Characteristics of health behaviours and health status indicators among pregnant women in Slovenia

Background: Pregnancy is a period when women reconsider their own health and health related behaviour for the sake of their future child. Along with their health providers, they are faced with a number of risk assessments and decisions, which become far more complex as their effect on two organisms rather than one is at play. This paper provides an overview of possible associations between self-reported health status, health behaviours and socio-demographics during pregnancy.Methods: Study data were obtained from the case-control research project “Analysis of folate metabolism biomarkers in the risk assessment for neural tube defects, orofacial clefts and congenital heart defects”, which recruited participants from May 2013 to September 2015. Questionnaires about maternal health, health related behaviour and socio-demographic characteristics were completed by 450 women. The data include pregnancies from the 1980s to 2015.Results: We observed that younger and less educated women more frequently reported positive smoking status during pregnancy, while higher prevalence of folate/multivitamin supplementation was found among more educated, older and nulliparous women. There was a U-shaped distribution of medication intake (over-the-counter and prescribed) with respect to educational level, with the highest intake in mothers with a masters/PhD degree and among those that completed elementary school. Higher medication usage was also reported among older women. With increasing maternal age there was an increase in medication intake, folate/multivitamin intake, as well as incidence of gestational diabetes over the studied time period, with the highest frequencies occurring in later decades. A higher incidence of chronic diseases was observed in a group of multiparous women than among monoparous women.Conclusions: Considerable socio-demographic disparities exist in health-related behaviour among pregnant women. Improved public health campaigns and individual health care counselling are needed to address specific requirements of socio-demographic groups at higher risks of adverse pregnancy outcomes.</p

From metabonomics to pharmacometabonomics: The role of metabolic profiling in personalized medicine

Variable patient responses to drugs are a key issue for medicine and for drug discovery and development. Personalised medicine, that is the selection of medicines for subgroups of patients so as to maximise drug efficacy and minimise toxicity, is a key goal of 21st century healthcare. Currently, most personalised medicine paradigms rely on clinical judgement based on the patient’s history, and on the analysis of the patients’ genome to predict drug effects i.e. pharmacogenomics. However, variability in patient responses to drugs is dependent upon many environmental factors to which human genomics is essentially blind. A new paradigm for predicting drug responses based on individual pre-dose metabolite profiles has emerged in the past decade: pharmacometabonomics, which is defined as ‘the prediction of the outcome (for example, efficacy or toxicity) of a drug or xenobiotic intervention in an individual based on a mathematical model of pre-intervention metabolite signatures’. The new pharmacometabonomics paradigm is complementary to pharmacogenomics but has the advantage of being sensitive to environmental as well as genomic factors. This review will chart the discovery and development of pharmacometabonomics, and provide examples of its current utility and possible future developments

Vaccinomics and adversomics in the era of precision medicine

Precision medicine approaches based on pharmacogenomics are now being successfully implemented to enable physicians to predict more efficient treatments and prevention strategies for a given disease based on the genetic background of the patient. This approach has already been proposed for vaccines, but research is lagging behind the needs of society, and precision medicine is far from being implemented here. While vaccinomics concerns the effectiveness of vaccines, adversomics concerns their side effects. This area has great potential to address public concerns about vaccine safety and to promote increased public confidence, higher vaccination rates, and fewer serious adverse events in genetically predisposed individuals. The aim here is to explore the contemporary scientific literature related to the vaccinomic and adversomic aspects of the three most-controversial vaccines: those against hepatitis B, against measles, mumps, and rubella, and against human Papilloma virus. We provide detailed information on the genes that encode human leukocyte antigen, cytokines and their receptors, and transcription factors and regulators associated with the efficacy and safety of the Hepatitis B and Measles, Mumps and Rubella virus vaccines. We also investigate the future prospects of vaccinomics and adversomics of a COVID-19 vaccine, which might represent the fastest development of a vaccine ever

Triclocarban, triclosan, bromochlorophene, chlorophene, and climbazole effects on nuclear receptors

Background: Endocrine-disrupting chemicals can interfere with hormonal homeostasis and have adverse effects for both humans and the environment. Their identification is increasingly difficult due to lack of adequate toxicological tests. This difficulty is particularly problematic for cosmetic ingredients, because in vivo testing is now banned completely in the European Union. Objectives: The aim was to identify candidate preservatives as endocrine disruptors by in silico methods and to confirm endocrine receptors activities through nuclear receptors in vitro. Methods: We screened preservatives listed in Annex V in the European Union Regulation on cosmetic products to predict their binding to nuclear receptors using the Endocrine Disruptome and VirtualToxLab version 5.8 in silico tools. Five candidate preservatives were further evaluated for androgen receptor (AR), estrogen receptor (ER[alpha]), glucocorticoid receptor (GR), and thyroid receptor (TR) agonist and antagonist activities in cell-based luciferase reporter assays in vitro in AR-EcoScreen, hER[alpha]-HeLa-9903, MDA-kb2, and GH3.TRE-Luc cell lines. Additionally, assays to test for false positives were used (nonspecific luciferase gene induction and luciferase inhibition). Results: Triclocarban had agonist activity on AR and ER[alpha] at 1[micro]M and antagonist activity on GR at 5[micro]M and TR at 1[micro]M. Triclosan showed antagonist effects on AR, ER[alpha], GR at 10[micro]M and TR at 5[micro]M, and bromochlorophene at 1[micro]M (AR and TR) and at 10[micro]M (ER[alpha] and GR). AR antagonist activity of chlorophene was observed [inhibitory concentration at 50% (IC50) IC50=2.4[micro]M], as for its substantial ER[alpha] agonist at >5[micro]M and TR antagonist activity at 10[micro]M. Climbazole showed AR antagonist (IC50=13.6[micro]M), ER[alpha] agonist at >10[micro]M, and TR antagonist activity at 10[micro]M

A comprehensive genetic analysis of Slovenian families with multiple cases of orofacial clefts reveals novel variants in the genes IRF6, GRHL3, and TBX22

Although the aetiology of non-syndromic orofacial clefts (nsOFCs) is usually multifactorial, syndromic OFCs (syOFCs) are often caused by single mutations in known genes. Some syndromes, e.g., Van der Woude syndrome (VWS1VWS2) and X-linked cleft palate with or without ankyloglossia (CPX), show only minor clinical signs in addition to OFC and are sometimes difficult to differentiate from nsOFCs. We recruited 34 Slovenian multi-case families with apparent nsOFCs (isolated OFCs or OFCs with minor additional facial signs). First, we examined IRF6, GRHL3, and TBX22 by Sanger or whole exome sequencing to identify VWS and CPX families. Next, we examined 72 additional nsOFC genes in the remaining families. Variant validation and co-segregation analysis were performed for each identified variant using Sanger sequencing, real-time quantitative PCR and microarray-based comparative genomic hybridization. We identified six disease-causing variants (three novel) in IRF6, GRHL3, and TBX22 in 21% of families with apparent nsOFCs, suggesting that our sequencing approach is useful for distinguishing syOFCs from nsOFCs. The novel variants, a frameshift variant in exon 7 of IRF6, a splice-altering variant in GRHL3, and a deletion of the coding exons of TBX22, indicate VWS1, VWS2, and CPX, respectively. We also identified five rare variants in nsOFC genes in families without VWS or CPX, but they could not be conclusively linked to nsOFC

Folate insufficiency due to MTHFR deficiency is bypassed by 5-methyltetrahydrofolate

Adequate levels of folates are essential for homeostasis of the organism, prevention of congenital malformations, and the salvage of predisposed disease states. They depend on genetic predisposition, and therefore, a pharmacogenetic approach to individualized supplementation or therapeutic intervention is necessary for an optimal outcome. The role of folates in vital cell processes was investigated by translational pharmacogenetics employing lymphoblastoid cell lines (LCLs). Depriving cells of folates led to reversible S-phase arrest. Since 5,10-methylenetetrahydrofolate reductase (MTHFR) is the key enzyme in the biosynthesis of an active folate form, we evaluated the relevance of polymorphisms in the MTHFR gene on intracellular levels of bioactive metabolite, the 5-methyltetrahydrofolate (5-Me-THF). LCLs (n = 35) were divided into low- and normal-MTHFR activity groups based on their genotype. They were cultured in the presence of folic acid (FA) or 5-Me-THF. Based on the cells\u27 metabolic activity and intracellular 5-Me-THF levels, we conclude supplementation of FA is sufficient to maintain adequate folate level in the normal MTHFR activity group, while low MTHFR activity cells require 5-Me-THF to overcome the metabolic defects caused by polymorphisms in their MTHFR genes. This finding was supported by the determination of intracellular levels of 5-Me-THF in cell lysates by LC-MS/MS. FA supplementation resulted in a 2.5-fold increase in 5-Me-THF in cells with normal MTHFR activity, but there was no increase after FA supplementation in low MTHFR activity cells. However, when LCLs were exposed to 5-Me-THF, a 10-fold increase in intracellular levels of this metabolite was determined. These findings indicate that patients undergoing folate supplementation to counteract anti-folate therapies, or patients with increased folate demand, would benefit from pharmacogenetics-based therapy choices

A common polymorphism in the MTHFD1 gene is a modulator of risk of congenital heart disease

Several environmental and genetic factors may influence the risk of congenital heart defects (CHDs), which can have a substantial impact on pediatric morbidity and mortality. We investigated the association of polymorphisms in the genes of the folate and methionine pathways with CHDs using different strategies: a case–control, mother–child pair design, and a family-based association study. The polymorphism rs2236225 in the MTHFD1 was confirmed as an important modulator of CHD risk in both, whereas polymorphisms in MTRR, FPGS, and SLC19A1 were identified as risk factors in only one of the models. A strong synergistic effect on the development of CHDs was detected for MTHFD1 polymorphism and a lack of maternal folate supplementation during early pregnancy. A common polymorphism in the MTHFD1 is a genetic risk factor for the development of CHD, especially in the absence of folate supplementation in early pregnancy