bluuebunny/crossref_metadata_2025_split huggingface dataset:
Bone Markers Are Diminished in Offspring of Long-Lived Families Compared With Matched Controls, but Respond Equally to T3 and rhTSH
Authors: Zutinic Anna , Roelfsema Ferdinand , van Heemst Diana 
Published: May 2021

Abstract
Objective: We explored the effects of T3 and rhTSH administration on bone turnover in subjects of the Leiden Longevity Study. Design: Twenty-six subjects (13 offspring and 13 matched controls), mean age 68 y, underwent a rhTSH (0.1 mg i.m) and a T3 challenge (100 µg orally) with an interval of at least 3 m. Bone markers were measured at baseline and hereafter once daily for 3–4 days. Outcome Measures: Bone markers and changes after T3 and rhTSH. The influence of sex, group and time, and relations with incremental changes in TSH, fT4 and T3. Results: CTX (bone resorption) was lower in offspring than controls (mean ± SEM), 0.324±0.026 vs 0.443±0.036 ng/mL, P= 0.02. P1NP (bone formation) was also lower in offspring than in controls (40.3±2.2 vs 59.0± 4.7 ng/mL, P=0.004). No sex differences were found. In offspring, CTX but not P1NP was positively related to TSH and fT4 (R=0.48, P=0.001 and R=0.55, P=0.005). In controls, CTX was negatively related to TSH (R=-0.50, P=0.009), while P1NP was positively related with fT4 (R=0.52, P=0.006). TSH administration increased bone resorption and formation (P&lt;0.0001 and 0.005, respectively). CTX was maximal at 48 h, increasing from 0.415±0.032 to 0.470 ±0.037 ng/mL, P=0.001. P1NP increased from 51.1±4.09 to a maximum of 56.2±3.9 ng/mL at 24 h (P=0.005). T3 also increased bone resorption (P=0.049) and formation (P=0.001). CTX increased from 0.386±0.034 to 0.410± 0.041 ng/mL, P=0.05, and P1NP from 48.9± 4.3 to 55.5±4.2 ng/mL, P=0.007), with maximal values at 48 h. Offspring and controls had similar responses and sex had generally no statistical impact. Significant linear regressions were found between the incremental changes of CTX and TSH at 24 h (R=0.44, P=0.003), but not later. Here, significant linear relation were found for the incremental fT4 and CTX (R=0.60, P=0.001 at 48 h, and R=0.49, P=0.013 at 72 h). For P1NP such relations were not present (R values between from 0.002 to 0.14). T3 changes did not correlate with bone markers at any time point. Conclusion: This study demonstrates that bone turnover is diminished in members of long-lived families where bone resorption was positively related to serum TSH and fT4. Nevertheless, the responses to TSH (and fT4) and T3 were similar in offspring and controls. Interestingly, the maximal effect of TSH increment on bone resorption preceded that of fT4, suggesting that TSH may have an independent stimulatory effect on bone resorption. At physiological TSH concentrations such stimulatory effect on bone resorption may be postulated in offspring, along with many other factors, e.g PTH, vitamin D, GH, sex hormones and cytokines.
In a Clinical Trial There Was No Effect of Vitamin D on Physical Performance in Either Black or White Women
Authors: Smith Lynette M , Gallagher J C 
Published: May 2021

Abstract
Introduction: The effect of vitamin D supplementation on physical performance is controversial. Longitudinal cohort studies show very low levels of serum 25OHD (&lt; 15- 20ng/ml) are associated with lower physical performance. There are few clinical trials of the effect of vitamin D on physical performance and results are mixed. Design: 163 white and 110 black independent living women entered a 12-month double blind randomized dose ranging study of daily vitamin D,400,800,1600,2400,3200,4,000,4800IU or placebo together with calcium supplement as needed for a total intake of 1200mg and mean diet vitamin D of 114 IU. Inclusion criteria: total serum 25OHD ≤ 20ng/ml (Diasorin RIA); no known disease or drugs affecting calcium or bone metabolism. Physical performance tests were performed at baseline and end as described in the Short physical performance battery (SPPB) that included Balance, Timed walk, Chair rising test. Additional tests included Timed up and Go, Grip strength and Balance (Biodex). Fall history was recorded at baseline and at 3-monthly visits. Serum 25OHD was measured by Diasorin RIA and LCMS, Free 25OHD was measured by Elisa (Future Diagnostics). Changes in physical performance and fallers were analyzed by dose groups and by quintiles of total and free serum 25OHD. This was a secondary analysis using Intent to treat strategy. Chi square and ANOVA determined association between dose, quintiles and tests. Results: Mean age 66.2 years (SD 7.3, range 57–87), mean BMI 30.3 kg/m2 (SD 5.9). Compliance, measured every 3 months, was 94% for vitamin D and 91% calcium. 147 White and 89 Black women completed study. There was significant better performance in physical performance in women &lt; age 70 years compared to &gt; age 70 years. Black women performed better with all tests except grip strength after adjustment for age and BMI. When the absolute change in test performance was examined according to serum total or free 25OHD quintiles there was no correlation between serum levels of 25OHD and change in any physical performance test except for an improvement in chair rising test in younger Black women. Conclusions: There is no significant effect of vitamin D on physical performance in either black or white women. In a previous analysis we found a significant U-shaped response in fall incidence in the serum 25OHD range 30-40ng/ml but in this analysis there is no correlation between physical performance of fallers versus non- fallers
Low Testosterone in Males May Warrant Liver Health Assessment and Intervention
Authors: DelConte Anthony , Bruno Benjamin J , Kim Kilyoung , Vangara Kiran , Papangkorn Kongnara , Chidambaram Nachiappan , Patel Mahesh 
Published: May 2021

Abstract
Low testosterone (T) is a serum marker of hypogonadism. Reportedly, diabetes mellitus, cardiovascular disease, peripheral artery disease, hypertension, hyperlipidemia, depression, obesity, metabolic syndrome, sleep apnea, chronic obstructive pulmonary disease (COPD), and opioid dependency, are associated with low testosterone. However, the association of chronic liver disease with low T is underappreciated. In one study, ~75% of biopsy confirmed Nonalcoholic Steatohepatitis (NASH) male patients had T levels of &lt;372 ng/dL. A study with patients receiving androgen deprivation therapy (ADT), with no pre-therapy evidence of liver disease, increased liver disease risk relative to no ADT suggesting low T can adversely affect liver health. However, prevalence of compromised liver health in hypogonadal males, and any beneficial effects of T therapy intervention on liver health are unclear. The objective of this investigation was to evaluate prevalence of liver disease in hypogonadal males, and to assess for potential beneficial effects of LPCN 1144, a novel oral T therapy candidate, on liver health of hypogonadal males. Investigation was performed through clinical studies in hypogonadal males, and a pre-clinical study. Clinical studies: (1) a one-year treatment, open label, active control, randomized study (NCT02081300); (2) a four-month treatment, open label, single arm study (NCT03868059); a 12-week study in a high-fat-diet (HFD) induced steatohepatitis and hepatic fibrosis rabbit model. 39% of hypogonadal males (N=210) tested had the elevated key liver injury marker (ALT&gt;30 U/L). LPCN 1144 intervention for 52 weeks in hypogonadal males with elevated ALT levels at baseline resulted in mean decrease about 15%. Moreover, abnormal ALT, AST, ALP, and GGT were normalized in 52%, 50%, 67%, 32% of patients, respectively. In the 4-month study, fatty (&gt;5%) liver disease was present in about 66% of a cohort of hypogonadal males (N=32), more than double the reported rate in the general population (25%). Post LPCN 1144 treatment, the proportion of fatty liver-free subjects increased by 94%. HFD induced substantial suppression of T levels in rabbits accompanied with histologically evidenced hepatic steatosis, inflammation, ballooning, and fibrosis. Upon 12 weeks of LPCN 1144 treatment in conjunction with HFD, histological ballooning, inflammation and fibrosis scores were improved. Importantly, relatively to control, % of hepatic fibrosis in the tissues were significantly reduced with LPCN 1144 treatment. In conclusion, compromised liver health is prevalent in hypogonadal males and may warrant a periodic assessment. Pre-clinical and clinical results with oral T therapy suggest potential beneficial effects on liver health in hypogonadal males. An ongoing study in biopsy-confirmed NASH male patients is expected to shed more light on the potential benefits of LPCN 1144.
Mild Autonomous Cortisol Secretion in Primary Aldosteronism Enhances Renal and Hemorrhagic Cerebrovascular Complications
Authors: Matsuba Ren , Katabami Takuyuki , Kurihara Isao , Ichijo Takamasa , Takeda Yoshiyu , Tsuiki Mika , Wada Norio , Ogawa Yoshihiro , Sone Masakatsu , Inagaki Nobuya , Yoshimoto Takanobu , Kobayashi Hiroki , Tanabe Akiyo , Naruse Mitsuhide ,   JPAS JRAS, study group
Published: May 2021

Abstract
Background: It is well known that primary aldosteronism (PA) is often associated with renal dysfunction and cardiovascular events (CVEs). However, the synergic effect of mild autonomous cortisol secretion (MACS) on the co-morbidities among PA has not been clarified yet. Thus, we retrospectively assessed whether the presence of MACS in PA patients with adrenal tumor, which may have MACS, to enhance the risk of the complications using a large Japanese multicenter database.
Methods: We enrolled patients with both confirmed PA and obvious adrenal tumor (diameter &gt; 1 cm) on computed tomography. The subtype of PA was diagnosed based on the results of adrenal venous sampling with ACTH stimulation. A total of 575 study subjects were stratified into two groups according to 1-mg dexamethasone suppression test (DST) results (cut-off post-DST serum cortisol 1.8 µg/dL): MACS group (N=174, 30.2%) and non-MACS group (N=401, 69.8%). Decreased estimated glomerular filtration rate (eGFR) was defined as &lt;60 ml/min per 1.73m2.
Results: The percentage of unilateral PA between the MACS and non-MACS group was equivalent (50.0% vs. 48.1%). Prevalence of decreased eGFR in the MACS group was higher than in the non-MACS group [odds ratio (OR) 1.91, 95% confidence interval (95% CI) 1.20–3.04, P=0.006]. Conversely, prevalence of MACS was higher in patients with decreased eGFR than those without decreased eGFR (42.7% vs 28.0%, P=0.008). Proteinuria was deteriorated with the increase in post-DST serum cortisol concentration as well as the basal plasma aldosterone concentration (PAC) (P=0.028 and P&lt;0.001, respectively), although PAC but not the presence of MACS was selected as an independent factor related with decreased eGFR. Prevalence of cerebral hemorrhage in the MACS group was higher than the non-MACS group. (OR 5.35, 95%CI 1.83–15.6, P=0.002). We found that MACS was the only significant factor which increased the odds of developing cerebral hemorrhage (OR 9.13, 95%CI 2.15–38.90, P=0.003). Prevalence of other CVEs between the two groups was similar. Regardless of the PA subtype, complication rate of decreased eGFR and cerebral bleeding in the MACS group were significantly or tend to be higher than non-MACS group.
Conclusion: Our date strongly suggested that co-secretion of cortisol in PA directly and/or indirectly increase renal and cerebrovascular comorbidities. Given that MACS is common in PA, endocrinological testing with DST is recommended in PA patients, especially those with adrenal tumor on imaging. (Supported by Research Grants of AMED:JP17ek0109122, JP20ek0109352; National Center for Global Health and Medicine:27–1402, 30–1008), and Ministry of Health, Labour, and Welfare, Japan (046).
Preoperative Renin Status Indicate the Clinical Outcome of Aldosterone-Producing Adenoma
Authors: Xu Felicity , Song Ying , Luo Ting , Li Qifu 
Published: May 2021

Abstract
Primary aldosteronism is widely recognized as renin-independent hypersecretion of aldosterone and aldosterone-producing adenoma(APA) represents the typical clinical subtype. Plasma renin below detection levels was considered as an important indicator for PA, and the suppressed renin level after confirmatory tests was considered to be a prerequisite when interpreting the results of confirmatory tests, before making the diagnosis of PA. Strictly, there is no specific definition of suppressed renin level in patients with PA. Clinically, the renin level of patients with APA varied greatly within the low to normal range. However, the clinical characteristics and outcomes in patients with APA having different renin status remain unclear. This retrospective study included 274 patients with APA who underwent unilateral laparoscopic adrenalectomy with at least a 12-month follow-up postoperatively. Patients were classified into the following 2 groups: low renin and non-low renin groups measured at 8.2 mU/L, according to the widely used criteria(defined as plasma renin activity&lt;1ng/ml/h≈PRC 8.2 mU/L). Only patients with two consecutive PRC less than 8.2 mU/L could be classified into the low renin group. For the screening test and the confirmatory tests, antihypertensive medication was withheld or changed according to the guideline. Chemiluminescence immunoassays showed the range of the plasma renin concentration as 0.4–41.5mU/L. Non-low renin APA patients (n=26) had higher presurgical SBP(p=0.028), DBP(p=0.001) and PRC post confirmatory tests(p&lt;0.001), compared with low renin APA patients(n=248). There was no significant difference in baseline PAC(p=0.507) and serum potassium(p=0.348) between the two groups. Intriguingly, non-low renin APA patients had higher PAC(p&lt;0.001) and PRC(p&lt;0.001) and lower serum potassium(p&lt;0.001) at follow-up. For non-low renin APA patients, the rate of complete clinical success after surgery was 42.3%, 25% lower than that of low renin APA
patients. APA patients with PRC&lt;0.5mU/L had the highest rate of complete clinical success(75%), followed by PRC 0.5~8.2 mU/L(65%) and 8.2~20 mU/L(50%), with the lowest rate in patients with PRC&gt;20 mU/L(33%). Multivariable logistic regression showed that the presence of baseline PRC&gt;8.2 mU/L was a strong independent predictor for the lack of complete clinical success[OR 3.7(1.5–8.9),p=0.004]. Plasma renin concentration is closely related to the clinical outcome of APA patients postoperatively. APA patients with higher baseline renin status are at high likelihood of persistent hypertension after surgery, in whom strengthened monitoring of blood pressure is necessary.
Rates of Primary Aldosteronism Screening Among High-Risk Populations
Authors: Grigoryan Seda , Konzen Sonja Marie , Turcu Adina F 
Published: May 2021

Abstract
Background: Primary aldosteronism (PA) is the most common form of secondary hypertension. PA is associated with higher cardiovascular and renal morbidity and mortality than equivalent essential hypertension. Data on PA screening rates are scarce.
Objective: To evaluate the rates of PA screening among at-risk populations.
Methods: We conducted a retrospective review of adult patients (age ≥ 18 years) with hypertension (HTN) seen in a University setting outpatient clinics between 2010–2019 who had: 1) resistant HTN; 2) HTN and hypokalemia; 3) HTN at age &lt;40; 4) HTN and known adrenal mass; or 5) HTN and obstructive sleep apnea (OSA). We excluded patients with known high-renin HTN, renovascular HTN, or congenital adrenal hyperplasia.
Results: We identified 11,627 patients with HTN meeting at least one of the inclusion criteria. Of these, only 3.27% were ever screened for PA. Patients screened were younger (47.5 ± 17.8 vs. 51.3 ±16.9, p &lt;0.0001), more often women (55.28% vs. 45.71%, p=0.0003), had lower serum K+ (3.4 ± 0.5 vs. 3.7 ± 0.4, p&lt;0.0001), and were more likely to have chronic kidney disease (29.27% vs. 17.5%, p&lt;0.0001) and cerebrovascular accidents (9.21% vs. 6.16%, p= 0.02) than those never screened. While most patients in this cohort were white (79.9% vs. 15.3% black, and 2.3% Asian), screening rates were overall higher in Asian (8.4%) and black (6.1%) than in white Americans (2.8%, p&lt;0.0001). Of the different indications for PA screening, the rates were highest among patients with adrenal nodules (35%) and lowest in patients with HTN and OSA (2.1%). The rates of screening were similar in patients younger vs. older than age 40 (3.2%, p=0.9). Among patients with resistant hypertension, those screened were on average 10 years younger (58.5 ± 14.0 vs. 68.7 ± 12.8, p&lt;0.0001) and twice as often black (20.7% vs. 10.1%) compared to those not screened for PA. Conversely, in patients with adrenal masses, there were no sex, age, or race differences between those screened vs. not screened for PA. PA screening was initiated most often by general internists (53.9%), followed by endocrinologists (15.8%), and rarely by nephrologists (9.5%), or cardiologists (4.2%).
Conclusions: Despite its high prevalence and associated cardio-renal morbidity, PA screening is pursued in only 3% of high-risk populations. While patients screened are generally younger and more often black than those not screened, the diagnosis is often suspected after complications have already developed. These data indicate that initiatives to encourage PA screening are crucial for preventing cardiovascular and renal morbidity in many patients with HTN.
Visualization of Ca Channel Blocker on Human Adrenal Tissue by Mass Spectrometry Imaging ~Its Predominant Distribution at Aldosterone-Producing Cells ~
Authors: Motomura Naoki , Yamazaki Yuto , Xin Gao , Tezuka Yuta , Omata Kei , Ono Yoshikiyo , Morimoto Ryo , Satoh Fumitoshi , Nakamura Yasuhiro , Sasano Hironobu 
Published: May 2021

Abstract
Primary aldosteronism (PA) is the main cause of secondary hypertension, accounting for approximately 5–10% of all hypertension. Amlodipine, a third-generation calcium channel blocker, is one of the most frequently administered pharmaceuticals medications of hypertension, binds specifically to Cav1.2, a calcium channel primarily localized in the cardiovascular system, and exerts antihypertensive effects through inhibiting calcium influx into the vascular smooth muscle cells. In addition, calcium influx also plays important roles in aldosterone production and amlodipine was also reported to influence in vitro functions of Cav1.3, a calcium channel involved in aldosterone secretion. Ca channel blockers were also reported to reduce plasma aldosterone concentration by some clinical studies although with mild degrees. However, in vivo effects of amlodipine to aldosterone secretion has remained virtually unknown. A novel technique “Matrix-Assisted Laser Desorption/Ionization Mass Spectrometry Imaging (MALDI-MSI)” has been recently developed, which did make it possible to visualize non-labeled small molecules on tissue sections. Therefore, in this study, we firstly applied MALDI-MSI to visualize amlodipine on human adrenal glands including aldosterone producing adenoma (APA). We performed selective imaging of amlodipine using MALDI-MSI on the resected adrenal tissues from APA patients. Frozen sections containing whole representative tumor area were coated with a matrix called CHCA (α-Cyano-4-hydroxycinnamic acid) by deposition as a pretreatment. We subsequently analyzed and detected a precursor ion with MS at m/z 407.1 and then an amlodipine-specific ion with MS/MS at m/z 318.1. We also examined the concordance of amlodipine distribution obtained by this method with immunohistochemistry. Human resected adrenal tissues obtained from the patients APAs treated with and without amlodipine before adrenalectomy were examined. Periadrenal adipose tissues were also analyzed as a control tissue of non-aldosterone-producing tissues. Amlodipine was specifically detected and visualized only in the administered cases. Amlodipine was more abundantly detected in adrenal tissues than periadrenal adipose tissues. On the other hand, significant different was not detected between tumors and adjacent adrenal glands by semi-quantification using MALDI-MSI. In this study, we firstly visualized amlodipine directly in human tissue sections using MALDI-MSI. Increased accumulation of amlodipine in APAs treated with amlodipine did indicate direct effects of amlodipine on aldosterone production but further investigations are required for clarification between neoplastic and non-neoplastic aldosterone producing cells.
Targeted Therapeutic Approach in Patients With Familial Partial Lipodystrophy Type 3
Authors: Cohen Benjamin , Mathias Priyanka , Stein Daniel T 
Published: May 2021

Abstract
Introduction: Familial partial lipodystrophy (FPLD) syndromes are genetic disorders characterized by selective lipoatrophy affecting the upper and lower extremities leading to severe insulin resistance and metabolic complications. We describe a patient diagnosed with a pathogenic variant in the peroxisome proliferator-activated receptor γ (PPARγ) gene that causes FPLD type 3 (FPLD3) subsequently treated with pioglitazone with excellent response.
Clinical Case: A 52-year-old Hispanic woman with type 2 diabetes mellitus and hypertension presented with epigastric pain and vomiting. Workup revealed elevated lipase to 1889 U/L and triglycerides to 4117 mg/dL, consistent with hypertriglyceridemia-induced pancreatitis. CT abdomen showed acute pancreatitis with hepatic steatosis. Family history was significant for hypertension, diabetes, and hyperlipidemia in her father, mother, and five siblings. Examination revealed facial and truncal obesity, lipoatrophy of her limbs and buttocks, acanthosis nigricans, and hepatomegaly. The patient was treated with an insulin drip with decline in triglyceride levels (450 mg/dL) and discharged on atorvastatin, fenofibrate, metformin, and pioglitazone. Laboratory evaluation revealed an HbA1c of 9%, normal thyroid and liver function tests, and a serum leptin of 1.2 ng/ ml (N females: 4.7–23.7 ng/ml). Lipoprotein electrophoresis showed type 4 lipoproteinemia. A liver fibroscan showed hepatic steatosis with portal fibrosis. Genetic testing was notable for an autosomal dominant pathogenic heterozygous loss-of-function mutation in the ligand binding domain AF-2 region of PPARγ (c.452 A&gt;G) confirming FPLD3. Pioglitazone was increased to 30mg/day with improvement in HbA1c to 8.3% and dyslipidemia at three-month follow up.
Conclusion: FPLD3 is caused by loss-of-function mutations in PPARγ, a transcription factor involved in adipogenesis1. FPLD is estimated to affect 1 per 1 million, with FPLD3 reported in approximately 30 individuals worldwide per National Organization for Rare Disorders. Treatment is currently directed at reducing insulin resistance, dyslipidemia, and their sequelae of pancreatitis and cardiovascular disease. Thiazolidinediones (TZDs), PPARγ agonists targeting insulin sensitivity and adipocyte differentiation, have been used in FPLD with variable results. Different mutations in the ligand-binding domains of PPARγ may affect the binding capacity to synthetic agonists, affecting clinical response. Use of TZDs in individuals with PPARγ mutations (R308P, A261E) have been shown to improve hyperglycemia and dyslipidemia2. Our patient was treated with pioglitazone with excellent response to therapy in three months. TZDs may offer a targeted approach to treat FPLD3 based on PPARγ ligand-dependent responsiveness.
References:
(1) Garg A. JCEM 2011;96:3313–3325(2) Agostini M. Diabetes. 2018;67(6):1086–1092