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Background: Glycosylation, i.e the enzymatic addition of oligosaccharides (or glycans) to proteins and lipids, known as glycosylation, is one of the most common co-/posttranslational modifications of proteins. Many important biological roles of glycoproteins are modulated by N-linked oligosaccharides. As glucose levels can affect the pathways leading to glycosylation of proteins, we investigated whether metabolic syndrome (MS) and type 2 diabetes mellitus (T2DM), pathological conditions characterized by altered glucose levels, are associated with specific modifications in serum N-glycome., Methods: We enrolled in the study 562 patients with Type 2 Diabetes Mellitus (T2DM) (mean age 65.6±8.2 years) and 599 healthy control subjects (CTRs) (mean age, 58.5±12.4 years). N-glycome was evaluated in serum glycoproteins., Results: We found significant changes in N-glycan composition in the sera of T2DM patients. In particular, α(1,6)-linked arm monogalactosylated, core-fucosylated diantennary N-glycans (NG1(6)A2F) were significantly reduced in T2DM compared with CTR subjects. Importantly, they were equally reduced in diabetic patients with and without complications (P<0.001) compared with CTRs. Macro vascular-complications were found to be related with decreased levels of NG1(6)A2F. In addition, NG1(6)A2F and NG1(3)A2F, identifying, respectively, monogalactosylated N-glycans with α(1,6)- and α(1,3)-antennary galactosylation, resulted strongly correlated with most MS parameters. The plasmatic levels of these two glycans were lower in T2DM as compared to healthy controls, and even lower in patients with complications and MS, that is the extreme "unhealthy" phenotype (T2DM+ with MS)., Conclusions: Imbalance of glycosyltransferases, glycosidases and sugar nucleotide donor levels is able to cause the structural changes evidenced by our findings. Serum N-glycan profiles are thus sensitive to the presence of diabetes and MS. Serum N-glycan levels could therefore provide a non-invasive alternative marker for T2DM and MS.

Background: Carbapenem-resistant Acinetobacter baumannii (CRAB) is of critical concern in healthcare settings, leading to limited treatment options. In this study, we conducted a comprehensive meta-analysis to assess the prevalence of CRAB by examining temporal, geographic, and bias-related variations. Methods: We systematically searched prominent databases, including Scopus, PubMed, Web of Science, and EMBASE. Quality assessment was performed using the JBI checklist. Subgroup analyses were performed based on the COVID-19 timeframes, years, countries, continents, and bias levels, antimicrobial susceptivity test method and guidelines. Results: Our comprehensive meta-analysis, which included 795 studies across 80 countries from 1995 to 2023, revealed a surge in carbapenem resistance among A. baumannii, imipenem (76.1%), meropenem (73.5%), doripenem (73.0%), ertapenem (83.7%), and carbapenems (74.3%). Temporally, 2020–2023 witnessed significant peaks, particularly in carbapenems (81.0%) and meropenem (80.7%), as confirmed by meta-regression, indicating a steady upward trend. Conclusion: This meta-analysis revealed an alarmingly high resistance rate to CRAB as a global challenge, emphasizing the urgent need for tailored interventions. Transparency, standardized methodologies, and collaboration are crucial for the accurate assessment and maintenance of carbapenem efficacy. [ABSTRACT FROM AUTHOR]

Aims: To explore factors that may contribute to a possible reduced compliance in patients with type 2 diabetes mellitus (T2DM) with a migrant (i.e. North African) background living in a western society. Methods: Semi-structured interviews with people with T2DM both of Moroccan and Belgian origin, recruited within the diabetes clinic of the University Hospital Brussel, Belgium. Data was analysed thematically using NVivo. Results: Participants indicated they were adequately informed about T2DM, however results show a demand for culturally tailored preventive education for Moroccan participants. Both groups generally had good knowledge of a healthy lifestyle and what is expected after diagnosis, but considered maintaining healthy lifestyle and correct medication adherence, intensive. Participants mentioned a wide range of themes that affected their compliance, both positively and negatively. Perceived barriers were social issues, lack of motivation, insufficient support from the environment, stress, forgetfulness, winter conditions and COVID. Culturally shaped views on eating habits, illness, medication use and health were clear barriers in the Moroccan group. Conclusion: Findings highlight the need for future in depth research into diabetes related knowledge within the Moroccan community living in Belgium (and similar other Western countries) whilst considering differences between generations of migrants, gender and level of education. [ABSTRACT FROM AUTHOR]

Introduction: Contradictory claims about the efficacy of several medicinal plants to promote glycemic control in patients with type 2 diabetes mellitus (T2DM) have been explained by divergences in the administration form and by extrapolation of data obtained from healthy individuals. It is not known whether the antidiabetic effects of traditional herbal medicines are influenced by gelatin capsules. This randomized crossover trial aimed to evaluate the acute effect of a single dose of raw cinnamon consumed orally either dissolved in water as a beverage or as ordinary hard gelatin capsules on postprandial hyperglycemia (>140 mg/dL; >7.8 mmol/L) in T2DM patients elicited by a nutritionally-balanced meal providing 50 g of complex carbohydrates. Methods: Fasting T2DM patients (n = 19) randomly ingested a standardized meal in five experimental sessions, one alone (Control) and the other after prior intake of 3 or 6 g of crude cinnamon in the form of hard gelatin capsules or powder dissolved in water. Blood glucose was measured at fasting and at 0.25, 0.5, 0.75, 1, 1.5 and 2 hours postprandially. After each breakfast, its palatability scores for visual appeal, smell and pleasantness of taste were assessed, as well as the taste intensity sweetness, saltiness, bitterness, sourness and creaminess. Results: The intake of raw cinnamon dissolved in water, independently of the dose, decreased the meal-induced large glucose spike (peak-rise of +87 mg/dL and Δ1-hour glycemia of +79 mg/dL) and the hyperglycemic blood glucose peak. When cinnamon was taken as capsules, these anti-hyperglycemic effects were lost or significantly diminished. Raw cinnamon intake did not change time-to-peak or the 2-h post-meal glycaemia, but flattened the glycemic curve (lower iAUC) without changing the shape that is typical of T2DM patients. Conclusions: This cinnamon's antihyperglycemic action confirms its acarbose-like property to inhibit the activities of the carbohydrate-digesting enzymes α-amylases/α-glucosidases, which is in accordance with its exceptionally high content of raw insoluble fiber. The efficacy of using raw cinnamon as a diabetes treatment strategy seems to require its intake at a specific time before/concomitantly the main hyperglycemic daily meals. Trial registration: Registro Brasileiro de Ensaios Clínicos (ReBEC), number RBR-98tx28b. [ABSTRACT FROM AUTHOR]

Mitochondrial dysfunction has been implicated in rare and common forms of type 2 diabetes (T2DM). Additionally, rare mitochondrial DNA (mtDNA) mutations have been shown to be causal for T2DM pathogenesis. So far, many studies have investigated the possibility that mtDNA variation might affect the risk of T2DM, however, when found, haplogroup association has been rarely replicated, even in related populations, possibly due to an inadequate level of haplogroup resolution. Effects of mtDNA variation on diabetes complications have also been proposed. However, additional studies evaluating the mitochondrial role on both T2DM and related complications are badly needed. To test the hypothesis of a mitochondrial genome effect on diabetes and its complications, we genotyped the mtDNAs of 466 T2DM patients and 438 controls from a regional population of central Italy (Marche). Based on the most updated mtDNA phylogeny, all 904 samples were classified into 57 different mitochondrial sub-haplogroups, thus reaching an unprecedented level of resolution. We then evaluated whether the susceptibility of developing T2DM or its complications differed among the identified haplogroups, considering also the potential effects of phenotypical and clinical variables. MtDNA backgrounds, even when based on a refined haplogroup classification, do not appear to play a role in developing T2DM despite a possible protective effect for the common European haplogroup H1, which harbors the G3010A transition in the MTRNR2 gene. In contrast, our data indicate that different mitochondrial haplogroups are significantly associated with an increased risk of specific diabetes complications: H (the most frequent European haplogroup) with retinopathy, H3 with neuropathy, U3 with nephropathy, and V with renal failure.

The burden of diabetes is rising in developing countries, and this is significantly linked to the increasing prevalence of poor glycemic control. The cost of glycated haemoglobin (HbA1c) testing is a barrier to timely glycemic assessments, but newer tests such as glycated albumin may be cheaper and tempting alternatives. Additional research must ascertain if glycated albumin (GA) can act as a viable supplement or alternative to conventional HbA1c measurements for glycemic control in diabetic individuals. GA as a biomarker is an emerging area of interest, particularly for those who display unreliable HbA1c levels or cannot afford the test. This study aims to investigate the prevalence of poor glycemic control in outpatient diabetic patients and the utility of glycated albumin in this population's monitoring of glycemic control. Method. A cross-sectional study of 203 diabetic patients will be conducted at the Dodoma Regional Referral Hospital and Benjamin Mkapa Hospital from August 1st, 2023, to August 31st, 2024. Patients diagnosed with diabetes mellitus for over six months will be screened for eligibility. Informed consent, history, clinical examination, and voluntary blood sample collection will be obtained from all eligible patients. Glycated Albumin levels will be obtained from the same blood samples collected. The glycemic status of all patients will be defined as per HbA1c, and a level of greater than 7% will considered as a poor control. The analysis will be computed with SPSS version 28.0, and a predictor variable, P<0.05, will be regarded as statistically significant, with the utility of GA determined by plotting the area under the ROC curve and the confusion matrix. [ABSTRACT FROM AUTHOR]

Background and objectives: Emerging research suggests that hyperammonemia may enhance the probability of hepatic encephalopathy (HE), a condition associated with elevated levels of circulating ammonia in patients with cirrhosis. However, some studies indicate that blood ammonia levels may not consistently correlate with the severity of HE, highlighting the complex pathophysiology of this condition. Methods: A systematic review and meta-analysis through PubMed, Scopus, Embase, Web of Science, and Virtual Health Library were conducted to address this complexity, analyzing and comparing published data on various laboratory parameters, including circulating ammonia, blood creatinine, albumin, sodium, and inflammation markers in cirrhotic patients, both with and without HE. Results: This comprehensive review, which included 81 studies from five reputable databases until June 2024, revealed a significant increase in circulating ammonia levels in cirrhotic patients with HE, particularly those with overt HE. Notably, significant alterations were observed in the circulating creatinine, albumin, sodium, interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNFα) in HE patients. Conclusions: These findings suggest an association between ammonia and HE and underscore the importance of considering other blood parameters such as creatinine, albumin, sodium, and pro-inflammatory cytokines when devising new treatment strategies for HE. [ABSTRACT FROM AUTHOR]

Background: A randomized clinical trial to evaluate the effect of a Mediterranean-style diet on vascular health indices such as endothelial function indices, serum lipid and ceramide plasma and some adipokine serum levels. We recruited all consecutive patients at high risk of cardiovascular diseases admitted to the Internal Medicine and Stroke Care ward at the University Hospital of Palermo between September 2017 and December 2020. Materials and methods: The enrolled subjects, after the evaluation of the degree of adherence to a dietary regimen of the Mediterranean-style diet, were randomised to a Mediterranean Diet (group A) assessing the adherence to a Mediterranean-style diet at each follow up visit (every three months) for the entire duration of the study (twelve months) and to a Low-fat diet (group B) with a dietary "counselling" starting every three months for the entire duration of the study (twelve months).The aims of the study were to evaluate: the effects of adherence to Mediterranean Diet on some surrogate markers of vascular damage, such as endothelial function measured by means of the reactive hyperaemia index (RHI) and augmentation index (AIX), at the 6-(T1) and 12-month (T2) follow-ups; the effects of adherence to Mediterranean Diet on the lipidaemic profile and on serum levels of ceramides at T1 and T2 follow-ups; the effects of adherence to Mediterranean Diet on serum levels of visfatin, adiponectin and resistin at the 6- and 12-month follow-ups. Results: A total of 101 patients were randomised to a Mediterranean Diet style and 52 control subjects were randomised to a low-fat diet with a dietary "counselling". At the six-month follow-up (T1), subjects in the Mediterranean Diet group showed significantly lower mean serum total cholesterol levels, and significantly higher increase in reactive hyperaemia index (RHI) values compared to the low-fat diet group. Patients in the Mediterranean Diet group also showed lower serum levels of resistin and visfatin at the six-month follow-up compared to the control group, as well as higher values ​​of adiponectin, lower values of C24:0, higher values of C22:0 and higher values of the C24:0/C16:0 ratio. At the twelve-month follow-up (T2), subjects in the Mediterranean Diet group showed lower serum total cholesterol levels and lower serum LDL cholesterol levels than those in the control group. At the twelve-month follow-up, we also observed a further significant increase in the mean RHI in the Mediterranean Diet group, lower serum levels of resistin and visfatin, lower values of C24:0 and of C:18:0,and higher values of the C24:0/C16:0 ratio. Discussion: The findings of our current study offer a further possible explanation with regard to the beneficial effects of a higher degree of adherence to a Mediterranean-style diet on multiple cardiovascular risk factors and the underlying mechanisms of atherosclerosis. Moreover, these findings provide an additional plausible interpretation of the results from observational and cohort studies linking high adherence to a Mediterranean-style diet with lower total mortality and a decrease in cardiovascular events and cardiovascular mortality. Trial registration: ClinicalTrials.gov Identifier: NCT04873167. https://classic.clinicaltrials.gov/ct2/show/NCT04873167. [ABSTRACT FROM AUTHOR]

Aims: To evaluate whether parameters of post-hypoglycemic hyperglycemia (PHH) correlated with glucose homeostasis during the first year after type 1 diabetes onset and helped to distinguish pediatric patients undergoing partial remission or not. Methods: In the GLUREDIA (GLUcagon Response to hypoglycemia in children and adolescents with new-onset type 1 DIAbetes) study, longitudinal values of clinical parameters, continuous glucose monitoring metrics and residual β-cell secretion from children with new-onset type 1 diabetes were analyzed during the first year after disease onset. PHH parameters were calculated using an in-house algorithm. Correlations between PHH parameters (i.e., PHH frequency, PHH duration, PHH area under the curve [PHHAUC]) and glycemic homeostasis markers were studied using adjusted mixed-effects models. Results: PHH parameters were strong markers to differentiate remitters from non-remitters with PHH/Hyperglycemia duration ratio being the most sensitive (ratio<0.02; sensitivity = 86% and specificity = 68%). PHHAUC moderately correlated with parameters of glucose homeostasis including TIR (R2 = 0.35, p-value < 0.05), coefficient of variation (R2 = 0.22, p-value < 0.05) and Insulin-Dose Adjusted A1c (IDAA1C) (R2 = 0.32, p-value < 0.05) and with residual β-cell secretion (R2= 0.17, p-value < 0.05). Classification of patients into four previously described glucotypes independently validated PHH parameters as reliable markers of glucose homeostasis and improved the segregation of patients with intermediate values of IDAA1C and estimated C-peptide (CPEPEST). Finally, a combination of PHH parameters identified groups of patients with specific patterns of hypoglycemia. Conclusion: PHH parameters are new minimal-invasive markers to discriminate remitters from non-remitters and evaluate glycemic homeostasis during the first year of type 1 diabetes. PHH parameters may also allow patient-targeted therapeutic management of hypoglycemic episodes. [ABSTRACT FROM AUTHOR]

The current study was proposed to explore the role of dietary propolis (PR) supplementation in alleviating the negative effects of columnaris disease (CD) challenge on the growth performance, plasma biochemicals, antioxidant activity, stress indicators, and immunological reactions of common carp (Cyprinus carpio) fish. Five hundred forty common carp juveniles were evenly placed in thirty-six 100-L tanks and stocked for acclimatization to the lab conditions with a control diet within a started period of 14 days. Fish (average initial weight of 7.11±0.06 g) were randomly distributed into one of six treatment groups (6 replicate tanks × 15 fish per tank in each treatment group). Fish in the first group was assigned as a negative control without CD challenge or PR supplementation. Fish in the other five groups were challenged with CD by immersion of fish for 60 min into a 10-L water bath supplemented with 6×106 CFU/mL (median lethal dose, LD50) of pathogenic F. columnare bacteria. After infection, the fish were restored to their tanks and fed on a basal diet supplemented with PR at 0, 3, 6, 9, or 12 g/kg diet. The experimental period continued for 6 consecutive weeks in which the feed was introduced twice a day (8:00 and 15:00 h) at a rate of 2% of the fish biomass. Ten percent of water was siphoned and renewed after each meal every day, in addition to 50% of water refreshment after cleaning the tank every three days. The tanks were continuously aerated and provided with standard rearing conditions for carp fish (24.0±1.12°C, 7.7±0.22 pH, 6.3±0.16 mg/L O2, and 14L/10D photoperiod). The growth performance traits such as feed intake (FI), weight gain (WG), final weight (FW), specific growth rate (SGR), feed efficiency (FE), and cumulative mortality rates (CM) were recorded during the experimental period. At the end of the trial, blood samples were obtained from the fish to evaluate some plasma biochemicals, including aspartate aminotransaminase (AST), alanine aminotransferase (ALT), creatinine (CRE), alkaline phosphatase (ALP), and lactate dehydrogenase (LDH), antioxidant biomarkers, including total antioxidant capacity (TAOC), total superoxide dismutase (TSOD), reduced glutathione (rGSH), and catalase (CAT), stress indicators, including heterophil to lymphocyte (H/L) ratio, cortisol (COR), malondialdehyde (MDA), and myeloperoxidase (MPO), and immunological reactions, including peripheral blood leukocyte proliferation (PBLP), phagocytosis activity (PHG), lysozyme activity (LYS), alternative complement hemolytic action (ACH50), and total immunoglobulin concentration (TIG). In addition, samples of infected fish gills were taken to quantify the number of F. columnare in the PR-supplemented groups using the quantitative real-time polymerase chain reaction (qPCR) technique. The results showed that incorporating PR into the dietary ingredients of common carp has a protective effect against the challenge with F. columnare infection. There were linear and quadratic positive trends (P < 0.05) in most parameters of growth performance, plasma biochemicals, antioxidant activity, stress indicators, and immunological reactions with the increased PR-supplemented levels in the diet of infected fish. The best results were obtained when using PR at 9 g/kg in the diet, while higher levels (12 g/kg PR) showed an adverse trend in the evaluated parameters. The FI, WG, FW, SGR, and FE were improved by approximately 37, 104, 34, 73, and 49% in the fish treated with 9 g/kg PR compared to none-PR-infected fish. In addition, adding PR at the 9 g/kg diet level was the best dose that reduced the H/L ratio, COR, MDA, and MPO by about 14, 52, 48, and 29%, respectively, in the infected fish. Furthermore, the mortality rate was reduced by 94%, and the number of pathogenic bacteria cells adherent to the fish gills was lowered by 96% in the infected fish treated with 9 g/kg PR compared to none-PR infected fish. Our results concluded that dietary supplementation with 9 g/kg PR could be a promising nutritional approach for improving the growth performance, physiological profile, and health status of common carp fish, particularly when challenged with F. columnare or similar bacterial infections. [ABSTRACT FROM AUTHOR]

Background/objectives: We aimed to determine whether serum uric acid (SUA) and body mass index (BMI) trajectories in childhood have longitudinal association with liver enzymes in adolescence. Methods: We conducted a study using data from the Ewha Birth and Growth Cohort. Individual trajectories of SUA (n = 203) and BMI (n = 206) from 5, 7, and 9 years were defined by group-based trajectory modeling. Also, liver function enzymes were collected at 11 to 12 year of age (Aspartate Aminotransferase [AST], Alanine transaminase [ALT], and Gamma-glutamyl transferase [γ–GTP]) (n = 206). Using a generalized linear model, the effects of SUA trajectory and BMI trajectory on liver function enzymes were assessed. We also assessed the interaction effect of SUA and BMI trajectories on liver enzymes. Results: For trajectory patterns, both SUA and BMI were classified into two distinct groups (High or Low). Both trajectory of SUA and BMI in childhood were positively associated with levels of liver enzymes at 11–12 years of age. The results showed that the combined effect of SUA and BMI trajectories on liver enzymes had a higher means in high-risk group (high SUA–high BMI trajectories group) than in low-risk group (low SUA-low BMI trajectories group) for ALT and γ–GTP, respectively. It remained significant association when adjusted for covariates. In addition, the interaction of BMI and SUA trajectories showed a significant synergistic effect. Conclusion: Elevated childhood SUA and BMI trajectories are associated with increased liver enzymes in beginning of adolescent. This finding suggesting that early interventions in SUA and BMI may need for optimization of liver enzymes as potential marker for development of related disease in later life. [ABSTRACT FROM AUTHOR]

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by deficits in communication, and social skills, as well as repetitive and/or restrictive interests and behaviors. The severity of ASD varies from mild to severe, drastically interfering with the quality of life of affected individuals. The current occurrence of ASD in the United States is about 1 in 44 children. The precise pathophysiology of ASD is still unknown, but it is believed that ASD is heterogeneous and can arise due to genetic etiology. Although various genes have been implicated in predisposition to ASD, metabotropic glutamate receptor 5 (mGluR5) is one of the most common downstream targets, which may be involved in autism. mGluR5 signaling has been shown to play a crucial role in neurodevelopment and neural transmission making it a very attractive target for understanding the pathogenesis of ASD. In the present study, we determined the effect of genetic ablation of mGluR5 (Grm5) on an ASD-like phenotype using a rat model to better understand the role of mGluR5 signaling in behavior patterns and clinical manifestations of ASD. We observed that mGluR5 Ko rats exhibited exaggerated self-grooming and increased marble burying, as well as deficits in social novelty. Our results suggest that mGluR5 Ko rats demonstrate an ASD-like phenotype, specifically impaired social interaction as well as repetitive and anxiety-like behavior, which are correlates of behavior symptoms observed in individuals with ASD. The mGluR5 Ko rat model characterized in this study may be explored to understand the molecular mechanisms underlying ASD and for developing effective therapeutic modalities. [ABSTRACT FROM AUTHOR]

Background: The COVID-19 pandemic claimed millions of lives worldwide without clear signs of abating despite several mitigation efforts and vaccination campaigns. There have been tremendous interests in understanding the etiology of the disease particularly in what makes it severe and fatal in certain patients. Studies have shown that COVID-19 patients with kidney injury on admission were more likely to develop severe disease, and acute kidney disease was associated with high mortality in COVID-19 hospitalized patients. Methods: This study investigated 819 COVID-19 patients admitted between January 2020-April 2021 to the COVID-19 ward at a tertiary care center in Lebanon and evaluated their vital signs and biomarkers while probing for two main outcomes: intubation and fatality. Logistic and Cox regressions were performed to investigate the association between clinical and metabolic variables and disease outcomes, mainly intubation and mortality. Times were defined in terms of admission and discharge/fatality for COVID-19, with no other exclusions. Results: Regression analysis revealed that the following are independent risk factors for both intubation and fatality respectively: diabetes (p = 0.021 and p = 0.04), being overweight (p = 0.021 and p = 0.072), chronic kidney disease (p = 0.045 and p = 0.001), and gender (p = 0.016 and p = 0.114). Further, shortness of breath (p<0.001), age (p<0.001) and being overweight (p = 0.014) associated with intubation, while fatality with shortness of breath (p<0.001) in our group of patients. Elevated level of serum creatinine was the highest factor associated with fatality (p = 0.002), while both white blood count (p<0.001) and serum glutamic-oxaloacetic transaminase levels (p<0.001) emerged as independent risk factors for intubation. Conclusions: Collectively our data show that high creatinine levels were significantly associated with fatality in our COVID-19 study patients, underscoring the importance of kidney function as a main modulator of SARS-CoV-2 morbidity and favor a careful and proactive management of patients with elevated creatinine levels on admission. [ABSTRACT FROM AUTHOR]

Objectives: To investigate the clinical characteristics, risk factors, and predictors of esophagogastric variceal bleeding in patients with hepatitis C virus (HCV)-induced liver cirrhosis. Methods: This comparative observational study was carried out on 100 patients suffering from post hepatitis cirrhosis and portal hypertension who were admitted to the Internal Medicine Department, Al-Azhar University Hospital, Damietta Egypt. Patients were classified into two groups: 50 of them presented with esophagogastric varices with acute variceal bleeding, and 50 patients presented without bleeding. Data were collected, coded, revised, and entered into the Stata software version 16. Results: The mean age of patients with bleeding was slightly higher than those without bleeding (55.58 ± 5.89 vs. 52.54 ± 9.01 years), p = 0.049. Mild ascites, positive H.Pylori, and Child-Pugh score B and C were an independent predictors of esophagogastric variceal bleeding (OR = 0.036, 95% CI: 0.0004–0.36; p = 0.005), (OR = 7.36, 95% CI: 1.44–37.59; p = 0.016), (OR = 19.0, 95% CI: 2.02–186.3; p = 0.010), and (OR = 40.51, 95% CI: 2.18–751.31; p = 0.013). The sensitivity of this model was 93.88%, specificity was 53.85%, PPV was 88.46%, NPV was 70.0%, correctly classified patients were 85.48%, and AUC was 90.27%. In the second model, pepsinogen level higher than 43.5 μg/l, AST (>54.5), Bilirubin (>1.45), and Hemoglobin (>11.5) were a significant independent predictors of esophagogastric variceal bleeding (OR = 1.18, 95% CI: 1.09–1.27; p<0.001), (OR = 1.14, 95% CI: 1.03–1.27; p = 0.007), (OR = 5.55, 95% CI: 1.21–25.43; p = 0.027), and (OR = 0.05, 95% CI: 0.008–0.32; p = 0.002), respectively. The sensitivity of this model was 92%, specificity was 98%, PPV was 97.87%, NPV was 92.45%, correctly classified patients were 95%, and AUC was 98.68%. Conclusion: The independent predictors of esophagogastric variceal bleeding were ascites, positive H. pylori, Child-Pugh score B and C, pepsinogen level higher than 43.5 μg/l, AST (>54.5), bilirubin (>1.45), and hemoglobin (>11.5). Laboratory investigations are more reliable in predicting variceal bleeding and excluding non-variceal bleeding; however, clinical symptoms should not be neglected, especially H. pylori infection, ascites, and Child-Pugh score. [ABSTRACT FROM AUTHOR]

Corn ethanol production has been growing in Brazil in the last ten years, generating by-products to feedlot diets. This study evaluates the effects of the inclusion of low-fat corn wet distillers grains (LF-WDG) on feeding behavior, ruminal health, liver abscesses and blood parameters of F1 Angus-Nellore bulls feedlot finished. Our hypothesis is that evaluation of data from feeding behavior, rumen and liver health would help to explain animal performance. In this trail, one-hundred animals were fed for 129 days with diets containing amounts of 0 (control), 15, 30 and 45% of LF-WDG replacing corn grain and soybean meal. Evaluations of fluctuation of dry matter intake (DMI) were carried out. Additionally, feeding behavior data were assessed by monitoring (24-h period) the feeding, rumination, time spent eating (TSE), and time expended on other activities (resting and number of meals per day). Blood variables such as pH, bicarbonate, total CO2 content, and base excess in extracellular fluid (Beecf) were determined. After slaughter, rumen epithelium was classified according to the incidence of lesions (rumenitis) and abnormalities (papillae clumped), and samples were collected for morphology and histology evaluations. Moreover, livers were scored for severity of abscesses as follow: as unabscessed (0), one or two small abscesses (A−), two to four small active abscesses (A) or one or more large, active abscesses (A+). The DMI (kg/day) differed (P = 0.03) among treatments and there is a tendency of 15 and 30 LF-WDG (% DM) had lower %DMI fluctuation compared to 0 or 45%. The TSE increased linearly (P < 0.01) as the amounts of inclusion of LF-WDG increased. Moreover, neutral detergent fiber (NDF) intake, NDF consumption rate and NDF rumination efficiency increased linearly (P < 0.01) in response to LF-WDG feeding. The incidence of rumenitis tended (P = 0.08) to be greater at 45% LF-WDG, while keratin thickness decreased linearly in bulls fed LF-WDG (P < 0.01). The severity of liver abscesses (score A+) increased linearly (P = 0.02). Regarding blood parameters, only Beecf decreased linearly (P < 0.01) in response to LF-WDG feeding. Therefore, the hypothesis of the current study was confirmed. We previous reported that F1 Angus-Nellore bulls fed LF-WDG show greater weight gain (1.94 ± 0.09 kg/day) and final body weight (620 ± 18.8 kg) when compare to control (1.8 ± 0.09 kg/day and 602 ± 18.8 kg, respectively). Here, we conclude that inclusion of 15 to 30% LF-WDG in feedlot diets improved feeding behavior without impairing ruminal health and blood parameters, driving performance and weigh gain of crossbred bulls. However, bulls fed 45% LF-WDG had greater severity of liver abscesses. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is one of the world's most risky diseases due to the lack of clear and cost-effective therapeutic targets. Currently, the toxicity of conventional chemotherapeutic medications and the development of multidrug resistance is driving research into targeted therapies. The nano-biomedical field's potential for developing an effective therapeutic nano-sized drug delivery system is viewed as a significant pharmaceutical trend for the encapsulation and release of numerous anticancer therapies. In this regard, current research is centered on the creation of biodegradable chitosan nanoparticles (CSNPs) for the selective and sustained release of bee venom into liver cancer cells. Furthermore, surface modification with polyethylene glycol (PEG) and GE11 peptide-conjugated bee venom-CSNPs allows for the targeting of EGFR-overexpressed liver cancer cells. A series of in vitro and in vivo cellular analyses were used to investigate the antitumor effects and mechanisms of targeted bee venom-CSNPs. Targeted bee venom-CSNPs, in particular, were found to have higher cytotoxicity against HepG2 cells than SMMC-7721 cells, as well as stronger cellular uptake and a substantial reduction in cell migration, leading to improved cancer suppression. It also promotes cancer cell death in EGFR overexpressed HepG2 cells by boosting reactive oxygen species, activating mitochondria-dependent pathways, inhibiting EGFR-stimulated MEK/ERK pathway, and elevating p38-MAPK in comparison to native bee venom. In hepatocellular carcinoma (HCC)-induced mice, it has anti-cancer properties against tumor tissue. It also improved liver function and architecture without causing any noticeable toxic side effects, as well as inhibiting tumor growth by activating the apoptotic pathway. The design of this cancer-targeted nanoparticle establishes GE11-bee venom-CSNPs as a potential chemotherapeutic treatment for EGFR over-expressed malignancies. Finally, our work elucidates the molecular mechanism underlying the anticancer selectivity of targeted bee venom-CSNPs and outlines therapeutic strategies to target liver cancer. [ABSTRACT FROM AUTHOR]

Background: Few studies have analyzed the relationship between glucose variability (GV) and adverse health outcomes in patients with differences in glycemic status. The present study tests the hypothesis that GV predicts all-cause mortality regardless of glycemic status after simple adjustment (age and sex) and full adjustment (age, sex, cardiovascular disease, hypertension, use of aspirin, statins, GLP-1 receptor agonists, SGLT-2 inhibitors and DPP-4 inhibitors, baseline FPG and average HbA1c). Methods: Prospective cohort study with 795 normoglycemic patients, 233 patients with prediabetes, and 4,102 patients with type 2 diabetes. GV was measured using the coefficient of variation of fasting plasma glucose (CV-FPG) over 12 years of follow-up. The outcome measure was all-cause mortality. Results: A total of 1,223 patients (657 men, 566 women) died after a median of 9.8 years of follow-up, with an all-cause mortality rate of 23.35/1,000 person-years. In prediabetes or T2DM patients, the fourth quartile of CV-FPG exerted a significant effect on all-cause mortality after simple and full adjustment. A sensitivity analysis excluding participants who died during the first year of follow-up revealed the following results for the highest quartile in the fully adjusted model: overall, HR (95%CI) = 1.54 (1.26–1.89); dysglycemia (prediabetes and T2DM), HR = 1.41 (1.15–1.73); T2DM, HR = 1.36 (1.10–1.67). Conclusion: We found CV-FPG to be useful for measurement of GV. It could also be used for the prognostic stratification of patients with dysglycemia. [ABSTRACT FROM AUTHOR]

Introduction: Neurotropic pathogens such as Toxoplasma gondii (T. gondii) which result in chronic infections in the brain are associated with mental illnesses. In view of this, a growing body of literature has revealed the possible interaction of schizophrenia and T. gondii infection. Method: A case-control study was conducted from February 2018 to January 2019 among 47 Schizophrenia patients and 47 age and sex-matched controls. Data was collected using a structured questionnaire. Serum was used for serological analysis of anti-T. gondii IgG and IgM antibodies through chemiluminescent immunoassay. Proportions and mean with standard deviations (SD) were used as descriptive measures and variables with p-values <0.05 were considered as statistically significant and independently associated with schizophrenia. Result: The mean ages of schizophrenia patients and controls were 29.64 ± 5.8 yrs and 30.98 ± 7.3 yrs, respectively. We found that 81.9% (77/94) of the study subjects had a positive anti-T. gondii IgG antibody. While the difference is statistically insignificant, schizophrenic patients have a marginally higher seroprevalence of toxoplasmosis than controls (87.2% vs 80.9%; p = 0.398). Schizophrenia cases who live in homes with soil floors have a significantly higher T. gondii infection as compared to those who live in homes with cement/ceramic floors (90.9% vs 33.3%; p = 0.004). Furthermore, there was a significantly lower T. gondii infection among schizophrenic cases who were taking antipsychotic medication for more than three yrs (79.3% vs 100.0%, p = 0.039). On the other hand, among all study subjects who have T. gondii infection, subjects who are addicted to khat and alcohol were about seven times more likely to develop schizophrenia (71.4% vs 47.7%, OR = 7.13, p = 0.024). Conclusion: Our data is not sufficient to show a significant positive correlation between T. gondii infection and schizophrenia. For study subjects with T. gondii infection, addiction to khat and alcohol is one of the risk factors for schizophrenia. [ABSTRACT FROM AUTHOR]

Background: Given the rapidly increasing number of immigrants, it is crucial to address health care issues involving immigrants to facilitate their safe and secure settlement. Especially for common chronic diseases, such as diabetes, immigrants face more complex obstacles to manage their chronic conditions than do native-born residents. Therefore, we aimed to assess differences in the incidence and associated risk factors of cardio-cerebrovascular (CCV) complications of immigrants compared with native-born Koreans with diabetes. Methods: Immigrants and native-born Koreans who had new diagnosis of diabetes and simultaneously received anti-diabetic prescriptions in 2012 were defined by using Korean National Health Insurance Claim Database(KNHICD). CCV complications were assessed at a 3-year follow-up from the index date. We assessed differences in the CCV complications and risk factors using multiple cox regression models. Results: In total, 4,008 patients (668 of immigrants and 3,340 of native-born Koreans) who had newly diagnosed diabetes and simultaneously received anti-diabetic prescriptions in 2012 were selected. Immigrants with diabetes were at a 1.39 times higher risk of having CCV complications than native-born Koreans with diabetes (95% CI: 1.021–1.881). Patients who had a usual sources of care (USC) presented a significantly reduced risk of cardio-cerebrovascular complication (HR: 0.452; 95% CI: 0.342–0.598) in both immigrants and native Koreans. In subgroup analysis in immigrants, patients having USC showed decreased risk of CCV incidence (HR: 0.35, 95% CI: 0.175–0.703), whereas >60 years old and Charlson comorbidity index (CCI) score >1 presented increased risk of CCV complications. Conclusion: Immigrants with diabetes have a higher risk of CCV complications than native-born Koreans with diabetes. However, having a USC significantly decreased the risk of CCV complications. Therefore, the utilization of USC will benefit to reduce diabetic complications in immigrants as well as reduction of overall health care cost burden, it would be necessary to implement USC in diabetes care at the initial disease stage. [ABSTRACT FROM AUTHOR]

Background: Polypharmacy, defined as the concurrent use of ≥5 medications, increases the risk of drug-drug and drug-disease interactions as well as non-adherence to drug therapy. This may have negative health consequences particularly among older adults due to age-related pharmacokinetic and pharmacodynamic changes. This study aims to uncover the occurrence of polypharmacy among older adults in Denmark and investigate how polypharmacy relates to mortality. Method: This nationwide register-based study included 1,338,058 adults aged 65+ years between January 2013 and December 2017 in Denmark. Polypharmacy prevalence was measured at time of inclusion while incidence and the association between polypharmacy and mortality were measured over the five-year follow-up using Cox regression. In an attempt to adjust for confounding by indication, propensity scores with overlap weighting were introduced to the regression model. Results: At time of inclusion, polypharmacy prevalence was 29% and over the five years follow-up, 47% of the remaining adults transitioned into polypharmacy. Identified risk factors included multimorbidity (2+ morbidities: HR = 3.51; 95% CI = 3.48–3.53), age (95+ years: HR = 2.85; 95% CI = 2.74–2.96), socioeconomic factors (Highest income quartile: HR = 0.81; 95% CI = 0.80–0.81), region of birth region (Non-western migrants: HR = 0.77; 95% CI = 0.75–0.79), marital status (Divorced: HR = 1.10; 95% CI = 1.10–1.12) and year of inclusion (2017: HR = 1.19; 95% CI = 1.19–1.22). Further analyses showed that polypharmacy involves many different drug cocktails with medication for the cardiovascular system (95%), blood and blood-forming organs (69%), alimentary tract and metabolism (61%) and nervous system (54%) contributing the most. After adjustment for propensity scores with OW, both polypharmacy (HR = 3.48, CI95% = 3.41–3.54) and excessive polypharmacy (HR = 3.48, CI95% = 3.43–3.53) increased the risk of death substantially. Conclusion: A considerable proportion of older adults in Denmark were exposed to polypharmacy dependent on health status, socio-economic status, and societal factors. The associated three- to four-fold mortality risk indicate a need for further exploration of the appropriateness of polypharmacy among older adults. [ABSTRACT FROM AUTHOR]

Patients with type 2 diabetes who have cardiovascular disease and are receiving empagliflozin have a lower rate of primary composite cardiovascular outcomes. In contrast, glimepiride increases cardiovascular hospitalization when combined with metformin. Here, we assessed the effects of empagliflozin and glimepiride on endothelial function using flow-mediated dilation (FMD). In this prospective, open-label, randomized, parallel-group study, 63 patients with type 2 diabetes received metformin and insulin glargine U100 for 12 weeks. This was followed by additional treatment with empagliflozin or glimepiride for 12 weeks. The primary outcome was the change in the FMD measurement (ΔFMDs) at 24 weeks of additional treatment. Secondary outcomes comprised changes in metabolic markers and body composition. The empagliflozin group (n = 33) and glimepiride group (n = 30) showed no significant differences in ΔFMDs (empagliflozin, −0.11 [95%CI: -1.02, 0.80]%; glimepiride, −0.34 [95%CI: -1.28, 0.60]%; P = 0.73). Additionally, changes in glycated hemoglobin were similar between the two groups. However, a significant difference in body weight change was observed (empagliflozin, −0.58 [95%CI: -1.60, 0.43] kg; glimepiride, 1.20 [95%CI: 0.15, 2.26] kg; P = 0.02). Moreover, a body composition analysis revealed that body fluid volume significantly decreased after empagliflozin treatment (baseline, 35.8 ± 6.8 L; after 12 weeks, −0.33 ± 0.72 L; P = 0.03). Hence, although empagliflozin did not improve endothelial function compared with glimepiride for patients with type 2 diabetes, it did decrease body fluid volumes. Thus, the coronary-protective effect of empagliflozin is not derived from endothelial function protection, but rather from heart failure risk reduction. Trial registration: This trial was registered on September 13, 2016; UMIN000024001. [ABSTRACT FROM AUTHOR]

This article studies trade-offs of farms in terms of economic sustainability (proxied here by technical efficiency), environmental sustainability (proxied here by farmers' commitment towards the environment) and social sustainability (proxied here by farmers' contribution to on farm well-being and communities' well-being). We use the latent class stochastic frontier model and create classes based on three separating variables, representing farms' environmental sustainability and social sustainability. The application to a sample of Spanish crop farms shows that more environmentally sustainable farms are likely to have lower levels of technical efficiency. However, improvements in social concerns, both towards own farm and the larger community, may lead to improved technical efficiency levels. In general, our study provides evidence of trade-offs for farms between economic sustainability and environmental sustainability, but also between environmental sustainability and social sustainability. [ABSTRACT FROM AUTHOR]

Mariculture is a well-known high-risk industry. However, mariculture insurance, which is an important risk management tool, is facing serious market failure. An important reason for this market failure lies in the unsound premium rate and pricing method. Due to a lack of long-term yield data, empirical rates are often adopted, but this adoption can lead to a high loss ratio. This paper provides an improved method for premium computation of mariculture insurance using an information diffusion model (IDM). An example of oyster insurance in China shows that, compared with the traditional pricing approach, the IDM can greatly improve the accuracy and stability of premium rate calculations, especially in cases of small samples. [ABSTRACT FROM AUTHOR]

Noninvasive techniques for evaluating the severity of nonalcoholic fatty liver disease (NAFLD) have shown limited diagnostic performance. MicroRNAs (miRNAs) are useful biomarkers for diagnosing and monitoring the progression and treatment response to several diseases. Here, we evaluated whether serum exosomal miRNAs could be used for the diagnosis and prognosis of NAFLD severity. Exosomal miRNAs were isolated from the sera of 41 patients with NAFLD (diagnosed using liver biopsy) for microarray profiling. The degree of NAFLD severity was determined using inflammation, steatosis, and ballooning scores and the NAFLD activity score (NAS). Correlations between miRNA expression, clinical and biochemical parameters, and mRNA expression were analyzed. Overall, 25, 11, 13, and 14 miRNAs correlated with the inflammation score, steatosis score, ballooning score, and NAS, respectively, with 33 significant correlations observed between 27 miRNAs and six clinical variables. Eight miRNAs (let-7b-5p, miR-378h, -1184, -3613-3p, -877-5p, -602, -133b, and 509-3p) showed anticorrelated patterns with the corresponding mRNA expression. In fibrosis, 52 and 30 interactions corresponding to high miRNA-low mRNA and low miRNA-high mRNA expression, respectively, were observed. The present results therefore suggest that serum exosomal miRNAs can be used to evaluate NAFLD severity and identify potential targets for NAFLD treatment. [ABSTRACT FROM AUTHOR]

Purpose: Gender minority (GM) adolescents, who have a different gender identity than their sex assigned at birth, may use substances as a coping strategy in response to GM-related stressors. This study examined longitudinal effects of gender minority stressors on substance use in GM adolescents, and related risk factors (internalized transphobia, depressive symptoms, anxious symptoms) and protective factors (resilience, gender-related pride, family functioning, social support, gender-related community connectedness). Methods: Participants were 30 GM adolescents, ages 13–17 years, from the U.S. community-based longitudinal Trans Teen and Family Narratives Project. Participants completed an online survey every 6 months across 2 years (5 waves; data collected 2015–2019). Results: Exposure to gender minority stressors was associated with higher odds of alcohol use. Across models, internalized transphobia (risk factor), resilience (protective factor), and gender-related pride (protective factor) were the most significant mediators of associations between gender minority stressors and substance use. Family functioning and social support (protective factors) significantly moderated the association between gender minority stressors and alcohol use, such that family functioning and social support were protective for alcohol use at lower levels of gender minority stress, but not at higher levels. Conclusion: Results suggest that GM adolescents engage in substance use as a coping strategy in response to gender minority stressors. A number of hypothesized risk and protective factors mediated or moderated these associations. Future interventions with GM adolescents should focus efforts on addressing internalized transphobia as a risk factor and strengthening resilience, gender-related pride, and family functioning as protective factors for substance use. [ABSTRACT FROM AUTHOR]

Glyphosate (GLY) is worldwide one of the most used active substances in non-selective herbicides. Although livestock might be orally exposed via GLY-contaminated feedstuffs, not much is known about possible hepatotoxic effects of GLY. As hepatic xenobiotic and nutrient metabolism are interlinked, toxic effects of GLY residues might be influenced by hepatic nutrient supply. Therefore, a feeding trial with lactating dairy cows was conducted to investigate effects of GLY-contaminated feedstuffs and different concentrate feed proportions (CFP) in the diets as tool for varying nutrient supply to the liver. For this, 61 German Holstein cows (207 ± 49 days in milk; mean ± standard deviation) were either fed a GLY-contaminated total mixed ration (TMR, GLY groups, mean GLY intake 122.7 μg/kg body weight/day) or control TMR (CON groups, mean GLY intake 1.2 μg/kg body weight/day) for 16 weeks. Additionally, both groups were further split into subgroups fed a lower (LC, 30% on dry matter basis) or higher (HC, 60% on dry matter basis) CFP resulting in groups CONHC (n = 16), CONLC (n = 16), GLYHC (n = 15), GLYLC (n = 14). Blood parameters aspartate aminotransferase, γ-glutamyltransferase, glutamate dehydrogenase, cholesterol, triglyceride, total protein, calcium, phosphorus, acetic acid and urea and histopathological evaluation were not influenced by GLY, whereas all mentioned parameters were at least affected by time, CFP or an interactive manner between time and CFP. Total bilirubin blood concentration was significantly influenced by an interaction between GLY and CFP with temporarily elevated concentrations in GLYHC, whereas the biological relevance remained unclear. Gene expression analysis indicated 167 CFP-responsive genes, while seven genes showed altered expression in GLY groups compared to CON groups. Since expression changes of GLY-responsive genes were low and liver-related blood parameters changed either not at all or only slightly, the tested GLY formulation was considered to have no toxic effects on the liver of dairy cows. [ABSTRACT FROM AUTHOR]

Maximal hyperaemia for fractional flow reserve (FFR) may not be achieved with the current recommended doses of intracoronary adenosine. Higher doses (up to 720 μg) have been reported to optimize hyperaemic stimuli in small dose-response studies. Real-world data from a large cohort of patients is needed to evaluate FFR results and the safety of high-dose escalation. This is a retrospective study aimed to evaluate the safety and frequency of FFR ≤0.8 after high-dose escalation of intracoronary adenosine. Data were extracted from the medical databases of two university hospitals. Increasing doses (100, 200, 400, 600, and 800 μg) of adenosine were administered as intracoronary boluses until FFR ≤0.8 was achieved or heart block developed. The percentage of FFR ≤0.8 after higher-dose escalation was compared with those at conventional doses, and the predictors for FFR ≤0.8 after higher doses were analysed. In the 1163 vessels of 878 patients, 402 vessels (34.6%) achieved FFR ≤0.8 at conventional doses and 623 vessels (53.6%) received high-dose escalation. An additional 84 vessels (13.5%) achieved FFR ≤0.8 after high-dose escalation. No major complications developed during high-dose escalation. Borderline FFR (0.81–0.85) at the conventional dose, stenosis >60%, and triple-vessel disease increased the likelihood of FFR ≤0.8 after high-dose escalation, but chronic kidney disease decreased it. For vessels of borderline FFR at conventional doses, 46% achieved FFR ≤0.8 after high-dose escalation. In conclusion, High-dose escalation of intracoronary adenosine increases the frequency of FFR ≤0.8 without major complications. It could be especially feasible for borderline FFR values near the 0.8 diagnostic threshold. [ABSTRACT FROM AUTHOR]

Glutamate dehydrogenase (GLDH) is a liver-specific biomarker of hepatocellular damage currently undergoing qualification as a drug development tool. Since GLDH is located within the mitochondrial matrix, it has been hypothesized that it might also be useful in assessing mitotoxicity as an initiating event during drug-induced liver injury. According to this hypothesis, hepatocyte death that does not involve primary mitochondrial injury would result in release of intact mitochondria into circulation that could be removed by high speed centrifugation and result in lower GLDH activity measured in spun serum vs un-spun serum. A single prior study in mice has provided some support for this hypothesis. We sought to repeat and extend the findings of this study. Accordingly, mice were treated with the known mitochondrial toxicant, acetaminophen (APAP), or with furosemide (FS), a toxicant believed to cause hepatocyte death through mechanisms not involving mitotoxicity as initiating event. We measured GLDH levels in fresh plasma before and after high speed centrifugation to remove intact mitochondria. We found that both APAP and FS treatments caused substantial hepatocellular necrosis that correlated with plasma alanine aminotransferase (ALT) and GLDH elevations. The plasma GLDH activity in both the APAP- and FS- treated mice was not affected by high-speed centrifugation. Interestingly, the ratio of GLDH:ALT was 5-fold lower during FS compared to APAP hepatotoxicity. Electron microscopy confirmed that both APAP- and FS-treatments had resulted in mitochondrial injury. Mitochondria within vesicles were only observed in the FS-treated mice raising the possibility that mitophagy might account for reduced release of GLDH in the FS-treated mice. Although our results show that plasma GLDH is not clinically useful for evaluating mitotoxicity, the GLDH:ALT ratio as a measure of mitophagy needs to be further studied. [ABSTRACT FROM AUTHOR]

The levels and activity of the enzyme paraoxonase 1 affect the vulnerability to the teratogenic effects of organophosphate pesticides. Mutant mice lacking the gene for paraoxonase1 (PON1-/-) are more susceptible to the toxic effects of chlorpyrifos, and were hypothesized to be more vulnerable to social behavior deficits induced by exposure to chlorpyrifos during gestation. Three experiments were performed comparing PON1-/- mice to PON1+/+ mice born to dams treated with 0.5 mg/kg chlorpyrifos or cornoil vehicle on gestational days 12–15. Chlofpyrifos-exposed male PON1-/- mouse pups had delayed development of reflexes in in the first experiment. In the second experiment, adult male and female PON1-/- mice and the female PON1+/+ mice all displayed lower social preference than the male vehicle-treated PON1+/+ mice. The PON1-/- mice and the female PON1+/+ mice displayed lower social preference compared to the PON1+/+ male mice. Male adult mice that had been exposed in utero to chlorpyrifos showed less conditioned social preference regardless of genotype. In the third study, the delayed reflex development was replicated in male and female PON1-/- mice, but chlorpyrifos did not augment this effect. Nest Odor Preference, a test of early social attachment to dam and siblings, was lower in PON1-/- mouse pups compared to PON1+/+ pups. This study shows for the first time that PON1-/- mice have a behavioral phenotype that indicates impaired reflex development and social behavior. Chlorpyrifos exposure during gestation tended to augment some of these effects. [ABSTRACT FROM AUTHOR]

Dietary fat is discussed to be critical in the development of non-alcoholic fatty liver disease. Here, we assess the effect of exchanging dietary fat source from butterfat to extra virgin olive oil on the progression of an already existing diet-induced non-alcoholic fatty liver disease in mice. Female C57BL/6J mice were fed a liquid butterfat-, fructose- and cholesterol-rich diet (BFC, 25E% from butterfat) or control diet (C, 12%E from soybean oil) for 13 weeks. In week 9, fat sources of some BFC- and C-fed mice were switched either to 25E% or 12E% olive oil (OFC and CO). Glucose and insulin tolerance tests were performed, and markers of liver damage and glucose metabolism were assessed. After 6 weeks of feeding, BFC-fed mice had developed marked signs of insulin resistance, which progressed to week 12 being not affected by the exchange of fat sources. Liver damage was similar between BFC- and OFC-fed mice. Markers of lipid metabolism and lipid peroxidation in liver and of insulin signaling in liver and muscle were also similarly altered in BFC- and OFC-fed mice. Taken together, our data suggest that exchanging butterfat with extra virgin olive oil has no effect on the progression of non-alcoholic fatty liver disease and glucose tolerance in mice. [ABSTRACT FROM AUTHOR]

The food environment can interact with cognitive processing and influence eating behaviour. Our objective was to characterize the impact of implicit olfactory priming on inhibitory control towards food, in groups with different weight status. Ninety-one adults completed a modified Affective Shifting Task: they had to detect target stimuli and ignore distractor stimuli while being primed with non-attentively perceived odours. We measured reactivity and inhibitory control towards food pictures. Priming effects were observed on reactivity: participants with overweight and obesity were slower when primed with pear and pound cake odour respectively. Common inhibitory control patterns toward foods were observed between groups. We suggest that non-attentively perceived food cues influence bottom-up processing by activating distinguished mental representations according to weight status. Also, our data show that cognitive load influences inhibitory control toward foods. Those results contribute to understanding how the environment can influence eating behaviour in individuals with obesity. [ABSTRACT FROM AUTHOR]

Serum activities of alanine and aspartate aminotransferases (ALT and AST) are used as gold standard biomarkers for the diagnosis of hepatocellular injury. Since ALT and AST lack liver specificity, the diagnosis of the onset of hepatocellular injury in patients with underlying muscle impairments is severely limited. Thus, we evaluated the potential of glutamate dehydrogenase (GLDH) as a liver specific alternative biomarker of hepatocellular injury. In our study, serum GLDH in subjects with Duchene muscular dystrophy (DMD) was equivalent to serum GLDH in age matched healthy subjects, while serum ALT was increased 20-fold in DMD subjects. Furthermore, serum GLDH in 131 subjects with variety of muscle impairments was similar to serum GLDH of healthy subjects while serum ALT corelated with serum creatine kinase, a widely accepted biomarker of muscle impairment. In addition, significant elevations of ALT, AST, and CK were observed in a case of a patient with rhabdomyolysis, while serum GLDH stayed within the normal range until the onset of hypoxia-induced liver injury. In a mouse model of DMD (DMDmdx), serum GLDH but not serum ALT clearly correlated with the degree of acetaminophen-induced liver injury. Taken together, our data support the utility of serum GLDH as a liver-specific biomarker of liver injury that has a potential to improve diagnosis of hepatocellular injury in patients with underlying muscle impairments. In drug development, GLDH may have utility as a biomarker of drug induced liver injury in clinical trials of new therapies to treat muscle diseases such as DMD. [ABSTRACT FROM AUTHOR]

Background: Higher alanine transaminase (ALT), indicating poor liver function, is positively associated with diabetes but inversely associated with body mass index (BMI) in Mendelian randomization (MR) studies, suggesting liver function affects muscle mass. To clarify, we assessed the associations of liver enzymes with muscle and fat mass observationally with two-sample MR as a validation. Methods: In the population-representative "Children of 1997" birth cohort (n = 3,455), we used multivariable linear regression to assess the adjusted associations of ALT and alkaline phosphatase (ALP) at ~17.5 years with muscle mass and body fat percentage observationally. Genetic variants predicting ALT, ALP and gamma glutamyltransferase (GGT) were applied to fat-free and fat mass in the UK Biobank (n = ~331,000) to obtain unconfounded MR estimates. Results: Observationally, ALT was positively associated with muscle mass (0.11 kg per IU/L, 95% confidence interval (CI) 0.10 to 0.12) and fat percentage (0.15% per IU/L, 95% CI 0.13 to 0.17). ALP was inversely associated with muscle mass (-0.03 kg per IU/L, 95% CI -0.04 to -0.02) and fat percentage (-0.02% per IU/L, 95% CI -0.03 to -0.01). Using MR, ALT was inversely associated with fat-free mass (-0.41 kg per 100% in concentration, 95% CI -0.64 to -0.19) and fat mass (-0.58 kg per 100% in concentration, 95% CI -0.85 to -0.30). ALP and GGT were unclearly associated with fat-free mass or fat mass. Conclusion: ALT reducing fat-free mass provides a possible pathway for the positive association of ALT with diabetes and suggests a potential target of intervention. [ABSTRACT FROM AUTHOR]

Non-alcoholic fatty liver disease (NAFLD) is a growing global health concern. With a propensity to progress towards non-alcoholic steatohepatitis (NASH), cirrhosis, and hepatocellular carcinoma, NAFLD is an important link amongst a multitude of comorbidities including obesity, diabetes, and cardiovascular and kidney disease. As several in vivo models of hyperglycemia and NAFLD are employed to investigate the pathophysiology of this disease process, we aimed to characterize an in vitro model of hyperglycemia that was amenable to address molecular mechanisms and therapeutic targets at the cellular level. Utilizing hyperglycemic cell culturing conditions, we induced steatosis within a human hepatocyte cell line (HepG2 cells), as confirmed by electron microscopy. The deposition and accumulation of lipids within hyperglycemic HepG2 cells is significantly greater than in normoglycemic cells, as visualized and quantified by Nile red staining. Alanine aminotransferase (ALT) and alkaline phosphatase (ALP), diagnostic biomarkers for liver damage and disease, were found to be upregulated in hyperglycemic HepG2 cells as compared with normoglycemic cells. Suppression of CEACAM1, GLUT2, and PON1, and elevation of CD36, PCK1, and G6PK were also found to be characteristic in hyperglycemic HepG2 cells compared with normoglycemic cells, suggesting insulin resistance and NAFLD. These in vitro findings mirror the characteristic genetic and phenotypic profile seen in Leprdb/J mice, a well-established in vivo model of NAFLD. In conclusion, we characterize an in vitro model displaying several key genetic and phenotypic characteristics in common with NAFLD that may assist future studies in addressing the molecular mechanisms and therapeutic targets to combat this disease. [ABSTRACT FROM AUTHOR]

Background: In the U.S., non-binary refers to transgender people who have a gender identity not aligned with their assigned sex at birth, and who identify outside of the traditional male-female binary, such as genderqueer, genderfluid, or gender nonconforming. Few data are available to characterize the health of non-binary adults. Methods: The current study sought to fill this gap by conducting a secondary analysis of data from a non-probability sample of transgender and/or gender nonconforming adults in Massachusetts (sample mean age 32.6 years, 63% female assigned sex at birth; 79.4% white non-Hispanic/Latinx). Multivariable models were fit to compare non-binary (e.g., genderqueer) vs. binary (e.g., man/trans man, woman/trans woman) respondents across a range of social and health indicators. Results: Overall, 40.9% identified their gender identity as non-binary. Non-binary respondents significantly differed from binary respondents on (all p<0.05): demographics (younger age, more female assigned sex at birth); gender affirmation (older age of identity recognition, lower current uptake of and future desires for medical gender affirmation); healthcare utilization (lower rates of being up-to-date in annual wellness visit, less mental healthcare utilization in past year); mental health and substance use (higher past-week depressive distress, higher hazardous alcohol use); social history (more unstably housed, more current students), violence victimization (lower rates of lifetime intimate partner violence), and social support (less family support). Conclusion: Gender diversity, including whether people endorse a binary or non-binary gender identity, is a prevalent and an important aspect of transgender health. Demographic measures of gender identity that include binary and non-binary response options are recommended to inform future research and clinical care. [ABSTRACT FROM AUTHOR]

Aims: The aim of the present study was to investigate the major determinants of diabetic peripheral neuropathy (DPN) in patients with type 2 diabetes (T2D), considering the traditional and newly discovered risk factors, including hypoglycaemia and glycemic variability. Methods: This retrospective case-control study was conducted in a tertiary care hospital in Taiwan. A total of 2,837 patients with T2D were recruited, medical history and biochemical data were obtained, and patients were screened for DPN using the Michigan Neuropathy Screening Instrument (MNSI). DPN was defined as an MNSI exam score > 2. A stepwise selection of variables was used based on the Akaike Information Criterion (AIC) and the Schwarz Criterion (SC). Multivariate analysis was performed using the identified variables obtained from the stepwise selection. Results: Among the recruited patients, 604 (21.3%) were found to have DPN. 275 patients with DPN were selected because of longer follow up period before enrollment and complete data of glycemic parameters, and paired with 351 patients with T2D without DPN and matched for age, gender, and diabetes duration. The results of the stepwise selection showed that the presence of moderately and severely increased albuminuria yielded the lowest values of AIC and SC, which indicate the best predictive performance. Multivariate analysis demonstrated that moderately and severely increased albuminuria and greater long-term glycemic variability significantly increased the risk of DPN, with a corresponding odds ratio of 1.85 and 1.61 (95%confidence intervals of 1.25–2.73and1.02–2.55, respectively), after adjusted for hypoglycaemia and types of diabetes treatment. Conclusions: Albuminuria is a potent predictor of DPN, and greater long-term glycemic variabilityis clearly associated with DPN in adults with T2D. These findings indicate that, in addition to achieve average blood glucose control, screening for albuminuria and reducing blood glucose fluctuations might be useful for improving diabetic microvascular complications. [ABSTRACT FROM AUTHOR]

Individual variability in word generation is a product of genetic and environmental influences. The genetic effects on semantic verbal fluency were estimated in 1,735 participants from the Brazilian Baependi Heart Study. The numbers of exemplars produced in 60 s were broken down into time quartiles because of the involvement of different cognitive processes—predominantly automatic at the beginning, controlled/executive at the end. Heritability in the unadjusted model for the 60-s measure was 0.32. The best-fit model contained age, sex, years of schooling, and time of day as covariates, giving a heritability of 0.21. Schooling had the highest moderating effect. The highest heritability (0.17) was observed in the first quartile, decreasing to 0.09, 0.12, and 0.0003 in the following ones. Heritability for average production starting point (intercept) was 0.18, indicating genetic influences for automatic cognitive processes. Production decay (slope), indicative of controlled processes, was not significant. The genetic influence on different quartiles of the semantic verbal fluency test could potentially be exploited in clinical practice and genome-wide association studies. [ABSTRACT FROM AUTHOR]

Researchers investigating cancer chemotherapy and management continue to search for agents that selectively kill malignant cells and leave healthy neighboring cells intact. Natural products provide relevant resources for anti-cancer drug discovery. However, the physicochemical properties of these compounds limit their efficient uptake and bioavailability. We introduced a nanocarrier system, namely, zinc-aluminum-layered double hydroxide (ZnAl-LDH) intercalated with protocatechuic acid. In this study, the efficacy and toxicity of protocatechuic acid intercalated in zinc aluminum-layered double hydroxide nanoparticles (PCA-ZnAl) against diethylnitrosamine/phenobarbital (DEN/PB)-induced hepatocellular carcinoma (HCC) in BALB/c mice was evaluated. HCC in male mice was induced by a single-dose intraperitoneal administration of DEN and was promoted by the introduction of PB via drinking water for 12 weeks. HCC induction was confirmed after the DEN/PB introduction period by measurement of the elevated level of serum α-feto protein (AFP). The results showed that the level of α-fetoprotein was significantly reduced in PCA-ZnAl (350±43.90 ng/mL), doxorubicin (DOX) (290±20.52 ng/mL) and ZnAl-LDH (390±19.65 ng/mL) treated animals compared to HCC mice treated with normal saline (580.4± 52.04 ng/mL). Superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH) levels were significantly increased, whereas the level of lipid peroxidation was significantly decreased in HCC mice treated with DOX, PCA-ZnAl and ZnAl-LDH compared with those in HCC mice treated with saline. Restoration of hepatocyte morphology was observed following treatment that was comparable to that in the normal control group. Deterioration of hepatic cells and a significant increase of aspartate transaminase (AST), alanine transaminase (ALT), and alkaline phosphatase (ALP) were observed in the cancer-induced untreated group compared with that in the groups treated with nanoparticles. The histopathological features of the liver obtained from PCA-ZnAl-treated mice showed a uniform size with a similar distribution of the nuclear-cytoplasmic ratio and nucleus centrally located in the cytoplasm, similar to the normal liver cells. The results underscored the potential of PCA-ZnAl for the treatment of hepatocellular carcinoma. [ABSTRACT FROM AUTHOR]

Background: Long-term variability of cardiometabolic risk factors have been suggested as the risk factors for cardiovascular disease and mortality. However, the effect of long-term variability of total cholesterol (TC) on incident atrial fibrillation (AF) has not been examined. Methods and findings: We explored whether visit-to-visit TC variability are associated with the risk of incident AF in 160,165 Korean adults, using the population-based Korean National Health Insurance Service–Health Screening Cohort (NHIS-HEALS) database, over a median duration of 8.4 years. TC variability was measured as coefficients of variance (TC-CV), standard deviation (TC-SD), and variability independent of the mean (TC-VIM). Kaplan–Meier analysis demonstrated a decreased disease-free probability in the highest quartile group of TC variability compared to that in the other groups. In the multivariate Cox proportional hazard analysis, the risk of AF increased significantly in the highest quartile group of TC variability. After multivariate adjustment for confounding variables including mean TC levels, the hazard ratio for incident AF was 1.15 (95% confidence interval 1.05–1.25; P = 0.0035) when comparing the highest with the lowest TC variability quartile (TC-CV). These relationships were consistent with TC variability defined using TC-SD or TC-VIM. Subgroup analyses, including age, sex, body mass index, and cardiometabolic disorders, showed similar results. Conclusions: The present study is the first to demonstrate that high TC variability was associated with an increased risk of AF. [ABSTRACT FROM AUTHOR]

People with Down syndrome (DS) are at high risk of developing Alzheimer disease (AD) with aging. The diagnosis and treatment trials are hampered by a lack of reliable blood biomarkers. Plasma neurofilament light chain (NfL) is one of the established biomarkers of AD, suggesting that it may be useful as an indicator of dementia in DS patients. The aims of this study were: 1) to examine whether plasma levels of NfL in DS patients are correlated with decreased adaptive behavior scores one year after sample collection, and 2) to compare plasma levels of NfL in adults with DS and an age-matched healthy control population. In this study, plasma levels of NfL in 24 patients with DS and 24 control participants were measured by the single-molecule immunoarray (Simoa) method. We observed significantly increased plasma NfL levels in the DS compared with the control group. There was a significant correlation between age and levels of plasma NfL in both groups. This age-dependent elevation was steeper in the DS compared with the control group. Moreover, elevated plasma NfL was associated with decreased adaptive behavior scores one year later, after age-adjustment. Previously reported blood-based biomarkers available in Simoa for DS, plasma total tau and phosphorylated tau, were not significantly correlated with the annual decrement of adaptive behavior scores after age-adjustment. These results suggest that plasma NfL has the potential to serve as an objective biomarker to predict dementia in adult DS patients. [ABSTRACT FROM AUTHOR]

Background & aims: Elastography point quantification is a convenient method for measuring liver stiffness. It can be performed simultaneously with conventional ultrasonography. This study aimed to evaluate its diagnostic performance for assessing hepatic fibrosis in patients with autoimmune liver disease (AILD), including autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC). Methods: The diagnostic performance of elastography point quantification (ElastPQ) was evaluated and compared with that of serum fibrosis markers, including the aspartate aminotransferase to platelet ratio index (APRI) and fibrosis-4 (FIB-4), using the receiver operating characteristics analysis with histologic evaluation as the reference standard. Results: In 49 AIH patients, sensitivity and specificity of ElastPQ were 93.6% and 44.4%, respectively, for significant fibrosis (≥ F2, cutoff 4.47 kPa), and 63.6% and 86.8% for cirrhosis (F4, cutoff 9.28 kPa). In 41 PBC patients, they were 81.8% and 73.3%, respectively, for significant fibrosis (≥ F2, cutoff 5.56 kPa), and 100% and 81.6%, respectively, for advanced fibrosis (≥ F3, cutoff 6.04 kPa). The areas under the receiver operating characteristic curves of ElastPQ for significant fibrosis (0.77, 95% CI 0.67–0.86) and cirrhosis (0.81, 95% CI 0.65–0.96) were higher than those of APRI and FIB-4 in AILD patients. According to the multivariable analysis, histological activity, steatosis, and body max index (BMI) were not significant factors that influenced the result of ElastPQ. Conclusions: ElastPQ exhibited better diagnostic performance–without the influence of confounding factors–for assessing hepatic fibrosis in AILD patients than serum fibrosis markers. [ABSTRACT FROM AUTHOR]

Background: Iron overload, resulting from blood transfusions in patients with chronic anemias, has historically been controlled with regular deferoxamine, but its parenteral requirement encouraged studies of orally-active agents, including deferasirox and deferiprone. Deferasirox, licensed by the US Food and Drug Administration in 2005 based upon the results of randomized controlled trials, is now first-line therapy worldwide. In contrast, early investigator-initiated trials of deferiprone were prematurely terminated after investigators raised safety concerns. The FDA declined market approval of deferiprone; years later, it licensed the drug as “last resort” therapy, to be prescribed only if first-line drugs had failed. We undertook to evaluate the long-term effectiveness and toxicities of deferiprone and deferasirox in one transfusion clinic. Methods and findings: Under an IRB-approved study, we retrospectively inspected the electronic medical records of consented iron-loaded patients managed between 2009 and 2015 at The University Health Network (UHN), Toronto. We compared changes in liver and heart iron, adverse effects and other outcomes, in patients treated with deferiprone or deferasirox. Results: Although deferiprone was unlicensed in Canada, one-third (n = 41) of locally-transfused patients had been switched from first-line, licensed therapies (deferoxamine or deferasirox) to regimens of unlicensed deferiprone. The primary endpoint of monitoring in iron overload, hepatic iron concentration (HIC), increased (worsened) during deferiprone monotherapy (mean 10±2–18±2 mg/g; p < 0.0003), exceeding the threshold for life-threatening complications (15 mg iron/g liver) in 50% patients. During deferasirox monotherapy, mean HIC decreased (improved) (11±1–6±1 mg/g; p < 0.0001). Follow-up HICs were significantly different following deferiprone and deferasirox monotherapies (p < 0.0000002). Addition of low-dose deferoxamine (<40 mg/kg/day) to deferiprone did not result in reductions of HIC to <15 mg/g (baseline 20±4 mg/g; follow-up, 18±4 mg/g; p < 0.2) or in reduction in the proportion of patients with HIC exceeding 15 mg/g (p < 0.2). During deferiprone exposure, new diabetes mellitus, a recognized consequence of inadequate iron control, was diagnosed in 17% patients, most of whom had sustained HICs exceeding 15 mg/g for years; one woman died after 13 months of a regimen of deferiprone and low-dose deferasirox. During deferiprone exposure, serum ALT increased over baseline in 65% patients. Mean serum ALT increased 6.6-fold (p < 0.001) often persisting for years. During deferasirox exposure, mean ALT was unchanged (p < 0.84). No significant differences between treatment groups were observed in the proportions of patients estimated to have elevated cardiac iron. Conclusions: Deferiprone showed ineffectiveness and significant toxicity in most patients. Combination with low doses of first-line therapies did not improve the effectiveness of deferiprone. Exposure to deferiprone, over six years while the drug was unlicensed, in the face of ineffectiveness and serious toxicities, demands review of the standards of local medical practice. The limited scope of regulatory approval of deferiprone, worldwide, should restrict its exposure to the few patients genuinely unable to tolerate the two effective, first-line therapies. [ABSTRACT FROM AUTHOR]

Recent studies have suggested that maternal high-fat (HF) diet caused inflammation changes in adipose tissue; however, it remains unclear if maternal diet intervention before pregnancy rescues such effects in offspring. To address this question, female mice were continued on a normal-fat (NF group), or a HF diet (HF group) or transitioned from a HF diet to a NF diet at 1 (H1N group), 5 (H5N group) or 9 weeks (H9N group) prior to pregnancy. Among the three intervention groups, the H9N offspring displayed less and steady body weight gain, and maintained glucose tolerance, whereas the H1N and H5N offspring showed exacerbate these phenotypes. The H1N and H5N, but not the H9N offspring, displayed adipocyte hypertrophy associated with increased expression of genes involved in fat deposition. The H1N and H5N, but not the H9N adipose tissue, displayed increased macrophage infiltration with enhanced expression of inflammatory cytokine genes. In addition, overactivation of the NF-κB and the JNK signaling were observed in the H1N adipose tissue. Overall, our study showed that a long-term but not a short- or medium-term diet intervention before pregnancy released offspring adipose tissue inflammation induced by maternal HF diet, which adds details in our understanding how the maternal environment either promotes or discourages onset of disease in offspring. Clinically, this study is of great value for providing evidence in the design of clinical trials to evaluate the urgently required intervention strategies to minimize the intergenerational cycle of obesity. [ABSTRACT FROM AUTHOR]

Are mathematical learning difficulties caused by impairment of the abilities that underlie mathematical talent? Or are mathematical difficulties and talent qualitatively different? The main goal of this study was to determine whether mathematical learning difficulties are explained by the same executive functions as mathematical talent. We screened a pool of 2,682 first-year high school students and selected 48 for evaluation, dividing them into three groups: those with mathematical learning difficulties (n = 16), those with typical performance (n = 16), and those with mathematical talent (n = 16). Adolescents from the learning difficulties and talented groups had age, reading skills, and verbal and non-verbal intelligence that were similar to those of the typical performance group. Participants were administered a suite of tasks to evaluate verbal and visual short-term memory and executive functions of inhibition, shifting, and updating. Different executive functions showed different contributions at the two ends of the math ability continuum: lower levels of performance in updating visual information were related to mathematical learning difficulties, while greater shifting abilities were related to mathematical talent. Effect sizes for the differences in performance between groups were large (Hedges' g > 0.8). These results suggest that different executive functions are associated with mathematical learning difficulties and mathematical talent. We discuss how these differences in executive functions could be related to the different types of mathematical abilities that distinguish the three groups. [ABSTRACT FROM AUTHOR]

Background: Dipeptidyl peptidase-4 (DPP-4) inhibitors may have protective effects on diabetic kidney disease (DKD) via specific antioxidant pathways. The DPP-4 inhibitor, linagliptin, was evaluated with the hypothesis that DPP-4 inhibition would ameliorate the development of DKD in a glucose-independent manner by altering specific antioxidant function. Methods: DBA/2J mice (a well-characterized model of DKD) and glucose 6-phosphate dehydrogenase (G6PD) deficient mice (a model of impaired antioxidant function) were evaluated. Diabetes was induced by streptozotocin. Mice were divided into: diabetic (DM), diabetic+linagliptin (DM+Lina), and non-diabetic control and treated for 12 weeks. Results: In DBA/2J mice, there was no difference in body weight and blood glucose between DM and DM+Lina groups. Linagliptin ameliorated albuminuria and kidney hypertrophy in DM DBA/2J mice and specifically increased the mRNA and protein levels for the antioxidants catalase and MnSOD. In G6PD deficient mice, however, increases in these mRNA levels did not occur and linagliptin renoprotection was not observed. Linagliptin also ameliorated histological trends toward mesangial expansion in wild-type mice but not in G6PD deficient mice. Conclusions: Linagliptin renoprotection involved glucose-independent but antioxidant-enzyme-system-dependent increases in transcription (not just increased protein levels) of antioxidant proteins in wild-type mice. These studies demonstrate that an intact antioxidant system, in particular including transcription of catalase and MnSOD, is required for the renoprotective effects of linagliptin. [ABSTRACT FROM AUTHOR]

We previously found higher level of endothelial cell (EC) activation in patients who suffered from in-stent restenosis after bare-metal stenting compared to subjects who underwent drug-eluting stenting (DES) showing no complications. Here we investigated the potential transcriptional and post-transcriptional regulatory mechanisms by which everolimus attenuated EC activation after DES. We studied the effect of everolimus on E-selectin (SELE) and VCAM1 mRNA levels when human coronary artery (HCAECs) and human umbilical vein ECs were challenged with recombinant TNF-α (100 ng/mL) for 1–24 hours in the presence or absence of everolimus using 0.5 μM concentration locally maintained by DES. EC activation was evaluated via the levels of IL-1β and IL-6 mRNAs with miR-155 expression by RT-qPCR as well as the nuclear translocation of nuclear factor kappa beta (NF-κB) detected by fluorescence microscopy. To investigate the transcriptional regulation of E-selectin and VCAM-1, TNF-α-induced enhancer RNA (eRNA) expression at p65-bound enhancers in the neighboring genomic regions of SELE and VCAM1 genes, including SELE_-11Kb and VCAM1_-10Kb, were measured in HCAECs. Mature and precursor levels of E-selectin and VCAM-1 repressor miR-181b were quantified to analyze the post-transcriptional regulation of these genes in HCAECs. Circulating miR-181b was analyzed in plasma samples of stented subjects by stem-loop RT-qPCR. TNF-α highly elevated E-selectin and VCAM-1 expression at transcriptional level in ECs. Levels of mature, pre- and pri-miR-181b were repressed in ECs by TNF-α, while everolimus acted as a negative regulator of EC activation via inhibited translocation of NF-κB p65 subunit into cell nuclei, lowered eRNA expression at SELE and VCAM1 genes-associated enhancers and modulated expression of their post-transcriptional repressor miR-181b. Significant negative correlation was observed between plasma miR-181b and soluble E-selectin and VCAM-1 in patients. In conclusion, everolimus attenuates EC activation via reduced NF-κB p65 translocation causing decreased E-selectin and VCAM-1 expression at transcriptional and post-transcriptional level after DES. [ABSTRACT FROM AUTHOR]

Introduction: Postoperative atrial fibrillation (POAF) is a common complication following cardiac surgery associated with increased morbidity and mortality. Although sustained hyperglycemia is a known risk factor of AF and poor ICU outcomes, emerging in-vitro studies reveal acute glycemic fluctuations to be an additional independent predictor of AF. The effect of acute glycemic fluctuations on the incidence of POAF in the clinical setting remains unclear. We aim to investigate the effect of the magnitude of acute perioperative glycemic fluctuations on the incidence of POAF in a multi-ethnic Southeast-Asian population. Methods: We obtained data from1743 patients who underwent elective CABG in a tertiary heart centre from 2009–2011. Patients were kept to a tight baseline glycemic control in accordance with hospital protocol. The magnitude of the difference between the highest and lowest perioperative glucose levels up till the first 48 postoperative hours was employed as a measure of glycemic fluctuation. Patients were divided into 4 groups for analysis based on the magnitude of glycemic fluctuation:A)0-2mmol/L(N = 147); B)>2-4mmol/L(N = 426); C)>4-6mmol/L(N = 513); D)>6mmol/L(N = 657).Our primary outcome was the incidence of POAF. Secondary outcomes included ICU and 30-day mortality and length of stay. Results: The overall incidence of POAF was 14.7%. This increased as the magnitude of glycemic fluctuation increased, and was statistically highest in Group D(16.4%) as compared with the other 3 sub-groups. Multivariate logistic regression revealed the magnitude of perioperative glycemic fluctuation to be an independent risk factor of POAF(O.R.1.06, 95% C.I.1.01–1.11, p = 0.014).ICU length of stay was statistically highest in Group D(63.1 hours, p = < .001). However, ICU and 30 day mortality rates were similar among the 4 groups. Conclusion: Increased magnitudes of acute perioperative glycemic fluctuations are associated with a significantly increased risk of POAF and length of ICU stay; and should therefore be minimised but balanced against the risks of hypoglycemia so as to avoid POAF and optimise patient outcomes. [ABSTRACT FROM AUTHOR]

: The HGMA1 architectural transcription factor is highly overexpressed in many human cancers. Because HMGA1 is a hub for regulation of many oncogenes, its overexpression in cancer plays a central role in cancer progression and therefore HMGA1 is gaining increasing attention as a target for development of therapeutic approaches to suppress either its expression or action in cancer cells. We have developed the strategy of introducing decoy hyper binding sites for HMGA1 into the nucleus of cancer cells with the goal of competetively sequestering overexpressed HMGA1 and thus suppressing its oncogenic action. Towards achieving this goal, we have introduced an HMGA1 decoy hyper binding site composed of six copies of a high affinity HMGA1 binding site into the genome of the replication defective adenovirus serotype 5 genome and shown that the engineered virus effectively reduces the viability of human pancreatic and cancer cells. Here we report the first pre-clinical measures of toxicity and biodistribution of the engineered virus in C57BL/6J Black 6 mice. The immune response to exposure of the engineered virus was determined by assaying the serum levels of key cytokines, IL-6 and TNF-α. Toxicity due to exposure to the virus was determined by measuring the serum levels of the liver enzymes aspartate aminotransferase and alanine aminotransferase. Biodistribution was measured following direct injection into the pancreas or liver by quantifying viral loads in the pancreas, liver, spleen and brain. [ABSTRACT FROM AUTHOR]

Obesity is associated with a series of metabolic complications, including dyslipidemia and insulin resistance (IR) that lack effective therapies. In recent years, intestinal inflammation has been suggested to contribute to obesity related metabolic syndrome and targeting gut inflammation with 5-ASA improves diet induced IR, however, its role in dyslipidemia is unknown and has never been explored. In the present study, we reported for the first time that administration of 5-ASA for 12 weeks significantly improved lipid profile by repressing plasma triglycerides and free cholesterol levels in mice fed high-fat cholesterol diet (HFC). In addition, liver lipids were significantly reduced by 5-ASA treatment in HFC-fed mice. Mechanistically, anti-inflammatory genes peroxisome proliferator-activated receptor-γ (Pparγ) and M2 marker, such as Mrc1 and Ym1, were remarkably upregulated, while pro-inflammation gene monocyte chemoattractant protein-1 (Mcp-1) were downregulated in small intestine of mice treated by 5-ASA. Further, 5-ASA improved gastrointestinal barrier by increasing the expression of the tight junction marker ZO-1. 5-ASA also enhanced cholesterol translocation by elevating genes expression of Npc1l1 and Abcg5/8. Moreover, mice fed HFC 5-ASA expressed increased Pparα in small intestinal and its target genes function in lipid oxidation and hydrolysis were remarkable elevated. Taken together, we reported a novel role of 5-ASA which may serve as a therapy target intestinal inflammation induced dyslipidemia. [ABSTRACT FROM AUTHOR]

A major unmet medical need to better manage Type 2 Diabetes (T2D) is the accurate disease prediction in subjects who show glucose dysmetabolism, but are not yet diagnosed as diabetic. We investigated the possibility to predict/monitor the progression to T2D in these subjects by retrospectively quantifying blood circulating microRNAs in plasma of subjects with i) normal glucose tolerance (NGT, n = 9); ii) impaired glucose tolerance (IGT, n = 9), divided into non-progressors (NP, n = 5) and progressors (P, n = 4) based on subsequent diabetes occurrence, and iii) newly diagnosed T2D (n = 9). We found that impaired glucose tolerance associated with a global increase of plasma circulating microRNAs. While miR-148 and miR-222 were specifically modulated in diabetic subjects and correlated with parameters of glucose tolerance, the most accentuated microRNA dysregulation was found in NP IGT subjects, with increased level of miR-122, miR-99 and decreased level of let-7d, miR-18a, miR-18b, miR-23a, miR-27a, miR-28 and miR-30d in comparison with either NGT or T2D. Interestingly, several of these microRNAs significantly correlated with parameters of cholesterol metabolism. In conclusion, we observed the major perturbation of plasma circulating microRNA in NP pre-diabetic subjects and identified a unique microRNA profile that may become helpful in predicting diabetic development. [ABSTRACT FROM AUTHOR]