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  • 1
    In: Scientific Reports, Springer Science and Business Media LLC, Vol. 13, No. 1 ( 2023-02-21)
    Abstract: This study aimed to develop a machine-learning algorithm to diagnose aldosterone-producing adenoma (APA) for predicting APA probabilities. A retrospective cross-sectional analysis of the Japan Rare/Intractable Adrenal Diseases Study dataset was performed using the nationwide PA registry in Japan comprised of 41 centers. Patients treated between January 2006 and December 2019 were included. Forty-six features at screening and 13 features at confirmatory test were used for model development to calculate APA probability. Seven machine-learning programs were combined to develop the ensemble-learning model (ELM), which was externally validated. The strongest predictive factors for APA were serum potassium (s-K) at first visit, s-K after medication, plasma aldosterone concentration, aldosterone-to-renin ratio, and potassium supplementation dose. The average performance of the screening model had an AUC of 0.899; the confirmatory test model had an AUC of 0.913. In the external validation, the AUC was 0.964 in the screening model using an APA probability of 0.17. The clinical findings at screening predicted the diagnosis of APA with high accuracy. This novel algorithm can support the PA practice in primary care settings and prevent potentially curable APA patients from falling outside the PA diagnostic flowchart.
    Type of Medium: Online Resource
    ISSN: 2045-2322
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2023
    detail.hit.zdb_id: 2615211-3
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  • 2
    In: Journal of Hypertension, Ovid Technologies (Wolters Kluwer Health), Vol. 39, No. 5 ( 2021-05), p. 1018-1024
    Abstract: Aldosterone synthase gene, CYP11B2 is regulated by potassium and angiotensin II (Ang II). We have reported that Ang II could change the DNA methylation status around transcription factor-binding sites and a transcription start site (TSS) and activate expression of CYP11B2 . Similar to Ang II, small increases in extracellular potassium levels also increase CYP11B2 mRNA levels. Methods and results: Adrenocortical H295R cells were treated with different doses of potassium. Methylation analysis of CYP11B2 promoter region was done by bisulfite sequencing. CYP11B2 mRNA and protein levels, chromatin accessibility, methylation and demethylation activity were estimated. The transcriptional ability of CYP11B2 promoter with or without methylation was assessed. Potassium stimulation caused DNA demethylation around cyclic AMP responsive element binding protein 1 (CREB1) and nuclear receptor subfamily 4 group A (NR4A) family-binding sites and a TSS; demethylation was accompanied by recruitment of CREB1 and NR4A1 and increased chromatin accessibility of the CYP11B2 promoter. DNA methylation activity decreased in the nucleus. DNA demethylation at CpG1 (Ad1), CpG2 (Ad5) and CpG3 were detected within 2 to 4 days after potassium (16 mmol/l) stimulation. The changes reached a maximum level by day 7. DNA at CpG2 (Ad5) and CpG3 was re-methylated to levels that were similar to those of nontreated cells at day 9. Potassium treatment significantly reduced DNA methylation activity at days 7 and 9. DNA demethylation activity was not changed by potassium. Conclusion : Potassium induced reversibly DNA demethylation, which switches the phenotype of CYP11B2 expression from an inactive to an active state.
    Type of Medium: Online Resource
    ISSN: 0263-6352 , 1473-5598
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2021
    detail.hit.zdb_id: 2017684-3
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  • 3
    In: Endocrine Journal, Japan Endocrine Society, Vol. 71, No. 3 ( 2024), p. 245-252
    Type of Medium: Online Resource
    ISSN: 0918-8959 , 1348-4540
    Language: English
    Publisher: Japan Endocrine Society
    Publication Date: 2024
    detail.hit.zdb_id: 2133773-1
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  • 4
    In: Internal Medicine, Japanese Society of Internal Medicine, Vol. 60, No. 7 ( 2021-4-1), p. 993-998
    Type of Medium: Online Resource
    ISSN: 0918-2918 , 1349-7235
    RVK:
    Language: English
    Publisher: Japanese Society of Internal Medicine
    Publication Date: 2021
    detail.hit.zdb_id: 2202453-0
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  • 5
    In: Endocrinology, Diabetes & Metabolism Case Reports, Bioscientifica, Vol. 2020 ( 2020-09-23)
    Abstract: Pheochromocytoma crisis results from the sudden release of large quantities of catecholamines and leads to progressive multiple organ dysfunction. Here we report a case of pheochromocytoma crisis with symptoms associated with acute coronary syndrome (ACS) and severe fluctuations in blood pressure (BP). A 43-year-old Japanese man with hypertension (240/120 mmHg) visited a general hospital for chest pain. Echocardiogram showed ST segment depression and blood test demonstrated elevated troponin T. However, emergent coronary angiography revealed normal findings. CT showed a large adrenal mass on the left side, which was suspected as the cause of chest pain and BP elevation. After the patient was transported to our hospital, his BP was found to oscillate between 70 and 240 mmHg, and level of consciousness was decreased. After hospitalization, he had a further decrease in consciousness, a rise in body temperature, and a gradual increase in the interval between the upper and lower systolic BP. His systolic BP varied between 30 mmHg and 300 mmHg at the intervals of 20-30 min. After a multimodality therapy, including α-blocker and high dose fluid replacement, the fluctuation in his BP was gradually decreased and got stabilized after approximately 24 h. Approximately 3 weeks later, he underwent left adrenalectomy. This case showed that pheochromocytoma with internal necrosis might be misdiagnosed as ACS. Furthermore, in cases with a large adrenal tumor and severe elevation or fluctuations of BP, pheochromocytoma should be suspected and treated with α-blockers and fluid replacements as soon as possible prior to surgery. Learning points: High catecholamine levels due to pheochromocytoma crisis might cause symptoms associated with acute coronary syndrome. Adrenal tumor with internal necrosis and the elevation or fluctuations of blood pressure should be suspected to be pheochromocytoma. If pheochromocytoma crisis is suspected, the specialist, such as an endocrinologist or a urologist, should intervene, and an α-blocker treatment with adequate fluid replacement therapy should be initiated as soon as possible. Pheochromocytoma multisystem crisis (PMC) is a fatal condition characterized by multiple organ failure, severe blood pressure variability, high fever, and encephalopathy. This is an extremely rare subtype of a very rare disease such as pheochromocytoma. However, because the fatality rate of PMC is high, clinicians should be aware of the symptoms that mark its onset.
    Type of Medium: Online Resource
    ISSN: 2052-0573
    Language: Unknown
    Publisher: Bioscientifica
    Publication Date: 2020
    detail.hit.zdb_id: 2785530-2
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  • 6
    Online Resource
    Online Resource
    MDPI AG ; 2023
    In:  International Journal of Molecular Sciences Vol. 24, No. 6 ( 2023-03-17), p. 5782-
    In: International Journal of Molecular Sciences, MDPI AG, Vol. 24, No. 6 ( 2023-03-17), p. 5782-
    Abstract: Aldosterone and cortisol serve important roles in the pathogenesis of cardiovascular diseases and metabolic disorders. Epigenetics is a mechanism to control enzyme expression by genes without changing the gene sequence. Steroid hormone synthase gene expression is regulated by transcription factors specific to each gene, and methylation has been reported to be involved in steroid hormone production and disease. Angiotensin II or potassium regulates the aldosterone synthase gene, CYP11B2. The adrenocorticotropic hormone controls the 11b-hydroxylase, CYP11B1. DNA methylation negatively controls the CYP11B2 and CYP11B1 expression and dynamically changes the expression responsive to continuous stimulation of the promoter gene. Hypomethylation status of the CYP11B2 promoter region is seen in aldosterone-producing adenomas. Methylation of recognition sites of transcription factors, including cyclic AMP responsive element binding protein 1 or nerve growth factor-induced clone B, diminish their DNA-binding activity. A methyl-CpG-binding protein 2 cooperates directly with the methylated CpG dinucleotides of CYP11B2. A low-salt diet, treatment with angiotensin II, and potassium increase the CYP11B2 mRNA levels and induce DNA hypomethylation in the adrenal gland. A close association between a low DNA methylation ratio and an increased CYP11B1 expression is seen in Cushing’s adenoma and aldosterone-producing adenoma with autonomous cortisol secretion. Epigenetic control of CYP11B2 or CYP11B1 plays an important role in autonomic aldosterone or cortisol synthesis.
    Type of Medium: Online Resource
    ISSN: 1422-0067
    Language: English
    Publisher: MDPI AG
    Publication Date: 2023
    detail.hit.zdb_id: 2019364-6
    SSG: 12
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  • 7
    Online Resource
    Online Resource
    The Endocrine Society ; 2019
    In:  Journal of the Endocrine Society Vol. 3, No. Supplement_1 ( 2019-04-15)
    In: Journal of the Endocrine Society, The Endocrine Society, Vol. 3, No. Supplement_1 ( 2019-04-15)
    Type of Medium: Online Resource
    ISSN: 2472-1972
    Language: English
    Publisher: The Endocrine Society
    Publication Date: 2019
    detail.hit.zdb_id: 2881023-5
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  • 8
    In: Journal of the Endocrine Society, The Endocrine Society, Vol. 7, No. 3 ( 2023-01-06)
    Abstract: Adrenal venous sampling (AVS) is the gold standard technique for subtype differentiation of primary aldosteronism (PA) and to obtain aldosterone and cortisol measurements; however, their secretion patterns show fluctuations during the day. Objective We aimed to examine the effects of AVS timing on AVS results. Methods This multicenter, retrospective, observational study included a total of 753 patients who were diagnosed with PA and underwent AVS in 4 centers in Japan. Among them, 504 and 249 patients underwent AVS in the morning (AM-AVS) and in the afternoon (PM-AVS), respectively. The outcome measures were the impact of AVS timing and hormone fluctuations in a day on AVS results. Results There were no differences in the success rate of AVS, diagnostic rate of disease type, or frequency of discrepancy in PA subtypes between the AM-AVS and PM-AVS groups. Regarding patients with unilateral PA, aldosterone concentrations in adrenal venous blood did not differ between the 2 groups on the dominant or nondominant side. Conversely, regarding patients with bilateral PA, aldosterone concentrations in adrenal venous blood were significantly higher in the AM-AVS than in the PM-AVS group. Conclusions The timing of AVS did not seem to have a significant impact on subtype diagnosis. The aldosterone levels in adrenal venous blood were significantly higher in patients with bilateral PA in the AM-AVS group, but there was no such difference between patients with unilateral PA in the AM-AVS and PM-AVS groups. Each subtype may have a different hormone secretion pattern in a day.
    Type of Medium: Online Resource
    ISSN: 2472-1972
    Language: English
    Publisher: The Endocrine Society
    Publication Date: 2023
    detail.hit.zdb_id: 2881023-5
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  • 9
    In: Journal of the Endocrine Society, The Endocrine Society, Vol. 5, No. Supplement_1 ( 2021-05-03), p. A439-A439
    Abstract: Objective: The renoprotective effect of sodium glucose cotransporter 2 inhibitor (SGL2i) has been reported in diabetic patients. Local renin-angiotensin-aldosterone system (RAAS) is activated in diabetes mellitus and hypertension. We examined the effects of SGL2i on the RAAS in the obese diabetic rats fed a high salt diet. Methods: Zucker-diabetic rats (ZDR) and control rats were fed a high or normal salt diet and were treated with canagliflozin for 8 weeks. Blood pressure (BP), blood glucose (BG), PRA, plasma aldosterone (PAC), urinary albumin excretion (UAE), urinary 8-hydroxy-2’-deoxyguanosine (8-OHdG), gene expression of angiotensinogen in the kidney were measured. Results: ZDR febd a high salt diet showed high BP, increased UAE and urinary 8-OHdG and elevated angiotensinogen mRNA levels. Treatment with canagliflozin significantly decreased BP, BG, UAE, urinary 8-OHdG and and renal angiotensinogen mRNA levels compared with control rats (p & lt0.05). Discussion and Conclusion: The closer mechanism of renoptotection of SGL2i in diabetes mellitus is unclear. We have reported that the repoprotective effects of type 2 angiotensin receptor antagonist or mineralocorticoid receptor blocker were partly due to the decreased RAAS in the kidney. Decreased renal RAAS by the treatment with canagliflozin may contribute to the renoprotection in DZR.
    Type of Medium: Online Resource
    ISSN: 2472-1972
    Language: English
    Publisher: The Endocrine Society
    Publication Date: 2021
    detail.hit.zdb_id: 2881023-5
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  • 10
    In: Journal of the Endocrine Society, The Endocrine Society, Vol. 6, No. Supplement_1 ( 2022-11-01), p. A241-A241
    Abstract: 11Beta-hydroxysteroid dehydrogenase 1 (11beta-HSD1) is the key enzyme of metabolic syndrome. The transcript-specific epigenetic regulation of 11b-HSD1 (HSD11B1) is reported. We examined the HSD11B1 mRNA level and methylation status of the promoter region of the HSD11B1 in the adipose tissue of patients with aldosterone-producing adenoma (APA). Methods We evaluated 10 adipose tissue specimens from patients with primary aldosteronism due to aldosterone-producing adenoma (APA) and 7 tissue specimens from patients with non-functioning adrenal adenoma (NFA). Primary aldosteronism was diagnosed according to the guideline of the Japanese Endocrine Society. The expression levels of HSD11B1 mRNA were quantified using a real time PCR. Isolated DNA was treated with bisulfite and amplified using primers specific for the humanHSD11B1promoter region. Results The glycohemoglobin level was significantly higher in patients with APA compared with those with NFA (p & lt;0. 05). Blood pressure was significantly elevated in patients with APA compared with those with NFA (p & lt;0. 01). TheHSD11B1 mRNA level and the enzyme activities were significantly increased in the adipose tissues of APA compared with NFA patients (p & lt;0. 05). The methylation ratio was not significantly different between APA and NFA patients. Conclusion These results may suggest that adipose11beta-HSD1 contributes to metabolic abnormalities in APA. The pathophysiological significance of epigenetic control of 11beta-HSD1 gene in the adipose tissue should be further studied. Presentation: No date and time listed
    Type of Medium: Online Resource
    ISSN: 2472-1972
    Language: English
    Publisher: The Endocrine Society
    Publication Date: 2022
    detail.hit.zdb_id: 2881023-5
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