Machine learning algorithms to the early diagnosis of fetal alcohol spectrum disorders.

Introduction: Fetal alcohol spectrum disorders include a variety of physical and neurocognitive disorders caused by prenatal alcohol exposure. Although their overall prevalence is around 0.77%, FASD remains underdiagnosed and little known, partly due to the complexity of their diagnosis, which shares some symptoms with other pathologies such as autism spectrum, depression or hyperactivity disorders. Methods: This study included 73 control and 158 patients diagnosed with FASD. Variables selected were based on IOM classification from 2016, including sociodemographic, clinical, and psychological characteristics. Statistical analysis included Kruskal-Wallis test for quantitative factors, Chi-square test for qualitative variables, and Machine Learning (ML) algorithms for predictions. Results: This study explores the application ML in diagnosing FASD and its subtypes: Fetal Alcohol Syndrome (FAS), partial FAS (pFAS), and Alcohol-Related Neurodevelopmental Disorder (ARND). ML constructed a profile for FASD based on socio-demographic, clinical, and psychological data from children with FASD compared to a control group. Random Forest (RF) model was the most efficient for predicting FASD, achieving the highest metrics in accuracy (0.92), precision (0.96), sensitivity (0.92), F1 Score (0.94), specificity (0.92), and AUC (0.92). For FAS, XGBoost model obtained the highest accuracy (0.94), precision (0.91), sensitivity (0.91), F1 Score (0.91), specificity (0.96), and AUC (0.93). In the case of pFAS, RF model showed its effectiveness, with high levels of accuracy (0.90), precision (0.86), sensitivity (0.96), F1 Score (0.91), specificity (0.83), and AUC (0.90). For ARND, RF model obtained the best levels of accuracy (0.87), precision (0.76), sensitivity (0.93), F1 Score (0.84), specificity (0.83), and AUC (0.88). Our study identified key variables for efficient FASD screening, including traditional clinical characteristics like maternal alcohol consumption, lip-philtrum, microcephaly, height and weight impairment, as well as neuropsychological variables such as the Working Memory Index (WMI), aggressive behavior, IQ, somatic complaints, and depressive problems. Discussion: Our findings emphasize the importance of ML analyses for early diagnoses of FASD, allowing a better understanding of FASD subtypes to potentially improve clinical practice and avoid misdiagnosis.

Effectiveness of a probiotic combination on the neurodevelopment of the very premature infant.

Probiotics have shown a benefit in reducing necrotising enterocolitis in the premature infant, however the study of their effect on premature neonates' neurodevelopment is limited. The aim of our study was to elucidate whether the effect of Bifidobacterium bifidum NCDO 2203 combined with Lactobacillus acidophilus NCDO 1748 could positively impact the neurodevelopment of the preterm neonates. Quasi-experimental comparative study with a combined treatment of probiotics in premature infants < 32 weeks and < 1500 g birth weight, cared for at a level III neonatal unit. The probiotic combination was administered orally to neonates surviving beyond 7 days of life, until 34 weeks postmenstrual age or discharge. Globally, neurodevelopment was evaluated at 24 months corrected age. A total of 233 neonates were recruited, 109 in the probiotic group and 124 in the non-probiotic group. In those neonates receiving probiotics, there was a significant reduction in neurodevelopment impairment at 2 years of age RR 0.30 [0.16-0.58], and a reduction in the degree of impairment (normal-mild vs moderate-severe, RR 0.22 [0.07-0.73]). Additionally, there was a significant reduction in late-onset sepsis (RR 0.45 [0.21-0.99]). The prophylactic use of this probiotic combination contributed to improving neurodevelopmental outcome and reduced sepsis in neonates born at < 32 weeks and < 1500 g.Per style, a structured abstract is not allowed so we have changed the structured abstract to an unstructured abstract. Please check and confirm.Accepted.

Relationship between COVID-19 Pandemic Confinement and Worsening or Onset of Depressive Disorders.

Several studies indicate that the pandemic and associated confinement measures may have had an impact on mental health, producing the onset or persistence of symptoms such as stress, anxiety, depression, and fear. This systematic review aims to identify the factors influencing the onset or worsening of depressive symptoms during COVID-19-related confinement. Our systematic search produced 451 articles from selected databases, 398 of which were excluded based on established criteria, while 53 were selected for review. Most studies have reported an increase in the prevalence of depressive symptoms in the general population during the first weeks of confinement. The predominant risk factors associated with the appearance of depressive symptoms included female sex, low educational level, young age, economic difficulties, comorbidities, and a history of previous depressive episodes. People with a pre-existing diagnosis of depressive disorder generally experienced a worsening of their symptoms during confinement in most of the reviewed studies. Moreover, symptomatology persisted at higher levels post-confinement, without significant improvement despite relief in confinement measures. Therefore, ongoing evaluations of post-pandemic depressive symptoms are necessary to advance the knowledge of the relationship between pandemics and depression, allowing accurate conclusions and associations to be made.

Effect of Postnatal Epigallocatechin-Gallate Treatment on Cardiac Function in Mice Prenatally Exposed to Alcohol.

Prenatal alcohol exposure affects the cardiovascular health of the offspring. Epigallocatechin-3-gallate (EGCG) may be a protective agent against it, but no data are available regarding its impact on cardiac dysfunction. We investigated the presence of cardiac alterations in mice prenatally exposed to alcohol and the effect of postnatal EGCG treatment on cardiac function and related biochemical pathways. C57BL/6J pregnant mice received 1.5 g/kg/day (Mediterranean pattern), 4.5 g/kg/day (binge pattern) of ethanol, or maltodextrin until Day 19 of pregnancy. Post-delivery, treatment groups received EGCG-supplemented water. At post-natal Day 60, functional echocardiographies were performed. Heart biomarkers of apoptosis, oxidative stress, and cardiac damage were analyzed by Western blot. BNP and Hif1α increased and Nrf2 decreased in mice prenatally exposed to the Mediterranean alcohol pattern. Bcl-2 was downregulated in the binge PAE drinking pattern. Troponin I, glutathione peroxidase, and Bax increased in both ethanol exposure patterns. Prenatal alcohol exposure led to cardiac dysfunction in exposed mice, evidenced by a reduced ejection fraction, left ventricle posterior wall thickness at diastole, and Tei index. EGCG postnatal therapy restored the physiological levels of these biomarkers and improved cardiac dysfunction. These findings suggest that postnatal EGCG treatment attenuates the cardiac damage caused by prenatal alcohol exposure in the offspring.

Prevalence of Potentially Inappropriate Prescriptions According to the New STOPP/START Criteria in Nursing Homes: A Systematic Review.

The demand for long-term care is expected to increase due to the rising life expectancy and the increased prevalence of long-term illnesses. Nursing home residents are at an increased risk of suffering adverse drug events due to inadequate prescriptions. The main objective of this systematic review is to collect and analyze the prevalence of potentially inadequate prescriptions based on the new version of STOPP/START criteria in this specific population. Databases (PubMed, Web of Science and Cochrane) were searched for inappropriate prescription use in nursing homes according to the second version of STOPP/START criteria. The risk of bias was assessed with the STROBE checklist. A total of 35 articles were assessed for eligibility. One hundred and forty nursing homes and more than 6900 residents were evaluated through the analysis of 13 studies of the last eight years. The reviewed literature returned prevalence ranges between 67.8% and 87.7% according to the STOPP criteria, according to START criteria prevalence ranged from 39.5% to 99.7%. The main factors associated with the presence of inappropriate prescriptions were age, comorbidities, and polypharmacy. These data highlight that, although the STOPP/START criteria were initially developed for community-dwelling older adults, its use in nursing homes may be a starting point to help detect more efficiently inappropriate prescriptions in institutionalized patients. We hope that this review will help to draw attention to the need for medication monitoring systems in this vulnerable population.

Detection of the Synthetic Cannabinoids AB-CHMINACA, ADB-CHMINACA, MDMB-CHMICA, and 5F-MDMB-PINACA in Biological Matrices: A Systematic Review.

New synthetic cannabinoids (SCs) are emerging rapidly and continuously. Biological matrices are key for their precise detection to link toxicity and symptoms to each compound and concentration and ascertain consumption trends. The objective of this study was to determine the best human biological matrices to detect the risk-assessed compounds provided by The European Monitoring Centre for Drugs and Drug Addiction: AB-CHMINACA, ADB-CHMNACA, MDMB-CHMICA, and 5F-MDMB-PINACA. We carried out a systematic review covering 2015 up to the present date, including original articles assessing detection in antemortem human biological matrices with detailed validation information of the technique. In oral fluid and blood, SC parent compounds were found in oral fluid and blood at low concentrations and usually with other substances; thus, the correlation between SCs concentrations and severity of symptoms could rarely be established. When hair is used as the biological matrix, there are difficulties in excluding passive contamination when evaluating chronic consumption. Detection of metabolites in urine is complex because it requires prior identification studies. LC-MS/MS assays were the most widely used approaches for the selective identification of SCs, although the lack of standard references and the need for revalidation with the continuous emergence of new SCs are limiting factors of this technique. A potential solution is high-resolution mass spectrometry screening, which allows for non-targeted detection and retrospective data interrogation.

Effects of Antioxidant Intake on Fetal Development and Maternal/Neonatal Health during Pregnancy.

During pregnancy, cycles of hypoxia and oxidative stress play a key role in the proper development of the fetus. Hypoxia during the first weeks is crucial for placental development, while the increase in oxygen due to the influx of maternal blood stimulates endothelial growth and angiogenesis. However, an imbalance in the number of oxidative molecules due to endogenous or exogenous factors can overwhelm defense systems and lead to excessive production of reactive oxygen species (ROS). Many pregnancy complications, generated by systemic inflammation and placental vasoconstriction, such as preeclampsia (PE), fetal growth restriction (FGR) and preterm birth (PTB), are related to this increase of ROS. Antioxidants may be a promising tool in this population. However, clinical evidence on their use, especially those of natural origin, is scarce and controversial. Following PRISMA methodology, the current review addresses the use of natural antioxidants, such as epigallocatechin gallate (EGCG), melatonin and resveratrol (RESV), as well as other classical antioxidants (vitamin C and E) during the prenatal period as treatment of the above-mentioned complications. We review the effect of antioxidant supplementation on breast milk in lactating mothers.

Indirect Methods To Measure Unfolded Proteins In Living Cells Using Fluorescent Proteins.

In the study of the unfolded protein response pathway, it is essential to determine the amount of unfolded proteins that the cell is accumulating. Besides being essential it is one of the most challenging technique because of the difficulty to detect unfolded proteins without producing protein denaturation with the method itself. Thus, indirect methods became very useful as the use of fluorescent proteins. In this chapter, we present some of the most used methods to indirectly measure protein folding in living cells using fluorescent proteins.

Therapeutic Effects of Catechins in Less Common Neurological and Neurodegenerative Disorders.

In recent years, neurological and neurodegenerative disorders research has focused on altered molecular mechanisms in search of potential pharmacological targets, e.g., imbalances in mechanisms of response to oxidative stress, inflammation, apoptosis, autophagy, proliferation, differentiation, migration, and neuronal plasticity, which occur in less common neurological and neurodegenerative pathologies (Huntington disease, multiple sclerosis, fetal alcohol spectrum disorders, and Down syndrome). Here, we assess the effects of different catechins (particularly of epigalocatechin-3-gallate, EGCG) on these disorders, as well as their use in attenuating age-related cognitive decline in healthy individuals. Antioxidant and free radical scavenging properties of EGCG -due to their phenolic hydroxyl groups-, as well as its immunomodulatory, neuritogenic, and autophagic characteristics, makes this catechin a promising tool against neuroinflammation and microglia activation, common in these pathologies. Although EGCG promotes the inhibition of protein aggregation in experimental Huntington disease studies and improves the clinical severity in multiple sclerosis in animal models, its efficacy in humans remains controversial. EGCG may normalize DYRK1A (involved in neural plasticity) overproduction in Down syndrome, improving behavioral and neural phenotypes. In neurological pathologies caused by environmental agents, such as FASD, EGCG enhances antioxidant defense and regulates placental angiogenesis and neurodevelopmental processes. As demonstrated in animal models, catechins attenuate age-related cognitive decline, which results in improvements in long-term outcomes and working memory, reduction of hippocampal neuroinflammation, and enhancement of neuronal plasticity; however, further studies are needed. Catechins are valuable compounds for treating and preventing certain neurodegenerative and neurological diseases of genetic and environmental origin. However, the use of different doses of green tea extracts and EGCG makes it difficult to reach consistent conclusions for different populations.

Toxic Elements in Traditional Kohl-Based Eye Cosmetics in Spanish and German Markets.

Kohl is a traditional cosmetic widely used in Asia and Africa. In recent years, demand for kohl-based eyelids and lipsticks has increased in Europe, linked to migratory phenomena of populations from these continents. Although the European legislation prohibits the use of heavy metals in cosmetics due to the harmful effects to human health, particularly to pregnant women and children, these elements are still present in certain products. The European Union recommended levels are Pb < 20 ppm, As < 5 ppm, Cd < 5 ppm, Sb < 100 ppm, and Ni < 200 ppm. In Germany, levels are more restrictive: Pb < 2 ppm, As < 0.5 ppm, Cd < 0.1 ppm, Sb < 0.5 ppm, and Ni < 10 ppm. Here, we analyzed 12 kohl-based cosmetics in different presentations (powder, paste, and pencil) that were purchased in Spanish and German local shops. An inductively coupled plasma optical emission spectrophotometer was used to identify toxic elements and heavy metals. Levels of Pb ranged between 1.7 and 410,000 ppm in six of the study samples, four of which had levels above the recommended limit of at least two heavy metals. Arsenic (a carcinogenic element) values were within the range allowed by the EU in only 58% of the studied samples. Moreover, two products doubled this limit, reaching levels of 9.2 and 12.6 ppm. In one of the products, cadmium, related to toxic keratitis, was four times higher (20.7 ppm) than that allowed, while in two other products, these limits were doubled (11.8 and 12.7 ppm). Our results indicate the need to supervise the manufacture of kohl-based traditional products and the analysis of their composition prior distribution in European countries.

Effects of Microbiota Imbalance in Anxiety and Eating Disorders: Probiotics as Novel Therapeutic Approaches.

Anxiety and eating disorders produce a physiological imbalance that triggers alterations in the abundance and composition of gut microbiota. Moreover, the gut-brain axis can be altered by several factors such as diet, lifestyle, infections, and antibiotic treatment. Diet alterations generate gut dysbiosis, which affects immune system responses, inflammation mechanisms, the intestinal permeability, as well as the production of short chain fatty acids and neurotransmitters by gut microbiota, which are essential to the correct function of neurological processes. Recent studies indicated that patients with generalized anxiety or eating disorders (anorexia nervosa, bulimia nervosa, and binge-eating disorders) show a specific profile of gut microbiota, and this imbalance can be partially restored after a single or multi-strain probiotic supplementation. Following the PRISMA methodology, the current review addresses the main microbial signatures observed in patients with generalized anxiety and/or eating disorders as well as the importance of probiotics as a preventive or a therapeutic tool in these pathologies.

Murine Models for the Study of Fetal Alcohol Spectrum Disorders: An Overview.

Prenatal alcohol exposure is associated to different physical, behavioral, cognitive, and neurological impairments collectively known as fetal alcohol spectrum disorder. The underlying mechanisms of ethanol toxicity are not completely understood. Experimental studies during human pregnancy to identify new diagnostic biomarkers are difficult to carry out beyond genetic or epigenetic analyses in biological matrices. Therefore, animal models are a useful tool to study the teratogenic effects of alcohol on the central nervous system and analyze the benefits of promising therapies. Animal models of alcohol spectrum disorder allow the analysis of key variables such as amount, timing and frequency of ethanol consumption to describe the harmful effects of prenatal alcohol exposure. In this review, we aim to synthetize neurodevelopmental disabilities in rodent fetal alcohol spectrum disorder phenotypes, considering facial dysmorphology and fetal growth restriction. We examine the different neurodevelopmental stages based on the most consistently implicated epigenetic mechanisms, cell types and molecular pathways, and assess the advantages and disadvantages of murine models in the study of fetal alcohol spectrum disorder, the different routes of alcohol administration, and alcohol consumption patterns applied to rodents. Finally, we analyze a wide range of phenotypic features to identify fetal alcohol spectrum disorder phenotypes in murine models, exploring facial dysmorphology, neurodevelopmental deficits, and growth restriction, as well as the methodologies used to evaluate behavioral and anatomical alterations produced by prenatal alcohol exposure in rodents.

Probiotic Supplementation During the Perinatal and Infant Period: Effects on Gut Dysbiosis and Disease.

The perinatal period is crucial to the establishment of lifelong gut microbiota. The abundance and composition of microbiota can be altered by several factors such as preterm delivery, formula feeding, infections, antibiotic treatment, and lifestyle during pregnancy. Gut dysbiosis affects the development of innate and adaptive immune responses and resistance to pathogens, promoting atopic diseases, food sensitization, and infections such as necrotizing enterocolitis (NEC). Recent studies have indicated that the gut microbiota imbalance can be restored after a single or multi-strain probiotic supplementation, especially mixtures of Lactobacillus and Bifidobacterium strains. Following the systematic search methodology, the current review addresses the importance of probiotics as a preventive or therapeutic tool for dysbiosis produced during the perinatal and infant period. We also discuss the safety of the use of probiotics in pregnant women, preterm neonates, or infants for the treatment of atopic diseases and infections.

Bioavailability of Epigallocatechin Gallate Administered With Different Nutritional Strategies in Healthy Volunteers.

The flavanol epigallocatechin gallate (EGCG) is being tested for the treatment of several diseases in humans. However, its bioavailability and pharmacokinetic profile needs a better understanding to enable its use in clinical trials. There is no consensus on the most appropriate concentration of EGCG in the body to obtain the maximum therapeutic effects. Therefore, the aim of this study is to analyze the bioavailability of EGCG orally administered alone or with different food supplements after overnight fasting in order to determine its optimal conditions (high concentrations in blood and the lowest interindividual variations) to be used as a pharmacological tool in human trials. Ten healthy volunteers (5 men and 5 women) aged 25 to 35 years were recruited prospectively. Three series of clinical experiments with a washout period of seven days among each were performed: 1) Teavigo® (EGCG extract) alone, 2) Teavigo® with a standard breakfast, and 3) FontUp® (Teavigo® commercially prepared with fats, carbohydrates, proteins, vitamins, and minerals). Blood samples were collected at 0, 30, 60, 90, 120, 180, 240, and 360 min after EGCG intake. Free EGCG in plasma was measured using a liquid chromatography and mass spectrometry UPLC-ESI-MS/MS analytical method. The pharmacokinetic variables analyzed statistically were area under the curve (AUC0-360), Cmax, Cav, Cmin, T1/2, and Tmax,. EGCG (Teavigo®) alone was the group with higher AUC0-360, Cmax, and Cav both in men (3.86 ± 4.11 µg/mL/kg/6 h; 5.95 ng/mL/kg; 2.96 ng/mL/kg) and women (3.33 ± 1.08 µg/mL/kg/6 h; 6.66 ng/mL/kg; 3.66 ng/mL). Moreover, FontUp® was the group with the highest value of T1/2 both in men (192 ± 66 min) and women (133 ± 28 min). Teavigo® intake after fasting overnight revealed the highest concentration of EGCG in plasma according to its pharmacokinetic profile, indicating that this is an excellent alternative of administration if the experimental design requires good absorption in the gastrointestinal tract. Moreover, EGCG taken along with food supplements (FontUp®) improved the stability of the molecule in the body, being the best choice if the experimental design wants to reduce interindividual variation.

Dermatoglyphic fluctuating asymmetry and total a-b ridge count as biomarkers of Foetal Alcohol Syndrome: Analysis in children adopted from Eastern Europe.

BACKGROUND: Dermatoglyphics, formed mainly during the second trimester of pregnancy have been used as markers of developmental disturbances. The aim of this study was to examine if dermatoglyphic variation in children adopted from Eastern European countries with differential prenatal alcohol exposure, could be associated with diagnosis of Foetal Alcohol Spectrum Disorder (FASD). METHODS: Total a-b ridge count (TABRC), total ATD angle (TATD), palpebral fissure asymmetry and fluctuating asymmetry of the a-b ridge count (FAABRC) and ATD angle (FAATD) were obtained from NO FASD (n = 40) and FASD (n = 145; FAS = 54, pFAS = 64; ARND = 13; ARBD = 14) individuals. NO FASD and FASD subgroups were statistically compared for dermatoglyphic variables. Correlations between dermatoglyphics and FASD diagnosis were also performed. RESULTS: TABRC showed significantly higher values in foetal alcohol syndrome (FAS, p = 0.006) and partial FAS (pFAS, p = 0.040) groups compared to NO FASD controls. Similar results were obtained for TATD (FAS, p = 0.015 and pFAS, p = 0.032) compared to controls. Significantly higher values in FAS, pFAS and alcohol-related neurodevelopmental disorders (ARND) groups were observed for FAABRC (p = 0.034, p = 0.007, p = 0.007 respectively) and for FAATD in FAS group (p = 0.014) compared to NO FASD. Additionally, FAS group with mean + 2SD in palpebral fissure asymmetry showed statistical significance compared to NO FASD (p = 0.018). Dermatoglyphic variables also correlated (rho, Spearman) significantly with FASD diagnosis. CONCLUSION: Dermatoglyphic pattern and FASD are related. The validation of dermatoglyphics as an associated marker with FASD together with the currently diagnostic tools would help clinicians to an early FASD diagnosis in children.

Serum concentrations of IGF-I/IGF-II as biomarkers of alcohol damage during foetal development and diagnostic markers of Foetal Alcohol Syndrome.

Foetal Alcohol Syndrome (FAS) is the most deleterious health effect derived from alcohol consumption during pregnancy and is placed at the end of the Foetal Alcohol Spectrum Disorders (FASD). Few studies have proposed potential molecular biomarkers of physical and neurological damage associated with prenatal alcohol exposure. We prospectively recruited 55 children from 8 to 12 years old, with a prenatal assessment for ethanol exposure using meconium analysis of fatty acid ethyl esters (FAEE). The control group was established for FAEE < 2 nmol/g (n = 31) and a Prenatal Ethanol Exposure (PEE) group for FAEEs > 2 nmol/g (n = 33). Moreover, 98 children adopted from Eastern European Countries (EEC) were also recruited to evaluate FASD diagnosis comprising 31 cases with complete FAS, 42 with partial FAS, 6 with ARBD and 5 with ARND. Serum values of IGF-I and IGF-II for all children recruited were determined by immunoassay. Anthropometric and neurocognitive evaluation showed severe impairments in FAS children, moderate effects in PEE and no harmful effects in the control group with no prenatal exposure to alcohol. Analysis of IGF-I and IGF-II serum concentrations revealed that FASD from EEC as well as PEE children showed significantly lower concentrations of both IGF-I and IFG-II than the control group and reference values. Moreover, Spearman correlations showed a significant effect of IGF-I on anthropometric measurements in girls, whereas IGF-II affected the neuropsychological variables in both genders. These findings validate the use of growth factors IGF-I and IGF-II as surrogate biomarkers of damage induced by prenatal exposure to ethanol and could be used in the diagnosis of foetal alcohol spectrum disorders.

Membrane fluidification by ethanol stress activates unfolded protein response in yeasts.

The toxic effect of ethanol is one of the most important handicaps for many biotechnological applications of yeasts, such as bioethanol production. Elucidation of ethanol stress response will help to improve yeast performance in biotechnological processes. In the yeast Saccharomyces cerevisiae, ethanol stress has been recently described as an activator of the unfolded protein response (UPR), a conserved intracellular signalling pathway that regulates the transcription of ER homoeostasis-related genes. However, the signal and activation mechanism has not yet been unravelled. Here, we studied UPR's activation after ethanol stress and observed the upregulation of the key target genes, like INO1, involved in lipid metabolism. We found that inositol content influenced UPR activation after ethanol stress and we observed significant changes in lipid composition, which correlate with a major membrane fluidity alteration by this amphipathic molecule. Then, we explored the hypothesis that membrane fluidity changes cause UPR activation upon ethanol stress by studying UPR response against fluidification or rigidification agents and by studying a mutant, erg2, with altered membrane fluidity. The results suggest that the membrane fluidification effects of ethanol and other agents are the signal for UPR activation, a mechanism that has been proposed in higher eukaryotes.

Prevalence of prenatal exposure to substances of abuse: questionnaire versus biomarkers.

Alcohol and drugs of abuse consumption in young adults, including women of childbearing age, has experienced significant increase over the past two decades. The use of questionnaires as the only measure to investigate prenatal alcohol and drugs of abuse exposure underestimates the real prevalence of exposure and could mislead to wrong conclusions. Therefore, the aim of this article was to compare reported rates of prenatal alcohol and drugs of abuse consumption with biomarkers of exposure by a comprehensive review of the available literature. We searched MEDLINE and EMBASE databases for articles catalogued between 1992 and 2015. We identified relevant published studies that assessed the comparison between prenatal exposure to alcohol and drugs of abuse assessed by self-reported questionnaire of consumption versus biomarkers of exposure. Thirteen studies were included regarding alcohol consumption, and seven of them about drugs of abuse. Women who admitted consumption during pregnancy by questionnaire varied from 0 to 37% for alcohol, from 0 to 4.3% for cocaine, and 2.9% for tetrahydrocannabinol (THC). Positive biomarkers results ranged from 16 to 44% for alcohol, 15.4% for cocaine, and from 4 to 12.4% for THC. Biomarkers should always complement questionnaires, as it has been shown that self-report may underestimate prenatal exposure to substances of abuse.

Ethanol Effects Involve Non-canonical Unfolded Protein Response Activation in Yeast Cells.

The unfolded protein response (UPR) is a conserved intracellular signaling pathway that controls transcription of endoplasmic reticulum (ER) homeostasis related genes. Ethanol stress has been recently described as an activator of the UPR response in yeast Saccharomyces cerevisiae, but very little is known about the causes of this activation. Although some authors ensure that the UPR is triggered by the unfolded proteins generated by ethanol in the cell, there are studies which demonstrate that protein denaturation occurs at higher ethanol concentrations than those used to trigger the UPR. Here, we studied UPR after ethanol stress by three different approaches and we concluded that unfolded proteins do not accumulate in the ER under. We also ruled out inositol depletion as an alternative mechanism to activate the UPR under ethanol stress discarding that ethanol effects on the cell decreased inositol levels by different methods. All these data suggest that ethanol, at relatively low concentrations, does not cause unfolded proteins in the yeasts and UPR activation is likely due to other unknown mechanism related with a restructuring of ER membrane due to the effect of ethanol.

Ethanol Cellular Defense Induce Unfolded Protein Response in Yeast.

Ethanol is a valuable industrial product and a common metabolite used by many cell types. However, this molecule produces high levels of cytotoxicity affecting cellular performance at several levels. In the presence of ethanol, cells must adjust some of their components, such as the membrane lipids to maintain homeostasis. In the case of microorganism as Saccharomyces cerevisiae, ethanol is one of the principal products of their metabolism and is the main stress factor during fermentation. Although, many efforts have been made, mechanisms of ethanol tolerance are not fully understood and very little evidence is available to date for specific signaling by ethanol in the cell. This work studied two S. cerevisiae strains, CECT10094, and Temohaya-MI26, isolated from flor wine and agave fermentation (a traditional fermentation from Mexico) respectively, which differ in ethanol tolerance, in order to understand the molecular mechanisms underlying the ethanol stress response and the reasons for different ethanol tolerance. The transcriptome was analyzed after ethanol stress and, among others, an increased activation of genes related with the unfolded protein response (UPR) and its transcription factor, Hac1p, was observed in the tolerant strain CECT10094. We observed that this strain also resist more UPR agents than Temohaya-MI26 and the UPR-ethanol stress correlation was corroborated observing growth of 15 more strains and discarding UPR correlation with other stresses as thermal or oxidative stress. Furthermore, higher activation of UPR pathway in the tolerant strain CECT10094 was observed using a UPR mCherry reporter. Finally, we observed UPR activation in response to ethanol stress in other S. cerevisiae ethanol tolerant strains as the wine strains T73 and EC1118. This work demonstrates that the UPR pathway is activated under ethanol stress occurring in a standard fermentation and links this response to an enhanced ethanol tolerance. Thus, our data suggest that there is a room for ethanol tolerance improvement by enhancing UPR response.