Striking and widespread microglial activation in the brains of Southdown lambs with type II glucocerebrosidosis (neuronopathic Gaucher disease).

Glucocerebrosidosis (termed Gaucher disease in humans) is a lysosomal storage disease, caused by a deficiency of the enzyme glucocerebrosidase, which results in accumulation of the glycolipid substrate glucocerebroside in the macrophage-monocyte system. Three principal forms are recognized in humans, two being neuronopathic and resulting in neurodegeneration. Only two spontaneously arising cases have been described in domestic animals, one in a dog and the other in a flock of Southdown sheep.

In Vivo Formation of Adrenal Organoids in a Novel Porcine Model of Adrenocortical Cell Transplantation.

Recognizing the limitations of current therapies for Addison's disease, novel treatments that replicate dynamic physiologic corticosteroid secretion, under control of ACTH, are required. The aim of these experiments was to evaluate the feasibility of adrenocortical cell transplantation (ACT) in a large animal model, adapting methods successfully used for intracutaneous pancreatic islet cell transplantation, using a fully biodegradable temporizing matrix. Autologous porcine ACT was undertaken by bilateral adrenalectomy, cell isolation, culture, and intracutaneous injection into a skin site preprepared using a biodegradable temporizing matrix (BTM) foam.

The role of orexin in Parkinson's disease.

Emerging evidence has implicated the orexin system in non-motor pathogenesis of Parkinson's disease. It has also been suggested the orexin system is involved in the modulation of motor control, further implicating the orexin system in Parkinson's disease. Parkinson's disease is the second most common neurodegenerative disease with millions of people suffering worldwide with motor and non-motor symptoms, significantly affecting their quality of life.

Avian riboflavin deficiency causes reliably reproducible peripheral nerve demyelination and, with vitamin supplementation, rapid remyelination.

Riboflavin deficiency produces severe peripheral neve demyelination in young, rapidly growing chickens. While this naturally-occurring vitamin B2 deficiency can cause a debilitating peripheral neuropathy, and mortality, in poultry flocks, it can also be a useful experimental animal model to study the pathogenesis of reliably reproducible peripheral nerve demyelination. Moreover, restitution of normal riboflavin levels in deficient birds results in brisk remyelination.

Targeting Acute Myeloid Leukemia Using Sphingosine Kinase 1 Inhibitor-Loaded Liposomes.

Acute myeloid leukemia (AML) kills 75% of patients and represents a major clinical challenge with a need to improve on current treatment approaches. Targeting sphingosine kinase 1 with a novel ATP-competitive-inhibitor, MP-A08, induces cell death in AML. However, limitations in MP-A08's "drug-like properties" (solubility, biodistribution, and potency) hinder its pathway to the clinic.

Haemostatic efficacy and inflammatory response of a novel beta-chitin patch in a cerebral small vessel injury model - A pilot study.

Objective: Rapid and efficacious haemostasis is paramount in neurosurgery. Assessing the efficacy and short- and long-term safety of haemostatic agents utilised within cerebral tissue is essential. This pilot study investigates the haemostatic efficacy and long-term safety of a novel beta-chitin patch against traditionally used agents, bipolar and Floseal, within cerebral tissue.

Colchicine exerts anti-atherosclerotic and -plaque-stabilizing effects targeting foam cell formation.

Colchicine is a broad-acting anti-inflammatory agent that has attracted interest for repurposing in atherosclerotic cardiovascular disease. Here, we studied its ability at a human equivalent dose of 0.5 mg/day to modify plaque formation and composition in murine atherosclerosis and investigated its actions on macrophage responses to atherogenic stimuli in vitro.

Red neurons in ovine polioencephalomalacia (cerebrocortical necrosis) are strongly amyloid precursor protein immunopositive.

The signature pathological feature of the pseudolaminar cerebrocortical necrosis found in polioencephalomalacia (PEM) of ruminants is the development of red (eosinophilic) neurons. These neurons are generally considered to be irredeemably injured but we have shown, for the first time, in ovine PEM cases, that most strongly express amyloid precursor protein (APP), which has a neuroprotective role in the brain. By contrast, neurons in unaffected cerebral cortices from control sheep were APP immunonegative.

Eukaryotic elongation factor 2 kinase regulates foam cell formation via translation of CD36.

Eukaryotic elongation factor 2 kinase (eEF2K) is an atypical protein kinase that controls protein synthesis in cells under stress. Although well studied in cancer, less is known about its roles in chronic inflammatory diseases. Here, we examined its regulation of macrophage cholesterol handling in the context of atherosclerosis.

Heterogeneous immunoreactivity of axonal spheroids in focal symmetrical encephalomalacia produced by type D epsilon toxin in sheep.

Since axonal injury (AI) is an important component of many veterinary neurologic disorders, we assessed the relative ability of a panel of antibodies (amyloid precursor protein, 3 subunits of neurofilament protein, protein gene product 9.5, ubiquitin, and synaptophysin) to detect axonal swellings or spheroids. Abundant axonal spheroids found in necrotic internal capsule foci produced in 4 sheep by chronic type D epsilon neurotoxicity provided a model system in which to evaluate this important diagnostic tool.

The susceptibility of the aortic root: porcine aortic rupture testing under cardiopulmonary bypass.

Background: In our earlier study on the functional limits of the aneurysmal aortic root we determined the pig root is susceptible to failure at high aortic pressures levels. We established a pig rupture model using cardiopulmonary bypass to determine the most susceptible region of the aortic root under the highest pressures achievable using continuous flow, and what changes occur in these regions on a macroscopic and histological level. This information may help guide clinical management of aortic root and ascending aorta pathology.

Reproduction-Associated Hormones and Adult Hippocampal Neurogenesis.

The levels of reproduction-associated hormones in females, such as estrogen, progesterone, prolactin, and oxytocin, change dramatically during pregnancy and postpartum. Reproduction-associated hormones can affect adult hippocampal neurogenesis (AHN), thereby regulating mothers' behavior after delivery. In this review, we first briefly introduce the overall functional significance of AHN and the methods commonly used to explore this front.

Expression of the Excitatory Postsynaptic Scaffolding Protein, Shank3, in Human Brain: Effect of Age and Alzheimer's Disease.

Shank3 is a postsynaptic scaffolding protein of excitatory synapses. Mutations or variations of are associated with various psychiatric and neurological disorders. We set to determine its normal expression pattern in the human brain, and its change, if any, with age and Alzheimer's disease (AD)-type β-amyloid (Aβ) and Tau pathogenesis.

Temporal Sequence of Post-Mortem Autolysis in the Mouse Retina.

In order to better differentiate ante-mortem lesions from post-mortem retinal autolysis, the temporal sequence of post-mortem changes was studied in a well-controlled mouse model. Mice were of the same strain, age and sex, and were held at a constant ambient temperature. Eyes were collected at various times up to 72 h after death and immersion-fixed in either Davidson's fixative or 10% neutral buffered formalin, paraffin-embedded and sections cut and stained with haematoxylin and eosin.

Histological regional analysis of the aortic root and thoracic ascending aorta: a complete analysis of aneurysms from root to arch.

Background: Although aortic root and ascending aortic aneurysms are treated the same, they differ in embryological development and pathological processes. This study examines the microscopic structural differences between aortic root and ascending aortic aneurysms, correlating these features to the macroscopic pathophysiological processes.

Methods: We obtained surgical samples from ascending aortic aneurysms (n = 11), aortic root aneurysms (n = 3), and non-aneurysmal patients (n = 7), Aortic collagen and elastin content were examined via histological analysis, and immunohistochemistry techniques used to determine collagen I, III, and IV subtypes.

A mouse model of endometriosis that displays vaginal, colon, cutaneous, and bladder sensory comorbidities.

Endometriosis is a painful inflammatory disorder affecting ~10% of women of reproductive age. Although chronic pelvic pain (CPP) remains the main symptom of endometriosis patients, adequate treatments for CPP are lacking. Animal models that recapitulate the features and symptoms experienced by women with endometriosis are essential for investigating the etiology of endometriosis, as well as developing new treatments.

Atrial Fibrillation and Obesity: Reverse Remodeling of Atrial Substrate With Weight Reduction.

Objectives: This study sought to evaluate the effect of weight loss on the atrial substrate for atrial fibrillation (AF).

Background: Whether weight loss can reverse the atrial substrate of obesity is not known.

Methods: Thirty sheep had sustained obesity induced by ad libitum calorie-dense diet over 72 weeks.

Early Dendritic Dystrophy in Human Brains With Primary Age-Related Tauopathy.

Dystrophic neurites (DNs) are found in many neurological conditions such as traumatic brain injury and age-related neurodegenerative diseases. In Alzheimer's disease (AD) specifically, senile plaques containing silver-stained DNs were already described in the original literature defining this disease. These DNs could be both axonal and dendritic in origin, while axonal dystrophy relative to plaque formation has been more extensively studied.

Endothelial, pericyte and tumor cell expression in glioblastoma identifies fibroblast activation protein (FAP) as an excellent target for immunotherapy.

Objectives: Targeted immunotherapies such as chimeric antigen receptor (CAR)-T cells are emerging as attractive treatment options for glioblastoma, but rely on identification of a suitable tumor antigen. We validated a new target antigen for glioblastoma, fibroblast activation protein (FAP), by undertaking a detailed expression study of human samples.

Methods: Glioblastoma and normal tissues were assessed using immunostaining, supported by analyses of published transcriptomic datasets.

Extracellular Sortilin Proteopathy Relative to β-Amyloid and Tau in Aged and Alzheimer's Disease Human Brains.

Amyloid plaques and neurofibrillary tangles (NFTs) are hallmark lesions of Alzheimer's disease (AD) related to β-amyloid (Aβ) deposition and intraneuronal phosphorylated tau (pTau) accumulation. tilin C-terminal gments (shortened as "sorfra") can deposit as senile plaque-like lesions within AD brains. The course and pattern of sorfra plaque formation relative to Aβ and pTau pathogenesis remain unknown.

Short-Term Environmental Enrichment is a Stronger Modulator of Brain Glial Cells and Cervical Lymph Node T Cell Subtypes than Exercise or Combined Exercise and Enrichment.

Physical exercise (PE) and environmental enrichment (EE) can modulate immunity. However, the differential effects of short-term PE, EE, and PE + EE on neuroimmune mechanisms during normal aging has not been elucidated. Hence, a cohort of 3-, 8-, and 13-month-old immunologically unchallenged C57BL/6 wild-type mice were randomly assigned to either Control, PE, EE, or PE + EE groups and provided with either no treatment, a running wheel, a variety of plastic and wooden objects alone or in combination with a running wheel for seven weeks, respectively.

Duration of Environmental Enrichment Determines Astrocyte Number and Cervical Lymph Node T Lymphocyte Proportions but Not the Microglial Number in Middle-Aged C57BL/6 Mice.

Environmental enrichment (EE) has been shown to modulate behavior and immunity. We recently reported that both short and long-term EE enhance baseline locomotion and alleviate depressive-like behavior, but only long-term EE affects locomotion adversely in a threatening environment and enhances anxiety-like behavior in middle-age mice. We have now investigated whether the observed changes in behavior after short- and long-term EE were associated with underlying immune changes.

A putative role for the aryl hydrocarbon receptor (AHR) gene in a patient with cyclical Cushing's disease.

Background: Apart from PRKAR1A mutations in a subset of cyclical Cushing's syndrome due to primary pigmented nodular adrenocortical disease, the molecular basis of cyclical Cushing's syndrome has not been investigated. We speculated that cyclical Cushing's syndrome may be due to mutations in the clock genes that govern circadian rhythms, including the hypothalamic-pituitary-adrenal axis.

Case Presentation: A 47-year-old man presented with mass effects from a sellar lesion.