Lights and shadows on the use of metformin in pregnancy: from the preconception phase to breastfeeding and beyond.

During pregnancy, the complex hormonal changes lead to a progressive decrease of insulin sensitivity that can drive the onset of gestational diabetes (GDM) or worsen an already-known condition of insulin resistance like type 2 diabetes, polycystic ovarian syndrome (PCOS), and obesity, with complications for the mother and the fetus. Metformin during pregnancy is proving to be safe in a growing number of studies, although it freely crosses the placenta, leading to a fetal level similar to maternal concentration. The aim of this literature review is to analyze the main available evidence on the use of metformin during, throughout, and beyond pregnancy, including fertilization, lactation, and medium-term effects on offspring. Analyzed studies support the safety and efficacy of metformin during pregnancy. In pregnant women with GDM and type 2 diabetes, metformin improves obstetric and perinatal outcomes. There is no evidence that it prevents GDM in women with pregestational insulin resistance or improves lipid profile and risk of GDM in pregnant women with PCOS or obesity. Metformin could have a role in reducing the risk of preeclampsia in pregnant women with severe obesity, the risk of late miscarriages and preterm delivery in women with PCOS, and the risk of ovarian hyperstimulation syndrome, increasing the clinical pregnancy rate in women with PCOS undergoing in vitro fertilization (IVF/FIVET). Offspring of mothers with GDM exposed to metformin have no significant differences in body composition compared with insulin treatment, while it appears to be protective for metabolic and cardiovascular risk.

Role of Oxidative Stress in the Pathogenesis of Atherothrombotic Diseases.

Oxidative stress is generated by the imbalance between reactive oxygen species (ROS) formation and antioxidant scavenger system's activity. Increased ROS, such as superoxide anion, hydrogen peroxide, hydroxyl radical and peroxynitrite, likely contribute to the development and complications of atherosclerotic cardiovascular diseases (ASCVD). In genetically modified mouse models of atherosclerosis, the overexpression of ROS-generating enzymes and uncontrolled ROS formation appear to be associated with accelerated atherosclerosis. Conversely, the overexpression of ROS scavenger systems reduces or stabilizes atherosclerotic lesions, depending on the genetic background of the mouse model. In humans, higher levels of circulating biomarkers derived from the oxidation of lipids (8-epi-prostaglandin F2α, and malondialdehyde), as well as proteins (oxidized low-density lipoprotein, nitrotyrosine, protein carbonyls, advanced glycation end-products), are increased in conditions of high cardiovascular risk or overt ASCVD, and some oxidation biomarkers have been reported as independent predictors of ASCVD in large observational cohorts. In animal models, antioxidant supplementation with melatonin, resveratrol, Vitamin E, stevioside, acacetin and n-polyunsaturated fatty acids reduced ROS and attenuated atherosclerotic lesions. However, in humans, evidence from large, placebo-controlled, randomized trials or prospective studies failed to show any athero-protective effect of antioxidant supplementation with different compounds in different CV settings. However, the chronic consumption of diets known to be rich in antioxidant compounds (e.g., Mediterranean and high-fish diet), has shown to reduce ASCVD over decades. Future studies are needed to fill the gap between the data and targets derived from studies in animals and their pathogenetic and therapeutic significance in human ASCVD.

Role of GDF-15, YKL-40 and MMP 9 in patients with end-stage kidney disease: focus on sex-specific associations with vascular outcomes and all-cause mortality.

BACKGROUND: Sex differences are underappreciated in the current understanding of cardiovascular disease (CVD) in association with chronic kidney disease (CKD). A hallmark of CKD is vascular aging that is characterised, amongst others, by; systemic inflammation, microbiota disbalance, oxidative stress, and vascular calcification-features linked to atherosclerosis/arteriosclerosis development. Thus, it is the necessary to introduce novel biomarkers related to athero-/arteriosclerotic damage for better assessment of vascular ageing in patients CKD. However, little is known about the relationship between uraemia and novel CVD biomarkers, such as growth differentiation factor-15 (GDF-15), cartilage glycoprotein-39 (YKL-40) and matrix metalloproteinase-9 (MMP-9). Therefore, we hypothesise that there are sex-specific relationships between GDF-15, YKL-40, MMP-9 levels in end-stage kidney disease (ESKD) patients in relation to gut microbiota, vascular calcification, inflammation, comorbidities, and all-cause mortality. METHODS: ESKD patients, males (n = 151) and females (n = 79), not receiving renal replacement therapy were selected from two ongoing prospective ESKD cohorts. GDF-15, YKL-40 and MMP9 were analysed using enzyme-linked immunosorbent assay kits. Biomarker levels were analysed in the context of gut microbiota-derived trimethylamine N-oxide (TMAO), vascular calcification, inflammatory response, oxidative stress, comorbidities, and all-cause mortality. RESULTS: Increased GDF-15 correlated with higher TMAO in females only, and with higher coronary artery calcification and IL-6. In females, diabetes was associated with elevated GDF-15 and MMP-9, whilst males with diabetes only had elevated GDF-15. No associations were found between biomarkers and CVD comorbidity. Deceased males and females had higher GDF-15 concentrations (p = 0.01 and p < 0.001, respectively), meanwhile only YKL-40 was increased in deceased males (p = 0.02). CONCLUSIONS: In conclusion, in males GDF-15 and YKL-40 were related to vascular calcification, inflammation, and oxidative stress, whilst in females GDF-15 was related to TMAO. Increased levels of YKL-40 and GDF-15 in males, and only GDF-15 in females, were associated with all-cause mortality. Our findings suggest that sex-specific associations of novel CVD biomarkers have a potential to affect development of cardiovascular complications in patients with ESKD.

Effects of propofol or sevoflurane anesthesia induction on hemodynamics in patients undergoing fiberoptic intubation for cervical spine surgery: A randomized, controlled, clinical trial.

BACKGROUND AND AIMS: In patients undergoing surgery for cervical myelopathy, induction of general anesthesia can induce systemic arterial hypotension that may worsen spinal cord hypoperfusion and precipitate spinal injury. In this randomized, controlled, clinical trial study, we compared the hemodynamic changes related to anesthesia induction with intravenous (IV) propofol- and sevoflurane-based inhalational induction in patients undergoing fiberoptic intubation for cervical spine surgery. MATERIAL AND METHODS: A total of 72 patients were studied. Hemodynamic effects were assessed measuring mean arterial pressure (MAP), and the echocardiographic evaluation of the left ventricular function. A Student's t-test with Bonferroni correction or Chi-squared test was used, when appropriate, to assess differences in hemodynamic (extent of MAP drop and incidence of episodes of severe arterial hypotension) and other variables (occurrence and duration of episodes of apnea). RESULTS: Patients assigned to total IV anesthetic approach had a lower MAP, and more significant changes in cardiac function compared to those who received the inhalational approach (68.1 ± 9.3 mmHg vs. 75.5 ± 10.3 mmHg; 25% vs. 5.5%). CONCLUSION: Anesthesia induction with both propofol or sevoflurane is safe and effective. However, total IV anesthesia induction is associated with more pronounced MAP drop which can worsen spinal cord hypoperfusion.

Spine Surgery and Blood Loss: Systematic Review of Clinical Evidence.

Spine surgery has been growing rapidly as a neurosurgical operation, with an increase of 220% over a 15-year period. Intraoperative blood transfusion is a major outcome determinant of spine procedures. Various approaches, including pharmacologic and nonpharmacologic therapies, have been tested to decrease both intraoperative and postoperative blood loss. The aim of this systematic review is to report clinical evidence on the relationship between intraoperative blood loss (primary outcome) and on transfusion requirements and postoperative complications (secondary outcomes) in patients undergoing spine surgery. A literature search of PubMed database was performed using 5 key words: spine surgery and transfusion; spine surgery and blood loss; spine surgery and blood complications; spine surgery and deep vein thrombosis; and spine surgery and pulmonary embolism. Clinical reports (randomized controlled trials, prospective and retrospective studies, and case reports) were selected. A total of 473 articles were examined; 450 were excluded, and 24 were selected for this systematic review. Selected articles were categorized into 3 subchapters: (1) drugs active on coagulation (12 studies): tranexamic acid, aminocaproic acid, aprotinin, and recombinant activated factor VII; (2) drugs not active on coagulation (5 studies): ketorolac, epoetin alfa, magnesium sulfate, propofol/sevoflurane, and omega-3 and fish oil; (3) nonpharmacologic approaches (7 studies): surgical tips, patient positioning, and general or spinal anesthesia. Several studies have shown a significant reduction in intraoperative bleeding during spine surgery and in the requirement for blood transfusion.