Addressing cortex dysregulation in youth through brain health check coaching and prophylactic brain development.

The Carter Center has estimated that the addiction crisis in the United States (US), if continues to worsen at the same rate, may cost the country approximately 16 trillion dollars by 2030. In recent years, the well-being of youth has been compromised by not only the coronavirus disease 2019 pandemic but also the alarming global opioid crisis, particularly in the US. Each year, deadly opioid drugs claim hundreds of thousands of lives, contributing to an ever-rising death toll. In addition, maternal usage of opioids and other drugs during pregnancy could compromise the neurodevelopment of children. A high rate of DNA polymorphic antecedents compounds the occurrence of epigenetic insults involving methylation of specific essential genes related to normal brain function. These genetic antecedent insults affect healthy DNA and mRNA transcription, leading to a loss of proteins required for normal brain development and function in youth. Myelination in the frontal cortex, a process known to extend until the late 20s, delays the development of proficient executive function and decision-making abilities. Understanding this delay in brain development, along with the presence of potential high-risk antecedent polymorphic variants or alleles and generational epigenetics, provides a clear rationale for embracing the Brain Research Commission's suggestion to mimic fitness programs with an adaptable brain health check (BHC). Implementing the BHC within the educational systems in the US and other countries could serve as an effective initiative for proactive therapies aimed at reducing juvenile mental health problems and eventually criminal activities, addiction, and other behaviors associated with reward deficiency syndrome.

Identification of stress-induced epigenetic methylation onto dopamine D2 gene and neurological and behavioral consequences.

The D2 dopamine receptor (DRD2) gene has garnered substantial attention as one of the most extensively studied genes across various neuropsychiatric disorders. Since its initial association with severe alcoholism in 1990, particularly through the identification of the DRD2 Taq A1 allele, numerous international investigations have been conducted to elucidate its role in different conditions. As of February 22, 2024, there are 5485 articles focusing on the DRD2 gene listed in PUBMED. There have been 120 meta-analyses with mixed results. In our opinion, the primary cause of negative reports regarding the association of various DRD2 gene polymorphisms is the inadequate screening of controls, not adequately eliminating many hidden reward deficiency syndrome behaviors. Moreover, pleiotropic effects of DRD2 variants have been identified in neuropsychologic, neurophysiologic, stress response, social stress defeat, maternal deprivation, and gambling disorder, with epigenetic DNA methylation and histone post-translational negative methylation identified as discussed in this article. There are 70 articles listed in PUBMED for DNA methylation and 20 articles listed for histone methylation as of October 19, 2022. For this commentary, we did not denote DNA and/or histone methylation; instead, we provided a brief summary based on behavioral effects. Based on the fact that Blum and Noble characterized the DRD2 Taq A1 allele as a generalized reward gene and not necessarily specific alcoholism, it now behooves the field to find ways to either use effector moieties to edit the neuroepigenetic insults or possibly harness the idea of potentially removing negative mRNA-reduced expression by inducing "dopamine homeostasis."

Psychostimulants for Children: Are We Over or Under Dosing?

An estimated 3% to 10% of school children meet the DSM-V criteria for ADHD (Attention-Deficit/Hyperactivity Disorder), however, to be over-diagnosed, the rate of children inappropriately diagnosed with ADHD (false positives) would have to be larger than the number of children with ADHD who are under-identified and not diagnosed (false negatives). Accordingly, a number of investigators take the position that under-treatment with psychostimulants, especially in children and adolescence, will result in continued ADHD symptomatology including future Substance Use Disorder (SUD). However, other researchers and clinicians believe otherwise and espouse laudable arguments for caution and prolonged methamphetamine treatment. While there is ongoing controversy of the role of genetics and epigenetics linked to ADHD, it seems clear that a number of dopaminergic genes and their risk polymorphisms act as DNA antecedents impacted by epigenetic induced methylation. Our hypothesis and literature review suggest that one possible solution is to embrace non addictive interventions to induce global dopamine homeostasis.

Use of Biolayer Interferometry to Identify Dominant Binding Epitopes of Influenza Hemagglutinin Protein of A(H1N1)pdm09 in the Antibody Response to 2010-2011 Influenza Seasonal Vaccine.

The globular head domain of influenza virus surface protein hemagglutinin (HA1) is the major target of neutralizing antibodies elicited by vaccines. As little as one amino acid substitution in the HA1 can result in an antigenic drift of influenza viruses, indicating the dominance of some epitopes in the binding of HA to polyclonal serum antibodies. Therefore, identifying dominant binding epitopes of HA is critical for selecting seasonal influenza vaccine viruses. In this study, we have developed a biolayer interferometry (BLI)-based assay to determine dominant binding epitopes of the HA1 in antibody response to influenza vaccines using a panel of recombinant HA1 proteins of A(H1N1)pdm09 virus with each carrying a single amino acid substitution. Sera from individuals vaccinated with the 2010-2011 influenza trivalent vaccines were analyzed for their binding to the HA1 panel and hemagglutination inhibition (HI) activity against influenza viruses with cognate mutations. Results revealed an over 50% reduction in the BLI binding of several mutated HA1 compared to the wild type and a strong correlation between dominant residues identified by the BLI and HI assays. Our study demonstrates a method to systemically analyze antibody immunodominance in the humoral response to influenza vaccines.

Futuristic Thinking about Engineering "Geneospirituality" to Help Prevent Relapse of Reward Deficiency Syndrome (RDS) Behaviors.

It is with a saddened heart that we are dedicating this article to the loving memory of our dear departed friend and associate B. William Downs. Bill was well known in the nutritional space worldwide for his major contributions to the health and welfare of millions around the globe. The founder of Victory Nutrition International (VNI) in conjunction with Kim Downs, as well as so many contributions to scientific literature, to those that knew him personally will forever be touched. Bill was a highly spirited human with a never ending love for caring and helping so many individuals. To know Bill is to walk in the face of a music lover playing drums, trained as a martial artist, and riding through the winds of a Beamer driven by an iconic man driven to victory. Our hearts may be saddened but Bills spirit to those that know him will be forever. In this article we discuss and review some potential futuristic concepts and technological advancements in terms of geneospirituality engineering to help prevent relapse and or even protect against an unwanted predisposition to RDS behaviors. Futuristic development may contribute to an attenuation of both DNA antecedents as well as epigenetic reward system insults leading to unwanted substance and non-substance addictive behaviors.

Use of Integrative, Complementary, and Alternative Medicine in Children with Epilepsy: A Global Scoping Review.

(1) Background: Epilepsy is one of the most common chronic neurological disorders in childhood. Complementary and alternative medicine (CAM) use is highly prevalent in patients with epilepsy. Despite CAM's widespread and increasing popularity, its prevalence, forms, perceived benefits, and potential risks in pediatric epilepsy are rarely explored. (2) Methods: We performed a scoping review of the available literature on the use of CAM in pediatric epilepsy. (3) Results: Overall, global cross-sectional studies showed a variable degree of CAM usage among children with epilepsy, ranging from 13 to 44% in prevalence. Popular types of CAMs reported were supplements, cannabis products, aromatherapy, herbal remedies, dietary therapy, massage therapy, and prayer. Families often report that CAM is effective, although there are limited objective measures of this. Potential risks lie in the use of CAM, such as herbal remedies, and/or unregulated, contaminated, or unpurified products. Studies also underscored inadequate patient-physician discussions regarding CAM. (4) Conclusions: A better understanding of this topic would aid clinicians in guiding patients/families on the use of CAM. Further studies on the efficacy of the different types of CAM used, as well as potential side effects and drug interactions are needed.

Elsberg Syndrome with Mixed Presentation as Meningitis Retention Syndrome: A Pediatric Case Report and Comprehensive Review of the Literature.

Elsberg syndrome is a typically infectious syndrome that may cause acute or subacute bilateral lumbosacral radiculitis and sometimes lower spinal cord myelitis. Patients often present with various neurological symptoms involving the lower extremities, including numbness, weakness, and urinary disturbances such as retention. A 9-year-old girl with no significant past medical history presented with altered mental status, fever, urinary retention, and anuria and was found to have encephalomyelitis. An extensive diagnostic workup led to ruling out possible etiologies until identifying Elsberg syndrome. In this report, we describe a case of Elsberg syndrome caused by West Nile virus (WNV). To the best of our knowledge, this is the first reported case of its kind in the pediatric population. Utilizing PubMed and Web of Science databases, we reviewed the literature to describe the neurogenic control of the urinary system in correlation to a multitude of neurologic pathologies.

Thrombectomy of an Acute Ischemic Stroke in a Child with COVID-19 and MIS-C: Case Analysis and Literature Context.

We describe a very young child who developed an acute ischemic stroke from a LAO, while affected by COVID-19 and MIS-C, and whom we treated successfully with thrombectomy. We compare his clinical and imaging findings with those of the existing case reports, and we explore the multifactorial nature of such a neurovascular complication, particularly in the context of the most recent publications regarding the multifactorial endothelial derangements produced by the illness.

SYT1-Associated Neurodevelopmental Disorder: A Narrative Review.

Synaptic dysregulations often result in damaging effects on the central nervous system, resulting in a wide range of brain and neurodevelopment disorders that are caused by mutations disrupting synaptic proteins. SYT1, an identified synaptotagmin protein, plays an essential role in mediating the release of calcium-triggered neurotransmitters (NT) involved in regular synaptic vesicle exocytosis. Considering the significant role of SYT1 in the physiology of synaptic neurotransmission, dysfunction and degeneration of this protein can result in a severe neurological impairment. Genetic variants lead to a newly discovered rare disorder, known as SYT1-associated neurodevelopment disorder. In this review, we will discuss in depth the function of SYT1 in synapse and the underlying molecular mechanisms. We will highlight the genetic basis of SYT1-associated neurodevelopmental disorder along with known phenotypes, with possible interventions and direction of research.

SCN1B Genetic Variants: A Review of the Spectrum of Clinical Phenotypes and a Report of Early Myoclonic Encephalopathy.

Background: Pathogenic variants in SCN1B, the gene encoding voltage-gated sodium channel b1/b1B subunits are associated with a spectrum of epileptic disorders. This study describes a child with early myoclonic encephalopathy and a compound heterozygous variant in the SCN1B gene (p.Arg85Cys and c.3G>C/p.Met1), along with the child's clinical response to anti-seizure medications (ASMs) and the ketogenic diet. We reviewed the current clinical literature pertinent to SCN1B-related epilepsy. Methods: We described the evaluation and management of a patient with SCN1B-related developmental and epileptic encephalopathy (DEE). We used the Medline and Pubmed databases to review the various neurological manifestations associated with SCN1B genetic variants, and summarize the functional studies performed on SCN1B variants. Results: We identified 20 families and six individuals (including the index case described herein) reported to have SCN1B-related epilepsy. Individuals with monoallelic pathogenic variants in SCN1B often present with genetic epilepsy with febrile seizures plus (GEFS+), while those with biallelic pathogenic variants may present with developmental and epileptic encephalopathy (DEE). Individuals with DEE present with seizures of various semiologies (commonly myoclonic seizures) and status epilepticus at early infancy and are treated with various antiseizure medications. In our index case, adjunctive fenfluramine was started at 8 months of age at 0.2 mg/kg/day with gradual incremental increases to the final dose of 0.7 mg/kg/day over 5 weeks. Fenfluramine was effective in the treatment of seizures, resulting in a 50% reduction in myoclonic seizures, status epilepticus, and generalized tonic-clonic seizures, as well as a 70−90% reduction in focal seizures, with no significant adverse effects. Following the initiation of fenfluramine at eight months of age, there was also a 50% reduction in the rate of hospitalizations. Conclusions: SCN1B pathogenic variants cause epilepsy and neurodevelopmental impairment with variable expressivity and incomplete penetrance. The severity of disease is associated with the zygosity of the pathogenic variants. Biallelic variants in SCN1B can result in early myoclonic encephalopathy, and adjunctive treatment with fenfluramine may be an effective treatment for SCN1B-related DEE. Further research on the efficacy and safety of using newer ASMs, such as fenfluramine in patients under the age of 2 years is needed.

A Review of the Multi-Systemic Complications of a Ketogenic Diet in Children and Infants with Epilepsy.

Ketogenic diets (KDs) are highly effective in the treatment of epilepsy. However, numerous complications have been reported. During the initiation phase of the diet, common side effects include vomiting, hypoglycemia, metabolic acidosis and refusal of the diet. While on the diet, the side effects involve the following systems: gastrointestinal, hepatic, cardiovascular, renal, dermatological, hematologic and bone. Many of the common side effects can be tackled easily with careful monitoring including blood counts, liver enzymes, renal function tests, urinalysis, vitamin levels, mineral levels, lipid profiles, and serum carnitine levels. Some rare and serious side effects reported in the literature include pancreatitis, protein-losing enteropathy, prolonged QT interval, cardiomyopathy and changes in the basal ganglia. These serious complications may need more advanced work-up and immediate cessation of the diet. With appropriate monitoring and close follow-up to minimize adverse effects, KDs can be effective for patients with intractable epilepsy.

Multiplex Detection of Antibody Landscapes to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)/Influenza/Common Human Coronaviruses Following Vaccination or Infection With SARS-CoV-2 and Influenza.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and influenza viruses continue to co-circulate, representing 2 major public health threats from respiratory infections with similar clinical presentations. SARS-CoV-2 and influenza vaccines can also now be co-administered. However, data on antibody responses to SARS-CoV-2 and influenza coinfection and vaccine co-administration remain limited. METHODS: We developed a 41-plex antibody immunity assay that can simultaneously characterize antibody landscapes to SARS-CoV-2/influenza/common human coronaviruses. We analyzed sera from 840 individuals (11-93 years), including sera from reverse transcription-polymerase chain reaction (RT-PCR)-confirmed SARS-CoV-2-positive (n = 218) and -negative (n = 120) cases, paired sera from SARS-CoV-2 vaccination (n = 29) and infection (n = 11), and paired sera from influenza vaccination (n = 56) and RT-PCR-confirmed influenza infection (n = 158) cases. Last, we analyzed sera collected from 377 individuals who exhibited acute respiratory illness (ARI) in 2020. RESULTS: This 41-plex assay has high sensitivity and specificity in detecting SARS-CoV-2 infections. It differentiated SARS-CoV-2 vaccination (antibody responses only to spike protein) from infection (antibody responses to both spike and nucleoprotein). No cross-reactive antibodies were induced to SARS-CoV-2 from influenza vaccination and infection, and vice versa, suggesting no interaction between SARS-CoV-2 and influenza antibody responses. However, cross-reactive antibodies were detected between spike proteins of SARS-CoV-2 and common human coronaviruses that were removed by serum adsorption. Among 377 individuals who exhibited ARI in 2020, 129 were influenza positive; none had serological evidence of SARS-CoV-2/influenza coinfections. CONCLUSIONS: Multiplex detection of antibody landscapes can provide in-depth analysis of the antibody protective immunity to SARS-CoV-2 in the context of other respiratory viruses, including influenza.

A review of fenfluramine for the treatment of Dravet syndrome patients.

INTRODUCTION: Dravet Syndrome (DS) is a rare epileptiform disorder typically presenting within the first year of life of a normally developing infant. It is characterized by several prolonged seizures that are often resistant to current anti-epileptic drug (AED) regimens. This paper outlines the history and clinical trials of the drug fenfluramine, a drug that when used in addition to AED regimens may provide hope to children affected by DS. BODY: Fenfluramine (3-trifulormethyl-N-ethylamphetamine) is an amphetamine derivative that primarily affects serotonin neurotransmitter levels. It was initially prescribed in the 1960s as an appetite suppressant marketed as a weight loss drug. However, it was removed from the markets due to its association with cardiac valvopathies. It continued to by studied in epilepsy by Gastaut in the 1980s in children with self-induced syncope and irretractable epilepsy. In 2012, Ceulemans et al. studied the use of fenfluramine in patients with DS. Following the success of that retrospective case study, Nabbout et al. and Legae et al. conducted two randomized control trials leading to the FDA approval of fenfluramine under its trade name Fintepla in 2020. DISCUSSION: The success of the randomized control trials suggests the addition of fenfluramine to current AED regimens may lead to better control of seizures in patients with DS. The side effects of fenfluramine prove to be manageable and the concern for valvopathies has not been reproducible with low dose fenfluramine.

Cannabidiol - A new fixture in childhood neurology.

This invited opinion article reviews current uses and controversies in vernacular and pharmacological cannabidiol use in pediatric neurologic disorders. Since the recent emergence of cannabidiol availability to the general public and recent Food and Drug Administration approval, it is important to highlight and expand understanding about CBD mechanism of action, long-term use, safety, and indications in children with neurological disorders.

Seizure frequency, quality of life, behavior, cognition, and sleep in pediatric patients enrolled in a prospective, open-label clinical study with cannabidiol.

OBJECTIVE: To evaluate the effects of oral pharmacological cannabidiol (CBD) on seizures, side effects, quality of life, behavior, mood, and sleep in children with drug-resistant epilepsy (DRE) during a phase II, prospective, open-label clinical study. METHODS: During a phase II expanded access program (EAP) study to evaluate the safety and efficacy of using cannabidiol (CBD) for the long-term treatment of children with drug-resistant epilepsy, secondary outcome measures were also performed, including quality of life (QOLCE), behavior (aberrant behavior checklist ABC), and sleep (children's sleep habit questionnaire, CSHQ). Participants between the ages of 2 and 16 years of age with drug-resistant epilepsy (n = 35) were included in this EAP. Primary outcomes included change in parent-recorded seizure frequency relative to baseline, as well as the safety and tolerability over the course of 24 months of CBD treatment. Secondary outcomes observed in the first 12 months included changes in child behavior, and cognitive function, and sleep quality. RESULTS: The median change in overall seizure frequency decreased from baseline (n = 33) by -61.3% ([n = 33], Inter Quartile Range (IQR): 43-88%) at month 3, -62.9% at month 6 ([n = 29], IQR: 48-92%), -74.7% at month 12 ([n = 29], IQR: 64-96%), and finally -83.7% ([n = 28], IQR: 68-100%) at the conclusion of 24 months of treatment. Seven (20%) of the 35 patients enrolled withdrew from treatment and observation by month 24: 2 failed inclusion criteria at baseline, 4 due to lack of treatment efficacy, and 1 was lost to follow-up. The 12-month recording of secondary measures revealed a significant improvement in Irritability (-39.4%, [n = 28], ABC), Hyperactivity (-45.4%, [n = 28], ABC), Cognition in Quality of Life (+14.2%, [n = 28], QOLCE), Behavioral function (+14.7%, [n = 28], QOLCE), General Health (+14.7%, [n = 28], QOLCE), Sleep duration (-33.9%, [n = 28], CSHQ), Daytime sleepiness (-23.8%, [n = 28], CSHQ), and nocturnal arousals (-36.2%, [n = 28], CSHQ). SIGNIFICANCE: The results of this phase II open-label study demonstrate that pharmacological CBD significantly reduces seizure frequency, and improves QOL, behavior deficits, and sleep disruption, in children with drug-resistant epilepsy. The results also suggest that CBD is efficacious in controlled seizures over a 2-year period in childhood DRE.

Psychoactive Drugs Like Cannabis -Induce Hypodopaminergic Anhedonia and Neuropsychological Dysfunction in Humans: Putative Induction of Dopamine Homeostasis via Coupling of Genetic Addiction Risk Severity (GARS) testing and Precision Pro-dopamine Regulation (KB220).

Many US states now embrace the medical and recreational use of Cannabis. Changes in the laws have heightened interest and encouraged research into both cannabinoid products and the potential harms of Cannabis use, addiction and intoxication. The major active ingredient of Cannabis sativa (marijuana), Δ9-tetrahydrocannabinol (THC) and it powerfully stimulates the type-1 cannabinoid (CB1) receptor. When used in the form of the plant marijuana, because of the many compounds that exist in the plant form they could inhibit the activity of the CB1 receptor thereby reducing many of the effects of THC. While this mechanism seems correct, in our opinion, Vallee., et al. incorrectly suggest that blocking CB1 receptors could open unforeseen approaches to the treatment of cannabis intoxication and addiction. We caution the scientific community that, other CB1 receptor blockers, such as, Rimonabant (SR141718) have been pulled off the market in Europe. In addition, CB1 receptor blockers were rejected by the FDA due to mood changes including suicide ideation. We argue that one issue facing the scientific community, has to do with the increasing legalization of Cannabis products in many states across America. We are in favor of some reform in terms of either decriminalization or restrictive legalization especially in control of legal limits of THC. Like other psychoactive compounds at high doses, it is our hypothesis that chronic use of these drugs including high THC content in its various forms (wax, smoke or vapor) resulting in brain reward dysfunction induces an imbalance of neurotransmission and subsequent hypodopaminergia and lead to aberrant substance and non-substance (behavioral) addictions. It is further proposed that in order to overcome THC and even other psychoactive drugs of abuse induced anhedonia the coupling of genetic risk testing and pro dopamine regulation is warranted.

Antibody Landscape Analysis following Influenza Vaccination and Natural Infection in Humans with a High-Throughput Multiplex Influenza Antibody Detection Assay.

To better understand the antibody landscape changes following influenza virus natural infection and vaccination, we developed a high-throughput multiplex influenza antibody detection assay (MIADA) containing 42 recombinant hemagglutinins (rHAs) (ectodomain and/or globular head domain) from pre-2009 A(H1N1), A(H1N1)pdm09, A(H2N2), A(H3N2), A(H5N1), A(H7N7), A(H7N9), A(H7N2), A(H9N2), A(H13N9), and influenza B viruses. Panels of ferret antisera, 227 paired human sera from vaccinees (children and adults) in 5 influenza seasons (2010 to 2018), and 17 paired human sera collected from real-time reverse transcription-PCR (rRT-PCR)-confirmed influenza A(H1N1)pdm09, influenza A(H3N2), or influenza B virus-infected adults were analyzed by the MIADA. Ferret antisera demonstrated clear strain-specific antibody responses to exposed subtype HA. Adults (19 to 49 years old) had broader antibody landscapes than young children (<3 years old) and older children (9 to 17 years old) both at baseline and post-vaccination. Influenza vaccination and infection induced the strongest antibody responses specific to HA(s) of exposed strain/subtype viruses and closely related strains; they also induced cross-reactive antibodies to an unexposed influenza virus subtype(s), including novel viruses. Subsequent serum adsorption confirmed that the cross-reactive antibodies against novel subtype HAs were mainly induced by exposures to A(H1N1)/A(H3N2) influenza A viruses. In contrast, adults infected by influenza B viruses mounted antibody responses mostly specific to two influenza B virus lineage HAs. Median fluorescence intensities (MFIs) and seroconversion in MIADA had good correlations with the titers and seroconversion measured by hemagglutination inhibition and microneutralization assays. Our study demonstrated that antibody landscape analysis by the MIADA can be used for influenza vaccine evaluations and characterization of influenza virus infections.IMPORTANCE Repeated influenza vaccination and natural infections generate complex immune profiles in humans that require antibody landscape analysis to assess immunity and evaluate vaccines. However, antibody landscape analyses are difficult to perform using traditional assays. Here, we developed a high-throughput, serum-sparing, multiplex influenza antibody detection assay (MIADA) and analyzed the antibody landscapes following influenza vaccination and infection. We showed that adults had broader antibody landscapes than children. Influenza vaccination and infection not only induced the strongest antibody responses to the hemagglutinins of the viruses of exposure, but also induced cross-reactive antibodies to novel influenza viruses that can be removed by serum adsorption. There is a good correlation between the median fluorescence intensity (MFI) measured by MIADA and hemagglutination inhibition/microneutralization titers. Antibody landscape analysis by the MIADA can be used in influenza vaccine evaluations, including the development of universal influenza vaccines and the characterization of influenza virus infections.

Channelopathy of Dravet Syndrome and Potential Neuroprotective Effects of Cannabidiol.

Dravet syndrome (DS) is a channelopathy, neurodevelopmental, epileptic encephalopathy characterized by seizures, developmental delay, and cognitive impairment that includes susceptibility to thermally induced seizures, spontaneous seizures, ataxia, circadian rhythm and sleep disorders, autistic-like behaviors, and premature death. More than 80% of DS cases are linked to mutations in genes which encode voltage-gated sodium channel subunits, SCN1A and SCN1B, which encode the Nav1.1α subunit and Nav1.1ß1 subunit, respectively. There are other gene mutations encoding potassium, calcium, and hyperpolarization-activated cyclic nucleotide-gated (HCN) channels related to DS. One-third of patients have pharmacoresistance epilepsy. DS is unresponsive to standard therapy. Cannabidiol (CBD), a non-psychoactive phytocannabinoid present in Cannabis, has been introduced for treating DS because of its anticonvulsant properties in animal models and humans, especially in pharmacoresistant patients. However, the etiological channelopathiological mechanism of DS and action mechanism of CBD on the channels are unclear. In this review, we summarize evidence of the direct and indirect action mechanism of sodium, potassium, calcium, and HCN channels in DS, especially sodium subunits. Some channels' loss-of-function or gain-of-function in inhibitory or excitatory neurons determine the balance of excitatory and inhibitory are associated with DS. A great variety of mechanisms of CBD anticonvulsant effects are focused on modulating these channels, especially sodium, calcium, and potassium channels, which will shed light on ionic channelopathy of DS and the precise molecular treatment of DS in the future.

Genetically and Antigenically Divergent Influenza A(H9N2) Viruses Exhibit Differential Replication and Transmission Phenotypes in Mammalian Models.

Low-pathogenicity avian influenza A(H9N2) viruses, enzootic in poultry populations in Asia, are associated with fewer confirmed human infections but higher rates of seropositivity compared to A(H5) or A(H7) subtype viruses. Cocirculation of A(H5) and A(H7) viruses leads to the generation of reassortant viruses bearing A(H9N2) internal genes with markers of mammalian adaptation, warranting continued surveillance in both avian and human populations. Here, we describe active surveillance efforts in live poultry markets in Vietnam in 2018 and compare representative viruses to G1 and Y280 lineage viruses that have infected humans. Receptor binding properties, pH thresholds for HA activation, in vitro replication in human respiratory tract cells, and in vivo mammalian pathogenicity and transmissibility were investigated. While A(H9N2) viruses from both poultry and humans exhibited features associated with mammalian adaptation, one human isolate from 2018, A/Anhui-Lujiang/39/2018, exhibited increased capacity for replication and transmission, demonstrating the pandemic potential of A(H9N2) viruses.IMPORTANCE A(H9N2) influenza viruses are widespread in poultry in many parts of the world and for over 20 years have sporadically jumped species barriers to cause human infection. As these viruses continue to diversify genetically and antigenically, it is critical to closely monitor viruses responsible for human infections, to ascertain if A(H9N2) viruses are acquiring properties that make them better suited to infect and spread among humans. In this study, we describe an active poultry surveillance system established in Vietnam to identify the scope of influenza viruses present in live bird markets and the threat they pose to human health. Assessment of a recent A(H9N2) virus isolated from an individual in China in 2018 is also reported, and it was found to exhibit properties of adaptation to humans and, importantly, it shows similarities to strains isolated from the live bird markets of Vietnam.