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Objectives: This study aims to investigate the prevalence of undiagnosed cardiovascular risk factors in patients with ischaemic heart disease (IHD)., Methods: We assessed the prevalence of previously undiagnosed cardiovascular risk factors, including elevated lipoprotein(a) [Lp(a)], among consenting patients with IHD who were admitted to hospital. Clinical information, including dietary history, from patients with newly diagnosed IHD and known IHD were compared., Results: Of the 555 patients, 82.3% were males and 48.5% of Chinese ethnicity. Overall, 13.3% were newly diagnosed with hypertension, 14.8% with hypercholesterolemia, and 5% with type 2 diabetes (T2DM). Patients with newly diagnosed IHD, compared to those with known IHD, had a higher prevalence of new diagnoses of hypercholesterolemia (29.1% vs. 2.0%, p  < 0.001), hypertension (24.5% vs. 3.4%, p  < 0.001) and T2DM (7.3% vs. 3.1%, p  = 0.023). Active smoking was prevalent in 28.3% of patients, and higher in newly diagnosed IHD (34.1% vs. 23.2%, p  = 0.005). Elevated Lp(a) of ≥120 nmol/L was detected in 15.6% of all patients, none of whom were previously diagnosed. Dietary habits of >50% of patients in both groups did not meet national recommendations for fruits, vegetables, wholegrain and oily fish intake. However, patients with known IHD had a more regular omega-3 supplement intake (23.4% vs. 10.3%, p  = 0.024)., Conclusion: Increased detection efforts is necessary to diagnose chronic metabolic diseases (hypertension, hypercholesterolemia, T2DM) especially among patients at high risk for IHD. Cardiovascular risk factors, in particular elevated Lp(a), smoking, and suboptimal dietary intake in patients with IHD deserve further attention., Competing Interests: The author TP declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Chua, Lam, Mak, Lee, Dacay, Yew, Puar, Khoo, Chow, Tan, Tong, Liew, Yeo and Loh.)

Introduction: Vitamin D deficiency is common in chronic kidney disease (CKD) and is associated with lower bone mineral density (BMD), decreased muscle strength, and increased hip fracture risk. Guidelines have suggested targeting 25-OH vitamin D (25(OH)D) levels between 20 and 30 ng/ml. However, vitamin D metabolism is altered in CKD, and threshold levels for optimal BMD are unknown. Methods: We included 1097 patients with hip fractures. CKD was defined as estimated glomerular filtration rate <60 ml/min/1.73 m (Mucsi et al., Clin. Nephrol., 2005, 64(4), 288-294) and low BMD defined as T score ≤ -2.5 at femoral neck. We assessed the association of 25(OH)D with low BMD in patients with and without CKD: using the conventional threshold 25(OH)D < 30 ng/dl, as well as a new threshold. Results: CKD was present in 479 (44%) patients. Using a threshold of 25(OH)D < 30 ng/ml, there were no significant differences in patients with CKD and low BMD when compared to the other groups. We identified 27 ng/ml as a better threshold with the Youden index. Using 25(OH)D < 27 ng/ml as a threshold, 360 of 482 patients (74.7%) with low 25(OH)D had low BMD, compared to only 185/276 (67%) of patients with adequate vitamin D, p = 0.02, which was irrespective of the presence or absence of CKD. Furthermore, patients with CKD and 25(OH)D < 27 ng/ml had a higher odds ratio of mortality upon follow-up, 1.61, 95% CI: 1.08-2.39, compared to those with CKD and 25(OH)D ≥ 27 ng/ml. Conclusion: We find that 25(OH)D < 27 ng/ml is associated with low BMD in patients with and without CKD. Further prospective studies targeting vitamin D repletion to at least 27 ng/ml and the outcome of hip fractures will be useful to validate these findings., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Roy, Ng, Kog, Yeon, Poh, Koduri, Chionh, Sultana and Hai Kiat Puar.)

Background: Diabetes mellitus is associated with inadequate delivery of oxygen to tissues. Cellular hypoxia is associated with mitochondrial dysfunction which increases oxidative stress and hyperglycaemia. Hyperbaric oxygenation therapy, which was shown to improve insulin sensitivity, is impractical for regular use. We evaluated the effects of water which is stably-enriched with oxygen (ELO water) to increase arterial blood oxygen levels, on mitochondrial function in the presence of normal- or high-glucose environments, and as glucose-lowering therapy in humans., Methods: We compared arterial blood oxygen levels in Sprague-Dawley rats after 7 days of ad libitum ELO or tap water consumption. Mitochondrial stress testing, and flow cytometry analysis of mitochondrial mass and membrane potential, were performed on human HepG2 cells cultured in four Dulbecco's Modified Eagle Medium media, made with ELO water or regular (control) water, at normal (5.5 mM) or high (25 mM) glucose concentrations. We also randomized 150 adults with type 2 diabetes (mean age 53 years, glycated haemoglobin HbA1c 8.9% [74 mmol/mol], average duration of diabetes 12 years) to drink 1.5 litres daily of bottled ELO water or drinking water., Results: ELO water raised arterial oxygen tension pO2 significantly (335 ± 26 vs. 188 ± 18 mmHg, p = 0.006) compared with tap water. In cells cultured in control water, mitochondrial mass and membrane potential were both significantly lower at 25 mM glucose compared with 5.5 mM glucose; in contrast, mitochondrial mass and membrane potential did not differ significantly at normal or high glucose concentrations in cells cultured in ELO water. The high-glucose environment induced a greater mitochondrial proton leak in cells cultured in ELO water compared to cells cultured in control medium at similar glucose concentration. In type 2 diabetic adults, HbA1c decreased significantly (p = 0.002) by 0.3 ± 0.7% (4 ± 8 mmol/mol), with ELO water after 12 weeks of treatment but was unchanged with placebo., Conclusions: ELO water raises arterial blood oxygen levels, appears to have a protective effect on hyperglycaemia-induced reduction in mitochondrial mass and mitochondrial dysfunction, and may be effective adjuvant therapy for type 2 diabetes., Competing Interests: Sponsorship of this study by Elomart Pte Ltd does not alter the authors’ adherence to PLOS ONE policies on sharing data and materials.

Context: Recurrence of hypercortisolism in patients after bilateral adrenalectomy for Cushing disease is extremely rare., Patient: We present a 27-year-old man who previously underwent bilateral adrenalectomy for Cushing disease with complete clinical resolution. Cushingoid features recurred 12 years later, with bilateral testicular enlargement. Hormonal tests confirmed adrenocorticotropic hormone (ACTH)-dependent Cushing disease. Surgical resection of the testicular tumors led to clinical and biochemical remission., Design and Results: Gene expression analysis of the tumor tissue by quantitative polymerase chain reaction showed high expression of all key steroidogenic enzymes. Adrenocortical-specific genes were 5.1 × 105 (CYP11B1), 1.8 × 102 (CYP11B2), and 6.3 × 104 (MC2R) times higher than nonsteroidogenic fibroblast control. This correlated with urine steroid metabolome profiling showing 2 fivefold increases in the excretion of the metabolites of 11-deoxycortisol, 21-deoxycortisol, and total glucocorticoids. Leydig-specific genes were 4.3 × 101 (LHCGR) and 9.3 × 100 (HSD17B3) times higher than control, and urinary steroid profiling showed twofold increased excretion of the major androgen metabolites androsterone and etiocholanolone. These distinctly increased steroid metabolites were suppressed by dexamethasone but unresponsive to human chorionic gonadotropin stimulation, supporting the role of ACTH, but not luteinizing hormone, in regulating tumor-specific steroid excess., Conclusion: We report bilateral testicular tumors occurring in a patient with recurrent Cushing disease 12 years after bilateral adrenalectomy. Using mRNA expression analysis and steroid metabolome profiling, the tumors demonstrated both adrenocortical and gonadal steroidogenic properties, similar to testicular adrenal rest tumors found in patients with congenital adrenal hyperplasia, suggesting the presence of pluripotent cells even in patients without congenital adrenal hyperplasia., (Copyright © 2017 by the Endocrine Society)

Context: Patients with pheochromocytomas and paragangliomas (PGLs) may have brown adipose tissue (BAT) activation induced by catecholamine excess. (18)F-fluorodeoxyglucose ((18)F-FDG) positron emission tomography (PET)/computed tomography (CT) can be used for the localization of both PGLs and BAT. It is unknown whether BAT is specifically affected by altered cellular energy metabolism in patients with SDHx- and VHL-related PGLs., Objective: The objective of the study was to determine endocrine and paracrine effects of catecholamine excess on BAT activation in patients with PGLs as detected by (18)F-FDG PET/CT, taking into account genetic variation., Design: Patients with PGLs who were fully genetically characterized underwent presurgical (18)F-FDG PET/CT imaging for tumor localization and to quantify BAT activation., Setting: The study was conducted at a single Dutch tertiary referral center., Patients and Intervention: Seventy-three patients, aged 52.4 ± 15.4 years, with a body mass index of 25.2 ± 4.1 kg/m(2), mean ± SD, were grouped into sporadic, cluster 1 (SDHx, VHL) and cluster 2 (RET, NF1, MAX) mutations., Main Outcome Measures: (18)F-FDG mean standard uptake values were assessed in predefined BAT locations, including perirenal fat., Results: Twenty-one of 73 patients (28.8%) exhibited BAT activation. BAT activation was absent in all six patients with nonsecreting PGLs. No difference in (18)F-FDG uptake by perirenal fat on the side of the pheochromocytoma and the contralateral side was observed (mean standard uptake value of 0.80 vs 0.78, respectively, P = .42). The prevalence of BAT activation did not differ between sporadic (28.9%), cluster 1 (40.0%), and cluster 2 patients (15.4%, P= .36)., Conclusion: Patients with PGLs exhibit a high prevalence of BAT activation on (18)F-FDG PET/CT. This is likely due to systemic catecholamine excess. BAT activation is not associated with specific germline mutations.