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Islay Pittaway,1 Anna Ishkova,1 Helena Bean,1 Stephanie McCarthy,1 Isabella Lay,1 Joanne Avraam,1 Andrew Dawson,1 Therese Thornton,1 Christian L Nicholas,1,2 John Trinder,1 Fergal J O’Donoghue,2,3 Melinda L Jackson,2,4 Amy S Jordan1,2 1Melbourne School of Psychological Sciences, The University of Melbourne, Parkville, VIC 3010, Australia; 2Institute for Breathing and Sleep, Austin Health, Heidelberg, VIC 3084, Australia; 3Department of Medicine, The University of Melbourne, Austin Hospital, Heidelberg, VIC 3084, Australia; 4Turner Institute for Brain and Mental Health, School of Psychological Sciences, Monash University, Clayton, VIC 3164, AustraliaCorrespondence: Amy S Jordan Tel +61 3 8344 6357Email ajordan@unimelb.edu.auPurpose: Obstructive sleep apnea (OSA) is less prevalent among women and is associated with different symptoms and consequences to OSA in men. The reasons for these differences are unknown and difficult to tease apart in clinical populations. If OSA could be temporarily induced in healthy men and women, the causes of some of these differences could be investigated. Nasal blocking has been used to induce OSA in healthy men but its effect in women has not been reported.Patients and Methods: A total of 14 healthy individuals (10 women) underwent in-laboratory diagnostic sleep studies on two occasions separated by a week. On one occasion, the nasal passages were blocked, whereas on the other occasion, participants slept naturally. In both conditions, a full-face mask was used to monitor respiratory events. Participants’ self-reported sleepiness, mood and performance on a motor learning task were assessed in the evening and morning of both sleep studies. Furthermore, endothelial function and self-reported sleep quality were assessed in the morning following each study.Results: Nasal blockage induced OSA in healthy young (age=22± 3 years) and slim (BMI=22.2± 3.2 kg/m2) women (control AHI=2.0± 2.6, blocked AHI=33.1± 36.7 events/hr, p=0.02). One night of OSA was associated with poorer self-reported sleep quality (p< 0.001) and increased self-reported snoring (p< 0.04), choking and gasping during sleep (p< 0.001) but was not associated with alterations in mood, neurocognitive or endothelial function on the following morning.Conclusion: Nasal blockage induces OSA in healthy, young, and normal weight women. However, whether the induced OSA is representative of naturally occurring OSA and the technique useful for future studies is unclear.Keywords: pathophysiology, upper airway collapse, sex, breathing route, obstructive sleep apnea, nasal blockage, female

Purpose: In patients with acromegaly, the long-term presence of elevated GH and IGF-1 levels is associated with an unfavorable cardiovascular risk profile. We aimed to assess the relationship of four-dimensional speckle tracking echocardiographic (4DSTE) measurements with growth differentiation factor-15 (GDF-15) levels and the Framingham Cardiovascular Risk Score (FRS) in patients with acromegaly., Methods: A single-center, cross-sectional study was conducted. The study included 40 acromegaly and 32 age- and gender-matched controls. Anthropometric, biochemical, and echocardiographic assessments were performed. GDF-15 levels were measured using ELISA., Results: In the controlled acromegaly group, global longitudinal (GLS), circumferential (GCS), area (GAS), and radial (GRS) strain measurements identified by 4DSTE were lower than those of the controls (p < 0.05). Moreover, strain parameters were lower in active acromegaly patients than in controls, but the difference was not statistically significant. The GLS was negatively correlated with age, the estimated disease duration, and FRS. Serum GDF-15 levels showed no significant difference between the acromegaly and control groups. In patients with acromegaly, serum GDF-15 levels were positively correlated with age, waist-to-hip ratio, systolic and diastolic blood pressure, FRS, fasting plasma glucose, and HbA1c, but not with strain parameters. The multiple regression analysis revealed that FRS was an independent factor associated with serum GDF-15 levels in patients with acromegaly and the overall cohort (p < 0.001)., Conclusion: Our study demonstrates that while LVEF was within normal limits, global strain parameters (GLS, GCS, GAS, and GRS) measured by using a novel imaging technique, 4DSTE, were lower in patients with acromegaly, suggesting the presence of subclinical systolic dysfunction in patients with acromegaly. GDF-15 can be a potential predictor of cardiovascular risk in patients with acromegaly., (© 2024. The Author(s), under exclusive licence to Hellenic Endocrine Society.)

Background: The aim is to compare the plasma levels of hyaluronic acid (HA) which is closely related to inflam-mation and vascular changes and arterial stiffness (AS) related values in patients with Alzheimer's disease (AD), amnestic type mild cognitive impairment (aMCI), and normal cognitive functions (NCF)., Methods: Ninety participants were categorized into three groups, patients with AD, MCI, and NCF. Arterial stiffness measurement in the nephrology outpatient clinic, and storage and analysis of plasma samples in the biochemistry laboratory., Results: Of the 90 patients, 32 had NCF, 32 had aMCI, and 26 had AD. Between groups, there was no difference in HA, pulse wave velocity, and augmentation index. The HA level had no statistically significant correlation with any of the other variables., Conclusions: Plasma HA levels will not be useful in the diagnosis of AD. More comprehensive studies with larger number of patients are needed.

Urinary omics has become a powerful tool for elucidating pathophysiology of glomerular diseases. However, no urinary omics analysis has been performed yet on renal AA amyloidosis. Here, we performed a comparative urine proteomic and metabolomic analysis between recently diagnosed renal AA amyloidosis (AA) and membranous nephropathy (MN) patients. Urine samples of 22 (8 AA, 8 MN and 6 healthy control) patients were analyzed with nLC-MS/MS and GC/MS for proteomic and metabolomic studies, respectively. Pathological specimens were scored for glomerulosclerosis and tubulointerstitial fibrosis grades. Functional enrichment analysis between AA and control groups showed enrichment in cell adhesion related sub-domains. Uromodulin (UMOD) was lower, whereas ribonuclease 1 (RNase1) and α-1-microglobulin/bikunin precursor (AMBP) were higher in AA compared to MN group. Correlations were demonstrated between UMOD-proteinuria (r = -0.48, p = 0.03) and AMBP-eGFR (r = -0.69, p = 0.003) variables. Metabolomic analysis showed myo-inositol and urate were higher in AA compared to MN group. A positive correlation was detected between RNase1 and urate independent of eGFR values (r = 0.63, p = 0.01). Enrichment in cell adhesion related domains suggested a possible increased urinary shear stress due to amyloid fibrils. UMOD, AMBP and myo-inositol were related with tubulointerstitial damage, whereas RNase1 and urate were believed to be related with systemic inflammation in AA amyloidosis. SIGNIFICANCE: Urinary omics studies have become a standard tool for biomarker studies. However, no urinary omics analysis has been performed yet on renal AA amyloidosis. Here, we performed a comparative urinary omics analysis between recently diagnosed renal AA amyloidosis (AA), membranous nephropathy (MN) patients and healthy controls. Pathological specimens were scored with glomerulosclerosis (G) and tubulointerstitial fibrosis (IF) grades to consolidate the results of the omics studies and correlation analyzes. Functional enrichment analysis showed enrichment in cell adhesion related sub-domains due to downregulation of cadherins; which could be related with increased urinary shear stress due to amyloid deposition and disruption of tissue micro-architecture. In comparative proteomic analyzes UMOD was lower, whereas RNase1 and AMBP were higher in AA compared to MN group. Whereas in metabolomic analyzes; myo-inositol, urate and maltose were higher in AA compared to MN group. Correlations were demonstrated between UMOD-proteinuria (r = -0.48, p = 0.03), AMBP-eGFR (r = -0.69, p = 0.003) and between RNase1-Urate independent of eGFR values (r = 0.63, p = 0.01). This study is the first comprehensive urinary omics analysis focusing on renal AA Amyloidosis to the best of our knowledge. Based on physiologic roles and clinicopathologic correlations of the molecules; UMOD, AMBP and myo-inositol were related with tubulointerstitial damage, whereas RNase1 and urate were believed to be increased with systemic inflammation and endothelial damage in AA amyloidosis., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Context: Nonalcoholic fatty liver disease (NAFLD) is a metabolical disorder and can lead to liver fibrosis. Because it is commonly seen, several noninvasive scores (NS) have been validated to identify high-risk patients. Patients with NAFLD have been shown to have higher serum angiopoietin-like protein-8 (ANGPTL-8) levels., Objective: The risk of NAFLD is known insufficiently in acromegaly. Moreover, the utility of the NS and the link between NAFLD and ANGPTL-8 in acromegaly is unknown., Methods: Thirty-two patients with acromegaly (n = 15, active [AA] and n = 17, controlled acromegaly [CA]) and 19 healthy controls were included. Magnetic resonance imaging (MRI)-proton density fat fraction (PDFF) was used to evaluate hepatic steatosis, and magnetic resonance elastography to evaluate liver stiffness measurement. ANGPTL-8 levels were measured with ELISA., Results: Median liver MRI-PDFF and NAFLD prevalence in AA were lower than in CA (P = .026 and P < .001, respectively). Median magnetic resonance elastography-liver stiffness measurement were similar across groups. Of the NS, visceral adiposity index, fatty liver index, hepatic steatosis index, and triglyceride-glucose index (TyG) all showed positive correlation with the liver MRI-PDFF in the control group. However, only TyG significantly correlated with liver fat in the AA and CA groups. There was no correlation between traditional NAFLD risk factors (body mass index, waist circumference, C-reactive protein, homeostasis model assessment for insulin resistance, visceral adipose tissue) and liver MRI-PDFF in the AA and CA. Patients with acromegaly with NAFLD had lower GH, IGF-1, and ANGPTL-8 levels than in those without NAFLD (P = .025, P = .011, and P = .036, respectively)., Conclusion: Active acromegaly may protect from NAFLD because of high GH. In patients with acromegaly, NAFLD risk cannot be explained with classical risk factors; hence, additional risk factors must be identified. TyG is the best score to evaluate NAFLD risk. Lower ANGPTL-8 in patients with acromegaly and NAFLD implies this hormone may be raised because of insulin resistance rather than being a cause for NAFLD., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.)

Background: Sphingolipid species in the lung epithelium have a critical role for continuity of membrane structure, vesicular transport, and cell survival. Sphingolipid species were reported to have a role in the inflammatory etiology of cystic fibrosis by previous work. The aim of the study was to investigate the levels of plasma sphingomyelin and ceramide in adult cystic fibrosis (CF) patients and compared with healthy controls., Materials and Methods: Blood samples were obtained from CF patients at exacerbation (n = 15), discharge (n = 13) and stable periods (n = 11). Healthy individuals (n = 15) of similar age served as control. Levels of C16-C24 sphingomyelin and C16-C24 ceramide were measured in the plasma by LC-MS/MS. Also, cholesterol and triglyceride levels were determined in plasma samples of the patients at stable period., Results: All measured sphingomyelin and ceramide levels in all periods of CF patients were significantly lower than healthy controls except C16 sphingomyelin level in the stable period. However, plasma Cer and SM levels among exacerbation, discharge, and stable periods of CF were not different. CF patients had significantly lower cholesterol levels compared to healthy individuals. We found significant correlation of cholesterol with C16 sphingomyelin., Conclusion: We observed lower plasma Cer and SM levels in adult CF patients at exacerbation, discharge, and stable periods compared to healthy controls. We didn't find any significant difference between patient Cer and SM levels among these three periods. Our limited number of patients might have resulted with this statistical insignificance. However, percentage of SM16 levels were increased at discharge compared to exacerbation levels, while percentage of Cer16 and Cer 20 decreased at stable compared to exacerbation. Inclusion of a larger number of CF patients in such a follow up study may better demonstrate any possible difference between exacerbation, discharge, and stable periods., Competing Interests: Declaration of Competing Interest All the other authors declare that they have no conflict of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

A uncommon inflammatory condition called morphea causes fibrosis in the skin and subcutaneous tissue. The key stages in the pathophysiology are vascular damage, immunological response, and fibrosis. Numerous research have examined the relationships between the immune system, fibrosis, and vitamin D, but the exact pathogenetic pathways of morphea remain poorly understood. The purpose of this study was to investigate serum 25(OH)D levels and the ApaI (rs7975232) and TaqI (rs731236) polymorphisms of the vitamin D receptor (VDR) in morphea patients. There were 48 age- and sex-matched controls and 41 morphea patients total. VDR polymorphisms were found using PCR tests and gel electrophoresis, and serum 25(OH)D levels were determined using liquid chromatography combined with tandem mass spectrometry (LC-MS/MS). The patient group consisted of 37 females (90.2%) and 4 males (9.8%). The patients' mean age was 38.68 ± 17.54 years. In terms of VDR ApaI and TaqI polymorphisms, there was no discernible difference between the patient and control groups. TaqI polymorphism heterozygosity was discovered in all patients with progressive disease, and this finding was statistically significant (p = 0.012). Patients' mean serum 25(OH)D levels were 16.98 ± 11.55 ng/mL, while those in the control group were 18.02 ± 14.30 ng/mL. VDR polymorphisms, vitamin D levels, disease subtype, age of onset, and responsiveness to treatment did not significantly correlate. In our research, we discovered that TaqI polymorphism may be related to the severity of the disease and that the polymorphisms of the VDR ApaI and TaqI were not associated with morphea susceptibility., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: To evaluate the association between diverse surrogate markers of insulin resistance and adiponectin concentrations. Methods: Four hundred healthy participants were included. Two different cohorts were formed according to the body mass index (BMI) values. Group 1 ( n  = 200) consisted of individuals with normal BMI values (18.50-24.99 kg/m 2 ), whereas in Group 2 ( n  = 200) there were overweight or obese individuals (BMI ≥25.00 kg/m 2 ). Homeostasis model assessment of insulin resistance (HOMA-IR), quantitative insulin sensitivity check index (QUICKI), and triglycerides-glucose index (TyG) were calculated. Serum adiponectin levels were measured by ELISA. A correlation analysis was performed to assess the association between serum adiponectin and HOMA-IR, QUICKI, and TyG. Results: Participants in Group 2 were older (age in years: Group 1, 33.3 ± 6.8 vs. Group 2, 36.4 ± 7.0, P  < 0.001). There was no gender difference between groups. Overweight or obese participants had higher BMI, waist circumference, fat mass, fat ratio, fasting plasma glucose, fasting plasma insulin, triglycerides, total cholesterol, and low-density lipoprotein cholesterol values, whereas high-density lipoprotein cholesterol was higher in participants with normal BMI measures. Overweight or obese subjects were more insulin resistant (higher TyG index and HOMA-IR) and less insulin sensitive (lower QUICKI), P  < 0.001 for all. Serum adiponectin levels were lower in Group 2 (serum adiponectin in ng/mL: Group 1, 11,880 ± 6838 vs. Group 2, 9115 ± 5766, P  < 0.001). The correlation between TyG index and adiponectin was stronger than the correlation between QUICKI and adiponectin, and HOMA-IR and adiponectin ( r for TyG and adiponectin -0.408, r for QUICKI and adiponectin 0.394, r for HOMA-IR and adiponectin -0.268, respectively, P  < 0.001 for all correlations). Conclusions: TyG has a stronger association with adiponectin than HOMA-IR and QUICKI.

Background: IgA vasculitis (IgAV) is the most common form of childhood vasculitis. A better understanding of its pathophysiology is required to identify new potential biomarkers and treatment targets., Objective: to assess the underlying molecular mechanisms in the pathogenesis of IgAV using an untargeted proteomics approach., Methods: Thirty-seven IgAV patients and five healthy controls were enrolled. Plasma samples were collected on the day of diagnosis before any treatment was initiated. We used nano-liquid chromatography-tandem mass spectrometry (nLC-MS/MS) to investigate the alterations in plasma proteomic profiles. For the bioinformatics analyses, databases including Uniprot, PANTHER, KEGG, Reactome, Cytoscape, and IntAct were used., Results: Among the 418 proteins identified in the nLC-MS/MS analysis, 20 had significantly different expressions in IgAV patients. Among them, 15 were upregulated and 5 were downregulated. According to the KEGG pathway and function classification analysis, complement and coagulation cascades were the most enriched pathways. GO analyses showed that the differentially expressed proteins were mainly involved in defense/immunity proteins and the metabolite interconversion enzyme family. We also investigated molecular interactions in the identified 20 proteins of IgAV patients. We extracted 493 interactions from the IntAct database for the 20 proteins and used Cytoscape for the network analyses., Conclusion: Our results clearly suggest the role of the lectin and alternate complement pathways in IgAV. The proteins defined in the pathways of cell adhesion may serve as biomarkers. Further functional studies may lead the way to better understanding of the disease and new therapeutic options for IgAV treatment.

The prevalence of allergic asthma is increasing on a global scale, reflecting changes in air pollution, climatic changes, and other environmental stimulants. In allergic conditions, oxidative stress occurs as a result of immune system activation. Oxidation of cholesterol leads to the formation of oxysterols. The main purpose of the study was to compare plasma levels of two oxysterols, namely 7-ketocholesterol (7-KC) and cholestane-3β, 5α, 6β-triol (C-triol), and a lipid peroxidation product, malondialdehyde (MDA) in allergic asthma patients with those of healthy controls, in order to provide information about the involvement of lipid peroxidation in allergic asthma., Oxysterols were quantified by LC-MS/MS in plasma samples of 120 asthma patients (90 females + 30 males) and 120 healthy controls (matched by age and sex). Plasma MDA level was analyzed by a spectrophotometric method., Plasma 7-KC (39.45 ± 20.37 ng/mL) and C-triol (25.61 ± 10.13 ng/mL) levels in patients were significantly higher than in healthy subjects (17.84 ± 4.26 ng/mL and 10.00 ± 3.90 ng/mL, respectively) ( P  < 0.001). Plasma MDA levels were also higher in asthmatic patients (4.98 ± 1.77 nmol/mL) than in healthy controls (1.14 ± 0.31 nmol/mL) ( P  < 0.001). All data support that lipid peroxidation products are involved in allergic asthma., Oxysterols were quantified for the first time in allergic asthma. Since the high plasma 7-KC and C-triol levels of allergic asthma patients correlate with high IgE levels, detection of these oxysterols by LC-MS/MS may be helpful in the clinical monitoring of allergic asthma. Current data may also lead to new approaches for the prevention, diagnosis, and treatment of the disease., Supplemental data for this article is available online at at.

Aims: To assess serum growth differentiation factor-15 (GDF-15) levels in patients with diabetic foot ulcer and to reveal whether any association exists between GDF-15 and the severity of diabetic foot ulcer., Design: A cross-sectional study including three age- and sex-matched cohorts comprising 17 patients (7 F, mean age: 52 ± 7 years) with diabetic foot ulcer (DMf), 17 patients with type 2 diabetes (6 F, mean age: 51 ± 6 years) with no foot complication (DM), and 20 healthy controls (8 F, mean age: 50 ± 8 years) (C) was conducted., Results: DMf had higher GDF-15 levels, followed by DM and C (GDF-15, median ± IQR (pg/mL), DMf: 1039 (884-1566), DM: 649 (375-1148), and C: 296 (212-534), p < 0.001). The severity of diabetic foot disease was positively associated with serum GDF-15 (GDF-15, median ± IQR (pg/mL), Wagner grade 1: 893 (698-1039), Wagner grade 3: 1705 (1348-2197), and Wagner grade 4: 3075 (1974-4176), p for trend = 0.006). In multivariate regression model, only Wagner grade (β = 0.55, 95% CI (87-753), p = 0.02) was found to be an independent factor affecting serum GDF-15 concentration., Conclusions: Serum GDF-15 levels are high in patients with diabetic foot ulcer. The level is higher in more advanced lesions. GDF-15 measurement can have clinical utility in the management of diabetic foot ulcers., (© 2022. The Author(s), under exclusive licence to Hellenic Endocrine Society.)

Aim: Muscle weakness, fatigue and speech problems can occur in neurofibromatosis type 1 (NF1). The pathogenesis of these symptoms is unclear, likely multifactorial. We examined motor function in limb and speech muscles in NF1 patients., Methods: We evaluated NF1 and control groups aged 4-18 years for muscle strength, tone and mobility using standard manual testing, joint motion and Beighton score measurements. Speech and language functions were assessed by speech articulation and resonance. As a marker of muscle tissue turnover, we determined collagen degradation products in urine before and after submaximal exercise., Results: NF1 patients had reduced strength in proximal limb muscles compared to control subjects. Speech articulation problems and hypernasality were more common in NF1 (47% and 38%, respectively). Collagen products excreted in urine correlated with gluteal and biceps muscle strength., Conclusion: Muscle dysfunction can be detected in some children with NF1 and may explain certain clinical features including fatigue, speech and articulation problems. If confirmed by further research, these findings may be relevant to the management of this condition., (© 2022 Paediatrics and Child Health Division (The Royal Australasian College of Physicians).)

Background: Metabolomics has the potential to provide putative biomarkers and insights into the pathophysiology and diagnosis of pediatric multiple sclerosis (pMS), which is an inflammatory demyelinating disorder of the central nervous system with a broad spectrum of clinical manifestations. In this study, we aimed to investigate serum metabolomics in pMS to help elucidate the pathophysiology of MS., Methods: An untargeted approach was applied using the quadrupole time-of-flight liquid chromatography/mass spectrometry (Q-TOF LC/MS) method to study plasma metabolites in patients with pMS (n = 33), patients with unclassified central nervous system demyelinating diseases (n = 6), and age-matched healthy control subjects (n = 40). The patient and control groups were compared for metabolites and the normalized peak areas differed statistically (p < 0.05), showing at least a 1.25-fold change between groups. Bioinformatic tools combined with a clinical perspective were employed for the identification of the putative metabolites. In addition to the untargeted metabolomics approach, targeted LC-MS/MS metabolite analysis was employed to compare the pMS group with the control group., Results: Significant differences between the patient and control groups were noted for tyramine, 4-hydroxyphenylacetaldehyde, sphingosine/3-dehydrosphinganine, prostaglandins/thromboxane A2, 20-hydroxy-leukotriene E4, 3α,7α,12α-trihydroxy-5β-cholestan26-al/calcitriol, pantetheine, ketoleucine/3-methyl-2-oxovaleric acid, L-arginine/D-arginine, coproporphyrinogen III, (S)-reticuline, carnosine, cytidine, and phosphoribosyl pyrophosphate. Additional tests for sphingosine 1-phosphate, sphingophosphocholines, ceramides, oxysterols, and calcitriol levels yielded significant metabolomic differences for the pMS group compared to the control group. The metabolomic data of 3/6 patients with unclassified demyelinating disorders matched the pMS group; their follow-up verified the diagnosis of pMS., Discussion: In general, plasma metabolites related to sphingolipid metabolism, myelin products, inflammatory pathways, mitochondrial dysfunction, and oxidative stress were found to be altered in cases of pMS. The method applied in this study, combining untargeted analysis with a targeted approach, can be applied to larger series of cases of pMS and other demyelinating disorders for further validation.

Objectives: Several metabolic disturbances are seen in acromegaly however, data regarding the contribution of irisin to these disturbances is currently insufficient. In a cohort of patients with acromegaly, we measured serum irisin levels in active and controlled cases and determined independent factors that effect serum irisin including fibronectin type III domain-containing protein 5 (FNDC5) genotyping., Methods: A cross-sectional case-control study including 46 patients with acromegaly (28 F/18 M, age: 50.3 ± 12.1 year, BMI: 30.7 ± 5.1 kg/m 2 ) and 81 age-, gender-, body mass index- and body composition-matched healthy controls was conducted. 15 acromegalic patients (33%) had active disease. Irisin levels were measured by enzyme-linked immunosorbent assay. Three different regions (rs3480, rs1746661, and rs16835198) of FNDC5 were subjected to polymorphism analyses., Results: Both groups were overweight and had similar body composition. Irisin levels were lower in patients with acromegaly than controls (median [IQR]: 44.8 [41.7-46.7] ng/mL vs. 51.7 [45.5-60.1] ng/mL, p≤0.001, respectively). Active and controlled patients had similar irisin levels. Irisin was not correlated with growth hormone (GH), insulin-like growth factor 1 (IGF-1), and IGF-1 index. In multiple linear regression model, somatostatin receptor ligand use ( β =-20.30, 95% CI [-34]-[-6], p=0.006) was determined as the only independent factor that affect serum irisin., Conclusions: Serum irisin levels are low in patients with acromegaly who are on somatostatin receptor ligand therapy. Single nucleotide polymorphisms (SNPs) of FNDC5 have no independent effects on circulating irisin levels under somatostatin ligand action. Endocrine muscle functions also seem to be regulated by somatostatin action, which requires further studies., (© 2022 Walter de Gruyter GmbH, Berlin/Boston.)

Demonstrating inter-device reliability is essential to use devices interchangeably, and accurately integrate, interpret, or compare data from different actigraphs. Despite this, there is a paucity of comparative literature over a timeframe exceeding one night. The aims of this study were to determine an optimal wake threshold for GENEActiv and to evaluate the concordance between Actiwatch-2 and GENEActiv using a common algorithm (Phillips Respironics). Data were collected from 33 individuals (20 female) aged 20-35 years ( M = 25.33, SD = 4.69) across a total 213 nights. Participants wore both devices simultaneously and continuously for seven days. The sleep parameters of interest were: total sleep time, sleep efficiency, sleep onset latency, and wake after sleep onset. Exploratory analyses of sensitivity, specificity, overall accuracy, mean bias, and paired samples t-tests indicated an optimal wake threshold of 115 for GENEActiv, compared with Actiwatch-2 at the 40 (medium, default) threshold. Using these thresholds, sensitivity, and overall accuracy of GENEActiv were both good (86% and 78%, respectively), however specificity was relatively low (40%). There were no significant inter-device differences for any sleep parameters, and all absolute mean biases were small. Overall, the findings from this study provide the first empirical evidence to support the reliability of GENEActiv against Actiwatch-2 over multiple nights using a common algorithm with device-specific wake thresholds.

Background: We have investigated the role of a cardiomyokine, follistatin-like 1 (FSTL1), and its single nucleotide polymorphism on acromegalic cardiomyopathy., Methods: The study was performed as a cross-sectional case research in a Tertiary Referral Centre. Forty-six patients with acromegaly (29 F-17 M, mean age: 50.3 ± 12.1 years) were included. FSTL1 levels were measured and the rs1259293 region of the FSTL1 gene was subjected to polymorphism analysis. 1.5 Tesla MRI was used to obtain cardiac images., Results: There were 15 active (6 F-9M) and 31 (22 F-9M) controlled patients. Active patients had a higher left ventricular mass (LVM) and left ventricular mass index (LVMi). GH levels were positively correlated with left ventricular end-diastolic volume index (LVEDVi), stroke volume index (SVi), cardiac index (Ci), LVM and LVMi; r  = 0.35, 0.38, 0.34, 0.39 and 0.39, respectively. IGF-1 index was positively correlated with LVEDVi, left ventricular end-systolic volume index (LVESVi), SVi, Ci, LVM and LVMi; r  = 0.36, 0.34, 0.32, 0.31, 0.42 and 0.42, respectively. Twenty out of 46 patients with acromegaly (43.5%) had myocardial fibrosis. FSTL1 levels were neither correlated with disease activity nor with any functional and structural cardiac parameter. Multivariate linear regression analysis revealed no association between FSTL1 and any study parameters. The rs1259293 variant genotype CC was significantly associated with low left ventricular mass., Conclusions: Serum FSTL1 levels are not associated with functional and structural measures of myocardium in patients with acromegaly. However, the risk of left ventricular hypertrophy is reduced in CC genotyped individuals of FSTL1.

Objective: This study aimed to examine patients with lead poisoning in terms of metabolomic profiles and bioactive lipids (oxysterols and sphingosine 1-phosphate [S1P]) before and after chelation therapy., Methods: Consent was obtained from 42 individuals diagnosed with lead poisoning and blood and urine samples were collected before and after chelation therapy. The levels of 7-ketocholesterol (7-KC), cholestan-3b,5a,6b-triol (Ctriol), and S1P were measured via LC-MS/MS. Metabolomic analysis was performed via GC-MS., Results: 7-KC and C-triol levels were detected higher before chelation therapy compared with after therapy (P < 0.001 for both). S1P levels were measured higher before the therapy. The results also showed that sphingolipid metabolism-related pathways were affected by lead toxicity as well as other related pathways., Conclusion: This preliminary study showed that lipid metabolism is affected in lead exposure and chelation therapy is effective in reversing possible damage., Competing Interests: Conflict of interest: All the authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 American College of Occupational and Environmental Medicine.)

We investigated plasma YKL-40 levels and chitotriosidase (CHIT1) activity in patients with cystic fibrosis (CF) lung disease and evaluated clinically relevant factors that may affect their levels. Plasma samples were obtained from pediatric (n = 19) and adult patients (n = 15) during exacerbation, discharge, and stable period of the disease. YKL-40 levels and chitotriosidase activity were measured by enzyme-linked immunosorbent assay and fluorometric assay, respectively. Data were compared with healthy children and adults of similar age. YKL-40 levels of pediatric and adult CF patients at all periods were significantly higher than controls (p < 0.001 and p < 0.05). CHIT1 activities of adult patients at all periods were significantly higher compared to controls (p < 0.05). On the other hand, CHIT1 activities of pediatric CF patients were similar with controls. YKL-40 levels of exacerbation period of adult CF patients were negatively correlated with forced vital capacity (FVC) (r =  - 0.800, p = 0.014) and forced expiratory volume in 1 s (FEV1) (r =  - 0.735, p = 0.008). YKL-40 levels in the exacerbation period of pediatric CF patients were negatively correlated with FVC (r =  - 0.697, p = 0.0082) and FEV1 (r =  - 0.720, p = 0.006). CHIT1 activity may be a valuable marker of chronic inflammation in adult CF patients who suffer from CF for a longer period compared to pediatric patients. Increased YKL-40 levels in both pediatric and adult patients compared to controls may point to a role in between CF pathology., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Oxidative stress is associated with various disease pathologies including Inborn Errors of Metabolism (IEMs), among the most important causes of childhood morbidity and mortality. At least as much as oxidative stress in cells, reductive stress poses a danger to the disruption of cell homeostasis. p62/SQSTM1, protects cells from stress by activation of Nrf2/Keap1 and autophagy pathways. In this study, we tested the role of cellular stress, mitochondrial dysfunction and autophagy via Nrf2/Keap1/p62 pathway in the pathophysiology of three main groups of IEMs. Our results showed that antioxidant and oxidant capacity alone would not be sufficient to reflect the true clinical picture of these diseases. ATP, ROS and mitochondrial membrane potantial (MMP) measurements demonstrated increased cellular stress and bioenergetic imbalance in methylmalonic acidemia (MMA), indicating mild mitochondrial dysfunction. In isovaleric acidemia (IVA), no major change was detected in ATP, ROS and MMP values. Propionic acidemia (PA), mitochondrial diseases (MIT) and mucopolysaccharidosis IV (MPS IV) might point out mitohormesis to cope with chronic reductive stress. Induction of Nrf2/Keap1/p62 pathway and increased expression of HMOX1 were detected in all IEMs. LC3B-II and p62 expression results indicated an impaired autophagic flux in MIT and MPS IV and an induction of autophagic flux in MMA, PA and IVA, but also partial expression of Beclin1, enables autophagy activation, was detected in all IEMs. We conclude that individual diagnosis and treatments are of great importance in IEMs. In addition, we assume that the application of therapeutic antioxidant or preventive treatments without determining the cellular stress status in IEMs may disrupt the sensitive oxidant-antioxidant balance in the cell, leading to the potential to further disrupt the clinical picture, especially in patients with reductive stress. To the best of our knowledge, this is the first study to simultaneously relate IEMs with cellular stress, mitochondrial dysfunction, and autophagy., (Copyright © 2021. Published by Elsevier Inc.)

This study aims to examine the acute and short-term effects of prebiotics, probiotics, and their combination on appetite, energy intake and satiety related hormones in two phases. The first phase was a randomized, double blind, placebo controlled crossover study. Prebiotic (16 g inulin), probiotic (Lactobacillus paracasei subsp. paracasei 431 (L. casei 431) (>10 6  cfu/ml), synbiotic (their combination) and control (16 g maltodextrin) dairy drinks were consumed by 16 healthy men with a standard breakfast on four separate test days, and the following satiety responses and ad libitum food intake at lunch and over 24 h were assessed. In the second phase, the effects of 21 days of synbiotic (n = 10) or control (n = 11) drink consumption on appetite sensation, energy intake, serum glucose, insulin, peptide YY, ghrelin, obestatin and adiponectin concentration were assessed in a randomized double-blind placebo-controlled design. In the first phase, energy intake values during ad libitum lunch were the lowest in the prebiotic drink, followed by probiotic, synbiotic and control drinks, respectively (p = 0.017); also the rest of the day and 24-h dietary energy intake was lower by prebiotic and probiotic drinks compared to the control drink (p < 0.05 for each). For short-term effects, no significant difference in anthropometric measurements, hunger-satiety scores and serum glucose, insulin, PYY, ghrelin, obestatin and adiponectin concentrations were recorded. Despite the potential of prebiotics and probiotics to reduce energy intake, further studies are required for a better understanding of their role in satiety related mechanisms., Competing Interests: Declaration of competing interest The authors declare no conflict of interest in the content of this study., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Previous studies have pointed out a link between vitamin D status and metabolic traits, however, consistent evidence has not been provided yet. This cross-sectional study has used a nutrigenetic approach to investigate the interaction between metabolic-genetic risk score (GRS) and dietary intake on serum 25-hydroxyvitamin D [25(OH)D] concentrations in 396 unrelated Turkish adults, aged 24-50 years. Serum 25(OH)D concentration was significantly lower in those with a metabolic-GRS ≥ 1 risk allele than those with a metabolic-GRS < 1 risk allele ( p = 0.020). A significant interaction between metabolic-GRS and dietary fat intake (energy%) on serum 25(OH)D levels was identified ( P interaction = 0.040). Participants carrying a metabolic-GRS ≥ 1 risk allele and consuming a high fat diet (≥38% of energy = 122.3 ± 52.51 g/day) had significantly lower serum 25(OH)D concentration ( p = 0.006) in comparison to those consuming a low-fat diet (<38% of energy = 82.5 ± 37.36 g/d). In conclusion, our study suggests a novel interaction between metabolic-GRS and dietary fat intake on serum 25(OH)D level, which emphasises that following the current dietary fat intake recommendation (<35% total fat) could be important in reducing the prevalence of vitamin D deficiency in this Turkish population. Nevertheless, further larger studies are needed to verify this interaction, before implementing personalized dietary recommendations for the maintenance of optimal vitamin D status.

Disorders of intracellular trafficking are a group of inherited disorders, which often display multisystem phenotypes. Vacuolar protein sorting (VPS) subunit C, composed of VPS11, VPS18, VPS16, and VPS33A proteins, is involved in tethering of endosomes, lysosomes, and autophagosomes. Our group and others have previously described patients with a specific homozygous missense VPS33A variant, exhibiting a storage disease phenotype resembling mucopolysaccharidosis (MPS), termed "MPS-plus syndrome." Here, we report two siblings from a consanguineous Turkish-Arabic family, who have overlapping features of MPS and intracellular trafficking disorders, including short stature, coarse facies, developmental delay, peripheral neuropathy, splenomegaly, spondylar dysplasia, congenital neutropenia, and high-normal glycosaminoglycan excretion. Whole exome sequencing and familial segregation analyses led to the homozygous NM&#95;022575.3:c.540G>T; p.Trp180Cys variant in VPS16 in both siblings. Multiple bioinformatic methods supported the pathogenicity of this variant. Different monoallelic null VPS16 variants and a homozygous missense VPS16 variant had been previously associated with dystonia. A biallelic intronic, probably splice-altering variant in VPS16, causing an MPS-plus syndrome-like disease has been very recently reported in two individuals. The siblings presented herein display no dystonia, but have features of a multisystem storage disorder, representing a novel MPS-plus syndrome-like disease, associated for the first time with VPS16 missense variants., (© 2021 John Wiley & Sons A/S . Published by John Wiley & Sons Ltd.)

Background: Auto-oxidized oxysterols are implicated in the pathogenesis of various chronic diseases. Their concentrations are indicators of oxidative stress in vivo and associated with atherosclerosis. Subclinical hypothyroidism is related with cardiac diseases and oxidative stress, but the exact mechanisms underlying these associations are not clear yet., Objective: To investigate the auto-oxidized oxysterols, 7-ketocholesterol (7-KC) and cholestane-3β,5α,6β-triol (chol-triol), in patients with subclinical hypothyroidism, as well as to evaluate the impact of restoring euthyroidism on oxysterol concentrations., Methods: In this prospective observational study, 64 patients with newly diagnosed autoimmune thyroiditis (41 with subclinical hypothyroidism and 23 euthyroidism), and 45 healthy controls were enrolled. Age, gender, and body mass index were matched among patient groups and healthy controls. Anthropometric measurements were obtained and fasting plasma 7-ketocholesterol and cholestane-3β,5α,6β-triol concentrations were measured by using liquid chromatography coupled with tandem mass spectrometry. Levothyroxine was then administered to all patients with subclinical-hypothyroidism. After three months, measurements of the oxysterols and serum cholesterols from the patients who have become euthyroid were repeated., Results: Concentrations of 7-ketocholesterol and cholestane-3β,5α,6β-triol were significantly higher in patients with subclinical-hypothyroidism when compared to both euthyroid patients and healthy controls (p < 0.001 for both oxysterols). After restoration of euthyroidism, concentrations of 7-ketocholesterol and cholestane-3β,5α,6β-triol decreased significantly and reached similar concentrations observed in healthy controls (p < 0.001 for both oxysterols)., Conclusions: Auto-oxidized oxysterol species are higher in patients with mild thyroid dysfunction, and supported the rationale for treating subclinical-hypothyroidism., (Copyright © 2021 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

The aim of the study was to investigate whether lifestyle factors modify the association between fat mass and obesity-associated (FTO) gene single nucleotide polymorphisms (SNPs) and obesity in a Turkish population. The study included 400 unrelated individuals, aged 24-50 years recruited in a hospital setting. Dietary intake and physical activity were assessed using 24-hour dietary recall and self-report questionnaire, respectively. A genetic risk score (GRS) was developed using FTO SNPs, rs9939609 and rs10163409. Body mass index and fat mass index were significantly associated with FTO SNP rs9939609 ( p  = 0.001 and p  = 0.002, respectively) and GRS ( p  = 0.002 and p  = 0.003, respectively). The interactions between SNP rs9939609 and physical activity on adiponectin concentrations, and SNP rs10163409 and dietary protein intake on increased waist circumference were statistically significant ( P interaction  = 0.027 and P interaction  = 0.044, respectively). Our study has demonstrated that the association between FTO SNPs and central obesity might be modified by lifestyle factors in this Turkish population.

Background: Klotho is a new identified anti-ageing gene with tumour suppressor activities. Current data suggest that there is a tight relationship between Klotho protein and growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis., Purpose: This study aimed to investigate the possible association of Klotho gene polymorphisms with acromegaly and to assess whether these polymorphisms contribute to clinical characteristics, comorbidities and biochemical variables in these patients., Methods: The study included 52 patients with acromegaly and 52 unrelated healthy subjects. The Klotho G395A and C1818T polymorphisms were assessed by Sanger sequencing. Serum levels of sKlotho were determined by ELISA method., Results: Subjects carrying GA genotype of Klotho G395A polymorphism had 3.27 times higher risk of developing acromegaly [odds ratio (OR), 3.27; 95% confidence interval (CI): 1.37-7.81; p = .023]. The A allele of G395A was significantly associated with acromegaly risk (OR, 2.27; 95% CI: 1.1-4.72; p = .022). No association was observed between the studied polymorphisms and disease characteristics including age at acromegaly diagnosis, size of adenoma, baseline GH and IGF-1 concentrations, and final outcome. G395A polymorphism was associated with the presence of malignancy (OR, 2.24, 95% CI: 1.63-3.08; p = .019) and colorectal polyps (OR, 1.99; 95% CI: 1.02-3.88; p = .047) in patients with acromegaly. Serum sKlotho levels were significantly higher and correlated with GH and IGF-1 levels among acromegaly patients. There was no association between the studied polymorphisms and sKlotho levels., Conclusions: Klotho G395A polymorphism is associated with acromegaly susceptibility and increased risk of malignancy and colorectal polyps in these patients., (© 2020 John Wiley & Sons Ltd.)

Background: Oligosaccharidoses are storage disorders due to enzymatic defects involved in the breakdown of the oligosaccharidic component of glycosylated proteins. The defect cause the accumulation of oligosaccharides (OS) and, depending on the lacking enzyme, results in characteristic profiles which are helpful for the diagnosis. We developed a new tandem mass spectrometry method for the screening of urinary OS which was applied to identify a large panel of storage disorders., Methods: The method was set-up in urine and dried urine spots (DUS). Samples were analysed, without derivatization and using maltoheptaose as internal standard, by UHPLC-MS/MS with MRM acquisition of target OS transitions, including Glc4, the biomarker of Pompe disease. The chromatographic run was < 30 min. Samples from patients with known storage disorders were used for clinical validation., Results: The method allowed to confirm the diagnosis of oligosaccharidoses (sialidosis, α-/β-mannosidosis, fucosidosis, aspartylglucosaminuria) and of GM1 and GM2 (Sandhoff type) gangliosidosis, by detecting specific OS profiles. In other storage disorders (mucolipidosis II and III, mucopolysaccharidosis type IVB) the analyisis revealed abnormal OS excretion with non-specific profiles. Besides Pompe disease, the tetrasaccharide Glc4 was increased also in disorders of autophagy (Vici syndrome, Yunis-Varon syndrome, and Danon disease) presenting cardiomuscular involvement with glycogen storage. Overall, results showed a clear separation between patients and controls, both in urine and in DUS., Conclusion: This new UHPLC/MS-MS method, which is suitable for rapid and easy screening of OS in urine and DUS, expands the detection of storage disorders from oligosaccharidoses to other diseases, including the novel category of inherited disorders of autophagy.

The present review aims to provide a complete and comprehensive summary of current literature relevant to oxysterols and related diseases. Oxidation of cholesterol leads to the formation of a large number of oxidized products, generally known as oxysterols. They are intermediates in the biosynthesis of bile acids, steroid hormones, and 1,25- dihydroxyvitamin D3. Although oxysterols are considered as metabolic intermediates, there is a growing body of evidence that many of them are bioactive, and their absence or excess may be part of the cause of a disease phenotype. These compounds derive from either enzymatic or non-enzymatic oxidation of cholesterol. This study provides comprehensive information about the structures, formation, and types of oxysterols even when involved in certain disease states, focusing on their effects on metabolism and linkages with these diseases. The role of specific oxysterols as mediators in various disorders, such as degenerative (age-related) and cancer-related disorders, has now become clearer. Oxysterol levels may be employed as suitable markers for the diagnosis of specific diseases or in predicting the incidence rate of diseases, such as diabetes mellitus, Alzheimer's disease, multiple sclerosis, osteoporosis, lung cancer, breast cancer, and infertility. However, further investigations may be required to confirm these mentioned possibilities., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: IgA vasculitis (IgAV) is the most common vasculitis of childhood. Renal involvement defines late morbidity of the disease. A better understanding of the pathophysiology of the progression to kidney disease and predictive biomarkers are required for better management of IgAV and its nephritis (IgAVN)., Objectives: An untargeted metabolomics approach was performed to reveal the underlying molecular mechanism of disease pathogenesis and to define potential biomarkers from plasma samples from IgAV and IgAVN patients., Methods: Forty-five active IgAV patients (H) and six healthy controls (C) were enrolled in the study. Plasma samples were collected on the same day of diagnosis and before any immunosuppressive treatment was initiated. At the time of diagnosis and sample collection, none of the patients had renal involvement. We used Quadrupole Time of Flight Mass Spectrometry (Q-TOF LC/MS) to investigate the alterations in plasma metabolomic profiles. Three separate pools were created: healthy controls (group C), active IgAV patients who did not develop renal involvement (group H), and patients who developed IgAVN at follow up (group N). Peak picking, grouping, and comparison parts were performed via XCMS (https://xcmsonline.scripps.edu/) software., Results: At follow-up, IgAVN developed in 6 out of 45 IgAV patients. The median time of renal involvement development is 23 days (range 5-45 days). Of these, 3 had nephritic proteinuria, one had nephrotic proteinuria, and 2 had microscopic hematuria. There were no significant differences in gender, age, clinical manifestations, and laboratory findings between the six patients who developed renal involvement and those who did not. In multivariate analysis, there was no significant association between any of the defined demographic and clinical characteristics (male sex, gastrointestinal system involvement, joint involvement, CRP, WBC, PLT) and the occurrence of renal involvement. Totally 2618 peaks were detected for group H, N, and C. Among them, 355 peaks were found to be statistically significant and reliable (p<0.05), and 155 of these peaks were found to be changed (fold change >1.5) between the groups C and H, and 66 peaks were found to be changed (fold change >1.5) between the groups H and N. The number of the peaks on the intersection of the peaks found to be different between the groups (C and H) and (H and N) was 39. Based on putative identification results, 15 putatively identified metabolites matched with 11 peaks were presented as biomarker candidates after careful evaluation with a clinical perspective., Conclusion: We suggest that DHAP (18:0), prostaglandin D2/I2, porphobilinogen, 5-methyltetrahydrofolic acid, and N-Acetyl-4-O-acetylneuraminic acid/N-Acetyl-7-O-acetylneuraminic acid may serve as biomarkers for predicting kidney disease. Future studies with larger groups of IgAV patients are needed to validate the identified metabolic profile., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objectives: The calcium-sensing receptor (CaSR), the major sensor of extracellular Ca 2+ , is expressed in various tissues, including the gastrointestinal tract. Although the essential ligand of CaSR is calcium, its activity can be regulated by aromatic L-amino acids. The expression of CaSR on enteroendocrine cells suggests that CaSR functions as a physiological amino acid sensor for gut hormone release. Here, we investigated the effects of L-tryptophan (L-Trp) on rat glucagon-like peptide-1 (GLP-1), peptide YY (PYY), and insulin secretion, and the role of CaSR in this mechanism in vivo . Methods: The effects of intraduodenal L-Trp on GLP-1, PYY, and insulin secretion were investigated. A CaSR antagonist, NPS 2143, was administered to determine whether CaSR plays a role in L-Trp-mediated gut hormone release. Male Wistar rats were divided into L-Trp, L-Trp+NPS 2143, and L-Trp+vehicle groups. Blood samples were collected, before and after the intraduodenal infusions, for determining plasma glucose, L-Trp, insulin, GLP-1, and PYY levels. Results: Our study showed a significant increase in plasma GLP-1 and insulin levels, but not plasma PYY and glucose levels, following the acute intraduodenal administration of L-Trp. We demonstrated that CaSR plays a role in L-Trp-mediated GLP-1 secretion due to attenuation of GLP-1 release with the CaSR antagonist NPS 2143. Discussion : We demonstrated that GLP-1, but not PYY, secretion following intraduodenal L-Trp administration was mediated through calcium-sensing receptors. This mechanism underlying protein sensing in the gastrointestinal system may be important for the development of new therapeutic strategies without side effects for obesity and diabetes.

Background: The present study has the objective to assess the zinc (Zn), copper (Cu), and oxysterols plasma levels in type 1 (DM1) (n = 26) and type 2 (DM2) (n = 80) diabetes patients, as compared to healthy controls (n = 71), in order to testify whether metal levels may have a significant impact on the association between oxysterols and diabetes., Methods: Plasma trace elements and plasma oxysterols were assessed using atomic absorption spectrometry and LC-MS/MS, respectively. Lifestyle, smoking status, alcohol intake, and drug usage, as well as microvascular complications, were also monitored and reported., Results: The obtained data demonstrated that both DM1 and DM2 patients were characterized by significantly elevated HbA1c, FBG, TC, LDL-C, VLDL-C, and TG levels as compared to controls. Plasma Zn levels and Zn/Cu ratio in DM1 and DM2 patients were about 3- and 2-fold lower than controls. No significant differences in plasma Cu levels were reported. The 7-ketocholesterol (7-kchol) levels in DM1 and DM2 patients exceeded these values in healthy individuals by 2.5 and 5-fold, respectively. Similarly, cholestan-3β, 5α, 6β-triol (chol-triol) levels were more than 3- and 6-fold higher when compared to the respective values in non-diabetic controls. In regression models decreased plasma Zn and elevated oxysterol levels were significantly associated with HbA1c and fasting plasma glucose levels, after adjustment for anthropometric and clinical variables, as well as routine biochemical markers., Conclusions: Plasma Zn concentration is inversely associated with both 7-kchol and chol-triol levels. Assessment of Zn and oxysterol levels may be used both for risk assessment and as targets for the treatment of diabetes mellitus., (Copyright © 2019 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Background: Apoptosis inhibitor of macrophage (AIM) and monocyte chemotactic protein-1 (MCP-1) are molecules that cause migration of M1 macrophages to visceral adipocytes, which is the first step in development of metabolic syndrome. The aim of this study is to evaluate the status of AIM and MCP-1 in metabolic syndrome and to investigate their use as biomarkers. Methods: Forty metabolic syndrome patients and 40 healthy individuals were enrolled in the study. Serum AIM, MCP-1, and C-reactive protein (CRP) levels were measured by enzyme-linked immunosorbent assay. Results: AIM, MCP-1, and CRP levels were significantly higher in the metabolic syndrome group ( P  < 0.01, P  < 0.01, and P  < 0.05, respectively). There was a positive correlation of serum AIM, MCP-1, and CRP levels with waist circumference ( r  = 0.480, r  = 0.663, and r  = 0.418, respectively; P  < 0.01). Receiver operating characteristic (ROC) curve analyses revealed AIM, MCP-1, and CRP cutoff points as 2383.7 ng/mL, 172.8 pg/mL, and 0.366 mg/dL, which could be used in the diagnosis of metabolic syndrome with highest sensitivity and specificity. In the logistic regression model, including age, AIM, CRP, and MCP-1 as covariates, having serum AIM and CRP levels above cutoffs were significant independent predictors for metabolic syndrome (odds ratios 13.8 and 21.3), whereas the serum MCP-1 level was not a significant independent predictor, although the odds ratio was 2.6 ( P  = 0.193). Conclusions: These results suggest that AIM and MCP-1 may play a role in the pathogenesis of metabolic syndrome. AIM and CRP levels may be used as biomarkers in the diagnosis of metabolic syndrome. Although MCP-1 is not an independent predictor, its elevation in metabolic syndrome is noteworthy, which warrants further analyses in larger groups.

We investigated plasma sphingomyelin (CerPCho) and ceramide (Cer) levels in pediatric patients with cystic fibrosis (CF) and primary ciliary dyskinesia (PCD). Plasma samples were obtained from CF (n = 19) and PCD (n = 7) patients at exacerbation, discharge, and stable periods. Healthy children (n = 17) of similar age served as control. Levels of 16-24 CerPCho and 16-24 Cer were measured by LC-MS/MS. Concentrations of all CerPCho and Cer species measured at exacerbation were significantly lower in patients with CF than PCD. 16, 18, 24 CerPCho, and 22, 24 Cer in exacerbation; 18, 24 CerPCho, and 18, 20, 22, 24 Cer at discharge; 18, 24 CerPCho and 24 Cer at stable period were significantly lower in CF patients than healthy children (p < 0.001 and p < 0.05). All CerPCho and Cer levels of PCD patients were significantly higher except 24 CerPCho and 24 Cer during exacerbation, 24 CerPCho at discharge, and 18, 22 CerPCho levels at stable period (p < 0.001 and p < 0.05) compared with healthy children. There was no significant difference among exacerbation, discharge, and stable periods in each group for Cer and CerPCho levels. This is the first study measuring plasma Cer and CerPCho levels in PCD and third study in CF patients. The dramatic difference in plasma levels of most CerPCho and Cer species found between two diseases suggest that cilia pathology in PCD and CFTR mutation in CF seem to alter sphingolipid metabolism possibly in opposite directions., (© 2020 AOCS.)

Silicosis is one of the prolonged and irreversible occupational diseases. Crystalline silica dust, which has been linked with silicosis, occurs in different industrial areas such as constructions, ceramic, quarry, and pottery. There are significant numbers of newly diagnosed cases every year in Turkey. Patients with silicosis suffer from inflammatory respiratory disorders and silicosis-related complications such as rheumatoid arthritis, systemic sclerosis, and vasculitis. Oxysterols are defined as 27-carbon intermediates or end products of cholesterol. They are also implicated in the etiology of disease states such as atherosclerosis, neurodegenerative, and inflammatory diseases. The aim of the study is to evaluate cholesterol oxidation products in the patients with silicosis and determination of sphingosine-1-phosphate (S1P) levels which is a sphingolipid metabolite. In addition to these parameters, it is aimed to determine the possible lipid peroxidation by different parameters. For this purpose, blood samples and urine were collected from 47 patients and 30 healthy individual with their consents. In order to evaluate oxysterols, 7-ketocholesterol and cholestan 3β,5α,6β-triol levels were measured by LC-MS/MS method. The measured levels of 7-KC were 0.101 ± 0.005 µmol/l in patient and 0.050 ± 0.003 µmol/l in control plasma samples. Triol levels were measured as 0.038 ± 0.005 µmol/l in patient group and 0.033 ± 0.004 µmol/l in control group (p < 0.001). In addition, lipid peroxidation products were measured by human-8-isoprostane, human-4-hydroxynonenal (4-HNE), and human malondialdehyde (MDA) ELISA kits. The measured levels of HNE in the patient and control groups were 735.14 ± 288.80 pg/ml and 595.72 ± 108.62 pg/ml in plasma and 606.02 + 118.23 pg/ml and 531.84 + 107.18 pg/ml in urine, respectively (p < 0.05). F2-iP results of patients and controls were 450.0 + 101.40 pg/dl and 386.9 + 112.7 pg/ml for urine and 432.7 ± 188,8 pg/dl and 321.9 ± 69.4 pg/dl for plasma, respectively (p < 0.05). MDA levels of plasma were measured as 44.1 ± 14.6 nmol/ml in the patient and 31.9 ± 10.5 nmol/ml in the control (p < 0.05). Levels of MDA for urine samples were 30.15 + 5.06 nmol/ml and 25.15 + 6.07 nmol/ml in patients and controls, respectively (p < 0.05). S1P levels were decreased in patients compared to control group (49.05 ± 10.87 and 67.57 ± 16.25, p < 0.001). The results not only indicate a correlation between cholesterol oxidation, lipid peroxidation, and silicosis, but also provide better understanding of the role of the lipids in the mechanism of this inflammatory disease.

Purpose: The relationship of plasma malondialdehyde (MDA) with major parameters of PSG was investigated to find out if there was a correlation between these variables., Methods: Polysomnograms were done on a total of 37 adults who do not have a history of any systemic illness, smoking, and supplement use. Plasma MDA measurements and their relationship with PSG parameters were analyzed., Results: The mean MDA concentrations in patients with lower AHI values were also lower than those in the patients with higher AHI (p < 0.001). Higher predominance of apnea in patients with similar AHI values, longer mean apnea durations, O 2 saturation dips to < 90%, and higher ODI values predicted higher plasma MDA concentrations., Conclusions: Higher oxidative stress measurements predicted more severe clinical picture. These findings show that oxidative stress measurement with MDA may provide a simple tool to screen patients for OSA and help select them for PSG study appropriately, if indicated.

Sickle cell disease (SCD) causes anemia, oxidative stress, chronic inflammation, and lipid abnormalities. Oxysterols are oxidized derivatives of cholesterol and affect cholesterol metabolism and eryptosis. Our aim was to determine whether the plasma concentrations of 7-ketocholesterol (7-KC) and cholestane-3β,5α,6β-triol (C-triol) were associated with hemolysis and lipid profile in patients with SCD. A total of 32 steady-state pediatric patients with SCD (22 HbSS and 10 HbSß + ) and 25 healthy controls were included in the study. Hemolysis parameters, ferritin, serum iron, lipids, 7-KC and C-triol concentrations of all subjects were measured. Oxysterols were quantified with N,N-dimethylglycine derivatization via LC-MS/MS. 7-KC and C-triol concentrations were found to be increased in SCD patients, while there was no difference between the HbSS and HbSß + subgroups. 7-KC concentrations s were correlated negatively with hemoglobin and positively with lactate dehydrogenase concentrations, while C-triol concentrations were negatively correlated with HDL cholesterol. Furthermore, while 7-KC and C-triol concentrations were highly correlated among controls, there was no correlation in patients. The findings of our study suggest that 7-KC and C-triol may have a role in SCD pathophysiology. The lack of correlation in patients' 7-KC and C-triol concentrations suggest alterations in oxysterol production in patients with SCD.

Background: Rosacea is a chronic disease that is characterized by facial skin inflammation and vascular abnormality. Vascular endothelial growth factor (VEGF) is a potent mediator of vascular permeability and inflammation that might play a role in the pathogenesis of rosacea., Objective: This study aimed to determine the association between VEGF gene polymorphisms and rosacea., Methods: A case-control study design was used to compare 100 patients with rosacea and 100 age- and gender-matched control subjects in terms of VEGF polymorphisms based on polymerase chain reaction and the serum level of VEGF and VEGF receptors based on enzyme-linked immunosorbent assay., Results: Heterozygous and homozygous +405C/G polymorphism of the VEGF gene was observed to increase the risk of rosacea 1.7-fold (95% confidence interval 1.2-4.2) and 2.3-fold (95% confidence interval 1.2-4.2), respectively. There was a significant positive correlation between the severity of rosacea and +405C/G polymorphism of the VEGF gene in patients with erythematotelangiectatic rosacea., Limitations: Serum VEGF and VEGF receptor levels were measured in the limited number of patients., Conclusion: The present findings indicate that +405C/G polymorphism of the VEGF gene increases the risk of rosacea., (Copyright © 2019 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Oxysterols have been shown to play a role in plaque formation while ischemia modified albumin (IMA) is widely accepted as an acute marker for ischemia. The effort test is one of the methods used to identify the presence of coronary artery disease. Thus, there may be a relationship between effort test result and the levels of IMA, 7-ketocholesterol (7-KC) and cholestane-3β,5α,6β-triol (C-triol)., Methods: Thirty patients who underwent effort test and 30 healthy subjects were included in the study. IMA levels were determined with the albumin-cobalt binding test, 7-KC and C-triol levels were determined with LC-MS/MS. Among the patients, two subgroups were identified according to the results of the effort test, group 1 consisted of patients with a positive effort test (n = 12), and group 2 consisted of patients who had a negative effort test (n = 18)., Results: 7-KC levels of patients were significantly higher compared to healthy subjects (39.87 ± 2.13 ng/mL, 20.26 ± 1.35 ng/mL; p=0.001). In patients, post-test 7-KC levels were significantly lower than pre-test levels (post-test vs. pre-test: 37.73 ± 2.44 ng/mL vs. 41.07 ± 2.18 ng/mL; p<0.001). There was a significant difference in post-test 7-KC levels among all study groups (negative, positive and healthy: 37.73 ± 2.44 ng/mL, 39.87 ± 2.13 ng/mL, 20.26 ± 1.35 ng/mL, respectively). There was no significant difference in IMA levels., Conclusions: Patients with positive effort test had significantly higher levels of 7-KC. Additionally, after the effort test, the 7-KC value was reduced. 7-KC is a biomarker of oxidative damage and its value or changes before and after the effort test may be used as a biomarker in the diagnosis and follow-up of coronary artery disease., Competing Interests: Conflict of interest Conflict of interest statement: The authors stated that they have no conflicts of interest regarding the publication of this article.

Comprehensive analytical and diagnostic performance of urinary quantitative GAG analysis with dimethylmethylene blue (DMB) and the age-specific reference ranges were determined in Turkish population, which has a high incidence of MPSs. Precision, linearity, recovery and accuracy/trueness, limits, stability, and effect of interferents were tested according to CLSI guideline. Clinical performance was evaluated with ROC analyses including 45 MPS patients. Intra-day and inter-day precisions were <5% and <11% (CV), respectively. LoD was 9.12mg/L and LoQ was 23.3mg/L. The highest reference values for urinary GAG excretion were determined in an age-specific manner. In the 2-13years age cohort, a cut-off of 89.86mg/g creatinine resulted in 98.07% sensitivity and 93.33% specificity. Proteinuria and hematuria interfered with analysis in some instances. Neither leukocyturia nor pH changes affected the assay. Stability analysis indicated that freezing urine samples for transfer is unnecessary. Of the 45 MPS patient samples evaluated, only three tested negative including MPS II, IVA and VI. Despite limitations due to low levels of urinary GAG excretion in some cases, urinary GAG analysis with DMB with its technical simplicity, low cost, and precise quantitative results, is a valuable screening method, particularly in populations with a high rate of MPSs., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background: Evidence regarding the vascular endothelial growth factor A (VEGFA) as a potent mediator of angiogenesis and inflammation in psoriasis has revealed variations in this gene as surrogate markers of psoriasis., Objective: VEGFA gene polymorphisms (-1540 C/A, -1512 Ins18, -460 T/C, and +405 C/G) in psoriasis susceptibility in Turkish population were investigated., Methods: A total of 200 age, sex and ethnicity-matched psoriatic and healthy individuals were examined for clinical type, response to therapy, serum VEGFA and its receptor levels, genotypes and haplotypes., Results: The +405 GG, +405 CG, -1540 CA, and -1512 +Ins18 genotypes conferred a significant risk for developing psoriasis. The C-InsTC haplotype in the controls and C+InsTG, A+InsTC, and A-InsTG haplotypes in psoriatic patients were observed to be significantly high. Increased serum levels of VEGFA were detected in psoriatic patients with the C-InsTC haplotype than that in the controls. The +405 GG genotype was significantly more frequent in psoriatic patients with a positive family history, and the moderate form of psoriasis was more frequent among C+InsTG haplotype carriers than that among the other patients. The +405 GG genotype was found to be more frequent in patients responding to oral retinoids. Serum VEGFR1/FLT1 and VEGFR2/KDR levels were not significantly different when psoriatic patients and controls were stratified based on the risk polymorphic variants., Conclusion: VEGFA gene +405 GG and CG, -1512+Ins18, and -1540 CA genotypes are associated with an increased risk of psoriasis in Turkish population. The G allele at +405 and an 18-bp insertion at -1512 are primarily the risk factors for psoriasis, and this risk is potentiated by the presence of the A allele at the -1540 locus.