Conditional frequency spectra as a tool for studying selection on complex traits in biobanks.

Natural selection on complex traits is difficult to study in part due to the ascertainment inherent to genome-wide association studies (GWAS). The power to detect a trait-associated variant in GWAS is a function of frequency and effect size - but for traits under selection, the effect size of a variant determines the strength of selection against it, constraining its frequency. To account for GWAS ascertainment, we propose studying the joint distribution of allele frequencies across populations, conditional on the frequencies in the GWAS cohort. Before considering these conditional frequency spectra, we first characterized the impact of selection and non-equilibrium demography on allele frequency dynamics forwards and backwards in time. We then used these results to understand conditional frequency spectra under realistic human demography. Finally, we investigated empirical conditional frequency spectra for GWAS variants associated with 106 complex traits, finding compelling evidence for either stabilizing or purifying selection. Our results provide insight into polygenic score portability and other properties of variants ascertained with GWAS, highlighting the utility of conditional frequency spectra.

ACR Appropriateness Criteria® Soft Tissue Vascular Anomalies: Vascular Malformations and Infantile Vascular Tumors (Non-CNS)-Child.

Soft tissue vascular anomalies may be composed of arterial, venous, and/or lymphatic elements, and diagnosed prenatally or later in childhood or adulthood. They are divided into categories of vascular malformations and vascular tumors. Vascular malformations are further divided into low-flow and fast-flow lesions. A low-flow lesion is most common, with a prevalence of 70%. Vascular tumors may behave in a benign, locally aggressive, borderline, or malignant manner. Infantile hemangioma is a vascular tumor that presents in the neonatal period and then regresses. The presence or multiple skin lesions in an infant can signal underlying visceral vascular anomalies, and complex anomalies may be associated with overgrowth syndromes. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision process support the systematic analysis of the medical literature from peer reviewed journals. Established methodology principles such as Grading of Recommendations Assessment, Development, and Evaluation or GRADE are adapted to evaluate the evidence. The RAND/UCLA Appropriateness Method User Manual provides the methodology to determine the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where peer reviewed literature is lacking or equivocal, experts may be the primary evidentiary source available to formulate a recommendation.

Increasing equity in science requires better ethics training: A course by trainees, for trainees.

Despite the profound impacts of scientific research, few scientists have received the necessary training to productively discuss the ethical and societal implications of their work. To address this critical gap, we-a group of predominantly human genetics trainees-developed a course on genetics, ethics, and society. We intend for this course to serve as a template for other institutions and scientific disciplines. Our curriculum positions human genetics within its historical and societal context and encourages students to evaluate how societal norms and structures impact the conduct of scientific research. We demonstrate the utility of this course via surveys of enrolled students and provide resources and strategies for others hoping to teach a similar course. We conclude by arguing that if we are to work toward rectifying the inequities and injustices produced by our field, we must first learn to view our own research as impacting and being impacted by society.

Surgical Management of Congenital Pulmonary Airway Malformations (CPAM) in an Infant and a Toddler: Case Report Depicting Two Distinct Surgical Techniques With Successful Outcomes.

Congenital pulmonary airway malformations (CPAM) compose the major part of congenital lung malformations (CLM) and have traditionally been treated by pulmonary lobectomy. In terms of surgical strategy, lobectomy has conventionally been the preferred treatment for CPAM localized to a single lobe. More recently, alternative approaches including lung-sparing resections (LSR), such as wedge or non-anatomic resections and segmentectomy, have been suggested. In asymptomatic CPAM early surgical resection is often shown to reduce infection and malignancy development. We describe two patients who were diagnosed with CPAM when being evaluated for respiratory tract infection. Patient 1 (P1) was a two-month-old infant weighing 4 kg with glucose-6-phosphate dehydrogenase (G6PD) deficiency and Patient 2 (P2) was a toddler aged one year, nine months weighing 9 kg. P1 underwent LSR for the CPAM diagnosed in the left upper lobe of the lung with conventional mechanical ventilation whilst right upper lobectomy was performed in P2 using one/single lung ventilation. In both cases, LSR and right upper lobectomy led to an uneventful postoperative recovery with no complications reported.

Conventional Rotary Technique and Piezosurgical Technique in the Removal of Impacted Mandibular Third Molar: A Comparative Study.

AIM: To compare the operating time, postoperative pain, edema, trismus, and patient acceptance following surgical removal of impacted third molar using piezosurgery and conventional rotary technique. MATERIALS AND METHODS: About 42 patients with impacted mesioangular mandibular third molars were included in this study. Subjects are divided into two groups: group I (treated with conventional rotary technique) and group II (treated with piezosurgery). Duration of surgery, pain, trismus, and swelling were assessed. The patients were evaluated on the 1st, 3rd, and 7th postoperative days. RESULTS: Postoperative pain, trismus, and edema were reduced with piezosurgery compared with conventional technique. Even though the duration of time was longer with piezosurgery, patient comfort was found to be better. CONCLUSION: Piezosurgery is a meticulous and innovative ultrasonic technique with selective bone cutting and better postoperative outcomes. However, it is expensive, and the operating time is prolonged. CLINICAL SIGNIFICANCE: Piezosurgery is an alternative in the surgical removal of third molars as it ensures precise and selective cutting, with no injury to the surrounding soft tissues. Postoperative outcome and patient acceptance are improved with piezosurgery.

A comparative evaluation of light cure calcium silicate and resin-modified glass ionomer as indirect pulp capping agent in primary molars: A randomized clinical trial.

Background: Minimally invasive techniques should be employed to maintain pulp vitality without affecting physiological tooth resorption for pediatric patients. This study aims to evaluate clinical and radiographic success of light cure calcium silicate and resin-modified glass ionomer (RMGI) as indirect pulp-capping agent in primary molars in children between 5 and 9 years. Materials and Methods: In this randomized clinical trial study, 40 primary molars with the International Caries Detection and Assessment System criteria 4-6 score were divided randomly into two groups after computerized randomization method. After caries excavation by minimally invasive dentistry principle, affected dentin was lined by either light cure calcium silicate (Group I) or RMGI (Group II) liner followed by composite restoration. Clinical success was determined with the absence of symptoms and bitewing radiographs were taken at baseline, 3, and 6 months' interval to measure increase in dentin increment using ImageJ software. Statistical analysis for intergroup comparison was done using Paired t-test, and Independent t-test was used for intragroup comparison. The level of statistical significance was set at P < 0.05. Results: Change in dentin increment seen from baseline to 6 months in Group I was 0.19 mm and in Group II was 0.20 mm (P = 0.924). Intragroup increment was statistically significant during all follow-up intervals for both the groups (Group I - P ≤ 0.001, Group II - P = 0.009). For baseline remaining dentin thickness >1.5 mm, statistically significant increase was observed in the dentin increment at 3 months' interval between both the groups. Conclusion: Both TheraCal LC and Vitrebond show acceptable clinical and radiographic results when used in primary molars as indirect pulp treatment agents. Both the liners are equivalent to each other in terms of feasibility and cost-effectiveness but TheraCal LC can be preferred due to better handling and avoiding the manipulation step thereby reducing treatment time.

Low-concentration Povidone-iodine and Normal Saline as Irrigant on Reducing Postoperative Complications after the Third-molar Surgery: A Comparative Study.

AIM: This study was conducted to compare the efficacy of using 0.5 mg/mL povidone-iodine solution as an irrigant and coolant in reducing postoperative sequelae like swelling, trismus, and pain with the conventional normal saline irrigation during the surgical removal of the impacted lower third molar. MATERIALS AND METHODS: The research was conducted out toward the MES Dental College in Perinthalmanna, Kerala, in the Department of Oral and Maxillofacial Surgery. After mandibular third-molar surgical removal, researchers studied 60 individuals, 30 of whom had normal saline irrigation (group I), and 30 of whom received 0.05% povidone-iodine irrigation (group II). The postoperative discomforts were measured on the second and seventh days after surgery, respectively. After that, the data were analyzed using SPSS. The data analysis considered p-values less than 0.05 to be significant. RESULTS: At the second postoperative visit, patients in the povidone-iodine group reported much less pain, swelling, and reduced mouth opening than those in the normal saline group. But on the seventh postoperative day, there was not much difference between either group. CONCLUSION: Following the surgical removal of teeth, it was revealed that povidone-iodine solution (0.5 mg/mL) was more effective as irrigation and cooling aid than regular saline solution. CLINICAL SIGNIFICANCE: Low-concentrated povidone-iodine is a better option in dentistry as irrigant.

Dynamic enlargement and mobilization of lipid droplets in pluripotent cells coordinate morphogenesis during mouse peri-implantation development.

Mammalian pre-implantation embryos accumulate substantial lipids, which are stored in lipid droplets (LDs). Despite the fundamental roles of lipids in many cellular functions, the significance of building-up LDs for the developing embryo remains unclear. Here we report that the accumulation and mobilization of LDs upon implantation are causal in the morphogenesis of the pluripotent epiblast and generation of the pro-amniotic cavity in mouse embryos, a critical step for all subsequent development. We show that the CIDEA protein, found abundantly in adipocytes, enhances lipid storage in blastocysts and pluripotent stem cells by promoting LD enlargement through fusion. The LD-stored lipids are mobilized into lysosomes at the onset of lumenogenesis, but without CIDEA are prematurely degraded by cytosolic lipases. Loss of lipid storage or inactivation of lipophagy leads to the aberrant formation of multiple cavities within disorganised epithelial structures. Thus, our study reveals an unexpected role for LDs in orchestrating tissue remodelling and uncovers underappreciated facets of lipid metabolism in peri-implantation development.

Genetic interactions drive heterogeneity in causal variant effect sizes for gene expression and complex traits.

Despite the growing number of genome-wide association studies (GWASs), it remains unclear to what extent gene-by-gene and gene-by-environment interactions influence complex traits in humans. The magnitude of genetic interactions in complex traits has been difficult to quantify because GWASs are generally underpowered to detect individual interactions of small effect. Here, we develop a method to test for genetic interactions that aggregates information across all trait-associated loci. Specifically, we test whether SNPs in regions of European ancestry shared between European American and admixed African American individuals have the same causal effect sizes. We hypothesize that in African Americans, the presence of genetic interactions will drive the causal effect sizes of SNPs in regions of European ancestry to be more similar to those of SNPs in regions of African ancestry. We apply our method to two traits: gene expression in 296 African Americans and 482 European Americans in the Multi-Ethnic Study of Atherosclerosis (MESA) and low-density lipoprotein cholesterol (LDL-C) in 74K African Americans and 296K European Americans in the Million Veteran Program (MVP). We find significant evidence for genetic interactions in our analysis of gene expression; for LDL-C, we observe a similar point estimate, although this is not significant, most likely due to lower statistical power. These results suggest that gene-by-gene or gene-by-environment interactions modify the effect sizes of causal variants in human complex traits.

Associations between Combined Influenza and Pneumococcal Pneumonia Vaccination and Cardiovascular Outcomes.

BACKGROUND: In 2017, the CDC listed heart disease as the leading cause of death, with pneumonia and influenza being the eighth cause of death. Several studies have suggested the protective effects of influenza vaccination on myocardial infarction (MI). Available evidence supports the use of influenza vaccination in decreasing cardiovascular events, and the Joint Commission considers influenza vaccination a metric of quality care for hospitalized patients. Our specific aim was to evaluate the combined use of pneumococcal pneumonia vaccine (PPV) and influenza vaccine on cardiovascular outcomes and mortality. METHODS: A retrospective observational study was conducted using the 2012-2015 US National Inpatient Sample (NIS) database, to compare cardiovascular events in adult patients who did and did not receive vaccination during their hospitalization. ICD-9 codes were used to extract data for specific variables. The outcomes included MI, transient ischemic attacks, cardiac arrest, stroke, heart failure, and death. Adjusted relative risks (RR) were calculated using survey-weighted generalized linear models after adjusting for gender, race, socioeconomic status, diabetes, hypertension, hyperlipidemia, smoking status, prior coronary artery disease, and cerebrovascular disease. The effect of vaccination on in-hospital mortality was assessed in each subgroup of cardiovascular events using RR regressions. RESULTS: This study included 22,634,643 hospitalizations, of which 21,929,592 did not receive immunization. Vaccination solely against influenza was associated with lower MI (RR = 0.84, 95% CI: 0.82-0.87, p < 0.001), TIA (RR = 0.93, 95% CI: 0.9-0.96, p < 0.001), cardiac arrest (RR = 0.36, 95% CI: 0.33-0.39, p < 0.001), stroke (RR = 0.94, 95% CI: 0.91-0.97, p < 0.001), and mortality (RR = 0.38, 95% CI: 0.36-0.4, p < 0.001). Vaccination with PPV alone was associated with MI (RR = 1.13, 95% CI: 1.11-1.16, p < 0.001), TIA (RR = 1.28, 95% CI: 1.26-1.31, p < 0.001), stroke (RR = 1.21, 95% CI: 1.18-1.24, p < 0.001), and lower mortality (RR = 0.47, 95% CI: 0.45-0.49, p < 0.001). Combined PPV and influenza vaccine was associated with lower mortality (2.21% vs. 1.03%, p < 0.001) and lower cardiac arrest (0.61% vs. 0.51%, p < 0.001). In the adjusted analysis, the RR was 0.46 (95% CI: 0.43, 0.49) for mortality in the combined vaccinated cohort. The combined vaccination group also had a significantly reduced risk of mortality among those admitted with MI (RR = 0.46), transient ischemic attacks (RR = 0.58), and stroke (RR = 0.42) compared to the nonvaccinated group. CONCLUSIONS: Our study shows a significantly reduced risk of mortality with influenza vaccine and PPV and with combined pneumococcal and influenza vaccination. These data suggest that in-hospital administration of pneumonia and influenza vaccines appears safe and supports the use of combined vaccination during hospitalization due to their cardiovascular benefits.

A longitudinal study to evaluate the bleeding pattern of patients on low dose aspirin therapy following dental extraction.

BACKGROUND AND AIMS: Antiplatelet dugs are often interrupted preceding invasive dental extraction because of concern of bleeding complications. The fear of uncontrolled bleeding often prompts medical and dental practitioners to stop aspirin intake for 7 to 10 days before any surgical procedure, which puts the patient at risk from adverse thrombotic events. The aim of the study conducted was to evaluate the bleeding pattern after routine dental extraction among patients on low dose long term aspirin therapy. METHODS: A total of 104 subjects in the age group of 30-65 years, who continued to have aspirin intake during extraction were included in the study. Dental extraction was performed without stopping aspirin therapy under local anesthesia. The post-operative blood loss was quantified by weighing the gauze pre and post operatively and adding total volume of fluid in the suction jar. RESULTS: Of these 104 patients treated, 87% of patients had mild bleeding (<20 ml) and 13% of patients had moderate bleeding (20-30 ml). The total study population showed a mean blood loss of 16.15 ± 3.5 ml. CONCLUSION: Within in the limitations, our study concluded that the routine dental extraction in patients under low dose aspirin therapy did not cause clinically significant post extraction hemorrhage. Aspirin intake can be continued during routine dental extraction as post extraction bleeding encountered will be negligible.

Study of Patterns of Maxillofacial Injuries: An Institution-based Observational Study.

Maxillofacial fractures are one of the common presentations in an emergency department. They are considered to be one of the significant and dominant conditions that requires treatment as the fractures can result in morbidity, mortality, psychological, functional disability, and facial mutilation. The incidence, patterns, and etiology of maxillofacial fractures vary from one country to another due to the geographical, cultural, social, and economic differences. The present study included 176 patients from January 2019 to September 2020 that aimed to evaluate the pattern of maxillofacial fractures and to learn the etiology for the same.

Postoperative pain, edema and trismus following third molar surgery - A comparitive study between submucosal and intravenous dexamethasone.

BACKGROUND: Third molar surgey always needs primary intervention as it can lead to various complications and pathologies. Considering other ways for postoperative anesthesia it was infered that submucosal group which showed simple injection technique and direct surgical site administration is more beneficial. It was noticed as a patient comfort method which can be the preferred as the drug of choice over intravenous route of dexamethasone injection. INTRODUCTION: Impaction of third molar is a common affliction and surgical removal is the only treatment option. The post-operative sequelae following the third molar surgery are pain, edema and trismus. The use of corticosteroids is to counteract it via various routes. Still, controversy exists in the literature regarding the administration of corticosteroids over the routes and time of administration. The purpose of this study was to compare the postoperative pain, edema and trismus following third molar surgery while using preoperative intravenous and submucosal routes of dexamethasone, in terms of pain, facial swelling, and trismus. MATERIALS AND METHODS: This study consisted of 64 patients presented with mesioangular impacted mandibular third molar for surgical removal. Preoperative measurements of edema, trismus were analyzed. Postoperative pain was estimated using visual analogue scale. Edema was assessed by the extra oral facial measurements. Trismus was measured by recording the interincisal opening in millimeters. Dexamethasone was administered intravenously or submucosally according to the choice of operating surgeon and were divided into 2 groups. RESULTS: Mean and standard deviation calculated for continuous variables. Changes in parameters was analysed using t test and Mann-Whitney U test. Here, submucosal group were reported with increased pain on the second postoperative day. On seventh postoperative day mean value turns to 0.7 ± 1 for submucosal and 0.6 ± 1.2 for intravenous group. On overall observation, intravenous group expressed statistically significant (P < 0.01) reduction in pain compared to the submucosal group during immediate and second postoperative days. CONCLUSION: Analyzing the previous studies, and from the experience of the present one, it could be reasonably found out that administration of submucosal dexamethasone is beneficial for overall patient compliance.

Nimodipine Reduces Dysfunction and Demyelination in Models of Multiple Sclerosis.

OBJECTIVE: Treatment of relapses in multiple sclerosis (MS) has not advanced beyond steroid use, which reduces acute loss of function, but has little effect on residual disability. Acute loss of function in an MS model (experimental autoimmune encephalomyelitis [EAE]) is partly due to central nervous system (CNS) hypoxia, and function can promptly improve upon breathing oxygen. Here, we investigate the cause of the hypoxia and whether it is due to a deficit in oxygen supply arising from impaired vascular perfusion. We also explore whether the CNS-selective vasodilating agent, nimodipine, may provide a therapy to restore function, and protect from demyelination in 2 MS models. METHODS: A variety of methods have been used to measure basic cardiovascular physiology, spinal oxygenation, mitochondrial function, and tissue perfusion in EAE. RESULTS: We report that the tissue hypoxia in EAE is associated with a profound hypoperfusion of the inflamed spinal cord. Treatment with nimodipine restores spinal oxygenation and can rapidly improve function. Nimodipine therapy also reduces demyelination in both EAE and a model of the early MS lesion. INTERPRETATION: Loss of function in EAE, and demyelination in EAE, and the model of the early MS lesion, seem to be due, at least in part, to tissue hypoxia due to local spinal hypoperfusion. Therapy to improve blood flow not only protects neurological function but also reduces demyelination. We conclude that nimodipine could be repurposed to offer substantial clinical benefit in MS. ANN NEUROL 2020 ANN NEUROL 2020;88:123-136.

Dynamic CpG methylation delineates subregions within super-enhancers selectively decommissioned at the exit from naive pluripotency.

Clusters of enhancers, referred as to super-enhancers (SEs), control the expression of cell identity genes. The organisation of these clusters, and how they are remodelled upon developmental transitions remain poorly understood. Here, we report the existence of two types of enhancer units within SEs typified by distinctive CpG methylation dynamics in embryonic stem cells (ESCs). We find that these units are either prone for decommissioning or remain constitutively active in epiblast stem cells (EpiSCs), as further established in the peri-implantation epiblast in vivo. Mechanistically, we show a pivotal role for ESRRB in regulating the activity of ESC-specific enhancer units and propose that the developmentally regulated silencing of ESRRB triggers the selective inactivation of these units within SEs. Our study provides insights into the molecular events that follow the loss of ESRRB binding, and offers a mechanism by which the naive pluripotency transcriptional programme can be partially reset upon embryo implantation.

A comparison study of size-specific dose estimate calculation methods.

BACKGROUND: The size-specific dose estimate (SSDE) has emerged as an improved metric for use by medical physicists and radiologists for estimating individual patient dose. Several methods of calculating SSDE have been described, ranging from patient thickness or attenuation-based (automated and manual) measurements to weight-based techniques. OBJECTIVE: To compare the accuracy of thickness vs. weight measurement of body size to allow for the calculation of the size-specific dose estimate (SSDE) in pediatric body CT. MATERIALS AND METHODS: We retrospectively identified 109 pediatric body CT examinations for SSDE calculation. We examined two automated methods measuring a series of level-specific diameters of the patient's body: method A used the effective diameter and method B used the water-equivalent diameter. Two manual methods measured patient diameter at two predetermined levels: the superior endplate of L2, where body width is typically most thin, and the superior femoral head or iliac crest (for scans that did not include the pelvis), where body width is typically most thick; method C averaged lateral measurements at these two levels from the CT projection scan, and method D averaged lateral and anteroposterior measurements at the same two levels from the axial CT images. Finally, we used body weight to characterize patient size, method E, and compared this with the various other measurement methods. Methods were compared across the entire population as well as by subgroup based on body width. RESULTS: Concordance correlation (ρc) between each of the SSDE calculation methods (methods A-E) was greater than 0.92 across the entire population, although the range was wider when analyzed by subgroup (0.42-0.99). When we compared each SSDE measurement method with CTDIvol, there was poor correlation, ρc<0.77, with percentage differences between 20.8% and 51.0%. CONCLUSION: Automated computer algorithms are accurate and efficient in the calculation of SSDE. Manual methods based on patient thickness provide acceptable dose estimates for pediatric patients <30 cm in body width. Body weight provides a quick and practical method to identify conversion factors that can be used to estimate SSDE with reasonable accuracy in pediatric patients with body width ≥20 cm.

Experimental autoimmune encephalomyelitis from a tissue energy perspective.

Increasing evidence suggests a key role for tissue energy failure in the pathophysiology of multiple sclerosis (MS). Studies in experimental autoimmune encephalomyelitis (EAE), a commonly used model of MS, have been instrumental in illuminating the mechanisms that may be involved in compromising energy production. In this article, we review recent advances in EAE research focussing on factors that conspire to impair tissue energy metabolism, such as tissue hypoxia, mitochondrial dysfunction, production of reactive oxygen/nitrogen species, and sodium dysregulation, which are directly affected by energy insufficiency, and promote cellular damage. A greater understanding of how inflammation affects tissue energy balance may lead to novel and effective therapeutic strategies that ultimately will benefit not only people affected by MS but also people affected by the wide range of other neurological disorders in which neuroinflammation plays an important role.

A multispectral microscope for in vivo oximetry of rat dorsal spinal cord vasculature.

Quantification of blood oxygen saturation (SO2) in vivo is essential for understanding the pathogenesis of diseases in which hypoxia is thought to play a role, including inflammatory disorders such as multiple sclerosis (MS) and rheumatoid arthritis (RA). We describe a low-cost multispectral microscope and oximetry technique for calibration-free absolute oximetry of surgically exposed blood vessels in vivo. We imaged the vasculature of the dorsal spinal cord in healthy rats, and varied inspired oxygen (FiO2) in order to evaluate the sensitivity of the imaging system to changes in SO2. The venous SO2 was calculated as 67.8 ± 10.4% (average ± standard deviation), increasing to 83.1 ± 11.6% under hyperoxic conditions (100% FiO2) and returning to 67.4 ± 10.9% for a second normoxic period; the venous SO2 was 50.9 ± 15.5% and 29.2 ± 24.6% during subsequent hypoxic states (18% and 15% FiO2 respectively). We discuss the design and performance of our multispectral imaging system, and the future scope for extending this oximetry technique to quantification of hypoxia in inflamed tissue.

Cause and prevention of demyelination in a model multiple sclerosis lesion.

OBJECTIVE: Demyelination is a cardinal feature of multiple sclerosis, but it remains unclear why new lesions form, and whether they can be prevented. Neuropathological evidence suggests that demyelination can occur in the relative absence of lymphocytes, and with distinctive characteristics suggestive of a tissue energy deficit. The objective was to examine an experimental model of the early multiple sclerosis lesion and identify pathogenic mechanisms and opportunities for therapy. METHODS: Demyelinating lesions were induced in the rat spinal dorsal column by microinjection of lipopolysaccharide, and examined immunohistochemically at different stages of development. The efficacy of treatment with inspired oxygen for 2 days following lesion induction was evaluated. RESULTS: Demyelinating lesions were not centered on the injection site, but rather formed 1 week later at the white-gray matter border, preferentially including the ventral dorsal column watershed. Lesion formation was preceded by a transient early period of hypoxia and increased production of superoxide and nitric oxide. Oligodendrocyte numbers decreased at the site shortly afterward, prior to demyelination. Lesions formed at a site of inherent susceptibility to hypoxia, as revealed by exposure of naive animals to a hypoxic environment. Notably, raising the inspired oxygen (80%, normobaric) during the hypoxic period significantly reduced or prevented the demyelination. INTERPRETATION: Demyelination characteristic of at least some early multiple sclerosis lesions can arise at a vascular watershed following activation of innate immune mechanisms that provoke hypoxia, and superoxide and nitric oxide formation, all of which can compromise cellular energy sufficiency. Demyelination can be reduced or eliminated by increasing inspired oxygen to alleviate the transient hypoxia.