Search

This article represents the proceedings of a symposium presented at the 2004 annual meeting of the International Society for Biomedical Research on Alcoholism, held in Mannheim, Germany. The presentations were as follows: 1) 'Antioxidants Prevent Ethanol-Induced Cell Death in Developing Brain and in Cultured Neural Cells' by M. Pascual, M. C. García-Minguillán, and Consuelo Guerri; 2) 'Rational Development of Ethanol Antagonists' by Michael E. Charness and Michael F. Wilkemeyer; 3) 'Choline Supplementation as a Treatment for Fetal Alcohol Effects' by Jennifer D. Thomas and Hector D. Dominguez; 4) 'Cerebellar and Cortical Plasticity After Neonatal Alcohol Exposure: Model of Intervention' by Anna Y. Klintsova, Charles R. Goodlett, and William T. Greenough; and 5) 'Circadian Rhythms in Prenatally Ethanol-Exposed Rats' by Hiromi Sakata-Haga. [ABSTRACT FROM AUTHOR]

AIM: To analyze the relationship between average volume of alcohol consumption and all-cause mortality in African Americans. DESIGN: Prospective cohort study--the NHANES Epidemiologic Follow-Up Study (NHEFS)--with baseline data collected 1971 through 1975 as part of the first National Health and Nutrition Examination Survey (NHANES I) and follow-up through 1992. PARTICIPANTS: The analytic data set consisted of 2054 African American men (n = 768) and women (n = 1,286), 25 to 75 years of age, who were followed for approximately 19 years. MEASUREMENT: Alcohol was measured with a quantity-frequency measure at baseline. OUTCOME: All-cause mortality. RESULTS: No J-shaped curve was found in the relationship between average volume of alcohol consumption and mortality for male or female African Americans. Instead, no beneficial effect appeared and mortality increased with increasing average consumption for more than one drink a day. The reason for not finding the J-shape in African Americans may be the result of the more detrimental drinking patterns in this ethnicity and consequently the lack of protective effects of alcohol on coronary heart disease. Taking into account sampling design did not substantially change the results from the models, which assumed a simple random sample. CONCLUSIONS: If this result can be confirmed in other samples, alcohol policy, especially prevention, should better incorporate patterns of drinking into programs. [ABSTRACT FROM AUTHOR]

COVID-19 led to a rapid increase in telemental health care via video or phone. It is important to examine contributors to the choice of video versus phone, as video may be more effective and preferred by patients. Medical mental health (MH) providers (e.g., psychiatrists) may conduct more phone and less video visits than nonmedical MH providers (e.g., psychologists). This study examined whether medical and nonmedical providers' perceptions of the quality and complexity of phone and video MH care may contribute to differences in use. A 32-item survey of 414 providers (79.5% response rate) assessed perceptions of care quality, factors contributing to modality choice, and telehealth challenges. The types of visits completed by providers in the months prior to the survey were extracted from administrative data. Medical and nonmedical providers generally viewed video care as higher quality and more preferred than phone, although to a lesser extent among medical providers. Nonmedical providers' decision making was more impacted by research regarding the modalities' relative effectiveness. Medical providers more frequently endorsed video challenges, including patient technical difficulties and lack of patient training. Administrative data demonstrated that medical providers conducted fewer video appointments than nonmedical providers. Medical providers may be less aware of research demonstrating that video care is effective and preferred by patients, and the complexity of video visits may be a barrier to use. Streamlining video processes, increasing technical support, and disseminating research that compares the quality of video and phone care may increase video use among medical providers. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Experimental evidence suggests that Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) remains viable within aerosols with a half-life of approximately 3 hours; however, it remains unclear how long airborne SARS-CoV-2 can transmit infection. Whole genome sequencing during an outbreak suggested in-room transmission of SARS-CoV-2 to two patients admitted nearly 2 and 5 hours, respectively, after discharge of an asymptomatic infected patient. These findings suggest that airborne SARS-CoV-2 may transmit infection for over 4 hours, even in a hospital setting., (Published by Elsevier Inc.)

Virtual care, including synchronous and asynchronous telehealth, remote patient monitoring, and the collection and interpretation of patient-generated health data (PGHD), has the potential to transform healthcare delivery and increase access to care. The Veterans Health Administration (VHA) Office of Health Services Research and Development (HSR&D) convened a State-of-the-Art (SOTA) Conference on Virtual Care to identify future virtual care research priorities. Participants were divided into three workgroups focused on virtual care access, engagement, and outcomes. In this article, we report the findings of the Outcomes Workgroup. The group identified virtual care outcome areas with sufficient evidence, areas in need of additional research, and areas that are particularly well-suited to be studied within VHA. Following a rigorous process of literature review and consensus, the group focused on four questions: (1) What outcomes of virtual care should we be measuring and how should we measure them?; (2) how do we choose the "right" care modality for the "right" patient?; (3) what are potential consequences of virtual care on patient safety?; and (4) how can PGHD be used to benefit provider decision-making and patient self-management?. The current article outlines key conclusions that emerged following discussion of these questions, including recommendations for future research., (© 2023. The Author(s).)

Sickness presenteeism among healthcare workers (HCW) risks nosocomial infection, but its prevalence among HCW with COVID-19 is unknown. Contemporaneous interviews revealed a sickness presenteeism prevalence of 49.8% among 255 HCW with symptomatic COVID-19. Presenteeism prevalence did not differ among HCW with and without specific COVID-19 symptoms or direct patient care.

Alcohol readily crosses the placenta and may disrupt fetal development. Harm from prenatal alcohol exposure (PAE) is determined by the dose, pattern, timing and duration of exposure, fetal and maternal genetics, maternal nutrition, concurrent substance use, and epigenetic responses. A safe dose of alcohol use during pregnancy has not been established. PAE can cause fetal alcohol spectrum disorders (FASD), which are characterized by neurodevelopmental impairment with or without facial dysmorphology, congenital anomalies and poor growth. FASD are a leading preventable cause of birth defects and developmental disability. The prevalence of FASD in 76 countries is >1% and is high in individuals living in out-of-home care or engaged in justice and mental health systems. The social and economic effects of FASD are profound, but the diagnosis is often missed or delayed and receives little public recognition. Future research should be informed by people living with FASD and be guided by cultural context, seek consensus on diagnostic criteria and evidence-based treatments, and describe the pathophysiology and lifelong effects of FASD. Imperatives include reducing stigma, equitable access to services, improved quality of life for people with FASD and FASD prevention in future generations., (© 2023. Springer Nature Limited.)

Importance: Aerosol-borne SARS-CoV-2 has not been linked specifically to nosocomial outbreaks., Objective: To explore the genomic concordance of SARS-CoV-2 from aerosol particles of various sizes and infected nurses and patients during a nosocomial outbreak of COVID-19., Design, Setting, and Participants: This cohort study included patients and nursing staff in a US Department of Veterans Affairs inpatient hospital unit and long-term-care facility during a COVID-19 outbreak between December 27, 2020, and January 8, 2021. Outbreak contact tracing was conducted using exposure histories and screening with reverse transcriptase-polymerase chain reaction (RT-PCR) for SARS-CoV-2. Size-selective particle samplers were deployed in diverse clinical areas of a multicampus health care system from November 2020 to March 2021. Viral genomic sequences from infected nurses and patients were sequenced and compared with ward nurses station aerosol samples., Exposure: SARS-CoV-2., Main Outcomes and Measures: The primary outcome was positive RT-PCR results and genomic similarity between SARS-CoV-2 RNA in aerosols and human samples. Air samplers were used to detect SARS-CoV-2 RNA in aerosols on hospital units where health care personnel were or were not under routine surveillance for SARS-CoV-2 infection., Results: A total of 510 size-fractionated air particle samples were collected. Samples representing 3 size fractions (>10 μm, 2.5-10 μm, and <2.5 μm) obtained at the nurses station were positive for SARS-CoV-2 during the outbreak (3 of 30 samples [10%]) and negative during 9 other collection periods. SARS-CoV-2 partial genome sequences for the smallest particle fraction were 100% identical with all 3 human samples; the remaining size fractions shared >99.9% sequence identity with the human samples. Fragments of SARS-CoV-2 RNA were detected by RT-PCR in 24 of 300 samples (8.0%) in units where health care personnel were not under surveillance and 7 of 210 samples (3.3%; P = .03) where they were under surveillance., Conclusions and Relevance: In this cohort study, the finding of genetically identical SARS-CoV-2 RNA fragments in aerosols obtained from a nurses station and in human samples during a nosocomial outbreak suggests that aerosols may have contributed to hospital transmission. Surveillance, along with ventilation, masking, and distancing, may reduce the introduction of community-acquired SARS-CoV-2 into aerosols on hospital wards, thereby reducing the risk of hospital transmission.

Importance: Clinician attitudes toward telehealth may impact utilization rates, and findings may differ based on specialty., Objective: To determine whether clinician beliefs regarding telehealth quality and ease of use were associated with the proportion of care delivered via video, phone, and in-person across specialties., Design, Setting, and Participants: This survey study used a voluntary, anonymous survey conducted from August to September 2021 in the Department of Veterans Affairs New England Healthcare System (VANEHS). Mental health (MH), primary care (PC), and specialty care (SC) clinicians were invited to participate. Data were analyzed from October 2021 to January 2022., Exposures: Participation in a 32-item survey., Main Outcomes and Measures: The main outcomes were clinicians' views on relative quality of video, phone, and in-person care; factors contributing to clinicians' modality choice; telehealth challenges; and clinician modality preferences and utilization when treating new and established patients., Results: There were 866 survey respondents (estimated 64% response rate); 52 respondents reported no video or phone telehealth use in the 3 months prior to survey completion and were excluded, resulting in a final sample of 814 respondents. Respondents were divided among MH (403 respondents [49.5%]), PC (153 respondents [18.8%]), and SC (258 respondents [31.7%]). Compared with PC and SC clinicians, MH clinicians rated the quality of video care the highest (eg, compared with in-person care with masks when treating new patients: χ2 = 147.8; P < .001) and were more likely to prefer video over phone when treating both new (χ2 = 26.6; P < .001) and established (χ2 = 100.4; P < .001) patients remotely. PC and SC clinicians were more likely to rate phone care as being at least equivalent in quality to video for both new (χ2 = 26.3; P < .001) and established (χ2 = 33.5; P < .001) patients. PC and SC clinicians were also more likely to endorse challenges of video care, including patient barriers and the inability to conduct a physical examination (χ2 = 292.0; P < .001). Most PC and SC clinicians either had no preference (46 PC respondents [36.2%]; 59 SC respondents [28.4%]) or preferred phone (36 PC respondents [28.3%]; 67 SC respondents [32.2%]) for remote care of established patients. Findings aligned with utilization rates within VANEHS, with MH clinicians conducting significantly more of their encounters via video (36 734 encounters [40.3%]) than PC (3201 encounters [3.9%]) and SC (1157 encounters [4.9%]) clinicians., Conclusions and Relevance: These findings suggest that clinician attitudes regarding telehealth quality and ease of use were associated with utilization rates. Moving forward, clinician use of telehealth may be impacted by additional data regarding the relative effectiveness of modalities as well as improvements in video telehealth workflows.

This article is part of a Festschrift commemorating the 50th anniversary of the National Institute on Alcohol Abuse and Alcoholism (NIAAA). Established in 1970, first as part of the National Institute of Mental Health and later as an independent institute of the National Institutes of Health, NIAAA today is the world's largest funding agency for alcohol research. In addition to its own intramural research program, NIAAA supports the entire spectrum of innovative basic, translational, and clinical research to advance the diagnosis, prevention, and treatment of alcohol use disorder and alcohol-related problems. To celebrate the anniversary, NIAAA hosted a 2-day symposium, "Alcohol Across the Lifespan: 50 Years of Evidence-Based Diagnosis, Prevention, and Treatment Research," devoted to key topics within the field of alcohol research. This article is based on Dr. Charness' presentation at the event. NIAAA Director George F. Koob, Ph.D., serves as editor of the Festschrift., Competing Interests: Disclosures The author declares no competing financial or nonfinancial interests.

Background: The coronavirus disease 2019 (COVID-19) pandemic has led to a dramatic increase in virtual care (VC) across outpatient specialties, but little is known regarding provider acceptance of VC., Objective: The objective of this study was to assess provider perceptions of the quality, efficiency, and challenges of VC versus in-person care with masks., Design: This was a voluntary survey., Participants: Mental health (MH), primary care, medical specialty, and surgical specialty providers across the 8 VA New England Healthcare System medical centers., Measures: Provider ratings of: (1) quality and efficiency of VC (phone and video telehealth) compared with in-person care with masks; (2) challenges of VC; and (3) percentage of patients that providers are comfortable seeing via VC in the future., Results: The sample included 998 respondents (49.8% MH, 20.6% primary care, 20.4% medical specialty, 9.1% surgical specialty; 61% response rate). Most providers rated VC as equivalent to or higher in quality and efficiency compared with in-person care with masks. Quality ratings were significantly higher for video versus phone (χ2=61.4, P<0.0001), but efficiency ratings did not differ significantly. Ratings varied across specialties (highest in MH, lowest in SS; all χ2s>24.1, Ps<0.001). Inability to conduct a physical examination and patient technical difficulties were significant challenges. MH providers were comfortable seeing a larger proportion of patients virtually compared with the other specialties (all χ2s>12.2, Ps<0.01)., Conclusions: Broad provider support for VC was stratified across specialties, with the highest ratings in MH and lowest ratings in SS. Findings will inform the improvement of VC processes and the planning of health care delivery during the COVID-19 pandemic and beyond., Competing Interests: S.L.C. was supported by a VISN 1 Career Development Award, Department of Veterans Affairs, Veterans Health Administration. The remaining authors declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Among 3926 healthcare personnel in a multisite healthcare system, the minimal population prevalence of coronavirus disease 2019 (COVID-19) was 4.4% (bootstrap 95% confidence interval [CI], 3.7%-5.0%), and the infection fatality rate was 0.6% (bootstrap 95% CI, 0.0%-1.7%). Rates reflected both local community prevalence and hospital exposures but not specifically exposure on COVID-19 units., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2020.)

Prenatal alcohol exposure (PAE) affects at least 10% of newborns globally and leads to the development of fetal alcohol spectrum disorders (FASDs). Despite its high incidence, there is no consensus on the implications of PAE on metabolic disease risk in adults. Here, we describe a cohort of adults with FASDs that had an increased incidence of metabolic abnormalities, including type 2 diabetes, low HDL, high triglycerides, and female-specific overweight and obesity. Using a zebrafish model for PAE, we performed population studies to elucidate the metabolic disease seen in the clinical cohort. Embryonic alcohol exposure (EAE) in male zebrafish increased the propensity for diet-induced obesity and fasting hyperglycemia in adulthood. We identified several consequences of EAE that may contribute to these phenotypes, including a reduction in adult locomotor activity, alterations in visceral adipose tissue and hepatic development, and persistent diet-responsive transcriptional changes. Taken together, our findings define metabolic vulnerabilities due to EAE and provide evidence that behavioral changes and primary organ dysfunction contribute to resultant metabolic abnormalities.

Background: Ethanol causes developmental neurotoxicity partly by blocking adhesion mediated by the L1 neural cell adhesion molecule. This action of ethanol is antagonized by femtomolar concentrations of the neuropeptide NAPVSIPQ (NAP), an active fragment of the activity-dependent neuroprotective protein (ADNP). How femtomolar concentrations of NAP antagonize millimolar concentrations of ethanol is unknown. L1 sensitivity to ethanol requires L1 association with ankyrin-G; therefore, we asked whether NAP promotes the dissociation of ankyrin-G and L1., Methods: L1-ankyrin-G association was studied using immunoprecipitation, Western blotting, and immunofluorescence in NIH/3T3 cells transfected with wild-type and mutated human L1 genes. Phosphorylation of the ankyrin binding motif in the L1 cytoplasmic domain was studied after NAP treatment of intact cells, rat brain homogenates, and purified protein fragments., Results: Femtomolar concentrations of NAP stimulated the phosphorylation of tyrosine-1229 (L1-Y1229) at the ankyrin binding motif of the L1 cytoplasmic domain, leading to the dissociation of L1 from ankyrin-G and the spectrin-actin cytoskeleton. NAP increased the association of L1 and EphB2 and directly activated EphB2 phosphorylation of L1-Y1229. These actions of NAP were reproduced by P7A-NAP, a NAP variant that also blocks the teratogenic actions of ethanol, but not by I6A-NAP, which does not block ethanol teratogenesis as potently. Finally, knockdown of EPHB2 prevented ethanol inhibition of L1 adhesion in NIH/3T3 cells., Conclusions: NAP potently antagonizes ethanol inhibition of L1 adhesion by stimulating EphB2 phosphorylation of L1-Y1229. EphB2 plays a critical role in synaptic development; its potent activation by NAP suggests that ADNP may mediate synaptic development partly by activating EphB2., (Published by Elsevier Inc.)

The Adolescent Brain Cognitive Development (ABCD) Study is an ongoing, nationwide study of the effects of environmental influences on behavioral and brain development in adolescents. The main objective of the study is to recruit and assess over eleven thousand 9-10-year-olds and follow them over the course of 10 years to characterize normative brain and cognitive development, the many factors that influence brain development, and the effects of those factors on mental health and other outcomes. The study employs state-of-the-art multimodal brain imaging, cognitive and clinical assessments, bioassays, and careful assessment of substance use, environment, psychopathological symptoms, and social functioning. The data is a resource of unprecedented scale and depth for studying typical and atypical development. The aim of this manuscript is to describe the baseline neuroimaging processing and subject-level analysis methods used by ABCD. Processing and analyses include modality-specific corrections for distortions and motion, brain segmentation and cortical surface reconstruction derived from structural magnetic resonance imaging (sMRI), analysis of brain microstructure using diffusion MRI (dMRI), task-related analysis of functional MRI (fMRI), and functional connectivity analysis of resting-state fMRI. This manuscript serves as a methodological reference for users of publicly shared neuroimaging data from the ABCD Study., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Although prenatal alcohol exposure causes craniofacial anomalies, growth retardation, neurological abnormalities, cognitive impairment, and birth defects, fetal alcohol spectrum disorder is underdiagnosed. Global prevalence of fetal alcohol spectrum disorder is 0·77%, with a higher prevalence of 2-5% in Europe and North America, highlighting the need for increased diagnosis and treatment. However, diagnosis remains challenging because of the poor reliability of self-reported maternal drinking histories, an absence of sensitive biomarkers, and the infrequency of diagnostic dysmorphic facial features among individuals with fetal alcohol spectrum disorder. Different diagnostic systems and disagreements over criteria have slowed progress in the diagnosis and management of the disorder. Neuroimaging shows abnormalities in brain structure, cortical development, white matter microstructure, and functional connectivity in individuals with fetal alcohol spectrum disorder. These abnormalities modify developmental trajectories and are associated with deficits in cognition, executive function, memory, vision, hearing, motor skills, behaviour, and social adaptation. Promising trials of nutritional interventions and cognitive rehabilitation therapies are underway, with the aim of treating cognitive deficits in fetal alcohol spectrum disorders., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Dr. Kathleen Sulik (Kathy) has spent 35 years studying fetal alcohol syndrome (FAS) and fetal alcohol spectrum disorders (FASD). Beginning with her landmark 1981 Science paper describing the early gestational window when alcohol can cause the craniofacial malformations characteristic of FAS, Kathy has contributed a vast amount of research furthering our knowledge of FASD. After her seminal work that definitively demonstrated that alcohol is the causative factor in FAS, she and her lab went on to explore and define the stage-dependent effects of early gestational alcohol exposure on the face and brain in numerous different ways throughout her career. She explored and discovered numerous mechanisms of alcohol's effects on the embryo, as well as describing several genetic factors that can modify susceptibility to developmental alcohol exposure. She did not restrict her research to the face and brain; her lab described in intricate detail the effects of developmental alcohol exposure on many different organs, including the heart, ears, kidneys, and limbs. In addition to her research, and in conjunction with NIAAA and the National Organization on Fetal Alcohol Syndrome (NOFAS), Kathy developed several FASD prevention curricula that are still in use today. Finally, as part of her drive to eradicate FAS and FASD, Kathy labored tirelessly with public policy makers to change how FASD is viewed by the public, how FASD is identified in affected individuals, and how FASD is studied by researchers. While no article could fully cover Kathy's contributions to FASD research and prevention, or her other contributions to embryology and teratology, this review will attempt to illustrate some of the highlights of Kathy's remarkable career., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Ethanol causes fetal alcohol spectrum disorders (FASDs) partly by inhibiting cell adhesion mediated by the L1 neural cell adhesion molecule. Ethanol interacts with an alcohol binding pocket in the L1 extracellular domain (ECD), and dephosphorylation of S1248 in the L1 cytoplasmic domain (CD) renders L1 adhesion insensitive to inhibition by ethanol (L1 insensitive). The mechanism underlying this inside-out signaling is unknown. Here we show that phosphorylation of the human L1-CD at S1152, Y1176, S1181, and S1248 renders L1 sensitive to ethanol by promoting L1 coupling with ankyrin-G and the spectrin-actin cytoskeleton. Knockdown of ankyrin-G or L1 mutations that uncouple L1 from ankyrin reduce L1 sensitivity to ethanol, but not methanol, consistent with a small conformational change in the extracellular alcohol binding pocket. Phosphorylation of Y1176 and ankyrin-G coupling with L1 are higher in NIH/3T3 clonal cell lines in which ethanol inhibits L1 adhesion than in ethanol-resistant NIH/3T3 clonal cell lines. Similarly, phosphorylation of Y1176 is higher in C57BL/6J mice that are sensitive to ethanol teratogenesis than in ethanol resistant C57BL/6N mice. Finally, polymorphisms in genes that encode ankyrin-G and p90rsk, a kinase that phosphorylates S1152, are linked to facial dysmorphology in children with heavy prenatal ethanol exposure. These findings indicate that genes that regulate L1 coupling to ankyrin may influence susceptibility to FASD.-Dou, X., Menkari, C., Mitsuyama, R., Foroud, T., Wetherill, L., Hammond, P., Suttie, M., Chen, X., Chen, S.-Y., Charness, M. E., Collaborative Initiative on Fetal Alcohol Spectrum Disorders. L1 coupling to ankyrin and the spectrin-actin cytoskeleton modulates ethanol inhibition of L1 adhesion and ethanol teratogenesis.

Importance: Fetal alcohol spectrum disorders are costly, life-long disabilities. Older data suggested the prevalence of the disorder in the United States was 10 per 1000 children; however, there are few current estimates based on larger, diverse US population samples., Objective: To estimate the prevalence of fetal alcohol spectrum disorders, including fetal alcohol syndrome, partial fetal alcohol syndrome, and alcohol-related neurodevelopmental disorder, in 4 regions of the United States., Design, Setting, and Participants: Active case ascertainment methods using a cross-sectional design were used to assess children for fetal alcohol spectrum disorders between 2010 and 2016. Children were systematically assessed in the 4 domains that contribute to the fetal alcohol spectrum disorder continuum: dysmorphic features, physical growth, neurobehavioral development, and prenatal alcohol exposure. The settings were 4 communities in the Rocky Mountain, Midwestern, Southeastern, and Pacific Southwestern regions of the United States. First-grade children and their parents or guardians were enrolled., Exposures: Alcohol consumption during pregnancy., Main Outcomes and Measures: Prevalence of fetal alcohol spectrum disorders in the 4 communities was the main outcome. Conservative estimates for the prevalence of the disorder and 95% CIs were calculated using the eligible first-grade population as the denominator. Weighted prevalences and 95% CIs were also estimated, accounting for the sampling schemes and using data restricted to children who received a full evaluation., Results: A total of 6639 children were selected for participation from a population of 13 146 first-graders (boys, 51.9%; mean age, 6.7 years [SD, 0.41] and white maternal race, 79.3%). A total of 222 cases of fetal alcohol spectrum disorders were identified. The conservative prevalence estimates for fetal alcohol spectrum disorders ranged from 11.3 (95% CI, 7.8-15.8) to 50.0 (95% CI, 39.9-61.7) per 1000 children. The weighted prevalence estimates for fetal alcohol spectrum disorders ranged from 31.1 (95% CI, 16.1-54.0) to 98.5 (95% CI, 57.5-139.5) per 1000 children., Conclusions and Relevance: Estimated prevalence of fetal alcohol spectrum disorders among first-graders in 4 US communities ranged from 1.1% to 5.0% using a conservative approach. These findings may represent more accurate US prevalence estimates than previous studies but may not be generalizable to all communities.

The adverse effects of prenatal alcohol exposure constitute a continuum of disabilities (fetal alcohol spectrum disorders [FASD]). In 1996, the Institute of Medicine established diagnostic categories delineating the spectrum but not specifying clinical criteria by which diagnoses could be assigned. In 2005, the authors published practical guidelines operationalizing the Institute of Medicine categories, allowing for standardization of FASD diagnoses in clinical settings. The purpose of the current report is to present updated diagnostic guidelines based on a thorough review of the literature and the authors' combined expertise based on the evaluation of >10 000 children for potential FASD in clinical settings and in epidemiologic studies in conjunction with National Institute on Alcohol Abuse and Alcoholism-funded studies, the Collaborative Initiative on Fetal Alcohol Spectrum Disorders, and the Collaboration on FASD Prevalence. The guidelines were formulated through conference calls and meetings held at National Institute on Alcohol Abuse and Alcoholism offices in Rockville, MD. Specific areas addressed include the following: precise definition of documented prenatal alcohol exposure; neurobehavioral criteria for diagnosis of fetal alcohol syndrome, partial fetal alcohol syndrome, and alcohol-related neurodevelopmental disorder; revised diagnostic criteria for alcohol-related birth defects; an updated comprehensive research dysmorphology scoring system; and a new lip/philtrum guide for the white population, incorporating a 45-degree view. The guidelines reflect consensus among a large and experienced cadre of FASD investigators in the fields of dysmorphology, epidemiology, neurology, psychology, developmental/behavioral pediatrics, and educational diagnostics. Their improved clarity and specificity will guide clinicians in accurate diagnosis of infants and children prenatally exposed to alcohol., (Copyright © 2016 by the American Academy of Pediatrics.)

Heavy prenatal alcohol exposure can have lifelong, disabling effects on brain and cognition. Unlike animal studies, research on light-to-moderate drinking in humans demonstrates less consistent impact. Discussions of negative research findings in popular media underestimate potential adverse outcomes and complicate decisions about risks versus benefits of light-to-moderate drinking during pregnancy., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Alcohol causes fetal alcohol spectrum disorders in part by disrupting the function of the neural cell adhesion molecule L1. Alcohol inhibits L1-mediated cell-cell adhesion in diverse cell types and inhibits L1-mediated neurite outgrowth in cerebellar granule neurons (CGNs). A recent report indicates that ethanol (EtOH) induces the translocation of L1 into CGN lipid rafts and that disruption of lipid rafts prevents EtOH inhibition of L1-mediated neurite outgrowth. The same butanol-pentanol cutoff was noted for alcohol-induced translocation of L1 into lipid rafts that was reported previously for alcohol inhibition of L1 adhesion, suggesting that EtOH might inhibit L1 adhesion by shifting L1 into lipid rafts., Methods: The NIH/3T3 cell line, 2A2-L1s , is a well-characterized EtOH-sensitive clonal cell line that stably expresses human L1. Cells were treated with 25 mM EtOH, 5 μM filipin, or both. Lipid rafts were enriched in membrane fractions by preparation of detergent-resistant membrane (DRMs) fractions. Caveolin-1 was used as a marker of lipid rafts, and L1 and Src were quantified by Western blotting in lipid-raft-enriched membrane fractions and by immunohistochemistry., Results: EtOH (25 mM) increased the percentage of L1, but not Src, in 2A2-L1s membrane fractions enriched in lipid rafts. Filipin, an agent known to disrupt lipid rafts, decreased the percentage of caveolin and L1 in DRMs from 2A2-L1s cells. Filipin also blocked EtOH-induced translocation of L1 into lipid rafts from 2A2-L1s cells but did not significantly affect L1 adhesion or EtOH inhibition of L1 adhesion., Conclusions: These findings indicate that EtOH does not inhibit L1 adhesion in NIH/3T3 cells by inducing the translocation of L1 into lipid rafts., (Copyright © 2014 by the Research Society on Alcoholism.)

There is a genetic contribution to fetal alcohol spectrum disorders (FASD), but the identification of candidate genes has been elusive. Ethanol may cause FASD in part by decreasing the adhesion of the developmentally critical L1 cell adhesion molecule through interactions with an alcohol binding pocket on the extracellular domain. Pharmacologic inhibition or genetic knockdown of ERK2 did not alter L1 adhesion, but markedly decreased ethanol inhibition of L1 adhesion in NIH/3T3 cells and NG108-15 cells. Likewise, leucine replacement of S1248, an ERK2 substrate on the L1 cytoplasmic domain, did not decrease L1 adhesion, but abolished ethanol inhibition of L1 adhesion. Stable transfection of NIH/3T3 cells with human L1 resulted in clonal cell lines in which L1 adhesion was consistently sensitive or insensitive to ethanol for more than a decade. ERK2 activity and S1248 phosphorylation were greater in ethanol-sensitive NIH/3T3 clonal cell lines than in their ethanol-insensitive counterparts. Ethanol-insensitive cells became ethanol sensitive after increasing ERK2 activity by transfection with a constitutively active MAP kinase kinase 1. Finally, embryos from two substrains of C57BL mice that differ in susceptibility to ethanol teratogenesis showed corresponding differences in MAPK activity. Our data suggest that ERK2 phosphorylation of S1248 modulates ethanol inhibition of L1 adhesion by inside-out signaling and that differential regulation of ERK2 signaling might contribute to genetic susceptibility to FASD. Moreover, identification of a specific locus that regulates ethanol sensitivity, but not L1 function, might facilitate the rational design of drugs that block ethanol neurotoxicity.

Pre-natal alcohol exposure causes fetal alcohol spectrum disorders (FASD), the most common, preventable cause of developmental disability. The developing cerebellum is particularly vulnerable to the effects of ethanol. We reported that ethanol inhibits the stimulation of axon outgrowth in cerebellar granule neurons (CGN) by NAP, an active motif of activity-dependent neuroprotective protein (ADNP), by blocking NAP activation of Fyn kinase and its downstream signaling molecule, the scaffolding protein Cas. Here, we asked whether ethanol inhibits the stimulation of axon outgrowth by diverse axon guidance molecules through a common action on the Src family kinases (SFK). We first demonstrated that netrin-1, glial cell line-derived neurotrophic factor (GDNF), and neural cell adhesion molecule L1 stimulate axon outgrowth in CGNs by activating SFK, Cas, and extracellular signal-regulated kinase 1 and 2 (ERK1/2). The specific SFK inhibitor, PP2, blocked the stimulation of axon outgrowth and the activation of the SFK-Cas-ERK1/2 signaling pathway by each of these axon-guidance molecules. In contrast, brain-derived neurotrophic factor (BDNF) stimulated axon outgrowth and activated ERK1/2 without first activating SFK or Cas. Clinically relevant concentrations of ethanol inhibited axon outgrowth and the activation of the SFK-Cas-ERK1/2 pathway by netrin-1, GDNF, and L1, but did not disrupt BDNF-induced axon outgrowth or ERK1/2 activation. These results indicate that SFK, but not ERK1/2, is a primary target for ethanol inhibition of axon outgrowth. The ability of ethanol to block the convergent activation of the SFK-Cas-ERK1/2 pathway by netrin-1, GDNF, L1, and ADNP could contribute significantly to the pathogenesis of FASD., (© VA Boston Healthcare Journal of Neurochemistry © 2012 International Society for Neurochemistry.)

Ethanol may cause fetal alcohol spectrum disorders (FASD) in part by inhibiting cell adhesion mediated by the L1 neural cell adhesion molecule. Azialcohols photolabel Glu-33 and Tyr-418, two residues that are predicted by homology modeling to lie within 2.8 Å of each other at the interface between the Ig1 and Ig4 domains of L1 (Arevalo, E., Shanmugasundararaj, S., Wilkemeyer, M. F., Dou, X., Chen, S., Charness, M. E., and Miller, K. W. (2008) Proc. Natl. Acad. Sci. U.S.A. 105, 371-375). Using transient transfection of NIH/3T3 cells with wild type (WT-L1) and mutated L1, we found that cysteine substitution of both residues (E33C/Y418C-L1) significantly increased L1 adhesion above levels observed for WT-L1 or the single cysteine substitutions E33C-L1 or Y418C-L1. The reducing agent β-mercaptoethanol (βME) reversibly decreased the adhesion of E33C/Y418C-L1, but had no effect on WT-L1, E33C-L1, or Y418C-L1. Thus, disulfide bond formation occurs between Cys-33 and Cys-418, confirming both the close proximity of these residues and the importance of Ig1-Ig4 interactions in L1 adhesion. Maximal ethanol inhibition of cell adhesion was significantly lower in cells expressing E33C/Y418C-L1 than in those expressing WT-L1, E33C-L1, or Y418C-L1. Moreover, the effects of βME and ethanol on E33C/Y418C-L1 adhesion were non-additive. The cutoff for alcohol inhibition of WT-L1 adhesion was between 1-butanol and 1-pentanol. Increasing the size of the alcohol binding pocket by mutating Glu-33 to Ala-33, increased the alcohol cutoff from 1-butanol to 1-decanol. These findings support the hypothesis that alcohol binding within a pocket bordered by Glu-33 and Tyr-418 inhibits L1 adhesion by disrupting the Ig1-Ig4 interaction.

The recent proposal to dissolve the National Institute on Alcohol Abuse and Alcoholism and National Institute on Drug Abuse and create a new institute for substance use, abuse, and addiction will require significant effort by the staff of both institutes, the Advisory Councils, and outside experts to overcome complex challenges that could threaten its success. Although integration of the grants portfolios can be achieved, harmonization of goals and policies related to legal use of alcohol versus illegal consumption of drugs will present serious challenges. Consolidating the infrastructure of the 2 existing institutes would entail avoiding encroachment on grant funding. A new institute for substance use, abuse, and addiction would require an enormous amount of cooperation from other institutes as the portfolios of research on alcohol, tobacco, and other drug abuse should logically be transferred to the new institute. In the near term, a structural reorganization would be less efficient and more costly than the individual institutes are currently. Increasing efficiency and reducing costs over time will necessitate careful strategic planning. Success in this difficult task would be made easier and less costly by first implementing carefully placed building blocks of increasing functional reorganization. The newly created institute should increase opportunities for specialization within disorders of addiction, attract new leadership, and build a novel strategic plan that will energize scientists and staff and incorporate ideas of stakeholders to advance the public good in preventing and treating alcohol, tobacco, and all addictions. Attention must be paid to the devil in the details., (Copyright © 2011 by the Research Society on Alcoholism.)

The neural cell adhesion molecule L1 is critical for brain development and plays a role in learning and memory in the adult. Ethanol inhibits L1-mediated cell adhesion and neurite outgrowth in cerebellar granule neurons (CGNs), and these actions might underlie the cerebellar dysmorphology of fetal alcohol spectrum disorders. The peptide NAP potently blocks ethanol inhibition of L1 adhesion and prevents ethanol teratogenesis. We used quantitative RT-PCR and Western blotting of extracts of cerebellar slices, CGNs, and astrocytes from postnatal day 7 (PD7) rats to investigate whether ethanol and NAP act in part by regulating the expression of L1. Treatment of cerebellar slices with 20 mM ethanol, 10(-12) M NAP, or both for 4 hours, 24 hours, and 10 days did not significantly affect L1 mRNA and protein levels. Similar treatment for 4 or 24 hours did not regulate L1 expression in primary cultures of CGNs and astrocytes, the predominant cerebellar cell types. Because ethanol also damages the adult cerebellum, we studied the effects of chronic ethanol exposure in adult rats. One year of binge drinking did not alter L1 gene and protein expression in extracts from whole cerebellum. Thus, ethanol does not alter L1 expression in the developing or adult cerebellum; more likely, ethanol disrupts L1 function by modifying its conformation and signaling. Likewise, NAP antagonizes the actions of ethanol without altering L1 expression.

The mechanisms by which ethanol damages the developing and adult central nervous system (CNS) remain unclear. Activity-dependent neuroprotective protein (ADNP) is a glial protein that protects the CNS against a wide array of insults and is critical for CNS development. NAPVSIPQ (NAP), a potent active fragment of ADNP, potentiated axon outgrowth in cerebellar granule neurons by activating the sequential tyrosine phosphorylation of Fyn kinase and the scaffold protein Crk-associated substrate (Cas). Pharmacological inhibition of Fyn kinase or expression of a Fyn kinase siRNA abolished NAP-mediated axon outgrowth. Concentrations of ethanol attained after social drinking blocked NAP-mediated axon outgrowth (IC(50) = 17 mM) by inhibiting NAP activation of Fyn kinase and Cas. These findings identify a mechanism for ADNP regulation of glial-neuronal interactions in developing cerebellum and a pathogenesis of ethanol neurotoxicity.

Prenatal ethanol exposure causes fetal alcohol spectrum disorders (FASD) in part by disrupting the neural cell adhesion molecule L1. L1 gene mutations cause neuropathological abnormalities similar to those of FASD. Ethanol and 1-butanol inhibit L1-mediated cell-cell adhesion (L1 adhesion), whereas 1-octanol antagonizes this action. To test the hypothesis that there are alcohol binding sites on L1, we used 3-azibutanol and 3-azioctanol, the photoactivatable analogs of 1-butanol and 1-octanol, to photolabel the purified Ig1-4 domain of human L1 (hL1 Ig1-4). 3-Azibutanol (11 mM), like ethanol, inhibited L1 adhesion in NIH/3T3 cells stably transfected with hL1, whereas subanesthetic concentrations of 3-azioctanol (14 microM) antagonized ethanol inhibition of L1 adhesion. 3-Azibutanol (100-1,000 microM) and 3-azioctanol (10-100 microM) photoincorporated into Tyr-418 on Ig4 and into two adjacent regions in the N terminus, Glu-33 and Glu-24 to Glu-27. A homology model of hL1 Ig1-4 (residues 33-422), based on the structure of the Ig1-4 domains of axonin-1, suggests that Glu-33 and Tyr-418 hydrogen-bond at the interface of Ig1 and Ig4 to stabilize a horseshoe conformation of L1 that favors homophilic binding. Furthermore, this alcohol binding pocket lies within 7 A of Leu-120 and Gly-121, residues in which missense mutations cause neurological disorders similar to FASD. These data suggest that ethanol or selected mutations produce neuropathological abnormalities by disrupting the domain interface between Ig1 and Ig4. Characterization of alcohol agonist and antagonist binding sites on L1 will aid in understanding the molecular basis for FASD and might accelerate the development of ethanol antagonists.

Background: SAL (SALLRSIPA) is a peptide fragment of activity-dependent neurotrophic factor. Both L- and D-SAL diminish ethanol's pathogenesis, however, the D-peptide is protease resistant, and can therefore be effectively administered in a diet. The present study tested the hypothesis that D-SAL provided in a liquid diet containing ethanol will prevent ethanol-induced teratogenicity in mice., Methods: Following an ethanol acclimation period, female C57Bl/6J mice were withdrawn from the ethanol, bred, and then returned during gestational days (GD) 7 and 8 to a control liquid diet or one containing 4.8% ethanol alone or in combination with 5.6 microg/ml D-SAL. At these doses, the mice received approximately 75 microg of D-SAL on each day and achieved peak blood-alcohol concentrations on GD 8 that ranged from 148-162 mg/dl. On GD 14, the fetuses were examined for the presence of ocular abnormalities including microphthalmia and irregularly shaped pupils, teratogenic effects known to result from this ethanol exposure paradigm., Results: Dietary D-SAL reduced the incidence of ocular defects in ethanol-exposed fetuses from 29 to 10% in the right eyes and from 21 to 7.5% in the left eyes; levels similar to those observed in pair-fed controls. In addition to decreasing their incidence, D-SAL also reduced the severity of the ocular defects., Conclusions: These results demonstrate that oral D-SAL can prevent ethanol-induced ocular defects. Because ocular defects are commonly associated with CNS damage, oral D-SAL may also prove valuable in preventing ethanol-induced brain defects.

Background: This work was conducted in an effort to establish an oral intake model system in which the effects of ethanol insult that occur during early stages of embryogenesis can be easily examined and in which agents that may modulate ethanol's teratogenicity can be readily tested in vivo. The model system described utilizes the alcohol deprivation effect to obtain teratogenic levels of maternal ethanol intake on days 7 and 8 of pregnancy in C57Bl/6J mice. Ocular defects including microphthalmia and uveal coloboma, which have previously been shown to result from ethanol administered by gavage or via intraperitoneal injection on these days, served as the developmental end point for this study. The ocular defects are readily identifiable and their degree of severity is expected to correlate with concurrently developing defects of the central nervous system (CNS)., Methods: Female C57Bl/6J mice were maintained on an ethanol-containing (4.8% v/v) liquid diet for 14 days and then mated during a subsequent abstinence period. Mice were then reexposed to ethanol on days 7 and 8 of pregnancy only. Control as well as ethanol-exposed dams were killed on their 14th day of pregnancy. Fetuses were then weighed, measured for crown rump length, photographed, and analyzed for ocular abnormalities. Globe size, palpebral fissure length, and pupil size and shape were noted for both the right and left eyes of all fetuses and informative comparisons were made., Results: This exposure paradigm resulted in peak maternal blood alcohol concentrations that ranged from 170 to 220 mg/dL on gestational day (GD) 8. Compared with the GD 14 fetuses from the normal control group, the pair-fed, acquisition controls, as well as the ethanol-exposed fetuses, were developmentally delayed and had reduced weights. Confirming previous studies, comparison of similarly staged control and treated GD 8 embryos illustrated reductions in the size of the forebrain in the latter. Subsequent ocular malformations were noted in 33% of the right eyes and 25% of the left eyes of the 103 GD 14 ethanol-exposed fetuses examined. This incidence of defects is twice that observed in the control groups. Additionally, it was found that the palpebral fissure length is directly correlated with globe size., Conclusions: The high incidence of readily identifiable ocular malformations produced by oral ethanol intake in this model and their relevance to human fetal alcohol spectrum disorders (FASD) makes this an excellent system for utilization in experiments involving factors administered to the embryo that might alter ethanol's teratogenic effects. Additionally, the fact that early ethanol insult yields ocular and forebrain abnormalities that are developmentally associated allows efficient specimen selection for subsequent detailed analyses of CNS effects in this in vivo mammalian FASD model.

The L1 cell adhesion molecule has been implicated in ethanol teratogenesis as well as NMDAR-dependent long-term potentiation (LTP) of synaptic transmission, a process thought to be critical for neural development. Ethanol inhibits LTP at least in part by interacting with NMDA receptors. Ethanol also inhibits L1-mediated cell adhesion in a manner that is prevented by an octapeptide, D-NAPVSIPQ (D-NAP), as well as long chain alcohols such as 1-octanol. Here we analyzed the effects of D-NAP and 1-octanol on ethanol modulation of LTP induced by theta burst stimulation in two subfields of the rat hippocampus, the dentate gyrus and area CA1. When theta burst stimulation was delivered in ethanol (50 mM), LTP was inhibited by about 50%. Surprisingly, when D-NAP (10(-7) M) and ethanol were co-applied or applied sequentially, LTP was completely absent. The effects of D-NAP were persistent, since delivery of a second theta burst stimulation following washout of D-NAP and ethanol elicited minimal plasticity. Application of D-NAP alone had no effect on LTP induction or expression. The synergistic effect of D-NAP on ethanol inhibition of LTP was concentration-dependent since D-NAP (10(-10) M) had an intermediate effect, while D-NAP (10(-13) M) had no effect on ethanol suppression of LTP. These observations were also replicated with a different ethanol antagonist, 1-octanol, in area CA1. To address the mechanisms underlying this long-lasting suppression of LTP, the sensitivity of pharmacologically isolated NMDAR extracellular field potentials to combinations of D-NAP and ethanol was determined. D-NAP (10(-7)M) alone had no effect on NMDA extracellular field potentials; however, the peptide significantly increased the inhibitory action of ethanol on NMDA extracellular field potential. The findings suggest that D-NAP and 1-octanol selectively interact with NMDA receptors in an ethanol-dependent manner, further implicating the L1 cell adhesion molecule in alcohol-related brain disorders.

Ethanol inhibition of L1-mediated cell adhesion may contribute to the spectrum of neurological, behavioral and morphological abnormalities associated with prenatal ethanol exposure. We showed previously that the neuroprotective peptides NAPVSIPQ (NAP) and SALLRSIPA (SAL) antagonize ethanol inhibition of L1 adhesion and prevent ethanol-induced growth retardation in mouse whole embryo culture. Here we ask whether NAP and SAL also prevent ethanol-induced major malformations of the nervous system. Gestational day 8.0 (3-5 somites) C57BL/6J mouse embryos were grown for 6 h in control medium, 100 mM ethanol and 10(-10) M peptides and then maintained for an additional 20 h in control medium. At the end of the culture period, only embryos having 18-19 somite pairs were examined and compared for the degree of neural tube closure. Ethanol exposure resulted in neural tube defects (NTDs) consistent with total dysraphia and anencephaly. Co-incubation with ethanol and L-NAP (all L-amino acids), D-NAP (all D-amino acids) or SAL significantly increased the percentage of embryos that had begun to close their neural folds at the level of the forebrain/midbrain junction or that had progressed beyond this stage of closure. P7A-NAP (NAPVSIAQ), which lacks neuroprotective activity, but retains activity as an antagonist of ethanol inhibition of L1 adhesion, was effective in preventing ethanol-induced NTDs. In contrast, I6A-NAP (NAPVSAPQ), which shows reduced efficacy as an ethanol antagonist but retains its neuroprotective efficacy, did not significantly diminish the induction of NTDs by ethanol. These findings demonstrate the ability of NAP and SAL to prevent ethanol-induced NTDs and support the hypothesis that ethanol teratogenesis is caused in part by ethanol inhibition of L1-mediated cell adhesion., (Copyright 2005 S. Karger AG, Basel.)

Increasing evidence suggests that ethanol damages the developing nervous system partly by disrupting the L1 cell adhesion molecule. Ethanol inhibits L1-mediated cell adhesion, and compounds that antagonize this action also prevent ethanol-induced embryotoxicity. Two such compounds are the small peptides NAPVSIPQ (NAP) and SALLRSIPA (SAL). We showed previously that NAP and SAL antagonize ethanol inhibition of L1 adhesion at femtomolar to picomolar concentrations. Here we demonstrate that, despite this extraordinary potency, both NAP and SAL lack stereospecificity. d-NAP, a peptide composed entirely of d-amino acids, was an effective ethanol antagonist in NIH/3T3 cells transfected with human L1 and in the NG108-15 neural cell line. Interestingly, Ala-substituted derivatives of d-NAP demonstrate the same structure-activity relation as the corresponding derivatives of l-NAP. The Ser-Ile-Pro motif was important for the ethanol antagonist activity of d-NAP, l-NAP, and l-SAL, with Ile being the most critical element in all three. Like l-NAP, d-NAP effectively reduced ethanol-induced growth retardation in mouse whole embryo culture. The potential resistance of d-peptides to proteases makes d-NAP a potentially attractive agent for the prevention of fetal alcohol syndrome.

Mitochondrial DNA (mtDNA) mutations can cause rare forms of dystonia, but the role of mtDNA mutations in other types of dystonia is not well understood. We now report identification by sequencing, restriction endonuclease analyses, and clonal analyses of a heteroplasmic missense A to G base pair substitution at nucleotide position 3796 (A3796G) in the gene encoding the ND1 subunit of mitochondrial complex I in a patient with adult-onset dystonia, spasticity, and core-type myopathy. The mutation converts a highly conserved threonine to an alanine. The same mutation subsequently was identified in 2 of 74 additional unrelated adult-onset dystonia patients. A muscle biopsy was obtained from 1 of these 2 subjects and this revealed abnormalities of electron transport chain (ETC) activities. The mutation was absent in 64 subjects with early onset dystonia, 82 normal controls, and 65 subjects with Parkinson's disease or multiple system atrophy. The A3796G mutation previously has been reported in 3 of 226 subjects from mitochondrial haplogroup H. Each of the 3 subjects in our study harboring the A3796G mutation was also from haplogroup H. However, a subgroup analysis of haplogroup H subjects from our study indicates that the A3796G mutation is significantly overrepresented among haplogroup H adult-onset dystonia subjects compared with haplogroup H controls (P<0.01). This difference remains significant even after excluding the index patient (P=0.04). These data suggest that, among haplogroup H subjects, the presence of the A3796G mutation increases the risk of developing adult-onset dystonia.

NAPVSIPQ (NAP), an active fragment of the glial-derived activity-dependent neuroprotective protein, is protective at femtomolar concentrations against a wide array of neural insults and prevents ethanol-induced fetal wastage and growth retardation in mice. NAP also antagonizes ethanol inhibition of L1-mediated cell adhesion (ethanol antagonism). We performed an Ala scanning substitution of NAP to determine the role of ethanol antagonism and neuroprotection in NAP prevention of ethanol embryotoxicity. The Ser-Ile-Pro region of NAP was crucial for both ethanol antagonism and protection of cortical neurons from tetrodotoxin toxicity (neuroprotection). Ala replacement of either Ser-5 or Pro-7 (P7A-NAP) abolished NAP neuroprotection but minimally changed the efficacy of NAP ethanol antagonism. In contrast, Ala replacement of Ile-6 (I6A-NAP) caused a decrease in potency (>2 logarithmic orders) with only a small reduction (<10%) in the efficacy of NAP neuroprotection but markedly reduced the efficacy (50%) and the potency (5 logarithmic orders) of NAP ethanol antagonism. Ethanol significantly reduced the number of paired somites in mouse whole-embryo culture; this effect was prevented significantly by 100 pM NAP or by 100 pM P7A-NAP, but not by 100 pM I6A-NAP. The structure-activity relation for NAP prevention of ethanol embryotoxicity was similar to that for NAP ethanol antagonism and different from that for NAP neuroprotection. These findings support the hypothesis that NAP antagonism of ethanol inhibition of L1 adhesion plays a central role in NAP prevention of ethanol embryotoxicity and highlight the potential importance of ethanol effects on L1 in the pathophysiology of fetal alcohol syndrome.