Study of the Structure of Hyperbranched Polyglycerol Coatings and Their Antibiofouling and Antithrombotic Applications.

While blood-contacting materials are widely deployed in medicine in vascular stents, catheters, and cannulas, devices fail in situ because of thrombosis and restenosis. Furthermore, microbial attachment and biofilm formation is not an uncommon problem for medical devices. Even incremental improvements in hemocompatible materials can provide significant benefits for patients in terms of safety and patency as well as substantial cost savings.

Type D Epsilon Toxin Causes Blood-Retinal Barrier Microvascular Damage and Diffuse Retinal Vasogenic Oedema.

type D epsilon toxin (ETX) causes severe retinal microvascular endothelial injury in the rat. The resulting blood-retinal barrier (BRB) breakdown leads to increased vascular permeability, which was detected immunohistochemically by the extravasation of plasma albumin as a vascular tracer, and ensuing severe, diffuse, vasogenic retinal oedema. This microvascular damage was also confirmed by a loss of endothelial barrier antigen, a marker of an intact BRB in rats.

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.

Pathology and Pathogenesis of Brain Lesions Produced by Type D Epsilon Toxin.

type D epsilon toxin (ETX) produces severe, and frequently fatal, neurologic disease in ruminant livestock. The disorder is of worldwide distribution and, although vaccination has reduced its prevalence, ETX still causes substantial economic loss in livestock enterprises. The toxin is produced in the intestine as a relatively inactive prototoxin, which is subsequently fully enzymatically activated to ETX.

Animal models of pediatric abusive head trauma.

Background: Abusive head trauma (AHT), previously known as the shaken baby syndrome, is a severe and potentially fatal form of traumatic brain injury in infant children who have been shaken, and sometimes also sustained an additional head impact. The clinical and autopsy findings in AHT are not pathognomonic and, due to frequent obfuscation by perpetrators, the circumstances surrounding the alleged abuse are often unclear. The concept has evolved that the finding of the combination of subdural hemorrhage, brain injury, and retinal hemorrhages ("the triad") is the result of shaking of an infant ("shaken baby syndrome") and has led to the ongoing controversy whether shaking alone is able to generate sufficient force to produce these lesions.

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.

The immunotoxicity, but not anti-tumor efficacy, of anti-CD40 and anti-CD137 immunotherapies is dependent on the gut microbiota.

Immune agonist antibodies (IAAs) are promising immunotherapies that target co-stimulatory receptors to induce potent anti-tumor immune responses, particularly when combined with checkpoint inhibitors. Unfortunately, their clinical translation is hampered by serious dose-limiting, immune-mediated toxicities, including high-grade and sometimes fatal liver damage, cytokine release syndrome (CRS), and colitis. We show that the immunotoxicity, induced by the IAAs anti-CD40 and anti-CD137, is dependent on the gut microbiota.

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.

The Role of Endoplasmic Reticulum Stress in Cell Survival and Death.

It is now increasingly recognized that endoplasmic reticulum (ER) stress, which is caused by the accumulation of overproduced or misfolded proteins in this organelle, contributes to the pathogenesis of a diverse range of human diseases. ER stress initiates the unfolded protein response (UPR) in an attempt to restore cellular protein homeostasis and promote cell survival. However, when ER stress is severe or protracted, and uncompensated, the UPR can fail, resulting in cell death, often by apoptosis.

Cep55 overexpression promotes genomic instability and tumorigenesis in mice.

High expression of centrosomal protein CEP55 has been correlated with clinico-pathological parameters across multiple human cancers. Despite significant in vitro studies and association of aberrantly overexpressed CEP55 with worse prognosis, its causal role in vivo tumorigenesis remains elusive. Here, using a ubiquitously overexpressing transgenic mouse model, we show that Cep55 overexpression causes spontaneous tumorigenesis and accelerates Trp53 induced tumours in vivo.

Longitudinal Magnetic Resonance Spectroscopy and Diffusion Tensor Imaging in Sheep (Ovis aries) With Quinolinic Acid Lesions of the Striatum: Time-Dependent Recovery of N-Acetylaspartate and Fractional Anisotropy.

We created an excitotoxic striatal lesion model of Huntington disease (HD) in sheep, using the N-methyl-d-aspartate receptor agonist, quinolinic acid (QA). Sixteen sheep received a bolus infusion of QA (75 µL, 180 mM) or saline, first into the left and then (4 weeks later) into the right striatum. Magnetic resonance spectroscopy (MRS) and diffusion tensor imaging (DTI) of the striata were performed.

Pathogenesis and diagnostic features of brain and ophthalmic damage produced by type D epsilon toxin.

type D epsilon toxin (EXT) causes an important neurologic disorder of sheep, goats and, rarely, cattle. The disease can occur in peracute, acute, subacute, and chronic forms. High circulating levels of ETX produce vasculocentric brain lesions, in which microvascular endothelial injury results in diagnostically useful perivascular and intramural extravasations of plasma protein, especially in sheep, and less frequently in goats.

Pericytes, inflammation, and diabetic retinopathy.

Diabetic retinopathy (DR) is a frequent complication of diabetes mellitus, and a common cause of vision impairment and blindness in these patients, yet many aspects of its pathogenesis remain unresolved. Furthermore, current treatments are not effective in all patients, are only indicated in advanced disease, and are associated with significant adverse effects. This review describes the microvascular features of DR, and how pericyte depletion and low-grade chronic inflammation contribute to the pathogenesis of this common ophthalmic disorder.

type D epsilon toxin produces a rapid and dose-dependent cytotoxic effect on cerebral microvascular endothelial cells in vitro.

type D epsilon toxin (ETX) is responsible for a severe and frequently fatal neurologic disorder in ruminant livestock. Light microscopic, immunohistochemical, and ultrastructural studies have suggested that ETX injury to the cerebral microvasculature, with subsequent severe, generalized vasogenic edema and increased intracranial pressure, is critically important in producing neurologic dysfunction. However, the effect of ETX on brain capillary endothelial cells in vitro has not been examined previously, to our knowledge.

Intramural Vascular Edema in the Brain of Goats With Clostridium perfringens Type D Enterotoxemia.

Enterotoxemia caused by Clostridium perfringens type D is an important disease of sheep and goats with a worldwide distribution. Cerebral microangiopathy is considered pathognomonic for ovine enterotoxemia and is seen in most cases of the disorder in sheep. However, these lesions are poorly described in goats.

Safety and efficacy of a bacteriophage cocktail in an in vivo model of Pseudomonas aeruginosa sinusitis.

Pseudomonas aeruginosa (PA) is a bacterial pathogen that frequently displays antibiotic resistance. Its presence within the sinuses of chronic rhinosinusitis sufferers is associated with poorer quality of life. Obligately lytic bacteriophages (phages) are viruses that infect, replicate within, and lyse bacteria, causing bacterial death.

Axonal spheroids in ovine neuroaxonal dystrophy are immunopositive to kinesin and dynein.

Neuroaxonal dystrophy (NAD) is a neurologic disorder of sheep characterized by accumulation of numerous axonal swellings (spheroids) in specific regions of the brainstem and spinal cord. Disruption of axonal transport, which is driven in anterograde and retrograde directions by the molecular motors, kinesin and dynein, respectively, is believed to contribute to spheroid development. Accordingly, we examined spheroids in ovine NAD cases immunohistochemically for kinesin and dynein and found both motor proteins, with dynein more strongly expressed than kinesin.

Dacomitinib-induced diarrhoea is associated with altered gastrointestinal permeability and disruption in ileal histology in rats.

Dacomitinib-an irreversible pan-ErbB tyrosine kinase inhibitor (TKI)-causes diarrhoea in 75% of patients. Dacomitinib-induced diarrhoea has not previously been investigated and the mechanisms remain poorly understood. The present study aimed to develop an in-vitro and in-vivo model of dacomitinib-induced diarrhoea to investigate underlying mechanisms.

Semiquantitation of Axonal Injury in Traumatically Damaged Brains Using Color Deconvolution.

Introduction: In traumatic brain injury biomechanics, macroscale biomechanical events need to be correlated with microscale neuropathologic changes and improved quantitation of microscopic axonal injury is an essential component of lesion evaluation.

Objectives: To develop a novel technique for automatically identifying injured amyloid precursor protein immunopositive axons and aggregating these observations over a macroscopic brain dissection.

Methods: A color deconvolution method was adapted into Matlab to identify clusters of pixels with colors typical of amyloid precursor protein positive tissue from large-scale brain dissection.

Electrophysiological, Electroanatomical, and Structural Remodeling of the Atria as Consequences of Sustained Obesity.

Background: Obesity and atrial fibrillation (AF) are public health issues with significant consequences.

Objectives: This study sought to delineate the development of global electrophysiological and structural substrate for AF in sustained obesity.

Methods: Ten sheep fed ad libitum calorie-dense diet to induce obesity over 36 weeks were maintained in this state for another 36 weeks; 10 lean sheep with carefully controlled weight served as controls.

Apoptosis in human compressive myelopathy due to metastatic neoplasia.

Study Design: Immunohistochemical assessment of apoptotic markers in human cases of compressive myelopathy due to neoplastic compression.

Objective: To characterize the role of apoptosis in neoplastic compressive myelopathy in human postmortem tissue with extramedullary tumor involvement.

Summary Of Background Data: Neoplasms, whether primary or metastatic, may lead to compression of the spinal cord and development of a compressive myelopathy syndrome.

A selective ATP-competitive sphingosine kinase inhibitor demonstrates anti-cancer properties.

The dynamic balance of cellular sphingolipids, the sphingolipid rheostat, is an important determinant of cell fate, and is commonly deregulated in cancer. Sphingosine 1-phosphate is a signaling molecule with anti-apoptotic, pro-proliferative and pro-angiogenic effects, while conversely, ceramide and sphingosine are pro-apoptotic. The sphingosine kinases (SKs) are key regulators of this sphingolipid rheostat, and are attractive targets for anti-cancer therapy.

Effect of long-term (2 years) exposure of mouse brains to global system for mobile communication (GSM) radiofrequency fields on astrocytic immunoreactivity.

This study was designed to determine whether long-term (2 years) brain exposure to mobile telephone radiofrequency (RF) fields produces any astrocytic activation as these glia react to a wide range of neural perturbations by astrogliosis. Using a purpose-designed exposure system at 900 MHz, mice were given a single, far-field whole body exposure at a specific absorption rate of 4 W/kg on five successive days per week for 104 weeks. Control mice were sham-exposed or freely mobile in a cage to control any stress caused by immobilization in the exposure module.

Pathology of traumatic brain injury.

Although traumatic brain injury (TBI) is frequently encountered in veterinary practice in companion animals, livestock and horses, inflicted head injury is a common method of euthanasia in domestic livestock, and malicious head trauma can lead to forensic investigation, the pathology of TBI has generally received little attention in the veterinary literature. This review highlights the pathology and pathogenesis of cerebral lesions produced by blunt, non-missile and penetrating, missile head injuries as an aid to the more accurate diagnosis of neurotrauma cases. If more cases of TBI in animals that result in fatality or euthanasia are subjected to rigorous neuropathological examination, this will lead to a better understanding of the nature and development of brain lesions in these species, rather than extrapolating data from human studies.