic activities, in accordance with elevated serum levels of osteocalcin and tartrate-resistant acid phosphatase-5b, respectively. Next we performed an open and stabilized femoral fracture using 8-week-old SAP-CNP-Tg mice and compared the healing process with age-matched wild-type mice. An immunohistochemical study revealed that CNP and its receptors, natriuretic peptide receptor-B and natriuretic peptide clearance receptor, are expressed in hard calluses of wild-type mice, suggesting a possible role of CNP/natriuretic peptide receptor-B signaling in fracture repair, especially in bone remodeling stage. On micro-CT analysis, a rapid decrease in callus volume was observed in SAP-CNP-Tg mice, followed by a generation of significantly higher new bone volume with a tendency of increased bone strength. In addition, a micro-CT analysis also showed that bone remodeling was accelerated in SAP-CNP-Tg mice, which was also evident from increased serum osteocalcin and tartrate-resistant acid phosphatase-5b levels in SAP-CNP-Tg mice at the remodeling stage of fracture repair. These results indicate that CNP activates bone turnover and remodeling in vivo and possibly accelerates fracture healing in our mouse model.

A comparison between 11C-methionine PET/CT and MIBI SPECT/CT for localization of parathyroid adenomas/hyperplasia.

OBJECTIVE: The purpose of this study was to compare the sensitivity of single-photon emission computed tomography/computed tomography (SPECT/CT) using 99mTc-sestamibi (MIBI) with that of PET/CT using 11C-methionine (MET) for localization of parathyroid adenomas/hyperplasia in primary hyperparathyroidism. MATERIALS AND METHODS: Twenty-three patients with primary hyperparathyroidism were analyzed. Fifteen patients underwent surgery, and the remaining eight did not, but these patients were clinically diagnosed as having primary hyperparathyroidism. Patients underwent both MET PET/CT and MIBI SPECT/CT scanning. The sensitivities of both modalities were evaluated on a per-patient basis, and on a per-lesion basis for parathyroid lesions detected by surgery. The size of the parathyroid adenoma/hyperplasia and serum intact parathyroid hormone levels were compared with the results of each of the two modalities. RESULTS: Per-patient sensitivities of MET PET/CT and MIBI SPECT/CT were 65 and 61%, respectively. Per-lesion sensitivities of MET PET/CT and MIBI SPECT/CT were 91 and 73% for histologically confirmed adenomas and 30 and 30% for hyperplastic glands, respectively. No significant differences were observed between the two modalities. The size of uptake-positive lesions was significantly larger than that of uptake-negative lesions in both modalities. Intact parathyroid hormone levels showed no significant difference between uptake-positive and uptake-negative patients in both modalities. CONCLUSION: The sensitivities of MET PET/CT and MIBI SPECT/CT were comparable. MET PET/CT has a complementary role in localizing parathyroid adenomas/hyperplasia when MIBI SPECT/CT is inconclusive.

Role of endogenous ACTH on circadian aldosterone rhythm in patients with primary aldosteronism.

We recently reported that stimulation with high-dose ACTH caused different responses in terms of aldosterone secretion in aldosterone-producing adenomas (APAs) and idiopathic hyperaldosteronism (IHA) in patients with primary aldosteronism (PA). However, the role of endogenous ACTH in aldosterone secretion in PA has not been systematically evaluated. In this study, we examined diurnal changes in plasma aldosterone concentration (PAC), and changes in PAC after dexamethasone administration in patients with suspected PA, in order to evaluate the effect of endogenous ACTH on aldosterone secretion. Seventy-three patients admitted to Kyoto University Hospital with suspected PA were included. The patients were classified into non-PA, IHA, and APA groups according to the results of captopril challenge test and adrenal venous sampling. PAC at 0900 h (PAC0900), 2300 h (PAC2300), and after 1-mg dexamethasone suppression test (PACdex) was measured and compared among the three groups. The PAC2300/PAC0900 and PACdex/PAC0900 ratios were also analyzed. PAC2300 and PACdex were lower than PAC0900 in all three groups. There were no significant differences in PAC2300/PAC0900 among the three groups. However, PACdex/PAC0900 was significantly lower in the APA group compared with the non-PA and IHA groups. The results of this study indicate that aldosterone secretion in APA patients is more strongly dependent on endogenous ACTH than in IHA and non-PA patients. The results also suggest that factors other than ACTH, such as clock genes, may cause diurnal changes in aldosterone secretion in IHA and non-PA patients.

Parathyroid hormone enhances hematopoietic expansion via upregulation of cadherin-11 in bone marrow mesenchymal stromal cells.

Parathyroid hormone (PTH) stimulates hematopoiesis in mouse models. The involvement of osteoblasts in this process has been well investigated; however, the effects of PTH on human hematopoiesis and bone marrow mesenchymal stromal cells (BM-MSCs) are unclear. Here, we show that BM-MSCs contribute to the hematopoiesis-stimulating effects of PTH via upregulation of cadherin-11 (CDH11). When culture-expanded human BM-MSCs were stimulated with PTH, their ability to expand cocultured CD34(+) hematopoietic progenitor cells (HPCs) was enhanced. Furthermore, when PTH-treated BM-MSCs were subcutaneously implanted into NOD/SCID mice, the induction of hematopoietic cells was enhanced. Culture-expanded human BM-MSCs expressed CDH11, and the level of CDH11 expression increased following PTH stimulation. Depletion of CDH11 expression in BM-MSCs using small interfering RNA abolished the enhancement of HPC expansion by PTH-treated BM-MSCs. In lethally irradiated mice that underwent BM transplantation, CDH11 expression in BM-MSCs was higher and survival was better in PTH-treated mice than in control mice. The number of hematopoietic cells in BM and the number of red blood cells in peripheral blood were higher in PTH-treated mice than in control mice. Our results demonstrate that PTH stimulates hematopoiesis through promoting the upregulation of CDH11 expression in BM-MSCs, at least in part. PTH treatment may be an effective strategy to enhance the ability of BM-MSCs to support hematopoiesis.

Serum proteome analysis in patients with rheumatoid arthritis receiving therapy with tocilizumab: an anti-interleukin-6 receptor antibody.

Rheumatoid arthritis (RA) is a chronic inflammatory disorder of the synovial membrane that results in the destruction of bone and cartilage in affected joints. Tocilizumab is a biological agent and an anti-interleukin-6 (IL-6) receptor monoclonal antibody that blocks IL-6-mediated inflammatory processes in RA patients. In order to identify novel disease-related proteins and candidate biomarkers, we analyzed the changes in the serum proteome profiles of patients with RA who were treated with tocilizumab. Serum samples were collected from the RA patients before and after tocilizumab treatment. Following immunodepletion of major proteins, the proteins were digested and labeled with isobaric tag, iTRAQ reagent. The proteins were identified and quantified using liquid chromatography-tandem mass spectrometry. Among a total of 311 proteins identified, seven were decreased and 16 were increased by tocilizumab treatment. Although some of the proteins are known to be related to RA, several are currently unknown with respect to their relationship to RA and may be involved in the development of this disease. This study is the first to perform a comparative serum proteomic analysis of RA patients treated with tocilizumab. Our results may contribute to the identification of novel disease-related proteins and enhance the understanding of the pathogenesis of RA.

Adrenal reserve function after unilateral adrenalectomy in patients with primary aldosteronism.

OBJECTIVE: After unilateral adrenalectomy (uADX) in patients with a unilateral aldosterone-producing adenoma (APA), the remaining contralateral adrenal gland is generally considered sufficient to support life. However, few studies have compared adrenal reserve function before and after uADX. Therefore, we closely evaluated adrenal cortisol secretory function before and after uADX in patients with unilateral APA. METHODS: Patients who were diagnosed with APA and underwent uADX for unilateral APA were initially included in this study. Patients with subclinical Cushing's syndrome (SCS) or Cushing's syndrome were excluded on suspicion of autonomous cortisol secretion. Fourteen patients were finally evaluated. Morning basal serum cortisol and plasma adrenocorticotropin hormone (ACTH) levels were measured, and ACTH stimulation tests under 1-mg dexamethasone suppression (dex-ACTH test) were performed before and after uADX. RESULTS: No patient developed clinical adrenal insufficiency. Basal cortisol levels were not significantly different before and after uADX. However, basal ACTH levels were significantly elevated after uADX. In addition, peak cortisol levels on the dex-ACTH test decreased in all patients after uADX. The peak cortisol level after uADX was 86.6 (81.4-92.4)% of the level before uADX. CONCLUSION: The adrenal cortisol secretory response to ACTH stimulation is mildly reduced after uADX in patients with unilateral APA without SCS or Cushing's syndrome, although their basal cortisol level is sustained by elevated ACTH. These data will be important as a point of discussion when patients with unilateral APA consider either uADX or specific pharmacotherapy as treatment options.

Human induced pluripotent stem cells differentiated into chondrogenic lineage via generation of mesenchymal progenitor cells.

Human induced pluripotent stem cells (hiPSCs) exhibit pluripotency, proliferation capability, and gene expression similar to those of human embryonic stem cells (hESCs). hESCs readily form cartilaginous tissues in teratomas in vivo; despite extensive effort, however, to date no efficient method for inducing mature chondrocytes in vitro has been established. hiPSCs can also differentiate into cartilage in vivo by teratoma formation, but as with hESCs, no reliable system for in vitro chondrogenic differentiation of hiPSCs has yet been reported. Here, we examined the chondrogenic differentiation capability of hiPSCs using a multistep culture method consisting of embryoid body (EB) formation, cell outgrowth from EBs, monolayer culture of sprouted cells from EBs, and 3-dimensional pellet culture. In this culture process, the cell density of monolayer culture was critical for cell viability and subsequent differentiation capability. Monolayer-cultured cells exhibited fibroblast-like morphology and expressed markers for mesenchymal stem cells. After 2-3 weeks of pellet culture, cells in pellets exhibited a spherical morphology typical of chondrocytes and were surrounded by extracellular matrix that contained acidic proteoglycans. The expression of type II collagen and aggrecan in pellets progressively increased. Histological analysis revealed that over 70% of hiPSC-derived pellets successfully underwent chondrogenic differentiation. Using the same culture method, hESCs showed similar histological changes and gene expression, but differentiated slightly faster and more efficiently than hiPSCs. Our study demonstrates that hiPSCs can be efficiently differentiated into the chondrogenic lineage in vitro via generation of mesenchymal progenitor cells, using a simplified, multistep culture method.

[Development of the Work Limitations Questionnaire Japanese version (WLQ-J): fundamental examination of the reliability and validity of the WLQ-J].

OBJECTIVE: It is reported that presenteeism costs more than absenteeism. However, it is difficult to measure presenteeism in Japan because there are few available instruments. We examined the reliability and validity of the Japanese version of the Work limitations Questionnaire (the WLQ-J). METHODS: We conducted an internet survey with the WLQ-J and Brief Job Stress Questionnaire (BJSQ) of 1,545 males and females working for an IT company and a medical institution (21-61 years of age). The number of employees of the IT company and nursing staff of the medical institution included in the analysis were 373 and 337, respectively (effective response rate: 46.0 %). RESULTS: The subjects' average age and the ratio of females were 33.2 ± 9.5 yr old and 60.3%, respectively. Factor analysis showed that the number of factors and items of subscales of the WLQ-J accorded with those of the original WLQ. This supports the factorial validity of the WLQ-J. Additionally, sufficient internal consistency was recognized by Cronbach's alpha (the whole scale=0.97, the subscales=0.88-0.95). Criterion-related validity was supported by the significant dose-response relationship between the subscale scores of the WLQ-J and the stress response of BJSQ as an external criterion (p<0.01). CONCLUSIONS: The study results demonstrate the reliability and validity of the WLQ-J. It is expected that human resource functions such as senior management, personnel affairs, line management, and occupational health staff over a wide range of industries will use the WLQ-J. Further studies are needed to verify the reliability and validity of the WLQ-J by examining differences in the WLQ-J arising from gender, age, industry, and occupation between multiple studies, and by finding relationships between the WLQ-J and other evaluation scales.

A case of myelolipoma with bilateral adrenal hyperaldosteronism cured after unilateral adrenalectomy.

Myelolipomas are adrenal tumors composed of both adipose and hematopoietic tissues which are rarely associated with primary aldosteronism (PA). Here, we report a case of myelolipoma associated with PA. Aldosterone hypersecretion from bilateral adrenal glands had been confirmed by adrenal venous sampling and pathological analyses, but PA was clinically cured after surgical removal of the unilateral adrenal gland together with the myelolipoma that was not producing aldosterone. It is suggested that myelolipomas may release some factors which stimulate aldosterone production in adrenal glands, although further investigation is necessary. Obesity-related hyperaldosteronism might in part participate in generation of hypertension in the present case.

Diabetic ketoacidosis accompanied by hypothermia: a case report.

Diabetic ketoacidosis (DKA) is an acute, life-threatening complication of diabetes mellitus and is caused by insulin insufficiency. Hypothermia is defined as a core temperature of less than 35°C and is sometimes accompanied by DKA. We report two patients with diabetes who were admitted for DKA accompanied by hypothermia.

Skeletal analysis of the long bone abnormality (lbab/lbab) mouse, a novel chondrodysplastic C-type natriuretic peptide mutant.

Long bone abnormality (lbab/lbab) is a strain of dwarf mice. Recent studies revealed that the phenotype is caused by a spontaneous mutation in the Nppc gene, which encodes mouse C-type natriuretic peptide (CNP). In this study, we analyzed the chondrodysplastic skeletal phenotype of lbab/lbab mice. At birth, lbab/lbab mice are only slightly shorter than their wild-type littermates. Nevertheless, lbab/lbab mice do not undergo a growth spurt, and their final body and bone lengths are only ~60% of those of wild-type mice. Histological analysis revealed that the growth plate in lbab/lbab mice, especially the hypertrophic chondrocyte layer, was significantly thinner than in wild-type mice. Overexpression of CNP in the cartilage of lbab/lbab mice restored their thinned growth plate, followed by the complete rescue of their impaired endochondral bone growth. Furthermore, the bone volume in lbab/lbab mouse was severely decreased and was recovered by CNP overexpression. On the other hand, the thickness of the growth plate of lbab/+ mice was not different from that of wild-type mice; accordingly, impaired endochondral bone growth was not observed in lbab/+ mice. In organ culture experiments, tibial explants from fetal lbab/lbab mice were significantly shorter than those from lbab/+ mice and elongated by addition of 10(-7) M CNP to the same extent as lbab/+ tibiae treated with the same dose of CNP. These results demonstrate that lbab/lbab is a novel mouse model of chondrodysplasia caused by insufficient CNP action on endochondral ossification.

Forkhead box A1 (FOXA1) and A2 (FOXA2) oppositely regulate human type 1 iodothyronine deiodinase gene in liver.

Type 1 iodothyronine deiodinase (D1), a selenoenzyme that catalyzes the bioactivation of thyroid hormone, is expressed mainly in the liver. Its expression and activity are modulated by several factors, but the precise mechanism of its transcriptional regulation remains unclear. In the present study, we have analyzed the promoter of human D1 gene (hDIO1) to identify factors that prevalently increase D1 activity in the human liver. Deletion and mutation analyses demonstrated that a forkhead box (FOX)A binding site and an E-box site within the region between nucleotides -187 and -132 are important for hDIO1 promoter activity in the liver. EMSA demonstrated that FOXA1 and FOXA2 specifically bind to the FOXA binding site and that upstream stimulatory factor (USF) specifically binds to the E-box element. Overexpression of FOXA2 decreased hDIO1 promoter activity, and short interfering RNA-mediated knockdown of FOXA2 increased the expression of hDIO1 mRNA. In contrast, overexpression of USF1/2 increased hDIO1 promoter activity. Short interfering RNA-mediated knockdown of FOXA1 decreased the expression of hDIO1 mRNA, but knockdown of both FOXA1 and FOXA2 restored it. The response of the hDIO1 promoter to USF was greatly attenuated in the absence of FOXA1. Taken together, these results indicate that a balance of FOXA1 and FOXA2 expression modulates hDIO1 expression in the liver.

Significance of adrenocorticotropin stimulation test in the diagnosis of an aldosterone-producing adenoma.

CONTEXT: Adrenal venous sampling is the "gold standard" test in the diagnosis of an aldosterone-producing adenoma (APA) among patients with primary aldosteronism (PA) but is available only in specialized medical centers. Meanwhile, an APA is reported to be generally more sensitive to ACTH than idiopathic hyperaldosteronism. OBJECTIVE: The aim was to evaluate the diagnostic accuracy of the ACTH stimulation test in the diagnosis of an APA among those with suspicion of PA. PATIENTS AND SETTING: Fifty-nine patients admitted to Kyoto University Hospital on suspicion of PA were included in the study. INTERVENTIONS: ACTH stimulation tests with 1-mg dexamethasone suppression were performed. MAIN OUTCOME MEASURE: Plasma aldosterone concentrations (PAC) were examined every 30 min after ACTH stimulation. Receiver-operated characteristics curve analysis was used to evaluate the diagnostic accuracy. RESULTS: PAC after ACTH stimulations were significantly higher in patients with an APA than in patients with idiopathic hyperaldosteronism or non-PA. Receiver-operated characteristics curve analyses showed that the PAC after ACTH stimulation was effective for the diagnosis of an APA among patients suspected of PA. The diagnostic accuracy was highest at 90 min after ACTH injection, with the optimal cutoff value greater than 37.9 ng/dl corresponding with sensitivity and specificity of 91.3 and 80.6% for the diagnosis of an APA. CONCLUSIONS: Our study indicates that the ACTH stimulation test is useful in the diagnosis of an APA among patients suspected of PA. This test can be used to select patients who are highly suspected of an APA and definitely require adrenal venous sampling.