A Two-Hit Approach Inducing Flurothyl Seizures in Fmr1 Knockout Mice Impacts Anxiety and Repetitive Behaviors.

Background: Fragile X Syndrome (FXS) is the leading monogenetic cause of autism spectrum disorder (ASD) and is associated with seizures. We examined the impact of repeated seizures on the behavioral and molecular changes in male Fmr1 knockout (KO) mice and wild-type (WT) mice.

Methods: Seizures were induced by administering three flurothyl seizures per day across postnatal days (PD) 7-11, for a total of 15 seizures.

Agomelatine Is Unable to Attenuate Kainic Acid-Induced Deficits in Early Life Communicative Behavior.

Early life seizures are associated with a variety of behavioral comorbidities. Among the most prevalent of these are deficits in communication. Auditory communicative behaviors in mice, known as ultrasonic vocalizations (USVs), can be used to assess potential treatments.

Neonatal immune stimulation results in sex-specific changes in ultrasonic vocalizations but does not affect seizure susceptibility in neonatal mice.

Neuroinflammation during the neonatal period has been linked to disorders such as autism and epilepsy. In this study, we investigated the early life behavioral consequences of a single injection of lipopolysaccharide (LPS) at postnatal day 10 (PD10) in mice. To assess deficits in communication, we performed the isolation-induced ultrasonic vocalizations (USVs) test at PD12.

Epilepsy and sudden unexpected death in epilepsy in a mouse model of human -linked developmental and epileptic encephalopathy.

Voltage-gated sodium channel β1 subunits are essential proteins that regulate excitability. They modulate sodium and potassium currents, function as cell adhesion molecules and regulate gene transcription following regulated intramembrane proteolysis. Biallelic pathogenic variants in , encoding β1, are linked to developmental and epileptic encephalopathy 52, with clinical features overlapping Dravet syndrome.

Antisense oligonucleotides restore excitability, GABA signalling and sodium current density in a Dravet syndrome model.

Dravet syndrome is an intractable developmental and epileptic encephalopathy caused by de novo variants in SCN1A resulting in haploinsufficiency of the voltage-gated sodium channel Nav1.1. We showed previously that administration of the antisense oligonucleotide STK-001, also called ASO-22, generated using targeted augmentation of nuclear gene output technology to prevent inclusion of the nonsense-mediated decay, or poison, exon 20N in human SCN1A, increased productive Scn1a transcript and Nav1.

Lipopolysaccharide-induced sickness behavior is not altered in male Fmr1-deficient mice.

Objectives: Fragile X syndrome is the main monogenetic cause of intellectual disability and autism. Alterations in the immune system are commonly found in these developmental disorders. We and others have demonstrated that Fmr1 mutant mice present an altered response to immune stimuli.

Prevalence of gastrointestinal malignancy in non-anemic iron deficiency and significance for endoscopic screening: A Western Australian multicenter cohort study.

Background And Aim: There is a paucity of evidence regarding non-anemic iron deficiency as a predictor for colorectal cancer and therefore the indication for endoscopic evaluation. This study explores the rates of malignancy in adults with iron deficiency with and without anemia.

Methods: A retrospective multicenter diagnostic cohort study was conducted across two Australian health services.

Vitamin D supplementation positively affects activity but impairs stimulus response behavior in an age and sex specific manner in C57BL/6 mice.

Several studies have begun to demonstrate the possible cognitive and physiological benefits of a fortified vitamin D diet. However, the behavioral effects of a high vitamin D fortified diet during adolescence has not been fully explored. In the present study, a 4-week vitamin D fortified diet (20,000 IU/Kg) compared to controls (1500 IU/Kg) was administered during the juvenile (4 weeks old) or early adult period (8 weeks old) in C57BL/6 J mice to investigate the effects of fortification on cognition, behavior, and their bone phenotype.

Therapeutic Potential of Targeting Regulated Intramembrane Proteolysis Mechanisms of Voltage-Gated Ion Channel Subunits and Cell Adhesion Molecules.

Several integral membrane proteins undergo regulated intramembrane proteolysis (RIP), a tightly controlled process through which cells transmit information across and between intracellular compartments. RIP generates biologically active peptides by a series of proteolytic cleavage events carried out by two primary groups of enzymes: sheddases and intramembrane-cleaving proteases (iCLiPs). Following RIP, fragments of both pore-forming and non-pore-forming ion channel subunits, as well as immunoglobulin super family (IgSF) members, have been shown to translocate to the nucleus to function in transcriptional regulation.

Subcellular dynamics and functional activity of the cleaved intracellular domain of the Na channel β1 subunit.

The voltage-gated Na channel β1 subunit, encoded by SCN1B, regulates cell surface expression and gating of α subunits and participates in cell adhesion. β1 is cleaved by α/β and γ-secretases, releasing an extracellular domain and intracellular domain (ICD), respectively. Abnormal SCN1B expression/function is linked to pathologies including epilepsy, cardiac arrhythmia, and cancer.

Neonatal Scn1b-null mice have sinoatrial node dysfunction, altered atrial structure, and atrial fibrillation.

Loss-of-function (LOF) variants in SCN1B, encoding the voltage-gated sodium channel β1/β1B subunits, are linked to neurological and cardiovascular diseases. Scn1b-null mice have spontaneous seizures and ventricular arrhythmias and die by approximately 21 days after birth. β1/β1B Subunits play critical roles in regulating the excitability of ventricular cardiomyocytes and maintaining ventricular rhythmicity.

Multiple Early-Life Seizures Alters Neonatal Communicative Behavior in Fmr1 Knockout Mice.

Fragile X syndrome (FXS) is the leading monogenic cause of intellectual disability and a significant contributor to Autism Spectrum Disorder. Individuals with FXS are subject to developing numerous comorbidities, one of the most prevalent being seizures. In the present study, we investigated how seizures affected neonatal communicative behavior in the FXS mouse model.

The awareness and usage of orthodontic apps and social media by orthodontists in the UK: A questionnaire-based study.

Objective: To assess the awareness and usage of mobile apps and social media among orthodontic clinicians to support patients with orthodontic treatment, support the professional development of orthodontists, and identify any relevant apps and social media platforms currently recommended to patients.

Design: Cross-sectional questionnaire-based study.

Setting: United Kingdom.

Development of a checklist to assess COVID-19 information on orthodontic webpages.

Objective: To create a COVID-19 information checklist and critique all available webpages of hospitals with an orthodontic department in England.

Design: Cross-sectional analysis.

Setting: World Wide Web.

A flurothyl-induced seizure does not disrupt hippocampal memory reconsolidation in C57BL/6Â J mice.

Memory deficits are a prevalent and pervasive comorbidity of epilepsy that significantly decrease an individual's quality of life. Numerous studies have investigated the effects of a seizure on the encoding process of memory; however, few studies have assessed the effect of a seizure on the reconsolidation process of memory. We investigated how a single seizure affects memory reconsolidation in C57BL/6 J adult mice using a predominately hippocampal-dependent paradigm.

Dietary rescue of adult behavioral deficits in the Fmr1 knockout mouse.

The current study aimed to further address important questions regarding the therapeutic efficacy of omega-3 fatty acids for various behavioral and neuroimmune aspects of the Fmr1 phenotype. To address these questions, our experimental design utilized two different omega-3 fatty acid administration timepoints, compared to both standard laboratory chow controls ("Standard") and a diet controlling for the increase in fat content ("Control Fat"). In the first paradigm, post-weaning supplementation (after postnatal day 21) with the omega-3 fatty acid diet ("Omega-3") reversed deficits in startle threshold, but not deficits in prepulse inhibition, and the effect on startle threshold was not specific to the Omega-3 diet.

Novel lysine-specific histone demethylase 1 inhibitor in acute myeloid leukaemia transformed from essential thrombocythaemia.

Background: While progress continues in the understanding of molecular abnormalities in acute myeloid leukaemia (AML), with some specific targeted therapies now available, it remains commonly fatal in the elderly. Leukaemic evolution and transformation from myeloproliferative neoplasms (MPN) may be associated with increased numbers of mutations in the genes associated with myeloid neoplasm and the prognosis in such patients is invariably dismal. Targeting of intracellular enzymes associated with integral cellular function has advanced understanding and promises improvements in treatments.

A vitamin D enriched diet attenuates sex-specific behavioral deficits, increases the lifespan, but does not rescue bone abnormalities in a mouse model of cortical dysplasia.

Individuals who experience recurrent spontaneous seizures often show behavioral and physiological comorbidities. Those with epilepsy are at a high risk of bone fractures (independent of seizure-related falls) and show a higher rate of a diagnosis of Autism Spectrum Disorder. The neural subset-specific (NS) Pten knockout (KO) mouse has an epilepsy phenotype, has been characterized to show autistic-like deficits, and has an osteoporosis phenotype.

Rapamycin, but not minocycline, significantly alters ultrasonic vocalization behavior in C57BL/6J pups in a flurothyl seizure model.

Epilepsy is one of the most common neurological disorders, with individuals having an increased susceptibility of seizures in the first few years of life, making children at risk of developing a multitude of cognitive and behavioral comorbidities throughout development. The present study examined the role of PI3K/Akt/mTOR pathway activity and neuroinflammatory signaling in the development of autistic-like behavior following seizures in the neonatal period. Male and female C57BL/6J mice were administered 3 flurothyl seizures on postnatal (PD) 10, followed by administration of minocycline, the mTOR inhibitor rapamycin, or a combined treatment of both therapeutics.

Sodium channel β1 subunits participate in regulated intramembrane proteolysis-excitation coupling.

Loss-of-function (LOF) variants in SCN1B, encoding voltage-gated sodium channel β1 subunits, are linked to human diseases with high risk of sudden death, including developmental and epileptic encephalopathy and cardiac arrhythmia. β1 Subunits modulate the cell-surface localization, gating, and kinetics of sodium channel pore-forming α subunits. They also participate in cell-cell and cell-matrix adhesion, resulting in intracellular signal transduction, promotion of cell migration, calcium handling, and regulation of cell morphology.

Prenatal High-Fat Diet Rescues Communication Deficits in Fmr1 Mutant Mice in a Sex-Specific Manner.

Using high-throughput analysis methods, the present study sought to determine the impact of prenatal high-fat dietary manipulations on isolation-induced ultrasonic vocalization production in both male and female Fmr1mutants on postnatal day 9. Prior to breeding, male FVB/129 Fmr1 wildtype and female Fmr1 heterozygous breeding pairs were assigned to 1 of 3 diet conditions: standard lab chow, omega-3 fatty acid-enriched chow, and a diet controlling for the fat increase. Prenatal exposure to omega-3 fatty acids improved reductions in the number of calls produced by Fmr1heterozygotes females.

Increased expression of Fragile X mental retardation protein in malformative lesions of patients with focal cortical dysplasia.

Objective: Focal cortical dysplasia (FCD) accounts for nearly half of all cases of medically refractory epilepsy in the pediatric and adult patient populations. This neurological disorder stems from localized malformations in cortical brain tissue due to impaired neuronal proliferation, differentiation, and migration patterns. Recent studies in animal models have highlighted the potential role of the Fragile X mental retardation protein (FMRP) levels in FCD.

A single episode of early-life status epilepticus impacts neonatal ultrasonic vocalization behavior in the Fmr1 knockout mouse.

Fragile X syndrome (FXS) is a genetic disorder caused by a trinucleotide (CGG) expansion mutation in the Fmr1 gene located on the X chromosome. It is characterized by hyperactivity, increased anxiety, repetitive-stereotyped behaviors, and impaired language development. Many children diagnosed with FXS also experience seizures during their lifetime.

An incidental dense bone island: A review of potential medical and orthodontic implications of dense bone islands and case report.

Dense bone islands (DBIs) are usually asymptomatic and do not require any treatment. This case report presents a DBI of an unusual presentation, which was an incidental finding on a radiograph of a 15-year-old orthodontic patient. The DBI lesion was 24 mm in size, occupying at least 50% of the alveolar process between the upper right canine and lateral incisor, extending up the lateral aspect of the anterior margin of the right nasal fossa.

Therapeutic role of targeting mTOR signaling and neuroinflammation in epilepsy.

Existing therapies for epilepsy are primarily symptomatic and target mechanisms of neuronal transmission in order to restore the excitatory/inhibitory imbalance in the brain after seizures. However, approximately one third of individuals with epilepsy have medically refractory epilepsy and do not respond to available treatments. There is a critical need for the development of therapeutics that extend beyond manipulation of excitatory neurotransmission and target pathological changes underlying the cause of the disease.