Effects of exenatide and liraglutide on heart rate, blood pressure and body weight : systematic review and meta-analysis

Objectives: To synthesise current evidence for the effects of exenatide and liraglutide on heart rate, blood pressure and body weight. Design: Meta-analysis of available data from randomised controlled trials comparing Glucagon-like peptide-1 (GLP-1) analogues with placebo, active antidiabetic drug therapy or lifestyle intervention. Participants: Patients with type 2 diabetes. Outcome measures: Weighted mean differences between trial arms for changes in heart rate, blood pressure and body weight, after a minimum of 12-week follow-up. Results: 32 trials were included. Overall, GLP-1 agonists increased the heart rate by 1.86 beats/min (bpm) (95% CI 0.85 to 2.87) versus placebo and 1.90 bpm (1.30 to 2.50) versus active control. This effect was more evident for liraglutide and exenatide long-acting release than for exenatide twice daily. GLP-1 agonists decreased systolic blood pressure by −1.79 mm Hg (−2.94 to −0.64) and −2.39 mm Hg (−3.35 to −1.42) compared to placebo and active control, respectively. Reduction in diastolic blood pressure failed to reach statistical significance (−0.54 mm Hg (−1.15 to 0.07) vs placebo and −0.50 mm Hg (−1.24 to 0.24) vs active control). Body weight decreased by −3.31 kg (−4.05 to −2.57) compared to active control, but by only −1.22 kg (−1.51 to −0.93) compared to placebo. Conclusions: GLP-1 analogues are associated with a small increase in heart rate and modest reductions in body weight and blood pressure. Mechanisms underlying the rise in heart rate require further investigation

Visceral adiposity index and 10-year cardiovascular disease incidence:the ATTICA study

Background and aims: Visceral adiposity index (VAI) has been proposed as a marker of visceral adipose tissue accumulation/dysfunction. Our aim was to evaluate potential associations between the VAI and the 10-year cardiovascular disease (CVD) incidence. Methods and results: During 2001-2002, 3042 Greek adults (1514 men; age: ≥18 years) without previous CVD were recruited into the ATTICA study, whilst the 10-year study follow-up was performed in 2011-2012, recording the fatal/non-fatal CVD incidence in 2020 (1010 men) participants. The baseline VAI scores for these participants were calculated based on anthropometric and lipid variables, while VAI tertiles were extracted for further analyses. During the study follow-up a total of 317 CVD events (15.7%) were observed. At baseline, the participants' age and the prevalence of hypertension, diabetes, hypercholesterolemia and metabolic syndrome increased significantly across the VAI tertiles. After adjusting for multiple confounders, VAI exhibited a significantly independent positive association with the 10-year CVD incidence (OR = 1.05, 95%CI: 1.01, 1.10), whereas the association of the body mass index (HR = 1.03, 95%CI: 0.99, 1.08), or the waist circumference (HR = 1.01, 95%CI: 0.99, 1.02) was less prominent. Sex-specific analysis further showed that VAI remained significantly predictive of CVD in men alone (HR = 1.06, 95%CI: 1.00, 1.11) but not in women (HR = 1.06, 95%CI: 0.96, 1.10). Conclusions: Our findings show for the first time in a large-sample, long-term, prospective study in Europe that the VAI is independently associated with elevated 10-year CVD risk, particularly in men. This suggests that the VAI may be utilized as an additional indicator of long-term CVD risk for Caucasian/Mediterranean men without previous CVD

The effect of online and in-person team-based learning (TBL) on undergraduate endocrinology teaching during COVID-19 pandemic

Availability of data and materials: The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.Copyright © The Author(s) 2022. Background: Team-based learning (TBL) combines active and collaborative learning, while incorporating aspects of the flipped classroom approach and problem-based learning. The COVID-19 pandemic presented certain challenges in the delivery of TBL in class. In this study, we investigated the impact of TBL on the academic performance of final year Biomedical Sciences’ undergraduate students in the context of an “Endocrine Disorders” study block. We did so by comparing the classical in-person approach and online delivery due to the COVID-19 pandemic. Methods: A non-compulsory TBL session was introduced to the curriculum of this block, which followed the traditional 2-h lecture delivery. Comparative analysis was performed for the exam and coursework performance of students who attended the TBL sessions (online and in-person) and those that did not. Results: Both cohorts of students who attended either in-person (n = 66) or online TBL sessions (n = 109) performed significantly better in their exams (p < 0.05) and a related coursework (p < 0.001 and p < 0.05, respectively) when compared to those that did not attend. For both these cohorts the exam mark distribution was much narrower compared to those that did not attend the TBL sessions where the majority of fails and “no shows” were recorded. Conclusions: Online and in-person TBL, can successfully supplement traditional lecture-based teaching and enhance the learning/performance, for complex medical subjects/topics. Our findings demonstrate that it is possible to deliver these sessions online with demonstrable benefit for students suggesting that there is greater flexibility in the use of TBL in higher education

Improved CRISPR-based suppression gene drives mitigate resistance and impose a large reproductive load on laboratory-contained mosquito populations

Abstract CRISPR-based genes drives bias their own inheritance and can be used to modify entire populations of insect vectors of disease as a novel form of sustainable disease control. Gene drives designed to interfere with female fertility can suppress populations of the mosquito vector of malaria, however laboratory demonstrations showed strong unintended fitness costs and high levels of resistant mutations that limited the potential of the first generation of gene drives to spread. We describe three new gene drives designed to restrict spatio-temporal nuclease expression by using novel regulatory sequences. Two of the three new designs dramatically improve fitness and mitigate the creation and selection of resistance. We dissect the relative contributions of germline CRISPR activity versus embryonic CRISPR activity resulting from parental deposition, showing that the improved performance of the new designs is due to tighter germline restriction of the nuclease activity and significantly lower rates of end-joining repair in the embryo. Moreover, we demonstrate in laboratory-contained population experiments that these gene drives show remarkably improved invasion dynamics compared to the first generation drives, resulting in greater than 90% suppression of the reproductive output and a delay in the emergence of target site resistance, even at a loosely constrained target sequence. These results illustrate important considerations for gene drive design and will help expedite the development of gene drives designed to control malaria transmission in Africa

Impact of gut hormone FGF-19 on type-2 diabetes and mitochondrial recovery in a prospective study of obese diabetic women undergoing bariatric surgery

Background: The ileal-derived hormone, fibroblast growth factor 19 (FGF-19), may promote weight loss and facilitate type-2 diabetes mellitus remission in bariatric surgical patients. We investigated the effect of different bariatric procedures on circulating FGF-19 levels and the resulting impact on mitochondrial health in white adipose tissue (AT). Methods: Obese and type-2 diabetic women (n = 39, BMI > 35 kg/m2) undergoing either biliopancreatic diversion (BPD), laparoscopic greater curvature plication (LGCP), or laparoscopic adjustable gastric banding (LAGB) participated in this ethics approved study. Anthropometry, biochemical, clinical data, serum, and AT biopsies were collected before and 6 months after surgery. Mitochondrial gene expression in adipose biopsies and serum FGF-19 levels were then assessed. Results: All surgeries led to metabolic improvements with BPD producing the greatest benefits on weight loss (↓30%), HbA1c (↓28%), and cholesterol (↓25%) reduction, whilst LGCP resulted in similar HbA1c improvements (adjusted for BMI). Circulating FGF-19 increased in both BPD and LGCP (χ2(2) = 8.088; P = 0.018), whilst, in LAGB, FGF-19 serum levels decreased (P = 0.028). Interestingly, circulating FGF-19 was inversely correlated with mitochondrial number in AT across all surgeries (n = 39). In contrast to LGCP and LAGB, mitochondrial number in BPD patients corresponded directly with changes in 12 of 14 mitochondrial genes assayed (P < 0.01). Conclusions: Elevated serum FGF-19 levels post-surgery were associated with improved mitochondrial health in AT and overall diabetic remission. Changes in circulating FGF-19 levels were surgery-specific, with BPD producing the best metabolic outcomes among the study procedures (BPD > LGCP > LAGB), and highlighting mitochondria in AT as a potential target of FGF-19 during diabetes remission

Exercise interventions significantly reduce fasting insulin, but not fasting glucose, in women with polycystic ovary syndrome when compared with no intervention: A systematic review and meta-analysis

Aims: Polycystic ovary syndrome (PCOS) is a common condition that affects approximately 20% of reproductive‐aged women. PCOS is also associated with insulin resistance; women with PCOS are more insulin resistant than body mass index–matched controls. Methods: A systematic review was completed; randomised controlled trials that compared physical activity with control groups were evaluated in a meta‐analysis. Outcomes related to glucose homeostasis were analysed. Change from baseline to end of intervention values were reported as mean difference (MD) and 95% confidence intervals (CI). Results: There was evidence of a favourable effect of exercise on fasting insulin levels (MD −2.62 μIU/ml, CI −4.46 to −0.77; I2 = 92%; 236 participants, eight trials), but not for fasting blood glucose. Reductions in fasting insulin were found for all exercise modalities (aerobic, resistance or combined exercise), but were strongest in resistance training groups (MD −3.99 μIU/ml, CI −5.97 to −2.00; I2 = 54%; 50 participants, three trials). Change from baseline HOMA index also favoured exercise (MD −0.59, CI −1.02 to −0.17; I2 = 89%; 146 participants, seven trials) but evidence of effect was only present in aerobic exercise groups (MD −0.77, CI −1.28 to −0.26; I2 = 65%; 75 participants, four trials). Summary: Exercise, regardless of modality, reduces fasting insulin, but not fasting blood glucose, in women with PCOS compared with those receiving no intervention. However, a cautious approach should be adopted in interpreting these findings due to the wide CIs and evidence of considerable heterogeneity. Despite the statistically significant results, it is unclear if these improvements are clinically relevant

Impact of environmentally relevant concentrations of Bisphenol A (BPA) on the gene expression profile in an in vitro model of the normal human ovary

Data Availability Statement: All data is publicly available from online repositories as indicated in the materials and methods section. Supplementary Materials: The following supporting information can be downloaded at: https: //www.mdpi.com/article/10.3390/ijms23105334/s1.Copyright © 2022 by the authors. Endocrine-disrupting chemicals (EDCs), including the xenoestrogen Bisphenol A (BPA), can interfere with hormonal signalling. Despite increasing reports of adverse health effects associated with exposure to EDCs, there are limited data on the effect of BPA in normal human ovaries. In this paper, we present a detailed analysis of the transcriptomic landscape in normal Human Epithelial Ovarian Cells (HOSEpiC) treated with BPA (10 and 100 nM). Gene expression profiles were determined using high-throughput RNA sequencing, followed by functional analyses using bioinformatics tools. In total, 272 and 454 differentially expressed genes (DEGs) were identified in 10 and 100 nM BPA-treated HOSEpiCs, respectively, compared to untreated controls. Biological pathways included mRNA surveillance pathways, oocyte meiosis, cellular senescence, and transcriptional misregulation in cancer. BPA exposure has a considerable impact on 10 genes: ANAPC2, AURKA, CDK1, CCNA2, CCNB1, PLK1, BUB1, KIF22, PDE3B, and CCNB3, which are also associated with progesterone-mediated oocyte maturation pathways. Future studies should further explore the effects of BPA and its metabolites in the ovaries in health and disease, making use of validated in vitro and in vivo models to generate data that will address existing knowledge gaps in basic biology, hazard characterisation, and risk assessment associated with the use of xenoestrogens such as BPA.Brunel University London Isambard Kingdom Brunel Research Scholarship (grant 10418139)

Host cell entry mediators implicated in the cellular tropism of SARS‑CoV‑2, the pathophysiology of COVID‑19 and the identification of microRNAs that can modulate the expression of these mediators (Review)

Copyright: © Katopodis et al. The pathophysiology of coronavirus disease 2019 (COVID‑19) is mainly dependent on the underlying mechanisms that mediate the entry of severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) into the host cells of the various human tissues/organs. Recent studies have indicated a higher order of complexity of the mechanisms of infectivity, given that there is a wide‑repertoire of possible cell entry mediators that appear to co‑localise in a cell‑ and tissue‑specific manner. The present study provides an overview of the ‘canonical’ SARS‑CoV‑2 mediators, namely angiotensin converting enzyme 2, transmembrane protease serine 2 and 4, and neuropilin‑1, expanding on the involvement of novel candidates, including glucose‑regulated protein 78, basigin, kidney injury molecule‑1, metabotropic glutamate receptor subtype 2, ADAM metallopeptidase domain 17 (also termed tumour necrosis factor‑α convertase) and Toll‑like receptor 4. Furthermore, emerging data indicate that changes in microRNA (miRNA/miR) expression levels in patients with COVID‑19 are suggestive of further complexity in the regulation of these viral mediators. An in silico analysis revealed 160 candidate miRNAs with potential strong binding capacity in the aforementioned genes. Future studies should concentrate on elucidating the association between the cellular tropism of the SARS‑CoV‑2 cell entry mediators and the mechanisms through which they might affect the clinical outcome. Finally, the clinical utility as a biomarker or therapeutic target of miRNAs in the context of COVID‑19 warrants further investigation

Neuropilin‑1 as a new potential SARS‑CoV‑2 infection mediator implicated in the neurologic features and central nervous system involvement of COVID‑19

Availability of data and materials: All data generated or analysed during this study are included in this published article.Copyright © 2020 Davies et al. Infection by the severe acute respiratory syndrome (SARS) coronavirus‑2 (SARS‑CoV‑2) is the cause of the new viral infectious disease (coronavirus disease 2019; COVID‑19). Emerging evidence indicates that COVID‑19 may be associated with a wide spectrum of neurological symptoms and complications with central nervous system (CNS) involvement. It is now well‑established that entry of SARS‑CoV‑2 into host cells is facilitated by its spike proteins mainly through binding to the angiotensin‑converting enzyme 2 (ACE‑2). Preclinical studies have suggested that neuropilin‑1 (NRP1), which is a transmembrane receptor that lacks a cytosolic protein kinase domain and exhibits high expression in the respiratory and olfactory epithelium, may also be implicated in COVID‑19 by enhancing the entry of SARS‑CoV‑2 into the brain through the olfactory epithelium. In the present study, we expand on these findings and demonstrate that the NRP1 is also expressed in the CNS, including olfactory‑related regions such as the olfactory tubercles and paraolfactory gyri. This furthers supports the potential role of NRP1 as an additional SARS‑CoV‑2 infection mediator implicated in the neurologic manifestations of COVID‑19. Accordingly, the neurotropism of SARS‑CoV‑2 via NRP1‑expressing cells in the CNS merits further investigation.No funding was received