"Be Healthy as a Fish" educational program - Presenting how zebrafish can improve our understanding of human diseases.

While mice and rats are still the most common choices for modeling human diseases, the use of zebrafish (Danio rerio) is becoming increasingly popular. In response to this growing potential, the International Institute of Molecular and Cell Biology in Warsaw (IIMCB) decided to introduce the Be Healthy as a Fish campaign in 2014. The program aims to educate school children on how the zebrafish can be used as a model organism to help scientists understand the way the human body works. Interactive workshops with the use of modern research equipment are part of the educational campaign, which also includes a short animated movie and a booklet. To make the program understandable and interesting for young audience, all of the materials and teaching aids were consulted with the Centre for Innovative Bioscience Education (BioCEN, Warsaw, Poland), whose mission is to popularize biology in society, especially through workshops for students and their teachers. As of October 31, 2018, nearly 900 primary school students participated in workshops. Nearly 2600 viewers have watched the movie on YouTube channel and more than 11,000 people received the book.

Blastocyst trophectoderm endocytic activation, a marker of adverse developmental programming.

The mouse preimplantation embryo is sensitive to its environment, including maternal dietary protein restriction, which can alter the developmental programme and affect lifetime health. Previously, we have shown maternal low-protein diet (LPD) causes a reduction in blastocyst mTORC1 signalling coinciding with reduced availability of branched-chain amino acids (BCAAs) in surrounding uterine fluid. BCAA deficiency leads to increased endocytosis and lysosome biogenesis in blastocyst trophectoderm (TE), a response to promote compensatory histotrophic nutrition. Here, we first investigated the induction mechanism by individual variation in BCAA deficiency in an in vitro quantitative model of TE responsiveness. We found isoleucine (ILE) deficiency as the most effective activator of TE endocytosis and lysosome biogenesis, with less potent roles for other BCAAs and insulin; cell volume was also influential. TE response to low ILE included upregulation of vesicles comprising megalin receptor and cathepsin-B, and the response was activated from blastocyst formation. Secondly, we identified the transcription factor TFEB as mediating the histotrophic response by translocation from cytoplasm to nucleus during ILE deficiency and in response to mTORC1 inhibition. Lastly, we investigated whether a similar mechanism responsive to maternal nutritional status was found in human blastocysts. Blastocysts from women with high body-mass index, but not the method of fertilisation, revealed stimulated lysosome biogenesis and TFEB nuclear migration. We propose TE lysosomal phenotype as an early biomarker of environmental nutrient stress that may associate with long-term health outcomes.

Surgical and embryological perspective of a big loop of internal carotid artery extending laterally beyond internal jugular vein.

Knowledge of variations of the internal carotid artery is significant to surgeons and radiologists. The internal carotid artery normally runs a straight course in the neck. Its anomalies can lead to its iatrogenic injuries. We report a case of a large loop of the internal carotid artery in a male cadaver aged about 75 years. The common carotid artery terminated by dividing it into the external carotid artery and internal carotid arteries at the level of the upper border of the thyroid cartilage. From the level of origin, the internal carotid artery coursed upwards, backwards and laterally, and formed a large loop behind the internal jugular vein. The variation was found on the left side of the neck and was unilateral. The uncommon looping of the internal carotid artery might result in altered blood flow to the brain and may lead to misperceptions in surgical, imaging, and invasive procedures.

Developmental programming of cardiovascular function: a translational perspective.

The developmental origins of health and disease (DOHaD) is a concept linking pre- and early postnatal exposures to environmental influences with long-term health outcomes and susceptibility to disease. It has provided a new perspective on the etiology and evolution of chronic disease risk, and as such is a classic example of a paradigm shift. What first emerged as the 'fetal origins of disease', the evolution of the DOHaD conceptual framework is a storied one in which preclinical studies played an important role. With its potential clinical applications of DOHaD, there is increasing desire to leverage this growing body of preclinical work to improve health outcomes in populations all over the world. In this review, we provide a perspective on the values and limitations of preclinical research, and the challenges that impede its translation. The review focuses largely on the developmental programming of cardiovascular function and begins with a brief discussion on the emergence of the 'Barker hypothesis', and its subsequent evolution into the more-encompassing DOHaD framework. We then discuss some fundamental pathophysiological processes by which developmental programming may occur, and attempt to define these as 'instigator' and 'effector' mechanisms, according to their role in early adversity. We conclude with a brief discussion of some notable challenges that hinder the translation of this preclinical work.

Light and Circadian Signaling Pathway in Pregnancy: Programming of Adult Health and Disease.

Light is a crucial environmental signal that affects elements of human health, including the entrainment of circadian rhythms. A suboptimal environment during pregnancy can increase the risk of offspring developing a wide range of chronic diseases in later life. Circadian rhythm disruption in pregnant women may have deleterious consequences for their progeny. In the modern world, maternal chronodisruption can be caused by shift work, jet travel across time zones, mistimed eating, and excessive artificial light exposure at night. However, the impact of maternal chronodisruption on the developmental programming of various chronic diseases remains largely unknown. In this review, we outline the impact of light, the circadian clock, and circadian signaling pathways in pregnancy and fetal development. Additionally, we show how to induce maternal chronodisruption in animal models, examine emerging research demonstrating long-term negative implications for offspring health following maternal chronodisruption, and summarize current evidence related to light and circadian signaling pathway targeted therapies in pregnancy to prevent the development of chronic diseases in offspring.

Prenatal therapeutics and programming of cardiovascular function.

Cardiovascular diseases (CVD) are a leading cause of mortality worldwide. Despite recognizing the importance of risk factors in dictating CVD susceptibility and onset, patient treatment remains a challenging endeavor. Increasingly, the benefits of prevention and mitigation of risk factors earlier in life are being acknowledged. The developmental origins of health and disease posits that insults during specific periods of development can influence long-term health outcomes; this occurs because the developing organism is highly plastic, and hence vulnerable to environmental perturbations. By extension, targeted therapeutics instituted during critical periods of development may confer long-term protection, and thus reduce the risk of CVD in later life. This review provides a brief overview of models of developmental programming, and then discusses the impact of perinatal therapeutic interventions on long-term cardiovascular function in the offspring. The discussion focuses on bioactive food components, as well as pharmacological agents currently approved for use in pregnancy; in short, those agents most likely to be used in pregnancy and early childhood.

[Role of Hormones in Perinatal and Early Postnatal Development: Possible Contribution to Programming/Imprinting Phenomena].

In parallel to formulating the paradigm of developmental origins of health and disease (DOHaD), the search began on mechanisms of programming/imprinting in ontogeny. Some recent evidence has revealed the important role of glucocorticoids in such mechanisms. However, in the last decades numerous data have been accumulated on participation of other hormones in developmental bioregulation. In present article we analyse these data, as referred to melatonin, but also to neuroactive steroids, somatolactogens and related peptides: insulin-like growth factor of type I (IGF-I) and oxytocin, i.e. peptide regulators related to growth and lactation respectively. Special attention was devoted to the evidence of glucocorticoid interactions with some of these hormones.

Has folate a role in the developing nervous system after birth and not just during embryogenesis and gestation?

It is now 30 years since the first publications stating that supplementation with folate could prevent neural tube defects appeared and 20 years since the definitive data, including prevention of other birth defects. Since then epidemiological studies and animal experiments have identified folate as a molecule at the crossroads of neural development. Fortification of food has greatly reduced the incidence of spina bifida. Much interest has focussed on long-term sequelae in children born to mothers severely deprived of folate (and other nutrients) such as during the Dutch Hunger Winter of 1944 and in poor parts of the world. In addition, deficiency in folate and B12 are increasingly discussed as a possible contributing factor in dementia and congenital orofacial and heart malformations. The year 2011 saw the publication of a study that implicated low folate intake in poorer school performance of adolescents as judged by school marks. This has enormous social implications but needs confirmation from other settings. This review assesses the current state of evidence and sets the data in context of whether folate has a role in the development and plasticity of the nervous system even after birth, with particular emphasis on childhood and adolescence.

Effects of marine toxins on the reproduction and early stages development of aquatic organisms.

Marine organisms, and specially phytoplankton species, are able to produce a diverse array of toxic compounds that are not yet fully understood in terms of their main targets and biological function. Toxins such as saxitoxins, tetrodotoxin, palytoxin, nodularin, okadaic acid, domoic acid, may be produced in large amounts by dinoflagellates, cyanobacteria, bacteria and diatoms and accumulate in vectors that transfer the toxin along food chains. These may affect top predator organisms, including human populations, leading in some cases to death. Nevertheless, these toxins may also affect the reproduction of aquatic organisms that may be in contact with the toxins, either by decreasing the amount or quality of gametes or by affecting embryonic development. Adults of some species may be insensitive to toxins but early stages are more prone to intoxication because they lack effective enzymatic systems to detoxify the toxins and are more exposed to the toxins due to a higher metabolic growth rate. In this paper we review the current knowledge on the effects of some of the most common marine toxins on the reproduction and development of early stages of some organisms.

The Role of Fe, Zn, and Cu in Pregnancy.

Iron (Fe), copper (Cu), and zinc (Zn) are microelements essential for the proper functioning of living organisms. These elements participatein many processes, including cellular metabolism and antioxidant and anti-inflammatory defenses, and also influence enzyme activity, regulate gene expression, and take part in protein synthesis. Fe, Cu, and Zn have a significant impact on the health of pregnant women and in the development of the fetus, as well as on the health of the newborn. A proper concentration of these elements in the body of women during pregnancy reduces the risk of complications such as anemia, induced hypertension, low birth weight, preeclampsia, and postnatal complications. The interactions between Fe, Cu, and Zn influence their availability due to their similar physicochemical properties. This most often occurs during intestinal absorption, where metal ions compete for binding sites with transport compounds. Additionally, the relationships between these ions have a great influence on the course of reactions in the tissues, as well as on their excretion, which can be stimulated or delayed. This review aims to summarize reports on the influence of Fe, Cu, and Zn on the course of single and multiple pregnancies, and to discuss the interdependencies and mechanisms occurring between Fe, Cu, and Zn.

Prenatal drug exposure and neurodevelopmental programming of glucocorticoid signalling.

Prenatal neurodevelopment is dependent on precise functioning of multiple signalling pathways in the brain, including those mobilised by glucocorticoids (GC) and endocannabinoids (eCBs). Prenatal exposure to drugs of abuse, including opioids, alcohol, cocaine and cannabis, has been shown to not only impact GC signalling, but also alter functioning of the hypothalamic-pituitary-adrenal (HPA) axis. Such exposures can have long-lasting neurobehavioural consequences, including alterations in the stress response in the offspring. Furthermore, cannabis contains cannabinoids that signal via the eCB pathway, which is linked to some components of GC signalling in the adult brain. Given that GCs are frequently used in pregnancy to prevent complications of prematurity, and also that rates of cannabis use in pregnancy are increasing, the likelihood of foetal co-exposure to these compounds is high and may have additional implications for long-term neurodevelopment. Here, we present a discussion of GC signalling and the HPA axis, as well as the effects of prenatal drug exposure on these pathways and the stress response, and we explore the interactions between GC and EC signalling in the developing brain and potential for neurodevelopmental consequences.

[Clinical guideline for the diagnosis and treatment of subclinical thyroid dysfunction in pregnancy. Working Group on Subclinical Thyroid Dysfunction of the Spanish Endocrinology Society]. / Guía clínica para el diagnóstico y el tratamiento de la disfunción tiroidea subclínica en la gestación. Grupo de Trabajo sobre la Disfunción Tiroidea Subclínica de la Sociedad Española de Endocrinología.

Subclinical thyroid disease is a biochemical diagnosis and is common during pregnancy. Because of the physiological hormonal changes that take place during pregnancy and the absence of normal ranges for thyroid hormones during this period, subclinical thyroid disease is difficult to interpret during pregnancy. Subclinical hyperthyroidism during pregnancy has few clinical consequences and no treatment is required. In contrast, subclinical hypothyroidism seems to improve with thyroxine treatment. Iodine supplements during pregnancy and lactation, even in iodine-sufficient areas, are also indicated.

Sex and gender differences in developmental programming of metabolism.

BACKGROUND: The early life environment experienced by an individual in utero and during the neonatal period is a major factor in shaping later life disease risk-including susceptibility to develop obesity, diabetes, and cardiovascular disease. The incidence of metabolic disease is different between males and females. How the early life environment may underlie these sex differences is an area of active investigation. SCOPE OF REVIEW: The purpose of this review is to summarize our current understanding of how the early life environment influences metabolic disease risk in a sex specific manner. We also discuss the possible mechanisms responsible for mediating these sexually dimorphic effects and highlight the results of recent intervention studies in animal models. MAJOR CONCLUSIONS: Exposure to states of both under- and over-nutrition during early life predisposes both sexes to develop metabolic disease. Females seem particularly susceptible to develop increased adiposity and disrupted glucose homeostasis as a result of exposure to in utero undernutrition or high sugar environments, respectively. The male placenta is particularly vulnerable to damage by adverse nutritional states and this may underlie some of the metabolic phenotypes observed in adulthood. More studies investigating both sexes are needed to understand how changes to the early life environment impact differently on the long-term health of male and female individuals.

Embryotoxic cytokines-Potential roles in embryo loss and fetal programming.

Cytokines in the reproductive tract environment at conception mediate a dialogue between the embryo and maternal tissues to profoundly influence embryo development and implantation success. Through effects on gene expression and the cell stress response, cytokines elicit an epigenetic impact with consequences for placental development and fetal growth, which in turn affect metabolic phenotype and long-term health of offspring. There is substantial evidence demonstrating that pro-survival cytokines, such as GM-CSF, CSF1, LIF, HB-EGF and IGFII, support embryos to develop optimally. Less attention has been paid to cytokines that adversely impact embryo development, including the pro-inflammatory cytokines TNF, TRAIL and IFNG. These agents elicit cell stress, impair cell survival and retard blastocyst development, and at sufficiently high concentrations, can cause embryo demise. Experiments in mice suggest these so-called 'embryotoxic' cytokines can harm embryos through pro-apoptotic and adverse programming effects, as well as indirectly suppressing uterine receptivity through the maternal immune response. Embryotrophic factors may mitigate against and protect from these adverse effects. Thus, the balance between embryotrophic and embryotoxic cytokines can impart effects on embryo development and implantation, and has the potential to contribute to endometrial 'biosensor' function to mediate embryo selection. Embryotoxic cytokines can be elevated in plasma and reproductive tract tissues in inflammatory conditions including infection, diabetes, obesity, PCOS and endometriosis. Studies are therefore warranted to investigate whether excessive embryotoxic cytokines contribute to infertility and recurrent implantation failure in women, and compromised reproductive performance in livestock animals.

The protective effect of polyunsaturated fatty acid intake during pregnancy against embryotoxicity of sodium valproate in mice.

Sodium valproate (VPA) is an anti-epileptic drug, but has a strong embryotoxicity due to its induced disturbance of folate-homocysteine (Hcy) metabolism and fatty acid metabolism. The aim of the present study was to investigate whether polyunsaturated fatty acid (PUFA) intake during pregnancy can relieve the embryotoxicity of VPA. VPA (dose: 500 mg kg-1, concentration: 38.5 mg ml-1) was intraperitoneally injected into pregnant mice on day 8.5 of gestation (E8.5d). PUFA intake significantly decreased fetal mortality and NTD incidence induced by VPA: n-3 long chain PUFAs (n-3 LCPUFAs) in fish oil had the best decreasing effect, followed by C18:3n-3 in flaxseed oil and then C18:2n-6 in corn oil. VPA administration inhibited the mRNA and protein expressions of a series of enzymes involved in folate-Hcy metabolism in the liver of pregnant mice; however, it led to the mRNA and protein overexpression of these enzymes in embryos. An elevated Hcy level in embryos was observed 6 h after VPA injection. n-3 PUFA intake effectively relieved this disturbance of folate-Hcy metabolism in pregnant mice and embryos, and this relieving effect of n-3 LCPUFAs and C18:3n-3 is better than that of C18:2n-6. In addition, n-3 PUFA intake also relieved the growth retardation induced by VPA. In conclusion, PUFA intake during pregnancy can effectively decrease embryotoxicity of VPA by relieving VPA-induced disturbance of folate-Hcy metabolism in pregnant mice and embryos, and n-3 LCPUFA in fish oil had the optimal protection effect.

The role of oxidative stress in spontaneous abortion and recurrent pregnancy loss: a systematic review.

UNLABELLED: Human reproduction is not considered a highly efficient biological process. Before the end of the first trimester, 30%-50% of conceptions end in spontaneous abortion. Most losses occur at the time of implantation. 15%-20% of clinical pregnancies end in spontaneous abortions. Recurrent pregnancy loss is a frustrating clinical problem both for clinicians and patients. Recurrent pregnancy loss affects 0.5%-3% of women in the reproductive age group, and between 50%-60% of recurrent pregnancy losses are idiopathic. Oxidative stress-induced damage has been hypothesized to play a role in spontaneous abortion, idiopathic recurrent pregnancy loss, hydatidiform mole, defective embryogenesis, and drug-induced teratogenicity. Some studies implicate systemic and placental oxidative stress in the pathophysiology of abortion and recurrent pregnancy loss. Oxidant-induced endothelial damage, impaired placental vascularization and immune malfunction have all been proposed to play a role in the pathophysiology of idiopathic recurrent pregnancy loss. Oxidative stress-induced placental dysfunction may be a common cause of the multifactorial and polygenic etiologies of abortion, recurrent pregnancy loss, defective embryogenesis, hydatidiform mole, and drug-induced teratogenic effects. Oxidative stress-induced modification of phospholipids has been linked to the formation of antiphospholipid antibodies in the antiphospholipid syndrome. The objective of this review was to examine the association between oxidative stress, spontaneous abortion and recurrent pregnancy loss, based on the published literature. We conducted an extensive literature search utilizing the databases of Medline, CINAHL, and Cochrane from 1986 to 2005. The following keywords were used: oxidative stress, abortion, recurrent pregnancy loss, reactive oxygen species, antioxidants, fetal development, and embryopathies. We conducted an electronic search, as well as a manual search of cross-references. We have included all studies in the English language found in the literature focusing on oxidative stress and its association with abortions, recurrent pregnancy loss and drug-induced teratogenicity. The role of antioxidant vitamins for primary prevention of oxidative stress-induced pathologies needs to be investigated further. TARGET AUDIENCE: Obstetricians & Gynecologists, Family Physicians. LEARNING OBJECTIVES: After completion of this article, the reader should be able to state that the causes of spontaneous and recurrent abortion are multifaceted, however, some of the causes may be preventable and also explain that the role of oxidative stress during pregnancy and adverse pregnancy outcomes has a basis in pathophysiology, although the role of oxidative stress and the treatment of oxidative stress during or before pregnancy remains speculative.

[Endocrine disruptor compounds and their role in the developmental programming of the reproductive axis]. / Compuestos disruptores endocrinos y su participación en la programación del eje reproductivo.

Different perturbations during fetal and postnatal development unleash endocrine adaptations that permanently alter metabolism, increasing the susceptibility to develop later disease, process known as "developmental programming." Endocrine disruptor compounds (EDC) are widely spread in the environment and display estrogenic, anti-estrogenic or anti-androgenic activity; they are lipophilic and stored for long periods in the adipose tissue. Maternal exposure to EDC during pregnancy and lactation produces the exposure of the fetus and neonate through placenta and breast milk. Epidemiological and experimental studies have demonstrated reproductive alterations as a consequence of intrauterine and/or neonatal exposure to EDC. Diethystilbestrol (DES) is the best documented compound, this synthetic estrogen was administered to pregnant women in the 1950s and 1960s to prevent miscarriage. It was implicated in urogenital abnormalities in children exposed in utero and was withdrawn from the market. The "DES daughters" are women with high incidence of vaginal hypoplasia, spontaneous abortion, premature delivery, uterine malformation, menstrual abnormalities and low fertility. The "DES sons" show testicular dysgenesis syndrome, which is characterized by hypospadias, cryptorchidism and low semen quality. This entity is also associated wtih fetal exposure to anti-androgens as flutamide. The effects on the reproductive axis depend on the stage of development and the window of exposure, as well as the dose and the compound. The wide distribution of EDC into the environment affects both human health and ecosystems in general, the study of their mechanisms of action is extremely important currently.

Hypoxia: From Placental Development to Fetal Programming.

Hypoxia may influence normal and different pathological processes. Low oxygenation activates a variety of responses, many of them regulated by hypoxia-inducible factor 1 complex, which is mostly involved in cellular control of O2 consumption and delivery, inhibition of growth and development, and promotion of anaerobic metabolism. Hypoxia plays a significant physiological role in fetal development; it is involved in different embryonic processes, for example, placentation, angiogenesis, and hematopoiesis. More recently, fetal hypoxia has been associated directly or indirectly with fetal programming of heart, brain, and kidney function and metabolism in adulthood. In this review, the role of hypoxia in fetal development, placentation, and fetal programming is summarized. Hypoxia is a basic mechanism involved in different pregnancy disorders and fetal health developmental complications. Although there are scientific data showing that hypoxia mediates changes in the growth trajectory of the fetus, modulates gene expression by epigenetic mechanisms, and determines the health status later in adulthood, more mechanistic studies are needed. Furthermore, if we consider that intrauterine hypoxia is not a rare event, and can be a consequence of unavoidable exposures to air pollution, nutritional deficiencies, obesity, and other very common conditions (drug addiction and stress), the health of future generations may be damaged and the incidence of some diseases will markedly increase as a consequence of disturbed fetal programming. Birth Defects Research 109:1377-1385, 2017.© 2017 Wiley Periodicals, Inc.

The microbiome-immune-host defense barrier complex (microimmunosome) and developmental programming of noncommunicable diseases.

Through its role as gatekeeper and filter to the external world, the microbiome affects developmental programming of physiological systems including the immune system. In turn, the immune system must tolerate, personalize, and prune the microbiome. Immune and host barrier status in early life significantly effects everything from embryo viability and pregnancy duration to the likelihood of misregulated inflammation, and risk of noncommunicable diseases (NCDs). Since the programming of and interactions among the microbiome, the host defense barrier, and the immune system can affect inflammation-driven health risks across the lifespan, a systems biology-type understanding of these three biological components may be useful. Here, I consider the potential utility of focusing on programming of a newly-defined systems biology unit termed the "microimmunosome."

Total Resection of Complex Spinal Cord Lipomas: How, Why, and When to Operate?

This article shows the long-term advantage of total resection of complex spinal cord lipomas over partial resection and over non-surgical treatment for children with asymptomatic lipomas. The classification, embryogenesis, and technique of total resection of complex lipomas are described. The 20-year outcome of 315 patients who had total resection is measured by overall progression-free survival (PFS, Kaplan-Meier), and by subgroup Cox multivariate hazard analysis for the influence of four variables: lipoma type, symptoms, prior surgery, and post-operative cord-sac ratio. These results are compared to 116 patients who underwent partial resection, and to two published series of asymptomatic lipomas followed without surgery. The PFS after total resection for all lipomas is 88.1% over 20 years vs. 34.6% for partial resection at 10.5 years (p < 0.0001). The PFS for total resection of asymptomatic virgin lipomas rose to 98.8% vs. 60% and 67% for non-surgical treatment. Partial resection also compares poorly to non-surgical treatment for asymptomatic lipomas. Multivariate analyses show that a low cord-sac ratio is the only independent variable that predicts good outcome. Pre-operative profiling shows the ideal patient for total resection is a young child with a virgin asymptomatic lipoma, who, with a PFS of 99.2%, is essentially cured. The technique of total resection can be learned by any neurosurgeon. Its long-term protection against symptomatic recurrence is better than partial resection and conservative management. The surgery should be done at diagnosis, except for asymptomatic small infants in whom surgery should be postponed till 6 months to minimize morbidity.