Myocardial glycophagy flux dysregulation and glycogen accumulation characterize diabetic cardiomyopathy.

Diabetic heart disease morbidity and mortality is escalating. No specific therapeutics exist and mechanistic understanding of diabetic cardiomyopathy etiology is lacking. While lipid accumulation is a recognized cardiomyocyte phenotype of diabetes, less is known about glycolytic fuel handling and storage.

Transmembrane α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor regulatory protein expression during the development of absence seizures in genetic absence epilepsy rats from Strasbourg.

The transmembrane α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) regulatory proteins (TARPs), γ2 (stargazin), γ3, γ4, γ5, γ7, and γ8, are a family of proteins that regulate AMPAR trafficking, expression, and biophysical properties that could have a role in the development of absence seizures. Here, we evaluated the expression of TARPs and AMPARs across the development of epilepsy in the genetic absence epilepsy rats from Strasbourg (GAERS) model of idiopathic generalized epilepsy (IGE) with absence seizures. Pre-epileptic (7-day-old), early epileptic (6-week-old), and chronically epileptic (16-week-old) GAERS, and age-matched male nonepileptic control rats (NEC) were used.

Integrative genomics reveals pathogenic mediator of valproate-induced neurodevelopmental disability.

Prenatal exposure to the anti-seizure medication sodium valproate (VPA) is associated with an increased risk of adverse postnatal neurodevelopmental outcomes, including lowered intellectual ability, autism spectrum disorder and attention-deficit hyperactivity disorder. In this study, we aimed to clarify the molecular mechanisms underpinning the neurodevelopmental consequences of gestational VPA exposure using integrative genomics. We assessed the effect of gestational VPA on foetal brain gene expression using a validated rat model of valproate teratogenicity that mimics the human scenario of chronic oral valproate treatment during pregnancy at doses that are therapeutically relevant to the treatment of epilepsy.

Altered cardiac structure and function is related to seizure frequency in a rat model of chronic acquired temporal lobe epilepsy.

Objective: This study aimed to prospectively examine cardiac structure and function in the kainic acid-induced post-status epilepticus (post-KA SE) model of chronic acquired temporal lobe epilepsy (TLE), specifically to examine for changes between the pre-epileptic, early epileptogenesis and the chronic epilepsy stages. We also aimed to examine whether any changes related to the seizure frequency in individual animals.

Methods: Four hours of SE was induced in 9 male Wistar rats at 10 weeks of age, with 8 saline treated matched control rats.

Inhibition of purinergic P2X receptor 7 (P2X7R) decreases granulocyte-macrophage colony-stimulating factor (GM-CSF) expression in U251 glioblastoma cells.

Glioblastoma is the most aggressive form of primary brain cancer, with a median survival of 12-15 months. The P2X receptor 7 (P2X7R) is upregulated in glioblastoma and is associated with increased tumor cell proliferation. The cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) is also upregulated in glioblastoma and has been shown to have both pro- and anti-tumor functions.

Improving mammography access for women with disabilities: Outcomes of the CDC's right to know campaign.

Women with disabilities share similar risks for breast cancer as other women yet experience a lack of access to cancer screening and are less likely to receive screening mammograms in accordance with recommended guidelines. The present study evaluated mammography centers across the state of Montana in response to the Centers for Disease Control and Prevention's Right to Know campaign, which focused on addressing barriers to breast cancer screening. Mammography centers were originally evaluated in 2009 and were reassessed in 2011 and 2015 after being given action plans to address accessibility barriers.

A rat model of valproate teratogenicity from chronic oral treatment during pregnancy.

Objective: Sodium valproate (VPA), the most effective antiepileptic drug for patients with genetic generalized epilepsy (GGE), is a potent human teratogen that increases the risk of a range of congenital malformations, including spina bifida. The mechanisms underlying this teratogenicity are not known, but may involve genetic risk factors. This study aimed to develop an animal model of VPA-induced birth defects.

An extraordinary Karenia mikimotoi "beer tide" in Kachemak Bay Alaska.

In autumn of 2013 an immense dinoflagellate bloom developed in Kachemak Bay, AK, USA. Much of the Bay was discolored a dark amber color and raised public concerns as small scale fish kills were reported in a few locations. Light microscopy revealed a monospecific bloom of gymnodinoid dinoflagellates that were previously unknown from the Bay.

Validation of reference genes for gene expression analysis following experimental traumatic brain injury in a pediatric mouse model.

Quantitative polymerase chain reaction (qPCR) is the gold standard method in targeted analysis of messenger RNA (mRNA) levels in a tissue. To minimize methodological errors, a reference gene (or a combination of reference genes) is routinely used for normalization to account for technical variables such as RNA quality and sample size. While presumed to have stable expression, reference genes in the brain can change during normal development, as well as in response to injury, such as traumatic brain injury (TBI).

The effects of cell therapy on seizures in animal models of epilepsy: protocol for systematic review and meta-analysis of preclinical studies.

Background: Epilepsy is one of the most common and serious brain conditions, characterised by recurrent unprovoked seizures. It affects about 1% of the population worldwide. Despite a range of antiepileptic drugs being available, one third of the patients do not achieve adequate seizure control.

An animal model of genetic predisposition to develop acquired epileptogenesis: The FAST and SLOW rats.

Epidemiological data and gene association studies suggest a genetic predisposition to developing epilepsy after an acquired brain insult, such as traumatic brain injury. An improved understanding of genetic determinants of vulnerability is imperative for early disease diagnosis and prognosis prediction, with flow-on benefits for the development of targeted antiepileptogenic treatments as well as optimal clinical trial design. In the laboratory, one approach to investigate why some individuals are more vulnerable to acquired epilepsy than others is to examine unique rodent models exhibiting either vulnerability or resistance to epileptogenesis.

Disease-modifying effects of a novel T-type calcium channel antagonist, Z944, in a model of temporal lobe epilepsy.

We evaluated whether pharmacologically targeting T-type Ca channels with Z944, a potent and selective antagonist, has disease-modifying effects in a model of temporal lobe epilepsy (TLE) that exhibits spontaneous recurrent seizures, and manifests behavioral and cognitive comorbidities commonly experienced by patients with this condition. Wistar rats underwent implantation of EEG electrodes and one week later 4 h of kainic acid-induced status epilepticus (SE). Animals were randomly assigned to one of 5 different groups: post-SE + Z944 (60 mg/kg/day, n = 8); post-SE + levetiracetam (200 mg/kg/day, n = 9); post-SE + vehicle (n = 8); sham + vehicle (n = 6) or sham + Z944 (60 mg/kg/day, n = 6).

Acquired cardiac channelopathies in epilepsy: Evidence, mechanisms, and clinical significance.

There is growing evidence that cardiac dysfunction in patients with chronic epilepsy could play a pathogenic role in sudden unexpected death in epilepsy (SUDEP). Recent animal studies have revealed that epilepsy secondarily alters the expression of cardiac ion channels alongside abnormal cardiac electrophysiology and remodeling. These molecular findings represent novel evidence for an acquired cardiac channelopathy in epilepsy, distinct from inherited ion channels mutations associated with cardiocerebral phenotypes.

Ca 3.2 T-type calcium channel mutation influences kindling-induced thalamic neuronal firing patterns in Genetic Absence Epilepsy Rats From Strasbourg.

Objective: Recent data indicate that amygdala kindling leads to significant changes in interictal neuronal firing patterns of thalamic reticular nucleus (TRN) neurons by decreasing the spontaneous firing rate and increasing burst firing in nonepileptic control (NEC) rats. Genetic Absence Epilepsy Rats From Strasbourg (GAERS) were resistant to these kindling-induced firing changes in TRN neurons, and are also resistant to the progression of kindling. We investigated whether a homozygous, missense, single nucleotide mutation (R1584P) in the Ca 3.

Environmental factors influencing the distribution and abundance of Alexandrium catenella in Kachemak bay and lower cook inlet, Alaska.

Despite the long history of paralytic shellfish poisoning (PSP) events in Alaska, little is known about the seasonal distribution and abundance of the causative organism, Alexandrium, or the environmental factors that govern toxic bloom development. To address this issue, a five year study (2012-2017) was undertaken in Kachemak Bay and lower Cook Inlet Alaska to determine how the occurrence of Alexandrium catenella, the dominant PSP-causing Alexandrium species, was influenced by temperature, salinity, nutrient concentrations, and other environmental factors. Cell concentrations from 572 surface water samples were estimated using quantitative PCR.

Ca 3.2 drives sustained burst-firing, which is critical for absence seizure propagation in reticular thalamic neurons.

Objective: Genetic alterations have been identified in the CACNA1H gene, encoding the Ca 3.2 T-type calcium channel in patients with absence epilepsy, yet the precise mechanisms relating to seizure propagation and spike-wave-discharge (SWD) pacemaking remain unknown. Neurons of the thalamic reticular nucleus (TRN) express high levels of Ca 3.

Gene therapy mediated seizure suppression in Genetic Generalised Epilepsy: Neuropeptide Y overexpression in a rat model.

Neuropeptide Y (NPY) is an important 36 amino acid peptide that is abundantly expressed in the mammalian CNS and is known to be an endogenous modulator of seizure activity, including in rat models of Genetic Generalised Epilepsy (GGE) with absence seizures. Studies have shown that viral-mediated "gene therapy" with overexpression of NPY in the hippocampus can suppress seizures in acquired epilepsy animal models. This study investigated whether NPY gene delivery to the thalamus or somatosensory cortex, using recombinant adeno-associated viral vector (rAAV), could produce sustained seizure suppression in the GAERS model of GGE with absence seizures.

Delayed myelination and neurodevelopment in male seizure-prone versus seizure-resistant rats.

Objective: Aberrant myelination and developmental delay have been reported in epilepsy. However, it is unclear whether these are linked to intrinsic mechanisms that support a predisposition toward seizures and the development of epilepsy. Thus, we compared rates of myelination and neurodevelopment in male rats selectively bred for enhanced susceptibility to kindling epileptogenesis (FAST) with male rats bred for resistance (SLOW).

Evaluating whole genome sequence data from the Genetic Absence Epilepsy Rat from Strasbourg and its related non-epileptic strain.

Objective: The Genetic Absence Epilepsy Rats from Strasbourg (GAERS) are an inbreed Wistar rat strain widely used as a model of genetic generalised epilepsy with absence seizures. As in humans, the genetic architecture that results in genetic generalized epilepsy in GAERS is poorly understood. Here we present the strain-specific variants found among the epileptic GAERS and their related Non-Epileptic Control (NEC) strain.

Differences in white matter structure between seizure prone (FAST) and seizure resistant (SLOW) rat strains.

Alterations in white matter integrity have been well documented in chronic epilepsy and during epileptogenesis. However, the relationship between white matter integrity and a predisposition towards epileptogenesis has been understudied. The FAST rat strain exhibit heightened susceptibility towards kindling epileptogenesis whereas SLOW rats are highly resistant.

Inhibition of microglial activation with minocycline at the intrathecal level attenuates sympathoexcitatory and proarrhythmogenic changes in rats with chronic temporal lobe epilepsy.

The incidence of sudden unexpected death in epilepsy (SUDEP) is highest in people with chronic and drug-resistant epilepsy. Chronic spontaneous recurrent seizures cause cardiorespiratory autonomic dysfunctions. Pituitary adenylate cyclase-activating polypeptide (PACAP) is neuroprotective, whereas microglia produce both pro- and anti-inflammatory effects in the CNS.

The pathophysiology of cardiac dysfunction in epilepsy.

Alterations in cardiac electrophysiology are an established consequence of long-standing drug resistant epilepsy. Patients with chronic epilepsy display abnormalities in both sinoatrial node pacemaker current as well as ventricular repolarizing current that places them at a greater risk of developing life-threatening cardiac arrhythmias. The development of cardiac arrhythmias secondary to drug resistant epilepsy is believed to be a key mechanism underlying the phenomenon of Sudden Unexpected Death in EPilepsy (SUDEP).

Interleukin-1β has trophic effects in microglia and its release is mediated by P2X7R pore.

Background: Enhanced expression of the purinergic P2X7 receptor (P2X7R) occurs in several neuroinflammatory conditions where increased microglial activation is a co-existing feature. P2X7 receptors can function either as a cation channel or, upon continued stimulation, a large pore. P2X7R-over-expression alone is sufficient to drive microglial activation and proliferation in a process that is P2X7R pore dependent, although the biological signaling pathway through which this occurs remains unclear.