Coexistence of bone and vascular disturbances in patients with endogenous glucocorticoid excess.

Purpose: Bone and vascular diseases are considered to share pathogenic mechanisms. Excess glucocorticoids, key regulators of cardiovascular and metabolic homeostasis, may promote both diseases simultaneously. We used endogenous Cushing's syndrome (CS) to investigate whether glucocorticoid excess underlies coexisting bone and vascular diseases. Methods: We included 194 patients with adrenal tumors (ATs): autonomous cortisol secretion (ACS, n = 97) and non-functional AT (n = 97). ACS was further classified into overt CS (n = 17) and subclinical CS (SCS, n = 80). Arterial stiffness was defined as a brachial-ankle pulse wave velocity (baPWV) ≥ 1800 cm/s. Results: Patients with ACS had higher coexistence rates of vertebral fracture and arterial stiffness (23 % vs. 2 %; p < 0.001) and vertebral fracture and abdominal aortic calcification (22 % vs. 1 %; p < 0.001) than those with non-functional AT. In patients with ACS, baPWV was negatively correlated with trabecular bone score (TBS, r = -0.33; p = 0.002), but not with bone mineral density, and vertebral fracture was associated with arterial stiffness in the logistic regression analysis. In the multivariate analysis of variance, the degree of cortisol excess (defined as CS, SCS, and non-functional AT) determined the correlation between TBS and baPWV (partial η2 = 0.07; p < 0.001). In the analysis of covariance, patients with coexisting vertebral fracture and arterial stiffness had higher levels of serum cortisol after the 1-mg dexamethasone suppression test than those without. Conclusion: In endogenous glucocorticoid excess, bone and vascular diseases frequently coexisted, and deteriorated bone quality, not bone loss, was related to arterial stiffness. Thus, glucocorticoid excess may perturb the bone-vascular axis.

Machine learning-based models for predicting clinical outcomes after surgery in unilateral primary aldosteronism.

Unilateral subtype of primary aldosteronism (PA) is a common surgically curable form of endocrine hypertension. However, more than half of the patients with PA who undergo unilateral adrenalectomy suffer from persistent hypertension, which may discourage those with PA from undergoing adrenalectomy even when appropriate. The aim of this retrospective cross-sectional study was to develop machine learning-based models for predicting postoperative hypertensive remission using preoperative predictors that are readily available in routine clinical practice. A total of 107 patients with PA who achieved complete biochemical success after adrenalectomy were included and randomly assigned to the training and test datasets. Predictive models of complete clinical success were developed using supervised machine learning algorithms. Of 107 patients, 40 achieved complete clinical success after adrenalectomy in both datasets. Six clinical features associated with complete clinical success (duration of hypertension, defined daily dose (DDD) of antihypertensive medication, plasma aldosterone concentration (PAC), sex, body mass index (BMI), and age) were selected based on predictive performance in the machine learning-based model. The predictive accuracy and area under the curve (AUC) for the developed model in the test dataset were 77.3% and 0.884 (95% confidence interval: 0.737-1.000), respectively. In an independent external cohort, the performance of the predictive model was found to be comparable with an accuracy of 80.4% and AUC of 0.867 (95% confidence interval: 0.763-0.971). The duration of hypertension, DDD of antihypertensive medication, PAC, and BMI were non-linearly related to the prediction of complete clinical success. The developed predictive model may be useful in assessing the benefit of unilateral adrenalectomy and in selecting surgical treatment and antihypertensive medication for patients with PA in clinical practice.

Whole Transcriptome Profiling of Adrenocortical Tumors Using Formalin-Fixed Paraffin-Embedded Samples.

Whole transcriptome profiling is a promising technique in adrenal studies; however, whole transcriptome profiling of adrenal disease using formalin-fixed paraffin-embedded (FFPE) samples has to be further explored. The aim of this study was to evaluate the utility of transcriptome data from FFPE samples of adrenocortical tumors. We performed whole transcriptome profiling of FFPE and fresh frozen samples of adrenocortical carcinoma (ACC, n = 3), aldosterone-producing adenoma (APA, n = 3), and cortisol-producing adenoma (CPA, n = 3), and examined the similarity between the transcriptome data. We further examined whether the transcriptome data of FFPE samples could be used to distinguish tumor types and detect marker genes. The number of read counts was smaller in FFPE samples than in fresh frozen samples (P < 0.01), while the number of genes detected was similar (P = 0.39). The gene expression profiles of FFPE and fresh frozen samples were highly correlated (r = 0.93, P < 0.01). Tumor types could be distinguished by consensus clustering and principal component analysis using transcriptome data from FFPE samples. In the differential expression analysis between ACC and APA-CPA, known marker genes of ACC (e.g., CCNB2, TOP2A, and MAD2L1) were detected in FFPE samples of ACC. In the differential expression analysis between APA and CPA, known marker genes of APA (e.g., CYP11B2, VSNL1, and KCNJ5) were detected in the APA of FFPE samples. The results suggest that FFPE samples may be a reliable alternative to fresh frozen samples for whole transcriptome profiling of adrenocortical tumors.

Impact of Cortisol on Reduction in Muscle Strength and Mass: A Mendelian Randomization Study.

CONTEXT: Prolonged exposure to pathological cortisol, as in Cushing's syndrome causes various age-related disorders, including sarcopenia. However, it is unclear whether mild cortisol excess, for example, accelerates sarcopenia due to aging or chronic stress. OBJECTIVE: We used Mendelian randomization (MR) analysis to assess whether cortisol was causally associated with muscle strength and mass. METHODS: Three single-nucleotide polymorphisms associated with plasma cortisol concentrations in the CORtisol NETwork consortium (n = 12 597) were used as instrumental variables. Summary statistics with traits of interest were obtained from relevant genome-wide association studies. For the primary analysis, we used the fixed-effects inverse-variance weighted analysis accounting for genetic correlations between variants. RESULTS: One SD increase in cortisol was associated with SD reduction in grip strength (estimate, -0.032; 95% CI -0.044 to -0.020; P = 3e-04), whole-body lean mass (estimate, -0.032; 95% CI, -0.046 to -0.017; P = 0.004), and appendicular lean mass (estimate, -0.031; 95% CI, -0.049 to -0.012; P = 0.001). The results were supported by the weighted-median analysis, with no evidence of pleiotropy in the MR-Egger analysis. The association of cortisol with grip strength and lean mass was observed in women but not in men. The association was attenuated after adjusting for fasting glucose in the multivariable MR analysis, which was the top mediator for the association in the MR Bayesian model averaging analysis. CONCLUSION: This MR study provides evidence for the association of cortisol with reduced muscle strength and mass, suggesting the impact of cortisol on the development of sarcopenia.

Protective Role of DHEAS in Age-related Changes in Bone Mass and Fracture Risk.

PURPOSE: Dehydroepiandrosterone sulfate (DHEAS) from the adrenal cortex substantially decreases with age, which may accelerate osteoporosis. However, the association of DHEAS with bone mineral density (BMD) and fracture is inconclusive. We conducted a Mendelian randomization (MR) analysis to investigate the role of DHEAS in age-related changes in BMD and fracture risk. METHODS: Single nucleotide polymorphisms (SNPs) associated with serum DHEAS concentrations were used as instrumental variables (4 SNPs for main analysis; 4 SNPs for men and 5 SNPs for women in sex-related analysis). Summary statistics were obtained from relevant genome-wide association studies. RESULTS: A log-transformed unit (µmol/L) increase in serum DHEAS concentrations was associated with an SD increase in estimated BMD at the heel (estimate, 0.120; 95% CI, 0.081-0.158; P = 9 × 10-10), and decreased fracture (odds ratio, 0.989; 95% CI, 0.981-0.996; P = 0.005), consistent with dual-energy X-ray absorptiometry-derived BMD at the femoral neck and lumbar spine. Their associations remained even after adjusting for height, body mass index, testosterone, estradiol, sex hormone-binding globulin, and insulin-like growth factor 1. The association of DHEAS with fracture remained after adjusting for falls, grip strength, and physical activity but was attenuated after adjusting for BMD. The MR-Bayesian model averaging analysis showed BMD was the top mediating factor for association of DHEAS with fracture. The association between DHEAS and BMD was observed in men but not in women. CONCLUSION: DHEAS was associated with increased BMD and decreased fracture. DHEAS may play a protective role in decreasing fracture risk, mainly by increasing bone mass.

Necessity of Utilizing Physiological Glucocorticoids for Managing Familial Mediterranean Fever.

BACKGROUND Familial Mediterranean fever is an auto-inflammatory disease caused by pyrin mutations. Glucocorticoids inhibit the production and secretion of inflammatory cytokines, including IL-6 and IL-1ß, from inflammatory cells and suppress the activation of nuclear factor-kappaB in the nucleus. However, the functions of physiological glucocorticoids in the disease remain unknown. CASE REPORT We report the case of a Japanese man with familial Mediterranean fever complicated by isolated adrenocorticotropic hormone deficiency. Patient non-compliance with hydrocortisone replacement therapy led to a series of pericarditis and fever episodes. Subsequently, the regular administration of colchicine alone could not prevent auto-inflammation. The clinical course of treatment suggested that the absence of physiological levels of glucocorticoids is crucial for familial Mediterranean fever attacks. Because familial Mediterranean fever is a pyrin abnormality-induced auto-inflammatory disease that subsequently activates cytokines via the nucleotide-binding domain, leucine-rich repeat/pyrin domain-containing 3 inflammasomes and the absence of glucocorticoids can exacerbate the severity of the auto-inflammatory disease. CONCLUSIONS Physiological glucocorticoid levels appear to be essential for the regulation of inflammasome activation via IL-6-negative regulation. However, pharmacological levels of glucocorticoids are not currently used for the prevention of familial Mediterranean fever attacks. Physicians should be aware of adrenal insufficiency as a possible disorder when they encounter cases of refractory familial Mediterranean fever.

Brown adipose activation and reversible beige coloration in adipose tissue with multiple accumulations of 18F-fluorodeoxyglucose in sporadic paraganglioma: A case report.

In pheochromocytoma/paraganglioma, nontumorous high 18F-fluorodeoxyglucose accumulations are observed in both beige and brown adipose tissues. Recognizing this feature of 18F-fluorodeoxyglucose accumulation can help physicians make precise diagnoses and help them avoid the pitfalls of a false-positive 18F-fluorodeoxyglucose positron emission tomography result, preventing unnecessary interventions.

Exchange interaction of 5,5'-(m- and p-phenylene)bis(10-phenyl-5,10-dihydrophenazine) dications and related analogues.

[structures: see text] 5,5'-(m-Phenylene)bis[(10-aryl-5,10-dihydrophenazine) dications, 3a2+ and 3b2+, and their p-analogues 4a2+ and 4b2+, were prepared, and their exchange interaction was investigated. The EPR spectra of these dications at 123 K in a butyronitrile matrix showed the population of a triplet state. The temperature dependence of the EPR signal intensity (absolute value(delta m(s)) = 2) showed that these dications had singlet ground states with deltaE(ST)/k(B) = -27 to -21 K for the m-isomer 3(2+) and with deltaE(ST)/k(B) = -10 to -8 K for the p-isomer 4(2+). Theoretical calculation of the exchange interaction J for these dications at the orthogonal torsion angle geometries was carried out for 3a2+ and 4a2+ and for (m- and p-phenylene)bisphenothiazine dications 1(2+) and 2(2+) using the broken-symmetry approach for the singlet states. A good correlation was observed between the calculated J and a MO-energy term in the triplet state, deltaE(TMO) = absolute value(HOMO(alpha) - (HOMO - 1)(alpha)). The calculated J values were negative in the order of 10 K for the m-dications (J/k(B) = -14.7 K for 1(2+), -11.5 K for 3a(2+)), but much smaller negative values were found for the p-isomers (J/k(B) = -0.9 K for 2(2+), -0.8 K for 4a2+). The smaller absolute value(J) values for the p-dications are qualitatively consistent with the experimental deltaE(ST) (2J) values.

Facile synthesis of 5,10-diaryl-5,10-dihydrophenazines and application to EL devices.

[structures: see text] An efficient method for the synthesis of 5,10-diaryldihydrophenazine was developed using a recently developed Pd(0)-mediated cross-coupling reaction. The products 1k and 3c showed excellent properties as hole injection materials in electroluminescent (EL) devices.