Conceptualizing Epigenetics and the Environmental Landscape of Autism Spectrum Disorders.

Complex interactions between gene variants and environmental risk factors underlie the pathophysiological pathways in major psychiatric disorders. Autism Spectrum Disorder is a neuropsychiatric condition in which susceptible alleles along with epigenetic states contribute to the mutational landscape of the ailing brain. The present work reviews recent evolutionary, molecular, and epigenetic mechanisms potentially linked to the etiology of autism. First, we present a clinical vignette to describe clusters of maladaptive behaviors frequently diagnosed in autistic patients. Next, we microdissect brain regions pertinent to the nosology of autism, as well as cell networks from the bilateral body plan. Lastly, we catalog a number of pathogenic environments associated with disease risk factors. This set of perspectives provides emerging insights into the dynamic interplay between epigenetic and environmental variation in the development of Autism Spectrum Disorders.

Managing Addiction and Overdose Deaths: The Debate Over America's Safe Injection Spaces.

In the decade between 2010 and 2020, the number of people killed by opioid overdoses more than tripled, reaching 68,630. Among drug users in their second and third decades of life, hepatitis B and C are also on the rise. New York City's two new supervised drug injection sites (SDISs) reversed 114 overdoses within two months, and 585 people injecting drugs visited the facility 4,974 times. By providing medical professionals and a sterile and safe environment, supervised injection sites reduce overdose risk and save lives. This suggests that SDISs could be an important adjunct to currently failing strategies to combat the nation's raging opioid crisis, particularly in the aftermath of the COVID-19 pandemic. Here, we examine the perception and impact of SDISs as well as efforts by the United States Congress (H.R. 7029 and H.R. 6159) toward their prevention. We look into the perspectives of major stakeholders, such as residents, business owners, drug users, legislators, taxpayers, and the general public, and investigate the short- and long-term consequences of SDISs based on crime statistics and published data on opioid use, overdose deaths, and blood-borne disease transmission rates.

Preliminary Effects of Osteopathic Manipulative Medicine on Reactive Oxygen Species in Parkinson's Disease: A Randomized Controlled Pilot Study.

Context Parkinson's disease (PD) is the second most common neurodegenerative disorder and causes many clinical manifestations including bradykinesia, tremor, postural instability, and musculoskeletal stiffness. Neurodegeneration is commonly associated with oxidative stress. Oxidative stress has not been measured in PD in relation to the manual techniques used in Osteopathic Manipulative Treatment (OMT). Objective To investigate the effect of OMT on oxidative stress biomarkers in PD. Methods In this randomized non-blinded study, 32 PD subjects were separated by block randomization into counseling and OMT groups, receiving respective interventions twice a week for six weeks. The counseling arm received informative sessions while the OMT arm received a set treatment protocol. Biomarkers of oxidative stress, malondialdehyde (MDA), dityrosine (DT), 3-nitrotyrosine (3-NT), 8-hydroxy-2-deoxyguanosine (8-OHdG), and 8-isoprostane were measured before and after the first session and at weeks three, six, and 10 (four weeks after conclusion of intervention). Results No significant changes were found in blood plasma levels of MDA, DT, 3-NT, or 8-OHdG during or after intervention compared to controls (p > 0.05). No significant changes were found in urine 8-OHdG or 8-isoprostane during or after intervention compared to controls (p > 0.05). Conclusion OMT used in this study did not significantly affect the chosen oxidative stress biomarkers, however many limitations of the study may have impeded possible findings.

Indoor Air Pollution and Decision-Making Behavior: An Interdisciplinary Review.

The human brain is constantly exposed to air pollutants, some of which might be disruptive or even lethal to certain neurons implicated in abstract features of cognitive function. In this review, we present new evidence from behavioral and neural studies in humans, suggesting a link between indoor fine particulate matter and decision-making behavior. To illustrate this relationship, we use qualitative sources, such as historical documents of the Vietnam War to develop hypotheses of how aerial transmission of pollutants might obstruct alternative choices during the evaluation of policy decisions. We first describe the neural circuits driving decision-making processes by addressing how neurons and their cognate receptors directly evaluate and transduce physical phenomena into sensory perceptions that allow us to decide the best course of action among competing alternatives. We then raise the possibility that indoor air pollutants might also impact cell-signaling systems outside the brain parenchyma to further obstruct the computational analysis of the social environment. We also highlight how particulate matter might be pathologically integrated into the brain to override control of sensory decisions, and thereby perturb selection of choice. These lines of research aim to extend our understanding of how inhalation of airborne particulates and toxicants in smoke, for example, might contribute to cognitive impairment and negative health outcomes.

Health Equity in a Post 'Roe Versus Wade' America.

For almost five decades, the US Supreme Court had protected the right to abortion care in the United States. However, the Court's decision in 'Dobbs versus Jackson Women's Health Organization' in 2022 established that the US Constitution does not confer a right to abortion, effectively overturning the Court's own previous judgment in 'Roe versus Wade' from 1973. How could a decision that overturns the precedent for nationwide access to abortion affect women, children, and physicians? How will state laws impact healthcare equity regarding reproductive rights going forward? How will geography affect who can access care financially, and how will this shape the conditions that unwanted children are born into? This work is a systematic analysis of the impact of overturning 'Roe versus Wade' considering the scientific and medical evidence as well as the conflicting political and moral viewpoints regarding abortion. Furthermore, we make constructive recommendations with a view to detoxifying the inflammatory rhetoric surrounding this topic and protecting key stakeholders such as patients seeking abortion and their physicians. The moment 'Roe v. Wade' was overturned, several US states began to enact laws, both protecting and restricting abortion. California and New York, for example, have since enacted laws that extend protection to both patients seeking abortion and the physicians who provide it. Oklahoma and Texas, on the other hand, have enacted laws that make it more difficult for patients to have abortion access, even after fetal death or when the birthing individual's life is in danger. These differences are likely to exacerbate the healthcare access divide across the country and increase the financial burden for those who can become pregnant. As differences in healthcare access and quality of care increase across the nation, an unmatched demand for maternity care, especially in the most restrictive states, could precipitate increased maternal and fetal morbidity and mortality while physician shortages are expected to worsen. It will be up to the US Congress to address these differences while weighing competing stakeholder interests. Currently, the nation is at the center of a seismic shift surrounding health policy with laws changing rapidly. This systematic health policy analysis paper will explore what the long-term consequences of this recent Supreme Court decision might look like while considering some of the most recently reported short-term consequences after the landslide decision.

The cannabidiol and marijuana research expansion act: Promotion of scientific knowledge to prevent a national health crisis.

While the use of medical and recreational cannabis is rapidly expanding under state jurisdiction, the convolution of federal regulations is obstructing research progress to the detriment of healthcare equity and the protection of vulnerable populations, such as the underaged. U.S. Senate bill S.253 is designed to accelerate the development of trusted preclinical and clinical principles based on scientific data to guide physicians in their daily practice, inform lawmakers, and thereby protect public health. This goes together with a reinforcement of the legal protection that practitioners have acquired over years of litigation with the federal government when working with their patients. S.253 supports open communication between physicians and their patients when discussing cannabis as a treatment option. The bill passed the U.S. Senate on March 24, 2022. Funding: This work was supported by intramural funding (NYIT College of Osteopathic Medicine) to the corresponding author, Dr. Joerg R. Leheste.

Early-Onset Parkinson's Disease With Multiple Positive Intraoperative Spinal Tissue Cultures for Cutibacterium acnes.

An estimated 95-97% of Parkinson's disease (PD) cases are idiopathic, emphasizing the absence of a clear etiologic linkage for this debilitating, neurodegenerative, and progressive motor disease. Increasing evidence suggests a peripheral disease origin and the gradual transition of a pathological process along the gut-brain axis and olfactory routes into the brain. This disease pattern is reminiscent of an infectious process and suggests the presence of one or multiple infectious agents, such as bacteria, viruses, fungi, or prion-like proteins. This unusual paradigm, known as Braak's hypothesis, was first described by the scientist who developed the staging standard for cellular PD pathology and. Here, we describe a case where the small, anaerobic, Gram-positive Cutibacterium acnes was recurrently isolated from intraoperative spinal tissues in a patient with early-onset PD. C. acnes is also the bacterium that we previously isolated from cadaveric PD brain tissue. Both observations are consistent with Braak's hypothesis underscoring the importance of homeostasis and maintained immune-competence for healthy aging of the body and mind.

Perspectives of Pitocin administration on behavioral outcomes in the pediatric population: recent insights and future implications.

Oxytocin plays an important role in the regulation of parturition as this peptide hormone promotes uterine smooth muscle contractility in gravid women undergoing labor. Here, we review the impact of Pitocin administration on behavioral outcomes in the pediatric population. Pitocin is a synthetic preparation of oxytocin widely used in the obstetric practice for the management of labor and postpartum hemorrhage. We begin by tracing the neuroanatomy of oxytocin-containing cells from an evolutionary perspective and then summarize key findings on behavioral and neural activity reported from offspring dosed with Pitocin during vaginal delivery. Finally, we discuss future directions that are experimentally tractable for understanding the developmental consequences of Pitocin administration on a small but growing subset of children worldwide. Given that fetal past experiences can shape the future behavior of the adult, further work on oxytocin signaling pathways will provide valuable references and insights for early-brain development and state-dependent regulation of behavioral outcome.

An Evolutionary Perspective of Neoplastic Diseases in the Universe.

The existence of exoplanets orbiting low mass-stars is one of the most significant discoveries of our time. Especially intriguing to us is the possibility that Earth-sized exoplanets within a habitable zone might harbor life-forms that resemble our own RNA/DNA-based species. We further narrow this theoretical possibility with the following question: if alien life does indeed exist elsewhere, would extraterrestrial life be burdened with earthly diseases? Given that the chemistry of the universe is subject to specific rules, restraints, and predictable outcomes, we argue that cancer-signaling pathways might be programmed into the life cycle of habitable exoplanets. This hypothetical prediction is also based on evolutionary convergence, the repeated emergence of biological similarity that occurs when disparate life-forms adapt to comparable selection pressures. The possibility that mutations and nucleotide base rearrangements that drive cancer growth might be fixed in the chemical hardware of alien life provides us with the opportunity to wonder and consider the origins, evolution, and ubiquity of disease beyond Earth.

Central and Peripheral Expression of DNA Double-Strand Breaks in Human and Mouse Tissues.

Mammalian cells accumulate DNA lesions when they undergo phases of the cell cycle or during normal cellular activity. In this regard, several DNA repair signaling pathways have evolved to maintain genome stability and avoid the potential acquisition of mutations. To define and further characterize the expression of DNA double-strand breaks in humans and mice, we used immunocytochemistry to localize a DNA damage signal within the spatial confines of the cell nucleus. We show that DNA double-strand breaks are abundantly expressed in postmitotic neurons of the human and mouse brain. Notably, DNA double-strand breaks are present in human hypothalamic and mouse striatal and hippocampal cells, with stable expression of the nuclear signal detected throughout the mammalian brain. Analysis of the mouse tongue, heart, and testis shows that expression of DNA double-strand breaks is only demonstrated in circumscribed populations of peripheral cells. These data suggest that levels of DNA double-strand breaks are tissue-specific with the tongue, heart and testicular tissue having different thresholds of DNA repair and DNA damage from those outlined at the brain level. Anat Rec, 301:1251-1257, 2018. © 2018 Wiley Periodicals, Inc.

Ketamine intervention limits pathogen expansion in vitro.

Ketamine is one of several clinically important drugs whose therapeutic efficacy is due in part to their ability to act upon ion channels prevalent in nearly all biological systems. In studying eukaryotic and prokaryotic organisms in vitro, we show that ketamine short-circuits the growth and spatial expansion of three microorganisms, Stachybotrys chartarum, Staphylococcus epidermidis and Borrelia burgdorferi, at doses efficient at reducing depression-like behaviors in mouse models of clinical depression. Although our findings do not reveal the mechanism(s) by which ketamine mediates its antifungal and antibacterial effects, we hypothesize that a function of L-glutamate signal transduction is associated with the ability of ketamine to limit pathogen expansion. In general, our findings illustrate the functional similarities between fungal, bacterial and human ion channels, and suggest that ketamine or its metabolites not only act in neurons, as previously thought, but also in microbial communities colonizing human body surfaces.

Linking Brain Arteriovenous Malformations With Anorectal Hemorrhoids: A Clinical and Anatomical Review.

Patients who harbor brain arteriovenous malformations are at risk for intracranial hemorrhage. These malformations are often seen in inherited vascular diseases such as hereditary hemorrhagic telangiectasia. However, malformations within the brain also sporadically occur without a hereditary-coding component. Here, we review recent insights into the pathophysiology of arteriovenous malformations, in particular, certain signaling pathways that might underlie endothelial cell pathology. To better interpret the origins, determinants and consequences of brain arteriovenous malformations, we present a clinical case to illustrate the phenotypic landscape of the disease. We also propose that brain arteriovenous malformations might share certain signaling dimensions with those of anorectal hemorrhoids. This working hypothesis provides casual anchors from which to understand vascular diseases characterized by arteriovenous lesions with a hemorrhagic- or bleeding-risk component. Anat Rec, 2017. © The Authors. The Anatomical Record published by Wiley Periodicals, Inc. on behalf of American Association of Anatomists. Anat Rec, 300:1973-1980, 2017. © 2017 The Authors. The Anatomical Record published by Wiley Periodicals, Inc. on behalf of American Association of Anatomists.

P. acnes-Driven Disease Pathology: Current Knowledge and Future Directions.

This review discusses the biology and behavior of Propionibacterium acnes (P. acnes), a dominant bacterium species of the skin biogeography thought to be associated with transmission, recurrence and severity of disease. More specifically, we discuss the ability of P. acnes to invade and persist in epithelial cells and circulating macrophages to subsequently induce bouts of sarcoidosis, low-grade inflammation and metastatic cell growth in the prostate gland. Finally, we discuss the possibility of P. acnes infiltrating the brain parenchyma to indirectly contribute to pathogenic processes in neurodegenerative disorders such as those observed in Parkinson's disease (PD).

The Glymphatic-Lymphatic Continuum: Opportunities for Osteopathic Manipulative Medicine.

The brain has long been thought to lack a lymphatic drainage system. Recent studies, however, show the presence of a brain-wide paravascular system appropriately named the glymphatic system based on its similarity to the lymphatic system in function and its dependence on astroglial water flux. Besides the clearance of cerebrospinal fluid and interstitial fluid, the glymphatic system also facilitates the clearance of interstitial solutes such as amyloid-ß and tau from the brain. As cerebrospinal fluid and interstitial fluid are cleared through the glymphatic system, eventually draining into the lymphatic vessels of the neck, this continuous fluid circuit offers a paradigm shift in osteopathic manipulative medicine. For instance, manipulation of the glymphatic-lymphatic continuum could be used to promote experimental initiatives for nonpharmacologic, noninvasive management of neurologic disorders. In the present review, the authors describe what is known about the glymphatic system and identify several osteopathic experimental strategies rooted in a mechanistic understanding of the glymphatic-lymphatic continuum.

Resveratrol: brain effects on SIRT1, GPR50 and photoperiodic signaling.

Silent information regulator-1 (SIRT1) deacetylase, a sensor of intermittent energy restriction, is inextricably intertwined with circadian regulation of central and peripheral clock genes. The purpose of this study was to identify SIRT1-specific target genes that are expressed in a circadian rhythm pattern and driven, in part, by specific components of foodstuffs. Using human cells and rats fed with a resveratrol diet we show that SIRT1 binds to, and transcriptionally regulates, a gene locus encoding the G protein-coupled receptor (GPR), GPR50 in the brain. GPR50 is the mammalian orthologue of the melatonin1c membrane-bound receptor which has been identified as a genetic risk factor for bipolar disorder and major depression in women. In general, our findings support and expand the notion that circadian clock signaling components and dietary interventions are adaptively linked, and suggest that the brain may be particularly sensitive to metabolic events in response to light-dark cycles.

Neurodevelopmental Malformations of the Cerebellar Vermis in Genetically Engineered Rats.

The cerebellar vermis is particularly vulnerable to neurodevelopmental malformations in humans and rodents. Sprague-Dawley, and Long-Evans rats exhibit spontaneous cerebellar malformations consisting of heterotopic neurons and glia in the molecular layer of the vermis. Malformations are almost exclusively found along the primary fissure and are indicative of deficits of neuronal migration during cerebellar development. In the present report, we test the prediction that genetically engineered rats on Sprague-Dawley or Long-Evans backgrounds will also exhibit the same cerebellar malformations. Consistent with our hypothesis, we found that three different transgenic lines on two different backgrounds had cerebellar malformations. Heterotopia in transgenic rats had identical cytoarchitecture as that observed in wild-type rats including altered morphology of Bergmann glia. In light of the possibility that heterotopia could affect results from behavioral studies, these data suggest that histological analyses be performed in studies of cerebellar function or development when using genetically engineered rats on these backgrounds in order to have more careful interpretation of experimental findings.

Molecular layer heterotopia of the cerebellar vermis in mutant and transgenic mouse models on a C57BL/6 background.

C57BL/6 mice exhibit spontaneous cerebellar malformations consisting of heterotopic neurons and glia in the molecular layer of the vermis (Tanaka and Marunouchi, 2005; Mangaru et al., 2013). Malformations are only found between folia VIII and IX and are indicative of deficits of neuronal migration during cerebellar development. In the present report we test the prediction that mutant and transgenic mouse models on a C57BL/6 background will also exhibit these same cerebellar malformations. Consistent with our hypothesis, we found that 2 spontaneous mutant models of Parkinson's disease on a C57BL/6 background had cerebellar malformations. In addition, we found that numerous transgenic mouse lines on a full or partial C57BL/6 background including eGFP-, YFP- and Cre-transgenic mice also exhibited heterotopia. These data suggest that histological analyses be performed in studies of cerebellar function or development when using C57BL/6 or other mice on this background in order for correct interpretation of research results.

A behavioral and molecular analysis of ketamine in zebrafish.

Ketamine exerts powerful anesthetic, psychotic, and antidepressant effects in both healthy volunteers and clinically depressed patients. Although ketamine targets particular glutamate receptors, there is a dearth of evidence for additional, alternative molecular substrates for the behavioral actions of this N-methyl-D-aspartate (NMDA) receptor antagonist drug. Here, we provide behavioral and molecular evidence for the actions of ketamine using a new vertebrate model for psychiatric disorders: the zebrafish. Subanesthetic doses of ketamine produced a variety of abnormal behaviors in zebrafish that were qualitatively analogous to those previously measured in humans and rodents treated with drugs that produce transient psychosis. In addition, we revealed that the transcription factor Phox2b is a molecular substrate for the actions of ketamine, particularly during periods of hypoxic stress. Finally, we also show that SIRT1, a histone deacetylase widely recognized for its link to cell survival is also affected by hypoxia crises. These results establish a relevant assay system in which the effects of psychotomimetic drugs can rapidly be assessed, and provide a plausible and novel neuronal mechanism through which ketamine affects critical sensory circuits that monitor breathing behavior.

Distribution analysis of deacetylase SIRT1 in rodent and human nervous systems.

Sirtuins function with other biogenic molecules to promote adaptation to caloric restriction in a broad spectrum of eukaryotic species. Sirtuin pathways also converge in the mammalian brain where they appear to protect neurons from nutrient stress. However, few anatomical studies on sirtuins (e.g., SIRT1) are available, particularly those detailing the spatial distribution and subcellular localization pattern of SIRT1 in the brain parenchyma. Here, we report the characterization of a panel of SIRT1-specific antibodies within rodent (i.e., rat and mouse) and human central nervous systems. Immunocytochemical and Western blot analyses indicate that the subcellular localization of SIRT1 is predominantly nuclear throughout the rodent brain and spinal cord. A similar subcellular distribution pattern of SIRT1 was detected in human central nervous system material. SIRT1 is ubiquitously present in areas of the brain especially susceptible to age-related neurodegenerative states (e.g., the prefrontal cortex, hippocampus and basal ganglia). Further, we show no apparent species-specific differences in the subcellular localization pattern of rodent versus human SIRT1. Finally, we identify the chemical phenotype of SIRT1-containing neurons in a number of brain sites that are strongly compromised by aging. These data provide additional and important anatomical findings for the role of SIRT1 in the mammalian brain and suggest that SIRT1 pathways are broadly distributed in neurons most susceptible to senescence injury. Activating endogenous sirtuin pathways may, therefore, offer a therapeutic approach to delay and/or treat human age-related diseases.

A ChIP-cloning approach linking SIRT1 to transcriptional modificationof DNA targets.

The mammalian protein deacetylase SIRT1 (sirtuin1) is widely recognized for its link to calorie restriction and longevity. SIRT1 not only modulates the function of protein targets such as p53 or NFkappaB, but it also affects gene transcription by causing hypoacetylation of associated nucleosomal histones. However, the identification of SIRT1-specific DNA targets that confer chromosomal stability and cell longevity have remained elusive. Here, we report the usefulness of a ChIP-cloning approach for the identification of an endogenous DNA target intimately linked with SIRT1 activity. Using the aforementioned technique, we identified a gene encoding the neuro-oncological ventral antigen2 (nova2) as a SIRT1 target. Nova2 regulates the alternative splicing of scn1a, which encodes the alpha-subunit of a neuronal sodium channel targeted by antiepileptic drugs. This finding demonstrates that ChIP-cloning is an innovative approach for the identification of SIRT1-specific DNA targets.