Endocrine Disruption and Immune DysfunctionDES Daughter
by the Collaborative on Health and the Environment
On this first in a series of calls on endocrine disrupting chemicals, Dr. Rodney Dietert discussed how the immune system is a target for endocrine disrupting chemicals, particularly during development. Numerous relatively ‘hidden’ effects can ensue from a single risk factor and emerge over a lifetime. He also discussed how current safety testing fails to appropriately assess misregulated inflammation as the greatest immune based health risk.
Sources: http://www.healthandenvironment.org/partnership_calls/13389
An Introduction to the Health Effects of Endocrine Disrupting Chemicals (EDCs)
by @toxipedia
* Toxipedia website;
http://www.toxipedia.org/display/toxipedia/Endocrine+Disruptors
* Endocrine Disruptors: Sexy Stuff:
http://desdaughter.wordpress.com/2012/12/16/endocrine-disruptors-sexy-stuff/
* All our posts about Endocrine Disruptors:
http://desdaughter.wordpress.com/tag/endocrine-disruptors/
What are Endocrine-disrupting chemicals (EDCs)?
What products contain endocrine disruptors?
How do endocrine disruptors work?(its Mechanisms of Action).
How are people exposed to endocrine disruptors?
Endocrine disrupting chemicals and their heath effects.
Pesticides:( DDT),human health consequences of exposure to DDT,and its scientific evidence and examples.
Steps to reduce exposure to endocrine disruptors
Endocrine Disruptors: Child healths
Vichit Supornsilchai, MD, PhD
Endocrine Unit, Department of Pediatric,
Faculty of Medicine,
King Chulalongkorn Memorial Hospital
Endocrine Disruption and Immune DysfunctionDES Daughter
by the Collaborative on Health and the Environment
On this first in a series of calls on endocrine disrupting chemicals, Dr. Rodney Dietert discussed how the immune system is a target for endocrine disrupting chemicals, particularly during development. Numerous relatively ‘hidden’ effects can ensue from a single risk factor and emerge over a lifetime. He also discussed how current safety testing fails to appropriately assess misregulated inflammation as the greatest immune based health risk.
Sources: http://www.healthandenvironment.org/partnership_calls/13389
An Introduction to the Health Effects of Endocrine Disrupting Chemicals (EDCs)
by @toxipedia
* Toxipedia website;
http://www.toxipedia.org/display/toxipedia/Endocrine+Disruptors
* Endocrine Disruptors: Sexy Stuff:
http://desdaughter.wordpress.com/2012/12/16/endocrine-disruptors-sexy-stuff/
* All our posts about Endocrine Disruptors:
http://desdaughter.wordpress.com/tag/endocrine-disruptors/
What are Endocrine-disrupting chemicals (EDCs)?
What products contain endocrine disruptors?
How do endocrine disruptors work?(its Mechanisms of Action).
How are people exposed to endocrine disruptors?
Endocrine disrupting chemicals and their heath effects.
Pesticides:( DDT),human health consequences of exposure to DDT,and its scientific evidence and examples.
Steps to reduce exposure to endocrine disruptors
Endocrine Disruptors: Child healths
Vichit Supornsilchai, MD, PhD
Endocrine Unit, Department of Pediatric,
Faculty of Medicine,
King Chulalongkorn Memorial Hospital
VCE Environmental Science - Unit 4: Pollution. The sources, sinks, human and environmental health effects of DDT and endocrine disruptors, including pthalates, are discussed in this presentation.
Endocrine Disruption of the Neuro-immune InterfaceDES Daughter
by the Collaborative on Health and the Environment
Building on the January 8, 2014 teleconference featuring Dr. Rodney Dietert on how the developing immune system is a target for endocrine disrupting chemicals, Dr. Jamie DeWitt discussed how certain cells of the immune system may mediate endocrine signals to direct aspects of brain development. She also described scenarios where endocrine disrupting chemicals can alter brain development by changing signals to the immune cells that can mediate development of sex specificity in the brain.
Sources: http://www.healthandenvironment.org/partnership_calls/13590
Genetic factors in pathogen colonisation is emerging as a new field of research as " infectogenomics". The susceptible host to periodontal disease directs towards genetic factors playing a role in periodontal disease pathogenesis. Earlier identification of gene polymorphisms associated with periodontal disease preogression may help in early diagnosis, treatment of such susceptible host.
Examining Neurobehavioral Toxicity of Patulin in Adult ZebrafishQuang Nguyen
The content of this PowerPoint is strictly for the purpose of submission to the Sigma Xi Research Showcase. Please do not quote/cite/reference materials in this file in its entirety. I am not responsible for any misrepresentation of its reproduction. Any reproduction must have the author's written approval.
Otherwise, I hope you enjoy the slides.
Check out my page at http://patulinzebrafish.tumblr.com/
Steelers Coach Completes Annual Trip to Pirates Spring Training Ryan Hoadley
Ryan Hoadley leverages more than a decade of experience in the financial industry to serve as an analyst for a hedge fund based in New York. Outside of work, Ryan Hoadley enjoys following sports and is particularly interested in Pittsburgh teams, such as the NFL’s Pittsburgh Steelers and the MLB’s Pittsburgh Pirates.
Marañón: Costo social de los impactos acumulativos de cinco proyectos hidroel...Crónicas del despojo
Estudio revela que 5 hidroeléctricas en el Marañón afectarían biodiversidad, pesca, agricultura y agravarían emisión de gases de efecto invernadero en la Amazonía.
VCE Environmental Science - Unit 4: Pollution. The sources, sinks, human and environmental health effects of DDT and endocrine disruptors, including pthalates, are discussed in this presentation.
Endocrine Disruption of the Neuro-immune InterfaceDES Daughter
by the Collaborative on Health and the Environment
Building on the January 8, 2014 teleconference featuring Dr. Rodney Dietert on how the developing immune system is a target for endocrine disrupting chemicals, Dr. Jamie DeWitt discussed how certain cells of the immune system may mediate endocrine signals to direct aspects of brain development. She also described scenarios where endocrine disrupting chemicals can alter brain development by changing signals to the immune cells that can mediate development of sex specificity in the brain.
Sources: http://www.healthandenvironment.org/partnership_calls/13590
Genetic factors in pathogen colonisation is emerging as a new field of research as " infectogenomics". The susceptible host to periodontal disease directs towards genetic factors playing a role in periodontal disease pathogenesis. Earlier identification of gene polymorphisms associated with periodontal disease preogression may help in early diagnosis, treatment of such susceptible host.
Examining Neurobehavioral Toxicity of Patulin in Adult ZebrafishQuang Nguyen
The content of this PowerPoint is strictly for the purpose of submission to the Sigma Xi Research Showcase. Please do not quote/cite/reference materials in this file in its entirety. I am not responsible for any misrepresentation of its reproduction. Any reproduction must have the author's written approval.
Otherwise, I hope you enjoy the slides.
Check out my page at http://patulinzebrafish.tumblr.com/
Steelers Coach Completes Annual Trip to Pirates Spring Training Ryan Hoadley
Ryan Hoadley leverages more than a decade of experience in the financial industry to serve as an analyst for a hedge fund based in New York. Outside of work, Ryan Hoadley enjoys following sports and is particularly interested in Pittsburgh teams, such as the NFL’s Pittsburgh Steelers and the MLB’s Pittsburgh Pirates.
Marañón: Costo social de los impactos acumulativos de cinco proyectos hidroel...Crónicas del despojo
Estudio revela que 5 hidroeléctricas en el Marañón afectarían biodiversidad, pesca, agricultura y agravarían emisión de gases de efecto invernadero en la Amazonía.
Balance Migratorio año 2016: El número de personas fallecidas intentando lleg...Crónicas del despojo
Andalucía, 23 de febrero de 2017. La Asociación Pro Derechos Humanos de Andalucía ha presentado hoy su Balance Migratorio 2016, en el que denuncia que el número de personas que han muerto o desaparecido en la Frontera Sur intentando alcanzar España se ha duplicado en solo dos años. El pasado año, 295 personas perdieron la vida, “fruto de las políticas de cierre de fronteras”.
El número de personas fallecidas intentando llegar a España se ha duplicado en solo dos años
La APDHA considera las vías legales y seguras como un deber moral y humanitario.
Las migraciones por nuestra Frontera Sur suponen apenas un 7% de las llegadas a Grecia e Italia
Pirates Sign Prospect to Minor League DealRyan Hoadley
Experienced financial professional Ryan Hoadley works in New York City as a hedge fund analyst at Newbrook Capital Advisors. Apart from this career in the financial sector, Ryan Hoadley enjoys watching professional baseball and is a fan of the Pittsburgh Pirates.
#MTC2017: E-wolucja sprzedaży - Rahim BlakMobile Trends
Wszystkie swoje umiejętności zdobyte w aktywnej sprzedaży bezpośredniej B2B, przeniosłem do social mediów i aplikacji mobilnych i to działa! Dzisiaj najwięcej zapytań ofertowych ze wszystkich kanałów sprzedaży dostaję na messengera mojego prywatnego profilu na facebooku :) Jak social media i mobile zmieniły sprzedaż bezpośrednią? Prezentacja zaczyna się od najbardziej tradycyjnych form aktywnej sprzedaży, po skalowanie i hackowanie sprzedaży produktów SaaS'owych przy użyciu najnowszych praktyk i technologii. Prelekcja wygłoszona podczas Mobile Trends Conference, 8-10 marca 2017 r. w Krakowie. www.MobileTrends.pl
#MTC2017: Od U do Z - jaka powinna być Twoja aplikacja na platformie iOS? - M...Mobile Trends
Tworzysz aplikację mobilną na platformę iOS i szukasz sposobów na to, by Twoja aplikacja była bardziej konkurencyjna w AppStore? Zanurzmy się w świat funkcji platformy iOS które Twoja aplikacja powinna posiadać. Prelekcja wygłoszona podczas Mobile Trends Conference, 8-10 marca 2017 r. w Krakowie. www.MobileTrends.pl
Factors Affecting Higher Education Quality in Bangladesh: An Attempt to Impro...IJSB
To meet the globalization challenges raising higher education quality to the world standard is essential. Because Economic Factors, An Era of Competition, Demographic Realities, lack of infrastectural development ,Governmental Political and Legal Challenges, Religious Factors, internal conflicts among educational institutions, corruption etc affect quality of higher education in Bangladesh. Bangladesh Govt. has taken initiatives to develop the quality of tertiary education. Govt. plans to prepare university graduates in such way that they can successfully compete in the context of international knowledge society. The Government prepared a Higher Education Strategic Plan 2006-26, which was fully homegrown with participation of front-line academics from both public and private universities and representatives from think-tanks and the private sector. Accordingly, the Ministry of Education, with the assistance of the World Bank, has undertaken a Higher Education Quality Enhancement Project (HEQEP). The project aims at improving the quality of teaching-learning and research capabilities of the tertiary education institutions through encouraging both innovation and accountability and by enhancing the technical and institutional capacity of the higher education sector. he Higher Education Quality Enhancement Project (HEQEP) will comprise of the following 4 (four) components: (i) promotion of academic innovation in teaching-learning and research through an Academic Innovation Fun (AIF) allocating funds on a competitive basis to public and private universities; (ii) institutional capacity building at the University Grants Commission (UGC) and the universities; (iii) connectivity capacity building for universities and research centers through the development of the Bangladesh Research and Education Network (BdREN) ; and (iv) support to the operation of the project implementation unit. The University Grants Commission of Bangladesh is the implementing agency of the project. A HEQEP Unit has been established in UGC for implementation, management, monitoring and evaluation of the activities.
Similar to Gene–environment interactions in development and disease lovely - 2016 - wiley interdisciplinary reviews: developmental biology - wiley online library
Who this is for: Health professionals.
Description: Dr. Sheila Bushkin-Bedient will be speaking on the prenatal origins of disease and why we should be focusing on studying possible connections between unconventional natural gas extraction and diabetes, obesity, and cancer.
About the Speaker: Sheila Bushkin is a member of the Institute of Health and the Environment at the State University at Albany, and Concerned Health Professionals of New York. She has been a member of the Medical Society of the State of New York for 15 years. Her specific areas of interest involve environmental health issues, chronic diseases, health concerns of older adults, and CME for physicians.
Child Development & Environmental Toxins - Resources for Healthy Children www.scribd.com/doc/254613619 - For more information, Please see Organic Edible Schoolyards & Gardening with Children www.scribd.com/doc/254613963 - Gardening with Volcanic Rock Dust www.scribd.com/doc/254613846 - Double Food Production from your School Garden with Organic Tech www.scribd.com/doc/254613765 - Free School Gardening Art Posters www.scribd.com/doc/254613694 - Increase Food Production with Companion Planting in your School Garden www.scribd.com/doc/254609890 - Healthy Foods Dramatically Improves Student Academic Success www.scribd.com/doc/254613619 - City Chickens for your Organic School Garden www.scribd.com/doc/254613553 - Huerto Ecológico, Tecnologías Sostenibles, Agricultura Organica www.scribd.com/doc/254613494 - Simple Square Foot Gardening for Schools - Teacher Guide www.scribd.com/doc/254613410 - Free Organic Gardening Publications www.scribd.com/doc/254609890 ~
Chemical Trespass - A Toxic Legacy - Resources for Healthy Children www.scribd.com/doc/254613619 - For more information, Please see Organic Edible Schoolyards & Gardening with Children www.scribd.com/doc/254613963 - Gardening with Volcanic Rock Dust www.scribd.com/doc/254613846 - Double Food Production from your School Garden with Organic Tech www.scribd.com/doc/254613765 - Free School Gardening Art Posters www.scribd.com/doc/254613694 - Increase Food Production with Companion Planting in your School Garden www.scribd.com/doc/254609890 - Healthy Foods Dramatically Improves Student Academic Success www.scribd.com/doc/254613619 - City Chickens for your Organic School Garden www.scribd.com/doc/254613553 - Huerto Ecológico, Tecnologías Sostenibles, Agricultura Organica www.scribd.com/doc/254613494 - Simple Square Foot Gardening for Schools - Teacher Guide www.scribd.com/doc/254613410 - Free Organic Gardening Publications www.scribd.com/doc/254609890 ~
Environmental Toxicants & Maternal & Child Health - An Emerging Public Health...v2zq
Environmental Toxicants & Maternal & Child Health - An Emerging Public Health Challenge - Resources for Healthy Children www.scribd.com/doc/254613619 - For more information, Please see Organic Edible Schoolyards & Gardening with Children www.scribd.com/doc/254613963 - Gardening with Volcanic Rock Dust www.scribd.com/doc/254613846 - Double Food Production from your School Garden with Organic Tech www.scribd.com/doc/254613765 - Free School Gardening Art Posters www.scribd.com/doc/254613694 - Increase Food Production with Companion Planting in your School Garden www.scribd.com/doc/254609890 - Healthy Foods Dramatically Improves Student Academic Success www.scribd.com/doc/254613619 - City Chickens for your Organic School Garden www.scribd.com/doc/254613553 - Huerto Ecológico, Tecnologías Sostenibles, Agricultura Organica www.scribd.com/doc/254613494 - Simple Square Foot Gardening for Schools - Teacher Guide www.scribd.com/doc/254613410 - Free Organic Gardening Publications www.scribd.com/doc/254609890 ~
Presentation that looks at the current clinical research on possible causes of Autism Spectrum Disorders. Includes brief mention of the use of Homeobotanicals in secondary symptom treatment management.
Birth Defects in Gaza: Prevalence, Types, Familiarity and Correlation with En...jhgbb
Naim A., Al Dalies H., El Balawi M., Salem E., Al Meziny K., Al Shawwa R., Minutolo R., Manduca P. Birth Defects in Gaza: Prevalence, Types, Familiarity and Correlation with Environmental Factors. International Journal of Environmental Research and Public Health. 2012; 9(5):1732-1747.
Fetal alcohol spectrum disorders the epigenetic perspective1 philip c. haycockBARRY STANLEY 2 fasd
An excellent account of the epigenetic consequences of preconceptual alcohol and prenatal alcohol. Although published ten years ago subsequent research confirms Dr Haycock’s conclusions.
Pesticide Health Risks to Children & the Unborn v2zq
Pesticide Health Risks to Children & the Unborn - Resources for Healthy Children www.scribd.com/doc/254613619 - For more information, Please see Organic Edible Schoolyards & Gardening with Children www.scribd.com/doc/254613963 - Gardening with Volcanic Rock Dust www.scribd.com/doc/254613846 - Double Food Production from your School Garden with Organic Tech www.scribd.com/doc/254613765 - Free School Gardening Art Posters www.scribd.com/doc/254613694 - Increase Food Production with Companion Planting in your School Garden www.scribd.com/doc/254609890 - Healthy Foods Dramatically Improves Student Academic Success www.scribd.com/doc/254613619 - City Chickens for your Organic School Garden www.scribd.com/doc/254613553 - Huerto Ecológico, Tecnologías Sostenibles, Agricultura Organica www.scribd.com/doc/254613494 - Simple Square Foot Gardening for Schools - Teacher Guide www.scribd.com/doc/254613410 - Free Organic Gardening Publications www.scribd.com/doc/254609890 ~ casle.ca
330 www.thelancet.comneurology Vol 13 March 2014Revie.docxtamicawaysmith
330 www.thelancet.com/neurology Vol 13 March 2014
Review
Neurobehavioural eff ects of developmental toxicity
Philippe Grandjean, Philip J Landrigan
Neurodevelopmental disabilities, including autism, attention-defi cit hyperactivity disorder, dyslexia, and other
cognitive impairments, aff ect millions of children worldwide, and some diagnoses seem to be increasing in frequency.
Industrial chemicals that injure the developing brain are among the known causes for this rise in prevalence. In 2006,
we did a systematic review and identifi ed fi ve industrial chemicals as developmental neurotoxicants: lead,
methylmercury, polychlorinated biphenyls, arsenic, and toluene. Since 2006, epidemiological studies have documented
six additional developmental neurotoxicants—manganese, fl uoride, chlorpyrifos, dichlorodiphenyltrichloroethane,
tetrachloroethylene, and the polybrominated diphenyl ethers. We postulate that even more neurotoxicants remain
undiscovered. To control the pandemic of developmental neurotoxicity, we propose a global prevention strategy.
Untested chemicals should not be presumed to be safe to brain development, and chemicals in existing use and all
new chemicals must therefore be tested for developmental neurotoxicity. To coordinate these eff orts and to accelerate
translation of science into prevention, we propose the urgent formation of a new international clearinghouse.
Introduction
Disorders of neurobehavioural development aff ect 10–15%
of all births,1 and prevalence rates of autism spectrum
disorder and attention-defi cit hyperactivity disorder seem
to be increasing worldwide.2 Subclinical decrements in
brain function are even more common than these
neurobehavioural developmental disorders. All these
disabilities can have severe consequences3—they diminish
quality of life, reduce academic achievement, and disturb
behaviour, with profound consequences for the welfare
and productivity of entire societies.4
The root causes of the present global pandemic of
neurodevelopmental disorders are only partly
understood. Although genetic factors have a role,5 they
cannot explain recent increases in reported prevalence,
and none of the genes discovered so far seem to be
responsible for more than a small proportion of cases.5
Overall, genetic factors seem to account for no more than
perhaps 30–40% of all cases of neurodevelopmental
disorders. Thus, non-genetic, environmental exposures
are involved in causation, in some cases probably by
interacting with genetically inherited predispositions.
Strong evidence exists that industrial chemicals widely
disseminated in the environment are important
contributors to what we have called the global, silent
pandemic of neurodevelopmental toxicity.6,7 The
developing human brain is uniquely vulnerable to toxic
chemical exposures, and major windows of
developmental vulnerability occur in utero and during
infancy and early childhood.8 During these sensitive life ...
Similar to Gene–environment interactions in development and disease lovely - 2016 - wiley interdisciplinary reviews: developmental biology - wiley online library (20)
Conclusions reached from my involvement with the Canadian criminal justice system. 2011.
amd- 2021
References of papers published by Dr Mansfield Mela, and others regarding FASD, PAE, Mental Health, and the Justice System.
Dr Mela is one of the very few Forensic Psychiatrists who understands and advocates for those with FASD.
The Nomenclature of the Consequences of Prenatal Alcohol Exposure: PAE, and t...BARRY STANLEY 2 fasd
An historical account of the nomenclature relating to the effects of alcohol on the developing fetus.
The significance of facial features; the dose/threshold question; epigenetics, transgenerational consequences, and adult health issues, are raised.
The inadequacy of the present nomenclature is detailed
Effects of Hyperbaric Oxygen Therapy on Brain Perfusion, Cognition and Behavi...BARRY STANLEY 2 fasd
Abstract
A 15-year-old girl diagnosed with FASD underwent 100 courses of hyperbasic oxygen therapy (HBOT). Prior to HBOT, single motion emission compute tomographic begin imaging (SPECT)
revealed areas of hypo-perfusion bilaterally in the orbitofrontal region, temporal lobes and right dorsolateral—frontal, as well the medial aspect of the left cerebellum. Following two sets of HBOT treatments (60 plus 40), over 6 months, there was improvement in perfusion to the left cerebellum as well as the right frontal lobe. This was paralleled by improvement in immediate cognitive tests and an increase in functional brain volume. A follow-up 18 months after HBOT showed sustained
improvement in attention with no need for methylphenidate, as well as in math skills and writing.
This year as a priority of Proof Alliance’s legislative platform, major legislation that requires all children entering foster care be screened for prenatal exposure to alcohol in Minnesota was passed and signed into law. It is believed Minnesota is the first state in the nation to pass this legislation.
Four year follow-up of a randomized controlled trial of choline for neurodeve...BARRY STANLEY 2 fasd
Abstract
Background
Despite the high prevalence of fetal alcohol spectrum disorder (FASD), there are few interventions targeting its core neurocognitive and behavioral deficits. FASD is often conceptualized as static and permanent, but interventions that capitalize on brain plasticity and critical developmental windows are emerging. We present a long-term follow-up study evaluating the neurodevelopmental effects of choline supplementation in children with FASD 4 years after an initial efficacy trial
Abstract
This presentation includes a brief review of research into boredom, normal brain resting state and corresponding default mode[s].
The possible equivalence to the brain activity of those with FASD in relation to “being bored” is explored, with reference to brain anatomy and function.
Actual FASD clinical cases are presented to illustrate what individuals with FASD mean by “boredom”: describing the role of perseveration as a relief process.
Finally, the manner in which these processes are misinterpreted is explored, with implications for Psychiatry and the Justice System.
Association Between Prenatal Exposure to Alcohol and Tobacco and Neonatal Bra...BARRY STANLEY 2 fasd
IMPORTANCE Research to date has not determined a safe level of alcohol or tobacco use during pregnancy. Electroencephalography (EEG) is a noninvasive measure of cortical function that has previously been used to examine effects of in utero exposures and associations with
neurodevelopment.
OBJECTIVE To examine the association of prenatal exposure to alcohol (PAE) and tobacco smoking (PTE) with brain activity in newborns.
CONCLUSIONS AND RELEVANCE These findings suggest that even low levels of PAE or PTE are
associated with changes in offspring brain development.
Submitted to –
National Institute for Health and Care Excellence Fetal alcohol spectrum disorder
Consultation on draft quality standard – deadline for comments 5pm on 03/04/20
Clinical course and risk factors for mortality of adult inpatients with covid...BARRY STANLEY 2 fasd
Interpretation The potential risk factors of older age, high SOFA score, and d-dimer greater than 1 μg/mL could help
clinicians to identify patients with poor prognosis at an early stage. Prolonged viral shedding provides the rationale
for a strategy of isolation of infected patients and optimal antiviral interventions in the future.
Outcomes of Online Mindfulness-Based Cognitive Therapy for Patients With Residual Depressive SymptomsA Randomized Clinical Trial
Zindel V. Segal, PhD1; Sona Dimidjian, PhD2; Arne Beck, PhD3; et alJennifer M. Boggs, PhD3; Rachel Vanderkruik, MA2; Christina A. Metcalf, MA2; Robert Gallop, PhD4; Jennifer N. Felder, PhD5; Joseph Levy, BA2
Author Affiliations
JAMA Psychiatry. Published online January 29, 2020. doi:10.1001/jamapsychiatry.2019.4693
Significance for fasd
Lung Cancer: Artificial Intelligence, Synergetics, Complex System Analysis, S...Oleg Kshivets
RESULTS: Overall life span (LS) was 2252.1±1742.5 days and cumulative 5-year survival (5YS) reached 73.2%, 10 years – 64.8%, 20 years – 42.5%. 513 LCP lived more than 5 years (LS=3124.6±1525.6 days), 148 LCP – more than 10 years (LS=5054.4±1504.1 days).199 LCP died because of LC (LS=562.7±374.5 days). 5YS of LCP after bi/lobectomies was significantly superior in comparison with LCP after pneumonectomies (78.1% vs.63.7%, P=0.00001 by log-rank test). AT significantly improved 5YS (66.3% vs. 34.8%) (P=0.00000 by log-rank test) only for LCP with N1-2. Cox modeling displayed that 5YS of LCP significantly depended on: phase transition (PT) early-invasive LC in terms of synergetics, PT N0—N12, cell ratio factors (ratio between cancer cells- CC and blood cells subpopulations), G1-3, histology, glucose, AT, blood cell circuit, prothrombin index, heparin tolerance, recalcification time (P=0.000-0.038). Neural networks, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS and PT early-invasive LC (rank=1), PT N0—N12 (rank=2), thrombocytes/CC (3), erythrocytes/CC (4), eosinophils/CC (5), healthy cells/CC (6), lymphocytes/CC (7), segmented neutrophils/CC (8), stick neutrophils/CC (9), monocytes/CC (10); leucocytes/CC (11). Correct prediction of 5YS was 100% by neural networks computing (area under ROC curve=1.0; error=0.0).
CONCLUSIONS: 5YS of LCP after radical procedures significantly depended on: 1) PT early-invasive cancer; 2) PT N0--N12; 3) cell ratio factors; 4) blood cell circuit; 5) biochemical factors; 6) hemostasis system; 7) AT; 8) LC characteristics; 9) LC cell dynamics; 10) surgery type: lobectomy/pneumonectomy; 11) anthropometric data. Optimal diagnosis and treatment strategies for LC are: 1) screening and early detection of LC; 2) availability of experienced thoracic surgeons because of complexity of radical procedures; 3) aggressive en block surgery and adequate lymph node dissection for completeness; 4) precise prediction; 5) adjuvant chemoimmunoradiotherapy for LCP with unfavorable prognosis.
New Directions in Targeted Therapeutic Approaches for Older Adults With Mantl...i3 Health
i3 Health is pleased to make the speaker slides from this activity available for use as a non-accredited self-study or teaching resource.
This slide deck presented by Dr. Kami Maddocks, Professor-Clinical in the Division of Hematology and
Associate Division Director for Ambulatory Operations
The Ohio State University Comprehensive Cancer Center, will provide insight into new directions in targeted therapeutic approaches for older adults with mantle cell lymphoma.
STATEMENT OF NEED
Mantle cell lymphoma (MCL) is a rare, aggressive B-cell non-Hodgkin lymphoma (NHL) accounting for 5% to 7% of all lymphomas. Its prognosis ranges from indolent disease that does not require treatment for years to very aggressive disease, which is associated with poor survival (Silkenstedt et al, 2021). Typically, MCL is diagnosed at advanced stage and in older patients who cannot tolerate intensive therapy (NCCN, 2022). Although recent advances have slightly increased remission rates, recurrence and relapse remain very common, leading to a median overall survival between 3 and 6 years (LLS, 2021). Though there are several effective options, progress is still needed towards establishing an accepted frontline approach for MCL (Castellino et al, 2022). Treatment selection and management of MCL are complicated by the heterogeneity of prognosis, advanced age and comorbidities of patients, and lack of an established standard approach for treatment, making it vital that clinicians be familiar with the latest research and advances in this area. In this activity chaired by Michael Wang, MD, Professor in the Department of Lymphoma & Myeloma at MD Anderson Cancer Center, expert faculty will discuss prognostic factors informing treatment, the promising results of recent trials in new therapeutic approaches, and the implications of treatment resistance in therapeutic selection for MCL.
Target Audience
Hematology/oncology fellows, attending faculty, and other health care professionals involved in the treatment of patients with mantle cell lymphoma (MCL).
Learning Objectives
1.) Identify clinical and biological prognostic factors that can guide treatment decision making for older adults with MCL
2.) Evaluate emerging data on targeted therapeutic approaches for treatment-naive and relapsed/refractory MCL and their applicability to older adults
3.) Assess mechanisms of resistance to targeted therapies for MCL and their implications for treatment selection
These simplified slides by Dr. Sidra Arshad present an overview of the non-respiratory functions of the respiratory tract.
Learning objectives:
1. Enlist the non-respiratory functions of the respiratory tract
2. Briefly explain how these functions are carried out
3. Discuss the significance of dead space
4. Differentiate between minute ventilation and alveolar ventilation
5. Describe the cough and sneeze reflexes
Study Resources:
1. Chapter 39, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 34, Ganong’s Review of Medical Physiology, 26th edition
3. Chapter 17, Human Physiology by Lauralee Sherwood, 9th edition
4. Non-respiratory functions of the lungs https://academic.oup.com/bjaed/article/13/3/98/278874
Ozempic: Preoperative Management of Patients on GLP-1 Receptor Agonists Saeid Safari
Preoperative Management of Patients on GLP-1 Receptor Agonists like Ozempic and Semiglutide
ASA GUIDELINE
NYSORA Guideline
2 Case Reports of Gastric Ultrasound
Title: Sense of Taste
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the structure and function of taste buds.
Describe the relationship between the taste threshold and taste index of common substances.
Explain the chemical basis and signal transduction of taste perception for each type of primary taste sensation.
Recognize different abnormalities of taste perception and their causes.
Key Topics:
Significance of Taste Sensation:
Differentiation between pleasant and harmful food
Influence on behavior
Selection of food based on metabolic needs
Receptors of Taste:
Taste buds on the tongue
Influence of sense of smell, texture of food, and pain stimulation (e.g., by pepper)
Primary and Secondary Taste Sensations:
Primary taste sensations: Sweet, Sour, Salty, Bitter, Umami
Chemical basis and signal transduction mechanisms for each taste
Taste Threshold and Index:
Taste threshold values for Sweet (sucrose), Salty (NaCl), Sour (HCl), and Bitter (Quinine)
Taste index relationship: Inversely proportional to taste threshold
Taste Blindness:
Inability to taste certain substances, particularly thiourea compounds
Example: Phenylthiocarbamide
Structure and Function of Taste Buds:
Composition: Epithelial cells, Sustentacular/Supporting cells, Taste cells, Basal cells
Features: Taste pores, Taste hairs/microvilli, and Taste nerve fibers
Location of Taste Buds:
Found in papillae of the tongue (Fungiform, Circumvallate, Foliate)
Also present on the palate, tonsillar pillars, epiglottis, and proximal esophagus
Mechanism of Taste Stimulation:
Interaction of taste substances with receptors on microvilli
Signal transduction pathways for Umami, Sweet, Bitter, Sour, and Salty tastes
Taste Sensitivity and Adaptation:
Decrease in sensitivity with age
Rapid adaptation of taste sensation
Role of Saliva in Taste:
Dissolution of tastants to reach receptors
Washing away the stimulus
Taste Preferences and Aversions:
Mechanisms behind taste preference and aversion
Influence of receptors and neural pathways
Impact of Sensory Nerve Damage:
Degeneration of taste buds if the sensory nerve fiber is cut
Abnormalities of Taste Detection:
Conditions: Ageusia, Hypogeusia, Dysgeusia (parageusia)
Causes: Nerve damage, neurological disorders, infections, poor oral hygiene, adverse drug effects, deficiencies, aging, tobacco use, altered neurotransmitter levels
Neurotransmitters and Taste Threshold:
Effects of serotonin (5-HT) and norepinephrine (NE) on taste sensitivity
Supertasters:
25% of the population with heightened sensitivity to taste, especially bitterness
Increased number of fungiform papillae
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Tom Selleck Health: A Comprehensive Look at the Iconic Actor’s Wellness Journeygreendigital
Tom Selleck, an enduring figure in Hollywood. has captivated audiences for decades with his rugged charm, iconic moustache. and memorable roles in television and film. From his breakout role as Thomas Magnum in Magnum P.I. to his current portrayal of Frank Reagan in Blue Bloods. Selleck's career has spanned over 50 years. But beyond his professional achievements. fans have often been curious about Tom Selleck Health. especially as he has aged in the public eye.
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Introduction
Many have been interested in Tom Selleck health. not only because of his enduring presence on screen but also because of the challenges. and lifestyle choices he has faced and made over the years. This article delves into the various aspects of Tom Selleck health. exploring his fitness regimen, diet, mental health. and the challenges he has encountered as he ages. We'll look at how he maintains his well-being. the health issues he has faced, and his approach to ageing .
Early Life and Career
Childhood and Athletic Beginnings
Tom Selleck was born on January 29, 1945, in Detroit, Michigan, and grew up in Sherman Oaks, California. From an early age, he was involved in sports, particularly basketball. which played a significant role in his physical development. His athletic pursuits continued into college. where he attended the University of Southern California (USC) on a basketball scholarship. This early involvement in sports laid a strong foundation for his physical health and disciplined lifestyle.
Transition to Acting
Selleck's transition from an athlete to an actor came with its physical demands. His first significant role in "Magnum P.I." required him to perform various stunts and maintain a fit appearance. This role, which he played from 1980 to 1988. necessitated a rigorous fitness routine to meet the show's demands. setting the stage for his long-term commitment to health and wellness.
Fitness Regimen
Workout Routine
Tom Selleck health and fitness regimen has evolved. adapting to his changing roles and age. During his "Magnum, P.I." days. Selleck's workouts were intense and focused on building and maintaining muscle mass. His routine included weightlifting, cardiovascular exercises. and specific training for the stunts he performed on the show.
Selleck adjusted his fitness routine as he aged to suit his body's needs. Today, his workouts focus on maintaining flexibility, strength, and cardiovascular health. He incorporates low-impact exercises such as swimming, walking, and light weightlifting. This balanced approach helps him stay fit without putting undue strain on his joints and muscles.
Importance of Flexibility and Mobility
In recent years, Selleck has emphasized the importance of flexibility and mobility in his fitness regimen. Understanding the natural decline in muscle mass and joint flexibility with age. he includes stretching and yoga in his routine. These practices help prevent injuries, improve posture, and maintain mobilit
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Ocular injury ppt Upendra pal optometrist upums saifai etawah
Gene–environment interactions in development and disease lovely - 2016 - wiley interdisciplinary reviews: developmental biology - wiley online library
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Gene–environment interactions in development and disease
First published:
14 September 2016 Full publication history
DOI:
10.1002/wdev.247 View/save citation
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C. Lovely , Mindy Rampersad, Yohaan Fernandes, Johann Eberhart
View issue TOC
Volume 6, Issue 1
January/February 2017
e247
Abstract
Developmental geneticists continue to make substantial jumps in our understanding of the genetic
pathways that regulate development. This understanding stems predominantly from analyses of
genetically tractable model organisms developing in laboratory environments. This environment is vastly
different from that in which human development occurs. As such, most causes of developmental defects
in humans are thought to involve multifactorial gene–gene and gene–environment interactions. In this
review, we discuss how gene–environment interactions with environmental teratogens may predispose
embryos to structural malformations. We elaborate on the growing number of gene–ethanol interactions
that might underlie susceptibility to fetal alcohol spectrum disorders. WIREs Dev Biol 2017, 6:e247. doi:
10.1002/wdev.247
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2. For further resources related to this article, please visit the WIREs website.
INTRODUCTION
Nature versus nurture, or the relative contributions of genetics versus the environment to traits, has long been
an area of great debate. Given that all organisms evolved within an environment that can be variable, it
comes as no surprise that ‘versus’ is a fairly contrived term in many instances. A classic example of this is the
disease progression of phenylketonuria, which requires both the mutation of PHENYLALANINE
HYDROXYLASE ( PAH ) and the presence of dietary phenylalanine. The maintenance of mutant alleles of
PAH in human populations is also likely due to gene–environment interactions. In some populations, such as
Irish, where the mutant PAH allele is at a relatively high frequency, maternal heterozygosity associates with
a reduced risk for miscarriage.[6] This is thought to be due to higher levels of phenylalanine in the blood of
heterozygotes protecting against the mycotoxin, ochratoxin A, which competes with phenylalanine for PAH
and is toxic to embryos.[6] Such gene–environment interactions abound in psychological and biological
systems, yet we still understand relatively little about these interactions.
This lack of understanding can confound many of the studies examining therapeutic approaches to diseases
and disorders. An example is the reduction of neural tube defects by folic acid supplementation. Studies
showing that folic acid supplementation reduces neural tube defects prompted the US medical community to
mandate folic acid fortification of grains.[7] However, subsequent work in mice showed that the protective
benefits of folic acid are dependent on genetic background and that, in varying genetic contexts, folic acid
supplementation can be detrimental.[8-10] Collectively, these findings with PAH and folic acid demonstrate
that neither a genotype nor an environmental factor can readily be a priori declared deleterious or beneficial.
Instead, development is highly context dependent and requires not only an understanding of genetic variation
but also of the environmental context in which the genotype is functioning.
Understanding the mechanism and breadth of gene–environment interactions requires careful analysis of
both the genetics of development and the preponderance of environmental influences. Recent work
published in the journal Nature has shown that extrinsic, or environmental, factors have a greater influence
on cancer risk than intrinsic factors.[11] Thus, genetic risk is only one part of a complicated equation
determining total cancer risk. Cancer can be thought of as a disease of development as many of the
pathways necessary for proper development have been implicated in many types of cancer. Ultimately, this
work shows that the interplay of both genetics and the environment is critical in understanding the etiology of
cancer and, by extension, development.
Teratogens are environmental factors that can disrupt normal development, causing birth defects. While the
timing (Figure 1) and dosage of teratogen exposure are critical variables that determine phenotypic
outcomes, genetic predisposition is also an important variable that is, in most instances, poorly understood.
In this review, we focus our discussion on gene–environment interactions with teratogenic agents that disrupt
early development. We first discuss a set of environmental agents that have been associated with gene–
environment interactions and elaborate on progress made on understanding gene–environment interactions
with the most common teratogen, ethanol.
3. Figure 1.
Open in figure viewer
Timing of teratogen exposure can dictate disrupted organ systems. The timing of development of
several organ systems discussed in this review is listed. The long development of the central
nervous system (CNS) makes it particularly susceptible to teratogenic insult.
ENVIRONMENTAL INFLUENCES: THE DARK SIDE OF
PROGRESS
Owing to human activity, the environment has changed drastically in the last 50 years. Currently, there are
more than 80,000 synthetic chemicals, and of these, approximately 3000 are produced in amounts at or
exceeding 1 million kg per year.[12] These 3000 chemicals are readily found in the environment and are in
measureable quantities in the blood of individuals.[12] In addition, there are 631 different pharmaceutical
agents found at measurable concentrations in the water worldwide and this number is likely an underestimate
due to a lack of testing.[13] Adding to these large numbers, there may be many more unknown metabolites
of these chemicals with unknown effects. Alarmingly, very few of these chemicals have been examined in a
developmental context.[12, 13] These industrial and pharmaceutical chemicals add to an already complex
environment (Figure 2), which includes disease, maternal factors (e.g., diet), natural factors (e.g., oxygen
levels), and drugs (e.g., alcohol). These facts demonstrate an ever-increasing likelihood for gene–
environment interactions but also have important implications, particularly in human studies that rely on self-
reported exposures, given that many exposures may be unknown to an individual.
4. There is growing evidence that chemicals originally considered safe can cause developmental defects.
Thalidomide is arguably the clearest example of this. Thalidomide was originally developed in the early 1950s
in Germany as a sedative and was actually prescribed to pregnant women as a treatment for morning
sickness in over 46 countries.[14] This resulted in severe birth defects, principally phocomelia, consisting
primarily of dramatically shortened limbs, though various other birth defects can and do present.[14] Owing to
the complex chemistry and actions of the drug, determining a mechanism of action has been difficult. Multiple
mechanisms have been proposed, including oxidative stress and antiangiogenic actions, though the direct
thalidomide targets and how they mediate teratogenesis are still not known.[15] Nitric oxide (NO) is a
promising target of thalidomide activity and exogenous NO has been shown to rescue thalidomide-induced
limb and eye deformities via reducing oxidative stress and increasing angiogenesis in both chicken and
zebrafish.[16] While no specific loci are known, a genetic susceptibility to thalidomide-induced birth defects is
possible as not all exposed embryos developed birth defects.[17] Understanding this potential genetic
susceptibility is critical because there is a resurgence of thalidomide use as an anticancer therapy.[18]
Recent work has shown that common pharmaceuticals may also increase the risk for developmental
disorders and that there is genetic susceptibility to these effects. Schill et al.[19] demonstrated that ibuprofen
inhibits migration and colonization of the bowel by enteric neural crest cells in zebrafish, chicken, and mouse.
Figure 2.
Open in figure viewer
Environmental influences on development. A developing embryo or fetus (center) can be exposed
to numerous environmental factors. These factors can interact with the genetic susceptibility of the
developing embryo or fetus to alter the outcome of development.
5. Mice lacking a single copy of Ret have increased sensitivity to ibuprofen. In humans, mutation of RET is a
risk factor for Hirschsprung disease, in which the bowel is not adequately colonized by enteric neural crest
cells.[20] Overall, this work suggests that, in sensitive genetic backgrounds, ibuprofen could increase the risk
for Hirschsprung disease. It should be of concern that this type of research is lacking for most of the 3000
pharmaceutical agents currently produced.
Similar concerns exist in the large numbers of other naturally occurring and synthetic chemicals. Chemicals
such as lead, methylmercury, toluene, and ethanol can all cause teratogenesis. Lead, used by humans for
thousands of years, has spread widely throughout the environment and human exposure can result in severe
neurotoxicity. Recent events in Flint, Michigan demonstrate the impact that environmental lead still has on our
society today. Prenatally, lead is able to pass the placental barrier and result in reduced cognitive
development and decreased intelligence quotient (IQ) scores.[21] Postnatally, young children are especially
sensitive where exposure can lead to cognitive impairments, decreased IQ scores, and behavioral problems,
and at later ages may cause a host of diseases including Alzheimer's and Parkinson's.[22, 23] The
differential progressive nature of lead-induced neurological damage across individuals suggests that
permanent changes in the central nervous system (CNS) may be mediated by genetic background. APOE
epsilon 4 ( ε4 ) associates with poorer prognosis following neural trauma,[24] implicating it in neural repair
and potentially lead-induced CNS defects. A study from 2002 has shown that APOEε4 may result in an
increased sensitivity to lead toxicity.[25] However, this study looked at adult exposures rather than in utero
exposure and did not hypothesize a potential mechanism for this gene–environmental interaction.
The APOEε4 –environment interaction is also observed in mercury toxicity. Methylmercury is formed in fresh
water environments from both natural and human-made sources of inorganic mercury. Methylmercury enters
the aquatic food chain where it accumulates in fishes. There is a long history of the toxic effects of
methylmercury dating back to 1865.[26] However, it was not until the 1950s that methylmercury was
identified as a teratogen, leading primarily to neurodevelopmental alterations, but also affecting overall
growth and limb development.[27, 28] Recent work has identified gene–mercury interactions with APOEε4
resulting in increased risk for neurodevelopmental deficits and maladaptive behavioral outcomes.[29, 30]
Additionally, work has shown that polymorphisms in other genes (ABC transporters and glutathione
processing enzymes) involved in the processing and elimination of methylmercury may lead to accumulation
of methylmercury in utero resulting in reduced birth weight.[31, 32] Thus, the genetic capacity of an embryo
(or potentially the mother) to clear an environmental contaminant may be critical in the risk of teratogenesis.
In addition to environmental contaminants, ‘life style’ can negatively impact development. While US smoking
rates are declining, as of 2014, 16.8% of adults still smoke cigarettes
(http://www.cdc.gov/tobacco/data_statistics/fact_sheets/adult_data/cig_smoking/). Smoking is a known risk
factor for birth defects, such as orofacial clefting.[33] Gene–smoking interactions associated with risk for
orofacial clefting have been identified predominantly by candidate approaches in humans. In a large study for
gene–smoking interactions underlying orofacial clefting, null and hypomorphic alleles for the detoxifying
enzymes GSTT1 and NAT2 , respectively, were found to associate with orofacial clefting.[34] Several
studies using candidate gene approaches have also identified genetic variants mediating risk to smoking-
induced orofacial clefting. These include genes associated with nicotine dependence ( DDC ),[35] DNA repair
( RAD51 ),[36] and orofacial clefting ( MSX1 and TGFB3 ).[37] It is of interest that other, similar, studies
failed to associate either MSX1 or TGFB3 and smoking in the risk for orofacial clefting.[38, 39] Many
possible reasons for such discrepancies exist and experiments in animal models where potential confounds
6. can be controlled would be of great assistance. Such animal models for the effects of smoking on
development are being generated[40] and should greatly increase our understanding of genetic risk to
smoking-induced birth defects as such models have done for our understanding of gene–ethanol interactions.
ETHANOL: THE EMPEROR OF ALL TERATOGENS
Humans have been consuming ethanol for millennia and alcohol consumption is socially acceptable in most
cultures. While the first evidence that ethanol exposure could damage developing embryos was published
more than a century ago,[41] it was not clinically appreciated that prenatal alcohol exposure could cause
human birth defects until 1968.[42] In 1973, the term fetal alcohol syndrome (FAS) was coined in reference to
a set of severe birth defects in individuals with prenatal alcohol exposure.[43] An FAS diagnosis requires the
presence of characteristic facial defects, such as a smooth philtrum, thin upper lip, and short palpebral
fissures or eye openings (Figure 3). Additionally, reduced growth and CNS deficits are present in FAS.[43]
While FAS requires the presence of this set of characteristic phenotypes, it is clear that much variability exists
in the phenotypic outcomes of ethanol exposure.
7. It is now well appreciated that ethanol can cause a wide range of structural, neural, and neurological
impairments. A more complete discussion of these ethanol-induced defects can be found elsewhere,[44] but
briefly prenatal alcohol exposure is a risk factor for orofacial clefting as well as cardiac and eye defects.[45]
Additionally, numerous structural defects of the brain are found in ethanol-exposed children, including
reduced size of the cerebellum and structural changes to the corpus callosum.[44, 46] Subsequently,
ethanol-exposed individuals may have learning and memory impairments.[47] These individuals frequently
lack the appropriate initiative to form and maintain friendships, leading to a lack of social relationships.[48,
Figure 3.
Open in figure viewer
Facial features characteristic of fetal alcohol syndrome.
8. 49] These deficits in social skills can result in employment problems, trouble with the law, inappropriate
sexual behavior, suicide, and depression.[50, 51] This full range of ethanol-induced phenotypes, with FAS at
the severe end, is collectively referred to as fetal alcohol spectrum disorders (FASD).[44]
Despite our understanding of FASD, significant numbers of individuals are exposed to at least some alcohol
prenatally. In the United States the numbers vary between studies, ranging as low as 12% to as high as 25%.
[52, 53] However, these numbers may be underestimates as more than 50% of women of childbearing age
consume ethanol and nearly half of pregnancies are unplanned.[52] Estimates of the prevalence of FASD are
as high as 1 in 100 live births in the United States.[54] More recent estimates give US prevalence rates of 2–
5%.[55] Recent studies in Italy and South Africa have shown even higher rates of FASD, 3.6 and 7.2%,
respectively.[55] These rates may well be underestimates because pediatricians frequently fail to recognize
FASD.[56] Collectively, research shows that FASD is strikingly common and has no single set of phenotypes
that define it. Instead, FASD is a highly complex disorder suggesting its genesis is multifactorial.
The variability of FASD and the comorbidity of other negative environments such as poor nutrition, tobacco or
drug use can confound human studies of FASD.[57, 58] Thus, animal models have been crucial in
developing our understanding of the pathogenesis of FASD. Indeed, it was work in animal models that
definitively showed ethanol was a clear teratogen.[59] Work across animal models has shown that ethanol
was capable of disrupting development of organ systems commonly disrupted in FASD, including the brain,
face, heart, and eyes.[41, 60-63] While development can be disrupted by ethanol at any developmental time
point, some of the most severe phenotypes are generated when exposure occurs during gastrulation, when
the progenitors of the CNS and the face are being generated. Therefore, disrupting embryonic development
during these developmental time windows can lead to a wide range of ethanol-induced phenotypes, including
growth retardation, facial dysmorphologies, and CNS abnormalities.[60] There is also interest in animal
studies of the behavioral outcomes of FASD and these studies have been extensively reviewed elsewhere.
[64] For the purpose of this review, we will focus primarily on the genesis of ethanol-induced structural
defects.
GENE–ETHANOL INTERACTIONS: A TALE OF TWO
INPUTS
Timing, dosage, pattern, and duration of ethanol exposure all impact the phenotypes in FASD.[65, 66]
Furthermore, multiple studies demonstrate that genetic predisposition also plays a role in FASD. Human twin
studies show that there is 100% concordance for FAS in monozygotic twins while only 64% concordance in
dizygotic twins.[67] In every animal model systems studied, zebrafish, chicken, mice, and rat, different inbred
strains show different sensitivity to ethanol-induced defects.[68] Thus, across species there is substantial
evidence that the risk for ethanol-induced developmental defects is genetically modulated.
Some of the insight into the genetic risk for FASD comes from phenotypes in individuals with FASD. While
FASD has an extremely wide spectrum of phenotypes, some of these mirror holoprosencephaly, which is also
highly phenotypically variable. Prenatal ethanol exposure is a risk factor for holoprosencephaly.[69] Mouse
studies have shown that ethanol exposure during days 7 and 8 of pregnancy results in a range of
holoprosencephaly-like phenotypes.[60] The genetics behind holoprosencephaly are complex, but most
genes are known to be involved in the genesis of holoprosencephaly function in the Sonic Hedgehog (Shh)
pathway.[70] Collectively, these findings initially suggested that mutations in the Shh pathway could enhance
9. the teratogenicity of ethanol.
Work in multiple animal model systems has demonstrated that mutations disrupting Shh signaling predispose
to ethanol teratogenesis. The study by Hong and Krauss[71] demonstrated that the Shh co-receptor Cdon
interacted with ethanol resulting in an increased incident of holoprosencephaly-like phenotypes in mutant
mice. Recent work has shown that heterozygosity for either Shh or Gli2 enhanced the facial and neural
defects caused by ethanol.[72] Additionally, work in zebrafish, using morpholinos, revealed that ethanol
interacts with shha leading to disrupted GABAergic and glutamatergic neural development.[73] Morpholinos
against agrin , which mediates Shh signaling, also interact with ethanol resulting in defects to ocular
development.[74] Thus, a substantial body of evidence exists suggesting that genetic attenuation of the Shh
pathway is a risk factor for FASD.
Several possibilities may explain these interactions of members of the Shh pathway with ethanol. First,
ethanol has been shown to disrupt lipid modification of Shh that is required for proper signaling.[75] Second,
it is possible that a source of Shh is undergoing apoptosis following ethanol treatment.[76] Third is that
ethanol disrupts retinoic acid levels. Retinoic acid is critical in inducing Shh expression in the notochord and
neural plate. The timing of ethanol exposure needed to phenocopy holoprosencephaly is just prior to the
induction of Shh expression. It has been proposed that ethanol is a competitive inhibitor of retinoic acid
synthesis,[77, 78] although this model remains contentious.[79] Numerous studies have examined if retinoic
acid supplementation can rescue ethanol-induced defects. Most relevant to whether retinoic acid is involved
in interactions between ethanol and the Shh pathway is the finding that retinoic acid supplementation can
rescue mid-hindbrain defects in ethanol-treated, shha morpholino-injected embryos.[80] The same study
found that retinoic acid did not rescue ocular defects under these same conditions. An inability of retinoic acid
to rescue ethanol-induced eye defects was independently demonstrated by Kashyap et al.[81] These
findings, among others detailed more extensively elsewhere,[68] suggest that the involvement of retinoic acid
in interactions between ethanol and the Shh pathway is likely to be context dependent. Given that Shh and
retinoic acid only explain a portion of the phenotypic spectrum in FASD, many other gene–ethanol
interactions must exist.
As with the teratogens discussed above, genes mediating clearance of ethanol are likely candidates to
modulate FASD risk. Early work in human populations focused on allelic differences in ethanol-metabolizing
enzymes. Across animal species, degradation of ethanol is a multistep process. Ethanol is metabolized
initially to acetaldehyde, primarily through the action of ALCOHOL DEHYDROGENASE (ADH), formed as a
complex of ADH1A, ADH1B, and ADH1C. Acetaldehyde is highly reactive and also potentially teratogenic. It
is converted to acetate via ALDEHYDE DEHYDROGENASE (ALDH). In several human studies, alleles of
ADH1B that are predicted to metabolize ethanol more quickly are underrepresented in children with FASD.
[82-86] Similarly, a slow metabolizing variant of ADH1C associates with orofacial clefting in ethanol-exposed
children.[87]
While ethanol metabolism may be protective against FASD, it also generates by-products that can be
deleterious to cells, making clearance of such by-products another potential level of gene–ethanol
interactions. Ethanol processing leads to reactive oxygen species production, disrupting the balance between
prooxidants and antioxidants leading to increased oxidative damage, including DNA damage.[88, 89]
Disrupting endogenous antioxidant production can lead to sensitivity to ethanol, which can be mitigated by
supplementation with the antioxidant vitamin E.[88] These approaches have been partially successful but
may be dependent on a range of factors including timing, dosage, cellular and tissue context, and genetic
Go To
10. background.[88, 90] In mice, maternal loss of Superoxide dismutase , responsible for clearing reactive
oxygen species, predisposes to ethanol teratogenesis.[91-93] Work in mouse has shown that combined loss
of Aldh2 and the Fanconi anemia DNA repair enzyme, Fancd2 , results in ethanol-induced exencephaly and
eye defects.[94] Thus, both reactive oxygen clearance and DNA damage repair are promising pathways to
mediate susceptibility to FASD.
Similar concerns are observed in reactive nitrogen species, in particular NO. Changes in NO have been
shown to play a role in ethanol teratogenesis with NO production being protective at low ethanol
concentrations and toxic at higher ethanol concentrations.[89, 95-97] However, attenuation of NO levels in
Nitric oxide synthase 1 mutants predisposes embryos to ethanol-induced neural defects.[95-97] These
studies used a third trimester model of exposure, demonstrating that deleterious gene–ethanol interactions
are not limited to early development. Collectively, these studies demonstrate that genes involved in clearing
ethanol and reversing potential deleterious consequences of ethanol and its metabolism are likely involved in
the genetic risk for FASD.
Other studies have taken broader approaches and demonstrated that the genetic susceptibility to ethanol is
likely more complex than what would be predicted based on overt phenotypes or ethanol metabolism. The
ease of performing genetic screens in zebrafish makes it an appealing model organism to understand genetic
risk for FASD. In an initial screen of five craniofacial mutants housed in our laboratory using doses of ethanol
that did not disrupt development in wild-type embryos, we found that pdgfra interacted with ethanol and this
interaction was highly synergistic.[98] Loss of Pdgfra results in orofacial clefting in zebrafish, mice, and
human.[99-102] Ethanol-treated pdgfra mutant zebrafish lose the entire palate.[98] In addition,
haploinsufficiency was observed in the majority of pdgfra heterozygous embryos. Pdgfra acts through the
PI3K/mTOR pathway to regulate cell survival, proliferation, and growth.[103, 104] We found that this pathway
mediates the pdgfra –ethanol interaction and elevating PI3K and mTOR signaling could partially rescue the
ethanol-treated mutants.[98] In humans, we identified single nucleotide polymorphisms (SNPs) in PDGFRA
and PDGFRB that associate with changes in outer canthal width and midfacial depth, respectively, in
ethanol-exposed individuals.[98] In a follow-up screen of 20 mutants available from the Zebrafish
International Resource Center (ZIRC), we found that mars , hinfp , plk1 , foxi1 , and vangl2 all genetically
interacted with ethanol.[105] The nature of these genetic interactions is of ongoing interest. These results
demonstrate the strength of genetic screens to identify risk factors and we are currently performing a forward
genetic screen to identify and characterize new ethanol-sensitive loci.
With the advent, and ever-decreasing cost, of deep sequencing, whole genome association studies in
humans are becoming more and more feasible. Aside from metabolic enzymes (discussed above), previous
candidate-based approaches of identifying risk factors in humans have had mixed results. Using a set of
genes implicated in human orofacial clefting, one study found an association between the Bmp target,
MSX1 , and ethanol.[39] However, two other studies failed to find a similar association.[37, 38] Recently, a
genome-wide association study found two loci, MLLT3 and SMC2 , which associated with ethanol exposure
and orofacial clefting.[106] Future studies will be essential to understand these interactions as neither gene
has been implicated in ethanol teratogenesis previously. Overall, this work along with the genetic screens
described above demonstrates that gene–ethanol interactions are not readily predicted. The phenotypes from
gene–ethanol interactions can be synergistic in nature, requiring a methodical approach to their identification.
Identifying genetic risk factors to one teratogen may help us understand other teratogens. Toluene is an
aromatic hydrocarbon used extensively as a solvent in the production of many industrial products, including
11. paint, varnish, lacquer, and glue. It is also used as a recreational drug via ‘sniffing or huffing,’ which can lead
to neurotoxic events.[107] The teratogenic effects of toluene (methylbenzene) exposure result in
microcephaly, craniofacial abnormalities, and neurological impairments,[107] strikingly similar to prenatal
ethanol exposure. ‘Fetal solvents syndrome’ was proposed to describe these features.[108] However, this
description is controversial because in some cases clinicians could not rule out concomitant exposure to
other teratogens.[107, 109] The phenotypic similarity between ethanol and toluene suggests that they may
share similar mechanisms of teratogenesis.[107, 110] In addition, the degradation of toluene uses several of
the same enzymatic steps as ethanol.[109] Genetic risk for toluene-induced birth defects is unknown, but it
will be of great interest to determine if our understanding of gene–ethanol interactions can inform the study of
gene–toluene interactions.
MECHANISMS OF GENE–ENVIRONMENT
INTERACTIONS
The interplay between genetic background and the environment plays a key role in a multitude of diseases
and disorders. Even among ‘simple’ Mendelian diseases there is substantial phenotypic variability that could
be due to gene–gene, gene–environment, or even more complicated multifactorial interactions. These more
complicated interactions that include environmental inputs probably abound in more complex disorders. A
significant problem remains though in identifying and then characterizing gene–environment interactions that
underlie disease as well as healthy development. A key observation across all of the teratogens discussed
here is that clearance of a teratogen is critical for healthy development and those genotypes that are slower
in this clearance are more susceptible to harm. For most teratogens, we know little more than this regarding
genetic risk.
With ethanol as a model, we see that genetic risk for teratogenesis is vastly more complicated than simply
clearing the substance from our system. A teratogenic insult must set off a cascade of deleterious events, be
that cellular damage or altered signaling. Sometimes, we can predict gene–environment interactions based
on mechanisms used to repair such damage (such as DNA damage repair) or based on similar phenotypes of
genetic mutants and teratogen-exposed embryos (such as holoprosencephaly-like phenotypes). However,
sometimes these interactions appear truly synergistic. For instance, it is only in embryos with both attenuated
Pdgf signaling, via mutation of pdgfra , and exposure to ethanol that exhibit a substantial elevation in the
death of facial progenitor cells. It is likely that casting a broad net to capture all possible gene–environment
interactions will serve us best in understanding this complex problem.
Once identified, understanding the nature of gene–environment interactions may represent a substantial
hurdle. We point readers to a recent manuscript detailing how some individual gene–environment interaction
researchers conceptualize these interactions and the challenges therein.[111] Even with gene–gene
interactions, there are several possible causes of a different phenotype occurring in a double mutant versus
either single mutant. Gene–environment interactions are no exception and if we consider teratogens there
are several possibilities.
The first is a direct, physical, interaction with a gene product. This is almost assuredly the case with gene–
environment interactions between loci encoding the enzymatic machinery needed to clear a teratogen.
Physical interactions between environmental contaminants and other gene products are difficult to detect,
although some examples exist. One example with ethanol is the L1 cell adhesion molecule (L1CAM). L1CAM
12. is a membrane-bound immunoglobulin-like protein that has multiple functions during neural development.
[112] The extracellular domain of L1CAM has an ethanol-binding pocket that when bound reduces L1CAM
function leading to neurodevelopmental defects.[113] While it is unknown if L1CAM itself is an ethanol-
sensitive locus, ERK-dependent phosphorylation of L1CAM alters the ethanol-binding pocket and modulates
ethanol sensitivity in a genetic background-dependent manner.[114] Thus, the physical interaction between
ethanol and a protein may also be genetically modulated by activity of signaling pathways.
The direct disruption of a signaling pathway is a second mechanism by which teratogens may interact with
genetic risk factors. In this case, ethanol attenuates, or potentially elevates, a signaling pathway upon which
the gene product impinges. This is likely to be the case for the pdgfra –ethanol interaction discussed above.
It is unlikely that ethanol is interacting directly with the Pdgfra protein because PI3K signaling immediately
downstream of the receptor, determined by phosphor-AKT levels, is actually elevated in the presence of
ethanol. It is only downstream of mTOR, phospho-Eif4b, where the pathway is attenuated.[98] In this
scenario, it is the combined genetic and environmental insults that result in a failure of the embryo to regulate
development.
A third likely mechanism is epigenetics. Teratogens such as ethanol have been shown to alter the levels of
small noncoding RNAs, microRNAs (miRNAs). Because each individual miRNA is capable of modulating the
levels of translation of many different genes, these small RNAs may well be an important target for ethanol
teratogenesis.[115] Ethanol also effects DNA methylation as well as histone methylation and acetylation.
[116] These types of modifications can give rise to transgenerational epigenetic inheritance, which can be
carried through both the male and female germline.[116]
There is a growing body of work in model organisms demonstrating transgenerational inheritance following
teratogen exposure. Recent work suggests that prenatal lead exposure can lead to heritable epigenetic
modifications in genes regulating immune response (e.g., APOA5 ) and neural development and function
(e.g., NDRG4 and NINJ2 ).[117] However, how these epigenetic modifications contribute to lead-induced
development disorders is currently not known. In zebrafish, failure of the embryo (or mother) to properly clear
methylmercury can lead to a build up to methylmercury in the developing embryo.[118] This accumulation of
methylmercury can alter DNA methylation patterns. If these modifications occur in the germ line cells of the
embryo, then subsequent generations may exhibit developmental impairments in the absence of the
environmental insult.[119] This work showed that F2 and F3 embryos from parents exposed embryonically to
methylmercury had persistent learning impairments even without a methylmercury exposure. Similar
transgenerational effects have been observed for other environmental toxins, including dioxin, bisphenol A,
17α-ethinylestradiol, and polyaromatic hydrocarbons.[120-123] Overall, this suggests that embryonic
exposure to teratogens can not only disrupt development in an exposed embryo but could also lead to
developmental defects in subsequent, naïve generations.
CONCLUSION
Gene–environment interactions are likely to underlie much of the variability and susceptibility to birth defects.
No single mechanism fully explains the breadth of phenotypes in these interactions. Rather multiple
interactions, all tissue and context dependent, are likely to produce the observed phenotypic spectrum.
The complexity of just what is a gene–environment interaction and how these impact human development are
major hurdles that must be overcome. How do we precisely define what is the environment? For instance, it
13. seems straightforward that a bottle of beer or a shot of whiskey is environmental, but what about blood
alcohol concentration (BAC)? BAC is a critical variable for ethanol teratogenicity, but it is, in itself, governed
by gene–environment interactions: ethanol-metabolizing enzymes and the amount and rate of ethanol
consumed (which itself has a genetic component modulated by environmental conditions). Thus, even in a
‘simple’ model of gene–environment interactions, it becomes clear that our resulting phenotype is driven by
interwoven, layered, and potentially interdependent gene–environment interactions (Figure 4).
Figure 4.
Open in figure viewer
Complexity of gene–environment interactions. Multiple gene–environment interactions are involved
in even the simplest model of ethanol teratogenesis. Prenatal alcohol exposure is required for the
development of fetal alcohol spectrum disorders (FASD), but is, itself, regulating by gene–
environment interactions that mediate both consumption patterns and ethanol metabolism. Prenatal
development, then, can be thought of as a set of complex, hierarchical, and often interrelated gene–
environment interactions.
ACKNOWLEDGMENTS
This work was supported by grants from NIH/NIDCR R01DE020884 and NIH/NIAAA R01AA023426 and
U24AA014811 (PI, Riley) to JKE and NIH/NIAAA K99AA023560 to CBL. Grant U24AA014811 is done in
conjunction with the Collaborative Initiative on Fetal Alcohol Spectrum Disorders (CIFASD). Additional
information about CIFASD can be found at www.cifasd.org.