bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Prevalence and Burden of Hypophosphatasia in an Ambulatory Endocrinology Practice
Authors: Quinn Hugh B , Busch Robert S , Kane Michael P 
Published: May 2021

Abstract
Introduction: Hypophosphatasia (HPP) is an autosomal disease resulting from loss-of-function mutations in the ALPL gene encoding tissue-nonspecific alkaline phosphatase (TNSALP). The presentation and severity of the disease is highly variable ranging from perinatal-onset HPP with mortality rates as high as 100%, to adult onset with little mortality but with high disease-burden. Overall estimated prevalence of HPP in the general population is 1:100,000 though it may be significantly higher in specific populations. Hypophosphatasia is a heterogeneous disease that can reveal itself at any age, presenting within a wide range of symptoms. Adult HPP typically presents during middle age and is often misdiagnosed or missed in practice. The objective of this study was to determine the prevalence and burden of hypophosphatasia in an ambulatory care endocrinology practice. Methods: Potential subjects were identified via a computerized text search of the laboratory fields of patient electronic medical records (EMR). Search terms included serum ALP levels of less than or equal to 40 mg/dL. Records of patients with at least two low ALP levels were reviewed manually to identify potential patients with a history consistent with HPP. Results: A total of 315 patients with ALP levels &lt; 40 mg/dL were identified via text search from an estimated 20,000 patient records. Fifty-six patients with a single low level were not considered for further review. The remaining 259 patients were reviewed for histories consistent with hypophosphatasia. These patients were predominantly white (64.9%), with an average age of 55 (+ 15) years, and an average BMI of 28 (+ 7) kg/m2. Ten of these patients had histories consistent with hypophosphatasia including musculoskeletal pain requiring scheduled use of pain medications, polyarthropathy, chondrocalcinosis, deformity secondary to fractures, low BMD, a history of nontraumatic fracture, delayed or incomplete fracture healing, a history of multiple orthopedic surgeries, fatigue, impaired mobility, impaired gait, impairment of daily activities, a history of renal stones or nephrocalcinosis, and/or high serum B6 levels. None of the identified ten patients were currently being treated or had previously been treated for hypophosphatasia and have subsequently been recommended for genetic testing. Conclusions: Hypophosphatasia is an uncommon condition with a highly variable presentation often resulting in a missed diagnosis. Surveillance of practices by identifying patients with low ALP levels is a reasonable screening approach to identifying potential patients with hypophosphatasia.
Causal Effect of Fibroblast Growth Factor 23 on Osteoporosis and Cardiometabolic Disorders: A Mendelian Randomization Study
Authors: Yokomoto-Umakoshi Maki , Umakoshi Hironobu , Miyazawa Takashi , Ogata Masatoshi , Sakamoto Ryuichi , Ogawa Yoshihiro 
Published: May 2021

Abstract
Pathological excess of fibroblast growth factor 23 (FGF23) causes mineral and bone disorders. However, the causality of FGF23 in the development of osteoporosis remains unknown. Whether FGF23 has systemic effects on cardio-metabolic disorders beyond regulating mineral metabolism is also controversial. In this study, we evaluated the causal effect of FGF23 on osteoporosis and cardiometabolic disorders using Mendelian randomization (MR) analysis. Summary statistics for single-nucleotide polymorphisms with traits of interest were obtained from the relevant genome-wide association studies. As a result, FGF23 was found to be inversely associated with femoral neck-BMD (odds ratio [OR] 0.682, 95% confidence interval [CI] 0.546–0.853, p = 8e-04) and heel estimated BMD (eBMD) (OR 0.898, 95%CI 0.820–0.985, p = 0.022) in the inverse-variance-weighted analysis, but not lumbar spine-BMD and fractures. The results were supported by the weighted-median analysis, and there was no evidence of pleiotropy in the MR-Egger analysis. FGF23 was directly associated with FN-BMD and eBMD after adjustment for estimated glomerular filtration rate, height, and body mass index in multivariable MR analysis. On the other hand, there was no association between FGF23 and cardiometabolic traits including cardio artery disease, brachial-ankle pulse wave velocity, intima-media thickness of carotid arteries, systolic and diastolic blood pressure, fasting glucose, high and low-density lipoprotein cholesterol, and triglycerides. Therefore, FGF23 has been causally associated with bone loss. In contrast, FGF23 has not been causally associated with cardiometabolic disorders. The data of this study provides important insights into the role of FGF23 in the pathogenesis of osteoporosis and cardiometabolic disorders.
Effect of Cholecalciferol Supplementation on Bone Turnover Markers in Children and Adolescents With Type 1 Diabetes Mellitus
Authors: Pankiv Volodymyr I , Pankiv Ivan V 
Published: May 2021

Abstract
Background: Cholecalciferol is known to play an important role in bone mineral metabolism. Its deficiency may affect growth and status of bone markers in children. Aim of the study: to evaluate the correlation between serum 25(OH)D and bone markers and impact of vitamin D supplementation on serum bone formation [procollagen type 1 amino-terminal propeptide (P1NP)] and bone resorption [β-cross laps (CTx)] markers among children and adolescents with type 1 diabetes mellitus (DM). Materials and Methods: Total 58 children and adolescents with type 1 DM, who were given 2000 UI of cholecalciferol supplementation, were included in the study. These 58 children with available anthropometry, serum biochemistry, 25-hydroxyvitamin D ([25(OH)D]), and parathormone (PTH) were evaluated for bone formation (procollagen type 1 amino-terminal propeptide [P1NP]) and resorption (β-cross laps [CTx]) markers. Results: The mean age and body mass index of these children were 11.6 ± 2.3 years (boys: 11.7 ± 2.4; girls: 12.2 ± 1.4 years; p = 0.04) and 18.2 ± 3.9 kg/m2 (boys: 18.1 ± 3.8; girls: 17.8 ± 3.4 kg/m2; p = 0.206), respectively. Baseline serum P1NP levels were positively correlated with serum phosphates (r = 0.281, p &lt; 0.001), PTH (r = 0.291, p &lt; 0.001), and CTx (r = 0.425, p &lt; 0.001) but not with age (r = -0.016, p = 0.404), BMI (r = -0.080, p = 0.032), serum calcium (r = -0.038, p = 0.107), and baseline 25(OH)D (r = -0.069, p = 0.035). Postsupplementation serum P1NP and CTx levels maintained similar correlations. There was a significant decline in serum P1NP (from 681 ± 223 ng/ml to 630 ± 279 ng/ml, p &lt; 0.01) and CTx (from 1.63 ± 0.51 ng/ml to 1.37 ± 0.53 ng/ml, p &lt; 0.01) following supplementation. Though decline in serum P1NP and CTx levels was observed in both boys and girls, among all supplementation patients, the effect was more marked in serum CTx than P1NP levels. Conclusions: Vitamin D supplementation in children resulted in decrease in both bone formation (P1NP) and resorption (CTx). The impact, however, was more marked on bone resorption than bone formation.
Endocrinology, Vitamin D and the UK’s Covid-19 Disaster
Authors: Anderson David Coussmaker , Grimes David S 
Published: May 2021

Abstract
The formation of cholecalciferol (Vitamin D3) in skin depends on solar UVB to break the B ring of 7-dehydrocholesterol. Its discovery more than a century ago resulted from the identification of rickets as due to deficient sunshine in latitudes far from the equator, exacerbated by the air pollution, factory work and indoor living. Rickets resulted from defective endocrine control of blood calcium, and was accompanied by epidemic tuberculosis from failure of the D3-dependent first-line immune system. The influenza pandemic of 2018 revealed the need for D3 to fight viruses. Half a century later the systemic hormone role of 1,25(OH)D3 of renal origin, under control of PTH, was a major stimulus to understanding the mechanism of action via the VDR-RXR heterodimer. It was soon realised that 1,25(OH)D3 is also produced and acts locally in many organs and tissues provided that there are adequate reserves of the (protein-bound) blood storage form, 25(OH)D. This is the common pool for 1-hydroxylation by any cells that need local activation of VDR for induction of specific genes. In the case of the immune system, the trigger is foreign proteins recognised as ‘non-self’. Local production and action of 1,25(OH)D, and then its local destruction by 24-hydroxylation must all occur below the ‘endocrine radar’, so as not to interfere with systemic calcium control. Coronaviruses through their ‘spike’ protein are internalised by interacting with the ACE-2 receptor, which in turn is down-regulated by Vitamin D. In the process, 25(OH)D is hydroxylated to the active 1,25(OH)D, which must later be degraded to 1,24,25(OH)D. So it is to be expected that when 25(OH)D reserves are low at the onset of infection, they will fall further, allowing virus to enter the cells and trigger a cytokine storm and other damage. Blood PTH will rise to claim any residual 25(OH)D for the dominating systemic role in calcium homeostasis. It follows that intake of vitamin D3 should always be much more than the minimum claimed by the globally-active endocrine system. Unfortunately, the UK’s Specialised Advisory Committee on Nutrition (SACN), does not recognise this. It is dominated by nutritionists, even though food sources of D3 are for most non-existent, and of D2, the vegetable substitute, highly variable. The 400IU of D3 reluctantly recommended for those ‘at risk’, based on endocrinology alone, is grossly inadequate; 4,000IU daily is needed to maintain a blood 25(OH)D at more than 30 ng/ml (75 nmol/l), and provide sufficient reserve for its many autocrine and paracrine functions. The dangers of letting the dominant endocrine function of 1,25(OH)D in ionic calcium control dictate the level of D3 supplements, have once again been underlined by the Covid-19 disaster.
Factors Associated With Low Bone Mineral Density in Adults With Type 1 Diabetes: A Cross-Sectional Study
Authors: Coll Julie-Catherine , Garceau Élodie , Michou Laëtitia , Weisnagel S John , Mac-Way Fabrice , Morin Suzanne N , Rabasa-Lhoret Remi , Gagnon Claudia 
Published: May 2021

Abstract
Context: Individuals with type 1 diabetes (T1D) have a two- to threefold increase in fracture risk at any site, and up to a sevenfold increase in hip fracture risk compared to those without diabetes. The mechanisms accounting for this bone fragility are not yet fully understood.
Objectives: 1) To determine factors associated with low bone mineral density (BMD) in patients with T1D; 2) To assess the association between skin advanced glycation end products (AGEs) and low BMD in patients with T1D.
Methods: These are preliminary data from patients with T1D included in a cross-sectional study aiming at comparing the prevalence of vertebral fractures between adult patients with T1D from two tertiary care centers and age- and sex-matched controls without diabetes. Patients were eligible if they were aged ≥20 years and had a diagnosis of T1D for at least 5 years. Patients were classified as having a low BMD if Z-score was ≤-2.0 at any site (lumbar spine, femoral neck, total hip, radius) in patients aged &lt;50 years or if T-score was ≤-1.0 at any site in patients aged ≥50 years or in postmenopausal women. Skin AGEs (surrogate marker of overall including bone AGEs) were measured by skin autofluorescence (AGE Reader ®). Unpaired t-tests or Chi-squared tests were used to compare characteristics between patients with or without a low BMD. Variables associated with a low BMD were determined by univariate analysis and were subsequently included in a multivariate logistic regression analysis if p&lt;0.1 in the univariate analysis. All variables were tested for multicollinearity.
Results: 106 patients with T1D were included (mean age 45.2±15.0 years; mean BMI 26.3±5.1 kg/m2; 54.7% women; mean duration of diabetes 28.2±13.6 years; 44.3% with a microvascular complication). Mean HbA1C over the past 3 years was 7.5±0.8%. A third of the patients (31.1%) had a low BMD (3 patients using Z-score; 30 patients using T-score). Patients with a low BMD were older (58.3 vs 39.3 years, p&lt;0.001), had a lower mean HbA1C over the past 3 years (7.3% vs 7.6%, p=0.047), a longer diabetes duration (36.1 vs 24.6 years, p&lt;0.001), higher skin AGEs (2.50 vs 2.03, p&lt;0.001), a higher prevalence of microvascular complications (63.6% vs 37.7%, p=0.02) and a higher prevalence of abnormal albumin to creatinine ratio (ACR ≥2.0) on the day of assessment (38.7% vs 11.8%, p=0.003). In multivariate regression analysis, age (p&lt;0.001), abnormal ACR (p=0.003) and lower mean HbA1C over the past 3 years (p=0.02) remained significantly associated with a low BMD. Skin AGEs were correlated with age (r=0.56) and diabetes duration (r=0.47).
Conclusion: In this population with T1D, a low BMD was independently associated with older age, abnormal ACR and, unexpectedly, with a lower mean HbA1C over the past 3 years, but not with skin AGEs.
Obesity, Dyslipidemia, Diabetes, and Vitamin D Levels
Authors: Moya Elena A Amoroso , Nicolalde Marcelo , Torres Herbarth 
Published: May 2021

Abstract
Context: There are several studies that refer to an association between vitamin D levels and the prevalence of atherogenic dyslipidemia and diabetes 2, however these studies present different non-conclusive results. Methods: A cross-sectional study was carried out with a propositional sequential sample of 110 patients at Rio and San Juan Hospital Riobamba -Ecuador 2020. The sample was divided into three groups according to BMI and vitamin D levels; 25 hydroxycalciferol, by cluster analysis, the final groups G1(56), G2(59), and G3(16) had a similar BMI average of 27 kg/m2, and significant differences in the average of vitamin D: G1 = 13.6, G2 = 24.5 and G3 = 45.3 ng/dl. Results: The prevalence of dyslipidemia increased gradually as the average level of vitamin D of the group increased as follows: G1 = 12.5%, G2 = 18.6%, G3 = 18.8%, the same behavior was observed in the prevalence of type 2 diabetes per analysis group: G1 = 30.4%, G2 = 45.8% and G3 = 50%. The differences found in the prevalence of atherogenic dyslipidemia and diabetes 2 were not statistically significant p&gt; 0.05. Conclusion: in the group of patients studied and divided by cluster analysis into three groups with different levels of vitamin D, there were no statistically significant differences with respect to the prevalence of atherogenic dyslipidemia and diabetes 2.
Androgen and Estrogen Receptor Activation Impacts Cardiac Function in a PCOS-Prone Rodent Model
Authors: Vine Donna Faye , Raggi Paolo , Proctor Spencer , Becher Harald 
Published: May 2021

Abstract
Introduction: The global risk and incidence of cardiovascular disease (CVD) is increased in polycystic ovary syndrome (PCOS). Early risk factors and subclinical CVD includes atherogenic dyslipidemia, obesity, insulin resistance, blood pressure, atherosclerosis and impaired cardiac function. Androgen exposure is associated with onset of adiposity, impaired insulin-glucose and lipid metabolism, and cardiac dysfunction. The mechanisms of increased risk of CVD and cardiac dysfunction in PCOS related to hyperandrogenemia, AR and estrogen receptor (ER) activation remain unclear. Aim: The aim of this study was to investigate the effect of androgen treatment on cardiac AR and ER activation, fatty acid metabolism and cardiac function in a PCOS-prone rodent model. Methods: A PCOS-prone rodent model at 6 wks of age with obesity, apoB-remnant lipemia and insulin resistance, and controls were treated with testosterone for 12 weeks. Cardiac function was assessed using transthoracic doppler echocardiography (M-Mode 2D-imaging), lipogenic, AR, ER and other metabolic gene and protein expression were assessed using RTPCR and SDS-PAGE western blot. Results: PCOS-prone animals exhibited left ventricular (LV) hypertrophy, with increased LV mass to body weight (551.6 ± 38.85 mg vs 999 ± 96.17 mg, p&lt;0.05), LV posterior wall diastolic diameter and LV internal diastolic diameter compared to controls. Isovolumetric relaxation time (IVRT) was prolonged (15.91 ± 1.591 msec vs 23.75 ± 0.722 msec, p&lt;0.05). Mild systolic dysfunction was evidenced by increased isovolumetric contraction time (IVCT; 22.5 ± 1.348 msec vs 28.96 ± 1.248 msec, p&lt;0.05) and decreased % ejection fraction and % fractional shortening in PCOS-prone compared to controls. T treatment increased LV mass, IVCT and IVRT in controls but did not exacerbate cardiac function in PCOS-prone animals. T treatment increased cardiac protein expression of PPAR-⍺ in PCOS-prone and controls, and T increased ACC in controls. AR protein expression tended to be reduced, and ER-⍺ was reduced in both T treated control and PCOS-prone animals. Conclusions: The PCOS-prone rodent model demonstrates early cardiac LV hypertrophy and diastolic-systolic dysfunction and T treatment alters fatty acid metabolism, and AR and ER activation are associated with altered cardiac morphology and function in the PCOS-prone and control conditions.
Feasibility of a Novel Nonhuman Primate Model of Age-Related Nonalcoholic Fatty Liver Disease
Authors: Azees Parveez Ahamed Abdul , Palavicini Juan Pablo , Han Xianlin , Salmon Adam , Kamat Amrita 
Published: May 2021

Abstract
The objective of the proposed study is to investigate the feasibility of the marmoset as an animal model to study age-associated nonalcoholic fatty liver disease (NAFLD). This chronic liver disease includes a spectrum of disorders ranging from increased triglyceride accumulation in the liver or hepatic steatosis to the more severe inflammatory form nonalcoholic steatohepatitis that can lead to cirrhosis and even hepatocellular carcinoma in individuals who do not have a history of alcohol abuse. Aging increases the prevalence of NAFLD and is strongly associated with the progression and severity of this disease. End-stage hepatic failure and liver cancer resulting from advanced NAFLD are leading indications for liver transplantation enhancing the burden on our healthcare systems. Accumulating clinical evidence also suggests that patients with NAFLD have a higher prevalence of cardiovascular disease. Pathogenetic mechanisms involved in the development and progression of NAFLD are poorly understood and as such, there is a lack of effective therapies. The common marmoset is a relatively short-lived non-human primate that recapitulates many of the physiological changes that occur in human aging. We hypothesized an age-associated increase in hepatic steatosis and alterations in serum lipid profile in the marmoset model. An increase in triglyceride levels and oil red o staining in liver tissues of old marmosets compared to young animals was observed suggesting an age-associated increase in hepatic steatosis in marmosets as observed in humans. Lipidomic studies were also performed using blood samples from male and female marmosets to investigate age-associated changes in specific lipid species, which are characteristic of aberrant lipid metabolism. Analysis of the results revealed significant decreases in several phosphatidylethanolamine, phosphatidylcholine, and sphingomyelin species in the plasma of old marmosets compared to young marmosets. We are now performing studies to determine whether the observed changes in different lipid species could influence the development of cardiovascular disease and provide new insights underlying the mechanisms of NAFLD development with aging.
Generation of Affinity Purified Antibody Reagents for Specific Determination of Efruxifermin in Biological Matrices
Authors: Kinne Adam S , Abdeen Sanofar J , Parmer Elijah S , Thystrup Jennifer A , Tillman Erik J , Rolph Timothy P , Bowsher Ronald R 
Published: May 2021

Abstract
Efruxifermin (EFX) is a novel Fc-fusion analog of human fibroblast growth factor 21 (FGF21), currently in clinical development as a potential treatment for non-alcoholic steatohepatitis (NASH). Each molecule of EFX consists of two modified FGF21 molecules, each attached at their N-termini to a human IgG1 Fc domain by a short polyglycine-serine linker. The FGF21 moiety of EFX incorporates three amino acid substitutions (L98R, P171G, and A180E relative to native FGF21). Two of these are proximal to the C-terminus (P171G and A180E), and reduce cleavage and inactivation by an endogenous protease, fibroblast activation protein (FAP), thereby prolonging its half-life. Fusion to human IgG1 Fc domain further extends circulating half-life, enabling once-weekly subcutaneous dosing. Accordingly, to support on-going clinical development of EFX, a specific assay is needed to distinguish intact EFX from both endogenous FGF21 and any in vivo biotransformation products of EFX that display reduced pharmacology. To maximize the antigenicity of EFX, FGF21 amino acid sequences were compared across species. Based on this, an antibody generation campaign was initiated in both rabbits and chickens. Comparison of titer responses against EFX and human FGF21 suggested that antisera from chickens was superior to rabbit antisera. Following a scaled-up, 12-week antibody campaign, antisera were purified by a combination of batch and column chromatographic procedures. By exploiting differences in structure and amino acid sequence of EFX relative to human FGF21, a purification strategy was designed to isolate chicken antibodies with increased specificity for EFX unique sequences. This reagent is being used as a capture antibody in the development of a noncompetitive ECLIA employing chemiluminescence detection. Presently, a number of different antibodies are being evaluated for potential pairing with the specific capture. We conclude that application of affinity purified chicken anti-EFX IgY will enable sensitive and specific determination of EFX in biological matrices with decreased cross-reactivity from endogenous hFGF21 and EFX metabolites.