Search

Abstract Bariatric surgery is an approved treatment for obesity that consistently improves metabolic syndrome, with well-documented beneficial effects on dyslipidemia, cardiovascular risk, nonalcoholic fatty liver disease and glucose homeostasis. In this study, we determined the differential expression genes in three periods after bariatric surgery: short-term (4-months), medium-term (1- and 2-years), and long-term (5-years) periods. Two microarray profiles were downloaded from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were identified by comparing the expression of adipose tissue genes before surgery compared to short, medium and long-term periods following surgery. Shared DEGs for the medium-term were evaluated by comparing the DEGs for both 1 and 2 years. 165, 65, and 59 DEGs were identified in short–medium–long periods. The protein–protein interactions were analyzed by STRING. A co-expression network was constructed by mapping the DEGs onto the GeneMANIA plugin of Cytoscape. Gene Ontology (GO) enrichment, Kyoto Encyclopedia of Genes and Genomes (KEGG) and wikipathway analysis were done for each group of DEGs. Interleukin-8 receptor activity, complement receptor activity and opsonin receptor activity/N-formyl peptide receptor activity in GO Function enrichment and cellular response to interleukin-8, positive regulation of hippocampal neuron apoptotic process, and positive regulation of hippocampal neuron apoptotic process in GO Process showed the best scores in short-, medium-, and long-term periods, respectively. Eight genes, including CCL2 (Chemokine ligand 2), CXCR4 (CXC motif chemokine receptor 4), EGR2 (Early Growth Response 2), FPR1 (Formyl Peptide Receptor 1), IL6 (interleukin-6), RGS2 (regulator of gene protein signaling2), SELPLG (Selectin P Ligand), and THBS1 (Thrombospondin 1) were identified as shared DEGs in the three periods after surgery. Importantly, results of DAVID database analysis showed 7, 6, 4, and 4 of these genes have roles in immune/ cancer/cardiovascular diseases, type 2 diabetes, myocardial infarct, and atherosclerosis, respectively.

Abstract The classical androgens, testosterone and dihydrotestosterone, together with dehydroepiandrosterone, the precusrsor to all androgens, are generally included in diagnostic steroid evaluations of androgen excess and deficiency disorders and monitored in androgen replacement and androgen suppressive therapies. The C11-oxy androgens also contribute to androgen excess disorders and are still often excluded from clinical and research-based steroids analysis. The contribution of the C11-oxy androgens to the androgen pool has not been considered in androgen deficiency. An exploratory investigation into circulating adrenal and gonadal steroid hormones in men was undertaken as neither the classical androgens nor the C11-oxy androgens have been evaluated in the context of concurrent measurement of all adrenal steroid hormones. Serum androgens, mineralocorticoids, glucocorticoids, progesterones and androgens were assessed in 70 healthy young men using ultra high performance supercritical fluid chromatography and tandem mass spectrometry. Testosterone, 24.5 nmol/L was the most prominent androgen detected in all participants while dihydrotestosterone, 1.23 nmol/L, was only detected in 25% of the participants. The 11-oxy androgens were present in most of the participants with 11-hydroxyandrostenedione, 3.37 nmol, in 98.5%, 11-ketoandrostenedione 0.764 in 77%, 11-hydroxytestosterone, 0.567 in 96% and 11-ketotestosterone: 0.440 in 63%. A third of the participants with normal testosterone and comparable 11-ketotestosterone, had significantly lower dehydroepiandrosterone (p

IntroductionThis study was undertaken to investigate whether sustained rather than a single measure of corneal nerve loss was associated with the onset of diabetic peripheral neuropathy (DPN) and the progression of neuropathic symptoms and deficits in individuals with type 2 diabetes (T2D).MethodsParticipants underwent clinical, metabolic testing and assessment of neuropathic symptoms, vibration perception threshold (VPT), sudomotor function, and corneal confocal microscopy (CCM) at baseline, 1, 2, and 4–7 years. Sustained corneal nerve loss was defined as abnormal corneal nerve fiber density (CNFD,

Abstract Background Patients with diabetic ketoacidosis (DKA), a potentially fatal complication of type 1 diabetes, have hyperglycemia, ketonemia and metabolic acidosis. Blood glucose and blood ketone results are often used to triage patients with suspected DKA. This study aimed to establish how effective blood glucose and blood ketone (beta-hydroxybutyrate, BOHB) measurements are in identifying patients with significant acidosis and sought to validate existing diagnostic BOHB thresholds. Methods Initial Emergency Department results on 161 presumptive DKA episodes in 95 patients (42 F, 53 M, age range 14–89 years) containing a complete dataset of D (glucose), K (BOHB) and A (Bicarbonate [HCO3] and pH) results. Results Blood glucose correlated poorly with BOHB (r = 0.28 p = 0.0003), pH (r= -0.25, p = 0.002) and HCO3 (r= -0.17, p = 0.04). BOHB, though better, was still limited in predicting pH (r = -0.44, p 13.9mmol/L, n = 8), ketonemic (≤ 3mmol/L, n = 9) or either (n = 5). Conclusions The commonly employed BOHB diagnostic cutoff of 3mmol/L could not be verified. Since acid-base status was poorly predicted by both glucose and BOHB, this highlights that, regardless of their results, pH and/or HCO3 should also be tested in any patient suspected of DKA.

Background. Perfluorinated alkyl acids (PFAAs) are persistent organic pollutants affected by BMI and ethnicity, with contradictory reports of association with vitamin D deficiency. Methods. Twenty-nine Caucasian women with non-obese polycystic ovary syndrome (PCOS) and age- and BMI-matched Caucasian control women (n = 30) were recruited. Paired serum samples were analyzed for PFAAs (n = 13) using high-performance liquid chromatography–tandem mass spectrometry. Tandem mass spectrometry determined levels of 25(OH)D3 and the active 1,25(OH)2D3. Results. Women with and without PCOS did not differ in age, weight, insulin resistance, or systemic inflammation (C-reactive protein did not differ), but the free androgen index was increased. Four PFAAs were detected in all serum samples: perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), and perfluorohexane sulfonic acid (PFHxS). Serum PFOS was higher in PCOS versus controls (geometric mean [GM] 3.9 vs. 3.1 ng/mL, p < 0.05). Linear regression modeling showed that elevated PFHxS had higher odds of a lower 25(OH)D3 (OR: 2.919, 95% CI 0.82–5.75, p = 0.04). Vitamin D did not differ between cohorts and did not correlate with any PFAAs, either alone or when the groups were combined. When vitamin D was stratified into sufficiency (>20 ng/mL) and deficiency (3 or the active 1,25(OH)2D3 in this Caucasian population, nor do they appear to be associated with vitamin D deficiency, suggesting that future studies must account for these factors in the analysis.

Introduction: Hypoglycemia has been associated with cardiovascular events, and glucose variability has been suggested to be associated with increased cardiovascular risk. Therefore, in this study, we examined the effect on proteomic cardiovascular risk protein markers of (i) mild iatrogenic hypoglycemia and (ii) severe iatrogenic hypoglycemia followed by rebound hyperglycemia. Methods: Two iatrogenic hypoglycemia studies were compared; firstly, mild hypoglycemia in 18 subjects (10 type 2 diabetes (T2D), 8 controls; blood glucose to 2.8 mmoL/L (50 mg/dL) for 1 h), and secondly, severe hypoglycemia in 46 subjects (23 T2D, 23 controls; blood glucose to Results: Baseline to euglycemia showed no change in any of the proteins measured in the T2D cohort. With severe hypoglycemia, the study controls showed an increase in Angiopoietin 1 (ANGPT1) (p < 0.01) and Dickkopf-1 (DKK1) (p < 0.01), but no changes were seen with mild hypoglycemia. In both the mild and severe hypoglycemia studies, at the point of hypoglycemia, T2D subjects showed suppression of Brother of CDO (BOC) (p < 0.01). At 1 h post-hypoglycemia, the changes in ANGPT1, DKK1, and BOC had resolved, with no additional protein biomarker changes despite rebound hyperglycemia from 1.8 ± 0.1 to 12.2 ± 2.0 mmol/L. Conclusions: Proteomic biomarkers of cardiovascular disease showed changes at hypoglycemia that resolved within 1 h following the hypoglycemic event and with no changes following hyperglycemia rebound, suggesting that any cardiovascular risk increase is due to the hypoglycemia and not due to glucose fluctuation per se.

IntroductionPolychlorinated biphenyls (PCBs) are organic lipophilic pollutants that accumulate in the body. Previous research has linked PCBs with menstrual function; therefore, this study was undertaken to investigate the correlation of PCBs with luteal phase hormonal parameters of menstrual function at day 21 in a group of non-obese women prior to in vitro fertilization (IVF).MethodsFifty-eight non-obese Caucasian women from a UK academic center, 29 with polycystic ovary syndrome (PCOS) and 29 without, were recruited. PCOS women all had anovulatory infertility. Non-PCOS women: five with unexplained infertility, the remainder with male factor infertility (n=14) or tubal problems (n=10). Blood was withdrawn at day 21 of the menstrual cycle for non-PCOS women, at the time of mock embryo transfer. PCBs were measured using high resolution gas chromatography.ResultsOnly PCB118, PCB153, PCB138 and PCB180 were detected in all samples, and levels did not differ between PCOS and non-PCOS subjects. In non-PCOS subjects, PCB153, PCB138 and PCB180 inversely correlated with estradiol (p

BackgroundA 12-year study comparing clinical outcomes following Roux-en-Y bariatric surgery showed long-term weight loss with remission/prevention of type-2-diabetes (T2D), hypertension and dyslipidemia. However, it is unknown whether the underlying homeostatic metabolic processes involving hepatokines, adipokines and myokines also normalize. Using this 12-year study, we determined whether metabolic indices improved in post-surgical (BMI:34.4kg/m2) versus non-surgical comparator-subjects-with-obesity (BMI:43.8kg/m2) at 12-year follow-up (both cohorts with baseline diabetes), and if post-surgical subjects normalized their metabolic processes to those of a normal-weight cohort without diabetes.MethodsCross-sectional design. Plasma from a cohort of Roux-en-Y bariatric surgery (n=50) and non-surgery (n=76) comparator-subjects-with-obesity (both cohorts at 12-year follow-up) plus a normal-weight cohort (n=39) was assayed by Luminex immunoassay or ELISA for hepatokines [angiopoietin-like proteins-(ANGPTL3; ANGPTL4; ANGPTL6); fibroblast growth factors-(FGF19; FGF21; FGF23)]; adipokines [adipsin; adiponectin; FGF19] and myonectin.ResultsAfter age and gender adjustment, surgery versus comparator-subjects-with-obesity had lower BMI (34.4 ± 1.0 vs 43.8 ± 0.9kg/m2; p

IntroductionPolychlorinated biphenyls (PCBs), organic lipophilic pollutants that accumulate through diet and increase with age, have been associated with polycystic ovary syndrome (PCOS) and shown to affect microRNA (miRNA) expression. This work aimed to determine if PCBs were associated with circulating miRNAs and whether there were any correlations with serum PCB/miRNA levels and hormonal changes.Methods29 non-obese PCOS and 29 healthy control women, with similar age and body mass index (BMI), had their serum miRNAs measured together with 7 indicator PCBs (PCB28, PCB52, PCB101, PCB118, PCB138, PCB153, PCB180) using high resolution gas chromatography coupled with high resolution mass spectrometry.ResultsIn the combined study cohort, four miRNAs (hsa-miR-139-5p, hsa-miR-424-5p, hsa-miR-195-5p, hsa-miR-335-5p) correlated with PCBs, but none correlated with metabolic parameters. hsa-miR-335-5p correlated with FSH. When stratified, 25 miRNAs correlated with PCBs in controls compared to only one (hsa-miR-193a-5p) in PCOS; none of these miRNAs correlated with the metabolic parameters of BMI, insulin resistance, or inflammation (C-reactive protein, CRP). However, of these 25 miRNAs in controls, hsa-miR-26a-5p, hsa-miR-193a-5p, hsa-miR-2110 and hsa-miR-195-5p positively correlated with luteinizing hormone (LH), hsa-miR-99b-5p and hsa-miR-146b-5p correlated with estradiol, hsa-miR-193a-5p correlated with progesterone, hsa-miR-195-5p correlated with follicle stimulating hormone (FSH), and hsa-miR-139-5p and hsa-miR-146b-5p negatively correlated with anti-müllerian hormone (AMH) (all p

Introduction Trehalose is a naturally occurring disaccharide of 2 glucose molecules, which has been suggested as a potential therapeutic agent to reduce blood glucose and ameliorate diabetes-related complications in type 2 diabetes (T2D). This study aimed to determine the efficacy of medium-term trehalose treatment in patients with T2D. Material and methods A double-blind, randomized, placebo-controlled trial in 40 patients with T2D was undertaken; 20 ingested trehalose 3.3 g/day and 20 placebo (sucrose), for 3 months. Parameters of glycaemic indices, high-sensitivity C-reactive protein (CRP), mood status, and quality of life were measured. Results CRP was significantly lower with trehalose treatment (–0.62 ±0.3 mg/l, p = 0.02); however, no differences in glycaemic indices of fasting blood glucose (FBG) (–7.1 ±10.7 mg/dl, p = 0.15), glycated hemoglobin (HbA1c) (–0.1 ±0.4%, p = 0.73), insulin (0.73 ±0.8 µU/ml, p = 0.39), or insulin resistance (HOMA-IR) (0.19 ±0.33, p = 0.56) were seen between groups after 12 weeks. Depression and stress scores were lower with trehalose compared to the placebo group (p = 0.02 and p = 0.05, respectively), whilst the quality-of-life score was higher with trehalose compared to placebo (p = 0.03) at the end of study. Between-group differences in these indices did not reach statistical significance (–2.36 ±1.20, –2.21 ±1.39 and 3.00 ±1.76 for depression, stress, and quality-of-life score, respectively) (p > 0.05). The pro-oxidant antioxidant balance (PAB) did not differ between groups (–4.6 ±12.8, p = 0.72). Conclusions 12 weeks of treatment with 3.3 g/day of oral trehalose significantly improves CRP as a marker of inflammation, with potential favourable effects on quality of life, depression, and stress levels, but overall glycaemic control and pro-oxidant-antioxidant balance were unaltered during this time frame.

Abstract Objective Severe hypoglycemia is associated with increased cardiovascular death risk, and platelet responses to hypoglycemia (hypo) have been described. However, the impact of deep transient hypo (deep-hypo) versus prolonged milder hypo (mild-hypo) on platelet response is unclear. Research Design and methods Two hypo studies were compared; firstly, mild-hypo in 18-subjects (10 type-2-diabetes (T2D), 8 controls), blood glucose to 2.8mmoL/L (50 mg/dL) for 1-hour; secondly deep-hypo in 46-subjects (23 T2D, 23 controls), blood glucose to

IntroductionDyslipidemia frequently occurs in women with polycystic ovary syndrome (PCOS), but it is unclear whether dyslipidemia is due to obesity and insulin resistance (IR) or is inherent to PCOS. To address this, proteomic analysis of proteins important in lipid metabolism, particularly for high-density lipoprotein cholesterol (HDL-C), was performed in non-obese, non-insulin resistant PCOS women compared to matched controls.MethodsWeight and aged-matched non-obese subjects with PCOS (n=24) and without IR were compared with control women (n=24). 19 proteins were measured by Somalogic proteomic analysis: alpha-1-antichymotrypsin, alpha-1-antitrypsin, apolipoproteins A-1, B, D, E, E2, E3, E4, L1, M, clusterin, complement C3, hemopexin, heparin cofactor-II (HCFII), kininogen-1, serum amyloid A-1, amyloid beta A-4 and paraoxonase-1.ResultsWomen with PCOS had a higher free androgen index (FAI) (p0.05). The triglyceride:HDL-cholesterol ratio was elevated (p=0.03) in PCOS. Alpha-1-antitrypsin levels were lower (p0.05). However, in PCOS, alpha-1-antichymotrypsin correlated negatively with BMI (r=-0.40, p

Abstract Favipiravir has antiviral activity against influenza, West Nile virus, and yellow fever virus and against flaviviruses. The objective of this pilot study was to compare three arms: favipiravir; hydroxychloroquine; standard care (no specific SARS-CoV-2 treatment) only, in symptomatic patients infected by SARS-CoV-2 in an open-labelled randomized clinical trial. The trial was registered with Bahrain National Taskforce for Combatting COVID-19 on the 7th of May 2020 (registration code: NCT04387760). 150 symptomatic patients with COVID-19 disease were randomized into one of three arms: favipiravir, hydroxychloroquine, or standard care only. The primary outcome was the clinical scale at the end of study follow up (day 14 or on discharge/death) based on a points scale. The secondary outcomes were viral clearance, biochemical parameter changes and mortality at 30-days. Baseline characteristics did not differ between groups. The proportion of patients who achieved a clinical scale

Background and aims: An association between hypoglycaemia and adverse cardiovascular events has been suggested from longitudinal and retrospective cohort studies. The complement pathway proteins in hypoglycemia are not well studied. Here, we hypothesized that these circulating proteins would be elevated in response to hypoglycemia in type 2 diabetes (T2D) through the inflammatory response. Methods: A prospective, parallel study in T2D (n = 23) and controls (n = 23). Subjects underwent insulin-induced hypoglycemia with blood sampling at baseline, hypoglycemia and post-hypoglycemia; SOMAscan proteomic analysis of complement pathway-related proteins, cytokines and inflammatory proteins was undertaken. Results: At baseline: Complement C2 (p

IntroductionWomen with polycystic ovary syndrome (PCOS) exhibit complement factor expression changes that may be obesity-driven rather than an intrinsic facet of PCOS; furthermore, complement changes have been associated with vitamin D deficiency, a common feature of PCOS. Therefore, complement pathway proteins and vitamin D levels may be linked in PCOS.MethodsWe measured plasma levels of complement pathway proteins by Slow Off-rate Modified Aptamer (SOMA)-scan plasma protein measurement for the classical (C4, C4a, and C4b) and alternative pathways (C3, C3b, iC3b, properdin, and factors B, D, and H) in weight and age-matched non-obese non-insulin resistant women with PCOS (n = 24) and control women (n = 24). Proteins that differed between groups were correlated with 25-hydroxyvitamin D3 (25(OH)D3) and 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), measured by isotope-dilution liquid chromatography tandem mass spectrometry.ResultsWomen with PCOS had a higher free androgen index and anti-Mullerian hormone, though insulin resistance was comparable to controls; likewise, C-reactive protein, a marker of inflammation, was comparable between cohorts. In the alternative complement pathway, C3, iC3b, and properdin were increased in PCOS (p

Context: Polycystic ovary syndrome (PCOS) is one of the commonest endocrine disorders affecting women of reproductive age, and metformin is a widely used medication in managing this condition. Aim: To review the available literature comprehensively on the therapeutic impact of metformin on the clinical and metabolic parameters of women with PCOS. Data source: We searched PubMed, MEDLINE, Scopus, Embase, Cochrane Library and the Web of Science and selected sources for grey literature from their inception to April 2020. An updated search in PubMed was performed in June 2022. Data synthesis: Two reviewers selected eligible studies and extracted data, and the review is reported following the 2020 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Results: In 24 eligible randomised controlled trials (RCTs) involving 564 participants who received metformin therapy, metformin was associated with significant reduction in body weight by 3.13 kg (95% CI: −5.33, −0.93), body mass index (BMI) by 0.82 kg/m² (95% CI: −1.22, −0.41), fasting blood glucose [standardised mean difference (SMD): −0.23; 95% CI: −0.40, −0.06], low-density lipoprotein cholesterol (LDL-C) (SMD: −0.41; 95% CI: −0.85, 0.03), total testosterone (SMD: −0.33; 95% CI: −0.49, −0.17), androstenedione (SMD: −0.45; 95% CI: −0.70, −0.20), 17-hydroxyprogesterone (17-OHP) (SMD: −0.58; 95% CI: −1.16, 0.00) and increase the likelihood of clinical pregnancy rate [odds ratio (OR): 3.00; 95% CI: 1.95, 4.59] compared with placebo. Conclusion: In women with PCOS, metformin use has shown a positive impact in reducing body weight, BMI, total testosterone, androstenedione, 17-OHP, LDL-C, fasting blood glucose and increasing the likelihood of pregnancy in women with PCOS.

Introduction: Upregulation of complement system factors are reported to be increased in polycystic ovary syndrome (PCOS) and may be due to obesity and insulin resistance rather than inherently due to PCOS. We directly compared complement factors from an obese, insulin-resistant PCOS population to a nonobese, non-insulin-resistant PCOS population in a proteomic analysis to investigate this. Methods: Plasma was collected from 234 women (137 with PCOS and 97 controls) from a biobank cohort and compared to a nonobese, non-insulin-resistant population (24 with PCOS and 24 controls). Slow off-rate modified aptamer (SOMA) scan plasma protein measurement was undertaken for the following complement system proteins: C1q, C1r, C2, C3, C3a, iC3b, C3b, C3d, C3adesArg, C4, C4a, C4b, C5, C5a, C5b-6 complex, C8, properdin, factor B, factor D, factor H, factor I, Mannose-binding protein C (MBL), complement decay-accelerating factor (DAF) and complement factor H-related protein 5 (CFHR5). Results: The alternative pathway of the complement system was overexpressed in both obese and nonobese PCOS, with increased C3 (p < 0.05) and properdin (p < 0.01); additionally, factor B increased in obese PCOS (p < 0.01). For inhibitors of this pathway, factor I was increased (p < 0.01) in both slim and obese PCOS, with an increase in CFHR5 and factor H in obese PCOS (p < 0.01). Complement factors iC3b, C3d and C5a, associated with an enhanced B cell response and inflammatory cytokine release, were increased in both slim and obese PCOS (p < 0.05). C3a and its product, C3adesArg, were both significantly elevated in nonobese PCOS (p < 0.05) but not in nonobese PCOS. There was no association with insulin resistance. BMI correlated positively in both groups with factor B, factor H and C5a. Additionally, in obese PCOS, BMI correlated with C3d, factor D, factor I, CFHR5 and C5a (p < 0.05), and in nonobese PCOS, BMI correlated with properdin, iC3b, C3, C3adesArg, C3a, C4, C5, C5a and C1q. In obese controls, BMI correlated with C3, C3desArg, C3a, C3d, C4, factor I, factor B, C5a and C5, whilst in nonobese controls, BMI only correlated negatively with C1q. Comparison of nonobese and obese PCOS showed that properdin, C3b, iC3b, C4A, factor D, factor H and MBL differed. Conclusion: The upregulation of the alternative complement pathway was seen in nonobese PCOS and was further exacerbated in obese PCOS, indicating that this is an inherent feature of the pathophysiology of PCOS that is worsened by obesity and is reflected in the differences between the nonobese and obese PCOS phenotypes. However, the increase in the complement proteins associated with activation was counterbalanced by upregulation of complement inhibitors; this was evident in both PCOS groups, suggesting that insults, such as a cardiovascular event or infection, that cause activation of complement pathways may be amplified in PCOS.

Introduction. Oxidative stress (OS) is recognized in the pathophysiology of polycystic ovary syndrome (PCOS). OS results in intracellular reactive oxygen species generation, causing oxidative protein damage that is protected by heat shock proteins (HSPs). Vitamin D is thought to reduce and protect against OS; therefore, OS, HSP, and vitamin D levels may be associated with PCOS. However, their expression in PCOS without underlying inflammation is unknown. Methods. In this exploratory study, the plasma levels of 7 OS proteins and 10 HSPs that are affected by the OS process were measured using Slow Off-rate Modified Aptamer (SOMA)-scan plasma protein measurements in non-obese, non-insulin resistant women with PCOS (n = 24) without systemic inflammation and control (n = 24) women; the cohorts were matched for weight and age. The OS proteins and HSPs were correlated with 25-hydroxy vitamin D3 (25(OH)D3) and the active form, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), as measured by isotope-dilution liquid chromatography tandem mass spectrometry. Results. The PCOS women versus the controls had comparable insulin resistance and systemic inflammation (C-reactive protein 2.0 mg/L vs. 2.3 mg/L, p > 0.05), but higher free androgen index and anti-mullerian hormone levels. Among the OS proteins, only esterase D (ESD; p < 0.01) was elevated in PCOS and the HSPs did not differ between the PCOS and control women. There was no correlation of 25(OH)D3 or 1,25(OH)2D3 with any of the proteins. Conclusions. In a PCOS population that was non-obese and without insulin resistance and systemic inflammation, only ESD was elevated in PCOS, whilst the other OS proteins and HSPs were not elevated. Further, none of the OS proteins or HSPs were correlated with either 25(OH)D3 or 1,25(OH)2D3 in either cohort of women or when both cohorts were combined, indicating that the OS and HSP responses were largely absent and not affected by vitamin D in a non-obese PCOS population.

Abstract Heat shock proteins contribute to diabetes-induced complications and are affected by glycemic control. Our hypothesis was that hypoglycemia-induced heat shock and related protein changes would be amplified in type 2 diabetes (T2D). This prospective, case–control study enrolled 23 T2D patients and 23 control subjects who underwent hyperinsulinemic-induced hypoglycemia (≤ 2.0 mmol/L (36 mg/dl)) with blood sampling at baseline, at hypoglycemia and after a 24-h post-hypoglycemia follow-up period. Proteomic analysis of heat shock-related and pro-inflammatory proteins was performed. At baseline, MAPKAPK5 (p = 0.02) and UBE2G2 (p = 0.003) were elevated and STUB1 decreased (p = 0.007) in T2D. At hypoglycemia: PPP3CA (p

Abstract Background Bariatric surgery, used to achieve effective weight loss in individuals with severe obesity, modifies the gut microbiota and systemic metabolism in both humans and animal models. The aim of the current study was to understand better the metabolic functions of the altered gut microbiome by conducting deep phenotyping of bariatric surgery patients and bacterial culturing to investigate causality of the metabolic observations. Methods Three bariatric cohorts (n = 84, n = 14 and n = 9) with patients who had undergone Roux-en-Y gastric bypass (RYGB), sleeve gastrectomy (SG) or laparoscopic gastric banding (LGB), respectively, were enrolled. Metabolic and 16S rRNA bacterial profiles were compared between pre- and post-surgery. Faeces from RYGB patients and bacterial isolates were cultured to experimentally associate the observed metabolic changes in biofluids with the altered gut microbiome. Results Compared to SG and LGB, RYGB induced the greatest weight loss and most profound metabolic and bacterial changes. RYGB patients showed increased aromatic amino acids-based host-bacterial co-metabolism, resulting in increased urinary excretion of 4-hydroxyphenylacetate, phenylacetylglutamine, 4-cresyl sulphate and indoxyl sulphate, and increased faecal excretion of tyramine and phenylacetate. Bacterial degradation of choline was increased as evidenced by altered urinary trimethylamine-N-oxide and dimethylamine excretion and faecal concentrations of dimethylamine. RYGB patients’ bacteria had a greater capacity to produce tyramine from tyrosine, phenylalanine to phenylacetate and tryptophan to indole and tryptamine, compared to the microbiota from non-surgery, normal weight individuals. 3-Hydroxydicarboxylic acid metabolism and urinary excretion of primary bile acids, serum BCAAs and dimethyl sulfone were also perturbed following bariatric surgery. Conclusion Altered bacterial composition and metabolism contribute to metabolic observations in biofluids of patients following RYGB surgery. The impact of these changes on the functional clinical outcomes requires further investigation. Video abstract

ObjectiveHypoglycemia in type 2 diabetes (T2D) increases morbidity and mortality but the underlying physiological response is still not fully understood, though physiological changes are still apparent 24 hours after the event. Small noncoding microRNA (miRNA) have multiple downstream biological effects that may respond rapidly to stress. We hypothesized that hypoglycemia would induce rapid miRNA changes; therefore, this pilot exploratory study was undertaken.MethodsA pilot prospective, parallel study in T2D (n=23) and controls (n=23). Insulin-induced hypoglycemia (2mmol/l: 36mg/dl) was induced and blood sampling performed at baseline and hypoglycemia. Initial profiling of miRNA was undertaken on pooled samples identified 96 miRNA that were differentially regulated, followed by validation on a custom designed 112 miRNA panel.ResultsNine miRNAs differed from baseline to hypoglycemia in control subjects; eight were upregulated: miR-1303, miR-let-7e-5p, miR-1267, miR-30a-5p, miR-571, miR-661, miR-770-5p, miR-892b and one was downregulated: miR-652-3p. None of the miRNAs differed from baseline in T2D subjects.ConclusionA rapid miRNA response reflecting protective pathways was seen in control subjects that appeared to be lost in T2D, suggesting that mitigating responses to hypoglycemia with blunting of the counter-regulatory response in T2D occurs even in patients with short duration of disease.Clinical trial registrationhttps://clinicaltrials.gov/ct2/show/NCT03102801?term=NCT03102801&draw=2&rank=1, identifier NCT03102801.

IntroductionComplement factors mediate the recruitment and activation of immune cells and are associated with metabolic changes during pregnancy. The aim of this study was to determine whether complement factors in the maternal serum and follicular fluid (FF) are associated with in vitro fertilization (IVF) outcomes in overweight/obese women.MethodsForty overweight/obese (BMI = 30.8 ± 5.2 kg/m2) female patients, 33.6 ± 6.3 years old, undergoing IVF treatment for unexplained infertility were recruited. Baseline demographic information, including biochemical hormonal, metabolic, and inflammatory markers, and pregnancy outcome, was collected. Levels of 14 complement markers (C2, C4b, C5, C5a, C9, adipsin, mannose-binding lectin, C1q, C3, C3b/iC3b, C4, factor B, factor H, and properdin) were assessed in the serum and FF and compared to IVF outcome, inflammatory, and metabolic markers using multivariate and univariate models.ResultsOut of 40 IVF cycles, 14 (35%) resulted in pregnancy. Compared to women with failed pregnancies, women with successful pregnancies had higher levels of adipsin in the serum and FF (p = 0.01) but lower C5a levels (p = 0.05). Serum adipsin levels were positively correlated with circulating levels of vitamin D (R = 0.5, p = 0.02), glucagon (R = 0.4, p = 0.03), leptin (R = 0.4, p = 0.01), resistin (R = 0.4, p = 0.02), and visfatin (R = 0.4, p = 0.02), but negatively correlated with total protein (R = −0.5, p = 0.03). Higher numbers of top-quality embryos were associated with increased levels of C3, properdin, C1q, factors H and B, C4, and adipsin, but with reduced C2 and C5a levels (p ≤ 0.01).ConclusionsHigher adipsin and lower C5a levels in the maternal serum during implantation are potential markers of successful outcome in obese women undergoing IVF-assisted pregnancies.

Abstract Convalescent plasma (CP) therapy in COVID-19 disease may improve clinical outcome in severe disease. This pilot study was undertaken to inform feasibility and safety of further definitive studies. This was a prospective, interventional and randomized open label pilot trial in patients with severe COVID-19. Twenty COVID-19 patients received two 200 ml transfusions of convalescent patient CP over 24-h compared with 20 who received standard of care. The primary outcome was the requirement for ventilation (non-invasive or mechanical ventilation). The secondary outcomes were biochemical parameters and mortality at 28 days. The CP group were a higher risk group with higher ferritin levels (p

Abstract Background Polycystic ovary syndrome (PCOS) is associated with obesity, diabetes, and insulin resistance. The circulating C1Q/TNF-related proteins (CTRP-2, CTRP-9) and growth differentiation factors (GDF-8, GDF-15) contribute to glucose and lipid homeostasis. The effects of intralipids and insulin infusion on CTRP-2, CTRP-9, GDF-8 and GDF-15 in PCOS and control subjects before and after chronic exercise training were examined. Methods Ten PCOS and nine healthy subjects were studied at baseline status and after moderate-intensity chronic exercise training (1 h exercise, 3 times per week, 8 weeks). All participants were infused with 1.5 mL/min of saline or intralipids (20%) for 5 h, and during the last 2 h of saline or intralipids infusion hyperinsulinemic-euglycemic clamp (HIEC) was performed. CTRP-2, CTRP-9, GDF-8 and GDF-15 levels were measured at 0, 3 and 5 h. Results Intralipids dramatically increased CTRP-2 levels in PCOS (P = 0.02) and control (P = 0.004) subjects, which was not affected by insulin infusion or by exercise. Intralipids alone had no effects on CTRP-9, GDF-8, or GDF-15. Insulin increased the levels of GDF-15 in control subjects (P = 0.05) during the saline study and in PCOS subjects (P = 0.04) during the intralipid infusion. Insulin suppressed CTRP9 levels during the intralipid study in both PCOS (P = 0.04) and control (P = 0.01) subjects. Exercise significantly reduced fasting GDF-8 levels in PCOS (P = 0.03) and control (P = 0.04) subjects; however, intralipids infusion after chronic exercise training increased GDF-8 levels in both PCOS (P = 0.003) and control (P = 0.05) subjects and insulin infusion during intralipid infusion reduced the rise of GDF-8 levels. Conclusion This study showed that exogenous lipids modulate CTRP-2, which might have a physiological role in lipid metabolism. Since chronic exercise training reduced fasting GDF-8 levels; GDF-8 might have a role in humoral adaptation to exercise. GDF-15 and CTRP-9 levels are responsive to insulin, and thus they may play a role in insulin responses.

Purpose: The COVID-19 pandemic has led to over 92 million cases and 1.9 million deaths worldwide since its outbreak. Public health responses have focused on identifying symptomatic individuals to halt spread. However, evidence is accruing that asymptomatic individuals are infectious and contributing to this global pandemic. Methods: Observational data of 320 index cases and their 1289 positive contacts from the National COVID-19 Database in Bahrain were used to analyze symptoms, infectivity rate and PCR Cycle threshold (Ct) values. Results: No significant difference (p = 1.0) in proportions of symptomatic (n = 160; 50.0%) and asymptomatic index cases (n = 160; 50.0%) were seen; however, SARS-CoV-2 positive contact cases were predominantly asymptomatic (n = 1127, 87.4%). Individuals aged 0−19 years constituted a larger proportion of positive contact cases (20.8%) than index cases (4.7%; p

Abstract Polycystic ovary syndrome (PCOS) women have a hypercoagulable state; however, whether this is intrinsically due to PCOS or, alternatively, a consequence of its metabolic complications is unclear. We determined plasma coagulation pathway protein levels in PCOS (n = 146) and control (n = 97) women recruited to a PCOS biobank. Circulating levels of a panel of 18 clotting pathway proteins were determined by Slow Off-rate Modified Aptamer-scan plasma protein measurement. Cohorts were age matched, though PCOS had elevated body mass index (p

Abstract Hyperactivation of the immune system through obesity and diabetes may enhance infection severity complicated by Acute Respiratory Distress Syndrome (ARDS). The objective was to determine the circulatory biomarkers for macrophage activation at baseline and after serum glucose normalization in obese type 2 diabetes (OT2D) subjects. A case-controlled interventional pilot study in OT2D (n = 23) and control subjects (n = 23). OT2D subjects underwent hyperinsulinemic clamp to normalize serum glucose. Plasma macrophage-related proteins were determined using Slow Off-rate Modified Aptamer-scan plasma protein measurement at baseline (control and OT2D subjects) and after 1-h of insulin clamp (OT2D subjects only). Basal M1 macrophage activation was characterized by elevated levels of M1 macrophage-specific surface proteins, CD80 and CD38, and cytokines or chemokines (CXCL1, CXCL5, RANTES) released by activated M1 macrophages. Two potent M1 macrophage activation markers, CXCL9 and CXCL10, were decreased in OT2D. Activated M2 macrophages were characterized by elevated levels of plasma CD163, TFGβ-1, MMP7 and MMP9 in OT2D. Conventional mediators of both M1 and M2 macrophage activation markers (IFN-γ, IL-4, IL-13) were not altered. No changes were observed in plasma levels of M1/M2 macrophage activation markers in OT2D in response to acute normalization of glycemia. In the basal state, macrophage activation markers are elevated, and these reflect the expression of circulatory cytokines, chemokines, growth factors and matrix metalloproteinases in obese individuals with type 2 diabetes, that were not changed by glucose normalisation. These differences could potentially predispose diabetic individuals to increased infection severity complicated by ARDS. Clinical trial reg. no: NCT03102801; registration date April 6, 2017.

In human population studies, organochlorine pesticides (OCPs) have been linked to vitamin D deficiency. Therefore, this study examined the association between OCPs, vitamin D3 (cholecalciferol, 25(OH)D3), and the active metabolite 1,25-dihydrovitamin D3 (1,25(OH)2D3) in a cohort of non-obese women. The serum samples of 58 female participants (age—31.9 ± 4.6 years; body mass index (BMI)—25.7 ± 3.7 kg/m2) were screened for 10 indicator OCPs. 25(OH)D3 and 1,25(OH)2D3 levels were determined via isotope dilution liquid chromatography tandem mass spectrometry. In this cohort, the 25(OH)D3 and 1,25(OH)2D3 levels were 22.9 ± 11.2 ng/mL and 0.05 ± 0.02 ng/mL, respectively, with 28 participants classified as 25(OH)D3-deficient (3. p,p′-dichlorodiphenyldichloroethylene (DDE) and ƩOCPs correlated positively with 1,25(OH)2D3, with the latter being negatively correlated with estimated glomerular filtration rate (eGFR). In women with sufficient 25(OH)D3 levels, p,p′-dichlorodiphenyltrichloroethan (DDT) was positively correlated with 1,25(OH)2D3, whilst in the deficient group, hexachlorobenzene (HCB) and p,p′-(DDE) were positively correlated with 1,25(OH)2D3, β-Hexachlorocyclohexane (HCH) was positively correlated with 25(OH)D3, and none of the OCPs were associated with measures of renal function. Overall, OCPs and ƩOCPs were not associated with 25(OH)D3, suggesting that they are unrelated to vitamin D deficiency, but p,p′-DDE and ƩOCPs correlated positively with active 1,25(OH)2D3, while ƩOCPs correlated negatively with eGFR, suggesting a possible renal effect. Analysis of vitamin D deficiency revealed an association between β-HCH and 25(OH)D3, and between HCB and p,p′-DDE and 1,25(OH)2D3, suggesting that OCP effects may be enhanced in cases of vitamin D deficiency.

Introduction. Serum lipoproteins, with the exception of high-density lipoprotein cholesterol (HDL-C), are increased in polycystic ovary syndrome (PCOS) and their levels may reflect the associated obesity and insulin resistance, but the nature of this association is not fully explained. Therefore, proteomic analysis of key proteins in lipoprotein metabolism was performed. Methods. In this cohort study, plasma was collected from 234 women (137 with PCOS and 97 controls without PCOS). Somalogic proteomic analysis was undertaken for the following 19 proteins involved in lipoprotein, and particularly HDL, metabolism: alpha-1-antichymotrypsin; alpha-1-antitrypsin; apolipoproteins A-1, B, D, E, E2, E3, E4, L1, and M; clusterin; complement C3; hemopexin; heparin cofactor II; kininogen-1; serum amyloid A-1; amyloid beta A-4; and paraoxonase-1. Results. The levels of apolipoprotein E were higher in PCOS (p = 0.012). However, the other isoforms of ApoE, ApoE2, E3, and E4, did not differ when compared with controls. ApoM was lower in PCOS (p = 0.000002). Complement C3 was higher in PCOS (p = 0.037), as was heparin cofactor II (HCFII) (p = 0.0004). The levels of the other proteins associated with lipoprotein metabolism did not differ between PCOS and controls. Conclusions. These data contribute to the concern of the deleterious dyslipidemia found in PCOS, with the novel combination reported here of higher levels of ApoE, C3 and HCFII together with lower ApoM. The dysregulation of these proteins could circumvent the protective effect of HDL-C and contribute to a more atherogenic profile that may increase cardiovascular risk.

Background: The frequency of asymptomatic SARS-CoV-2 infection with viral spread is unclear. Asymptomatic SARS-CoV-2 infection development and progression was investigated in subjects undergoing mandatory quarantine on airport arrival. Methods: 2714 subjects were tested for SARS-CoV-2 and all were quarantined for 2 weeks. Viral retesting was undertaken on symptom development and routinely at 14 days if asymptomatic. Asymptomatic, positive patients underwent viral testing every 2 days to determine viral clearance. Results: 188/2714 (6.9%) patients became SARS-CoV-2 positive. On arrival, 136/188 tested positive, with 44/188 (23.4%) symptomatic and 92/188 (48.9%) asymptomatic. All 92 patients remained asymptomatic and were retested every 2 days until viral clearance. 2526 quarantined subjects remained virus free at 14 days. Viral clearance did not differ between symptomatic and asymptomatic patients (12.6 ± 1.0 days and 12.1 ± 0.4 days, respectively). Of the 52/188 (27.7%) testing negative on arrival, 27/52 subsequently became positive and developed symptoms 2–13 days after arrival. 25/188 (13.3%) remained asymptomatic and tested positive at day 14, with viral testing undertaken every 2 days in these subjects; of these, 24 remained asymptomatic, with viral clearance at 9.4 ± 0.7 days — less than for those who were asymptomatic on arrival (p < 0.002). Conclusion: Asymptomatic patients with COVID-19 were more prevalent than those exhibiting symptoms, and are an infection reservoir.

Abstract Background Vitamin D deficiency is diagnosed by total serum 25-hydroxyvitamin D (25(OH)D) concentration and is associated with poor health and increased mortality; however, some populations have low 25(OH) D concentrations without manifestations of vitamin D deficiency. The Vitamin D Metabolite Ratio (VMR) has been suggested as a superior indicator of vitamin D status. Therefore, VMR was determined in a population with type 2 diabetes at high risk for vitamin D deficiency and correlated with diabetic complications. Research design and methods Four hundred sisty patients with type 2 diabetes (T2D) were recruited, all were vitamin D3 supplement naive. Plasma concentration of 25-hydroxyvitamin D3 (25(OH)D3) and its metabolites 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) and 24,25-dihydroxyvitamin D3 (24,25(OH)2D3) and its epimer, 3-epi-25-hydroxyvitamin D3 (3-epi-25(OH)D3), were measured by LC-MS/MS analysis. VMR-1 was calculated as a ratio of 24,25(OH)2D3:25(OH)D3; VMR-2 as a ratio of 1,25(OH)2D3:25(OH)D3; VMR-3 was calculated as a ratio of 3-epi-25(OH)D3: 25(OH)D3. Results An association means that there were significant differences between the ratios found for those with versus those without the various diabetic complications studied. VMR-1 was associated with diabetic retinopathy (p = 0.001) and peripheral artery disease (p = 0.012); VMR-2 associated with hypertension (p

Abstract Background Pregnant women with gestational diabetes mellitus (GDM) or type 2 diabetes mellitus (T2DM) are at increased risks of pre-term labor, hypertension and preeclampsia. In this study, metabolic profiling of blood samples collected from GDM, T2DM and control pregnant women was undertaken to identify potential diagnostic biomarkers in GDM/T2DM and compared to pregnancy outcome. Methods Sixty-seven pregnant women (21 controls, 32 GDM, 14 T2DM) in their second trimester underwent targeted metabolomics of plasma samples using tandem mass spectrometry with the Biocrates MxP® Quant 500 Kit. Linear regression models were used to identify the metabolic signature of GDM and T2DM, followed by generalized linear model (GLMNET) and Receiver Operating Characteristic (ROC) analysis to determine best predictors of GDM, T2DM and pre-term labor. Results The gestational age at delivery was 2 weeks earlier in T2DM compared to GDM and controls and correlated negatively with maternal HbA1C and systolic blood pressure and positively with serum albumin. Linear regression models revealed elevated glutamate and branched chain amino acids in GDM + T2DM group compared to controls. Regression models also revealed association of lower levels of triacylglycerols and diacylglycerols containing oleic and linoleic fatty acids with pre-term delivery. A generalized linear model ROC analyses revealed that that glutamate is the best predictors of GDM compared to controls (area under curve; AUC = 0.81). The model also revealed that phosphatidylcholine diacyl C40:2, arachidonic acid, glycochenodeoxycholic acid, and phosphatidylcholine acyl-alkyl C34:3 are the best predictors of GDM + T2DM compared to controls (AUC = 0.90). The model also revealed that the triacylglycerols C17:2/36:4 and C18:1/34:1 are the best predictors of pre-term delivery (≤ 37 weeks) (AUC = 0.84). Conclusions This study highlights the metabolite alterations in women in their second trimester with diabetes mellitus and identifies predictive indicators of pre-term delivery. Future studies to confirm these associations in other cohorts and investigate their functional relevance and potential utilization for targeted therapies are warranted.

Abstract Aims Vitamin D measurement is a composite of vitamin D2 (25(OH)D2) and D3 (25(OH)D3) levels, and its deficiency is associated with the development of type 2 diabetes (T2DM) and diabetic complications; vitamin D deficiency may be treated with vitamin D2 supplements. This study was undertaken to determine if vitamin D2 and D3 levels differed between those with and without T2DM in this Middle Eastern population, and the relationship between diabetic microvascular complications and vitamin D2 and vitamin D3 levels in subjects with T2DM. Methods Four hundred ninety-six Qatari subjects, 274 with and 222 without T2DM participated in the study. Plasma levels of total vitamin D2 and D3 were measured by LC-MS/MS analysis. Results All subjects were taking vitamin D2 and none were taking D3 supplements. Vitamin D2 levels were higher in diabetics, particularly in females, and higher levels were associated with hypertension and dyslipidemia in the diabetic subjects (p

Abstract Cardiovascular diseases (CVDs) are globally the major causes of morbidity and mortality. Evidence shows that smaller and denser low-dense lipoprotein (sdLDL) particles are independent atherogenic risk factors for CVD due to their greater susceptibility to oxidation, and permeability in the endothelium of arterial walls. sdLDL levels are an independent risk factor and of more predictive value than total LDL-C for the assessment of coronary artery disease and metabolic syndrome. Functional food ingredients have attracted significant attention for the management of dyslipidemia and subsequently increase cardio-metabolic health. However, to date there is no study that has investigated the effect of these bioactive natural compounds on sdLDL levels. Therefore, the aim of the present review is to summarize the evidence accrued on the effect of special dietary ingredients such as omega-3 polyunsaturated fatty acids, nutraceuticals and herbal medicines on the levels of sdLDL, LDL particle number, and LDL particle size. Based on the results of the existing clinical trials this review suggests that natural products such as medicinal plants, nutraceuticals and omega-3 fatty acids can be used as adjunct or complementary therapeutic agents to reduce sdLDL levels, LDL particle numbers or increase LDL particle size and subsequently may prevent and treat CVD, with the advantage that theses natural agents are generally safe, accessible, and inexpensive.

BackgroundHeat stress (HS) in cattle is a major debilitating problem, affecting health and milk yield. Physiologically, HS has been shown to lower blood glucose levels to 2.5 mmol/l (45 mg/dl) and results in upregulation of heat shock proteins (HSPs), eliciting the heat shock response (HSR) of which HSP90, 70 and 27 have been shown to be protective. However, it is unclear if the HSP response is blunted by decreased glucose, thereby preventing adaptive mechanisms. To address this question, this exploratory reverse translational study on the effects of hypoglycemia on the HSP pathway was undertaken.MethodsA human prospective, study in healthy control individuals (n = 23) was undertaken. Subjects underwent hyperinsulinemic-induced hypoglycemia [≤2.0 mmol/L (36 mg/dl)] with blood sampling at baseline, at hypoglycemia and for a 24-h post-hypoglycemia follow-up period. Proteomic analysis of the heat shock-related protein pathway, the pathway associated with HS in cattle, was performed.ResultsIn response to hypoglycemia, HS pathway proteins were significantly decreased (p < 0.05): HSP70 and HSP27 (at hypoglycemia); DnaJ homolog subfamily B member 1 (DNAJB1), Stress-induced-phosphoprotein 1 (STIP1) and the ubiquitin pathway proteins, Ubiquitin-conjugating enzyme (UBE2L3) and Ubiquitin-conjugating enzyme E2 N (UBE2N) (at 30-min post-hypoglycemia); HSP90 (at 2-h post-hypoglycemia). STIP1, UBE2L3, and UBE2N remained suppressed at 24-h.ConclusionHeat stress in cattle reduces blood glucose that, in turn, may blunt the HS pathway protective response, including HSP 90, 70, 27 and the ubiquitin proteins, leading to adverse outcomes. Monitoring of blood glucose in susceptible cattle may allow for earlier intervention and may also identify those animals at greatest risk to ensure that milk yield is not compromised.

Cardiovascular diseases (CVDs) are the leading cause of death globally as well as the leading cause of mortality and morbidity in type 2 diabetes (T2D) patients. Results from large interventional studies have suggested hyperglycemia and poor glycemic control to be largely responsible for the development of CVDs. However, the association between hypoglycemia and cardiovascular events is also a key pathophysiological factor in the development of CVDs. Hypoglycemia is especially prevalent in T2D patients treated with oral sulfonylurea agents or exogenous insulin, increasing the susceptibility of this population to cardiovascular events. The adverse cardiovascular risk of hypoglycemia can persist even after the blood glucose levels have been normalized. Hypoglycemia may lead to vascular disease through mechanisms such as enhanced coagulation, oxidative stress, vascular inflammation, endothelial dysfunction, and platelet activation. In the following review, we summarize the evidence for the role of hypoglycemia in platelet activation and the subsequent effects this may have on the development of CVD. In addition, we review current evidence for the effectiveness of therapies in reducing the risk of CVDs.

Background and Purpose: Patients with type 2 diabetes (T2D) have increased risk of cardiovascular disease (CVD), encompassing myocardial infarction, stroke, and peripheral vascular disease. We hypothesized that those biomarkers indicative of acute ischemic stroke (AIS) seen in large vessel occlusion (LVO) may also be elevated in T2D and further enhanced by stress conditions; therefore, these proteins represent potentially predictive biomarkers for those T2D patients at high risk of AIS.Methods: We performed an exploratory proteomic analysis in control subjects (n = 23) versus those with type 2 diabetes (T2D) (n = 23) who underwent a hyperinsulinemic clamp study to transient severe hypoglycemia [blood glucose

Objective: Small non-coding RNAs, known as microRNAs (miRNAs), have emerging regulatory functions within the ovary that have been related to fertility. This study was undertaken to determine if circulating miRNAs reflect the changes associated with the parameters of embryo development and fertilization.Methods: In this cross-sectional pilot study. Plasma miRNAs were collected from 48 sequentially presenting women in the follicular phase prior to commencing in vitro fertilization (IVF). Circulating miRNAs were measured using locked nucleic acid (LNA)-based quantitative PCR (qPCR), while an updated miRNA data set was used to determine their level of expression.Results: Body mass index and weight were associated with the miRNAs let7b-3p and miR-375, respectively (p < 0.05), with the same relationship being found between endometrium thickness at oocyte retrieval and miR-885-5p and miR-34a-5p (p < 0.05). In contrast, miR-1260a was found to be inversely associated with anti-Mullerian hormone (AMH; p = 0.007), while miR-365a-3p, miR122-5p, and miR-34a-5p correlated with embryo fertilization rates (p < 0.05). However, when omitting cases of male infertility (n = 15), miR122-5p remained significant (p < 0.05), while miR-365a-3p and miR-34a-5p no longer differed; interestingly, however, miR1260a and mir93.3p became significant (p = 0.0087/0.02, respectively). Furthermore, age was negatively associated with miR-335-3p, miR-28-5p, miR-155-5p, miR-501-3p, and miR-497-5p (p < 0.05). Live birth rate was negatively associated with miR-335-3p, miR-100-5p, miR-497-5p, let-7d, and miR-574-3p (p < 0.05), but these were not significant when age was accounted for.However, with the exclusion of male factor infertility, all those miRNAs were no longer significant, though miR.150.5p emerged as significant (p = 0.042). A beta-regression model identified miR-1260a, miR-486-5p, and miR-132-3p (p < 0.03, p = 0.0003, p < 0.00001, respectively) as the most predictive for fertilization rate. Notably, changes in detectable miRNAs were not linked to cleavage rate, top quality embryos (G3D3), and blastocyst or antral follicle count. An ingenuity pathway analysis showed that miRNAs associated with age were also associated with the variables found in reproductive system diseases.Conclusion: Plasma miRNAs prior to the IVF cycle were associated with differing demographic and IVF parameters, including age, and may be predictive biomarkers of fertilization rate.

Introduction: Coronavirus disease 2019 (COVID-19) is caused by a newly identified strain of the coronavirus family that has been shown to affect the hemoglobin beta chain, the same chain that has sickle cell disease (SCD) mutation. This study was undertaken to see if COVID-19 infection increased disease severity in patients with SCD. Methods: Mass screening of the Bahraini population was undertaken between February and April 2020. Results: A total of 38,092 Bahraini people were tested for COVID-19 during this period; 378 (1%) were SCD patients. Six patients with SCD had COVID-19 (1.6%): three remained asymptomatic, two had mild symptoms and one required oxygen therapy. The SCD patients had a similar average length of stay when compared with non-SCD COVID-19 patients (10.7 days). Conclusion: The infection rate, clinical course and viral clearance seen for the SCD patients with COVID-19 were no different to those without SCD.

Objective: The prevalence of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis (NAFLD/NASH) is increasing. NAFLD/NASH may progress to cirrhosis and hepatocellular carcinoma. However, most patients with NAFLD/NASH will die from a vascular cause. There are no approved pharmacological treatments for NASH/NAFLD. Many clinical trials have been, or are being, undertaken; however, the challenge is the assessment of the clinical endpoint. The main objective of this narrative review was to evaluate the efficacy of drugs used in clinical trials for the treatment of NAFLD/NASH that included a liver biopsy as the gold standard. Methods: A literature search was conducted using 3 databases (PubMed, Scopus, and Google Scholar) to identify the clinical trials that included liver biopsy assessment before and after treatment. Results: Interventional clinical trials (n = 33) involving 18 different agents, alone and in combination, were identified. Pioglitazone is the only agent that has shown consistent benefit and efficacy in clinical trials. Pentoxifylline, rosiglitazone, and ursodeoxycholic acid had both positive and negative results from clinical trials. There is also evidence for vitamin E and metformin. Other drugs, including bicyclol, cysteamine bitartrate, l-carnitine, liraglutide, obeticholic acid, oligofructose, selonsertib, silymarin, and statins, each had a single clinical study. Conclusions: In summary, the available molecules demonstrated a significant improvement in NASH and/or liver fibrosis in a minority of patients; thus, other drugs should be identified, possibly those acting on alternative pathophysiological pathways, and tested for their safety and efficacy.