Characterising a New Sheep Model of Parkinson's Disease Using Unilateral Intracerebral Injection of 6-Hydroxydopamine Into the Substantia Nigra.

New therapeutic agents developed for treating neurological disorders are often tested successfully on rodents. Testing in an appropriate large animal model where there is longer lifespan and comparable brain size to humans should improve translational success and is frequently expected by regulatory bodies. In this project, we aimed to establish a novel sheep model of Parkinson's disease as a large-brained experimental model for translational research.

Alpha-1 Antitrypsin Therapy Modifies Neutrophil Adhesion in Patients with Obstructive Lung Disease.

Alpha-1 antitrypsin deficiency (AATD) is characterized by neutrophil-dominated inflammation resulting in emphysema. The cholesterol-rich neutrophil outer plasma membrane plays a central role in adhesion and subsequent transmigration to underlying tissues. This study aimed to investigate mechanisms of increased neutrophil adhesion in AATD and whether alpha-1 antitrypsin (AAT) augmentation therapy abrogates this effect.

and modulation of NADPH oxidase activity and reactive oxygen species production in human neutrophils by α-antitrypsin.

Oxidative stress from innate immune cells is a driving mechanism that underlies COPD pathogenesis. Individuals with α-1 antitrypsin (AAT) deficiency (AATD) have a dramatically increased risk of developing COPD. To understand this further, the aim of this study was to investigate whether AATD presents with altered neutrophil NADPH oxidase activation, due to the specific lack of plasma AAT.

Safety and neurochemical profiles of acute and sub-chronic oral treatment with agmatine sulfate.

Agmatine (decarboxylated arginine) exerts numerous central nervous system (CNS) dependent pharmacological effects and may potentially modulate altered neurochemistry seen in neurological disorders. In preclinical studies, injection has been the predominant route of systemic administration. However, a significant translational step would be the use of oral agmatine treatment at therapeutic doses and better understanding of L-arginine metabolic profiles in the CNS post-treatment.

Integrating Model-Based Approaches into a Neuroscience Curriculum-An Interdisciplinary Neuroscience Course in Engineering.

Contribution: This paper demonstrates curricular modules that incorporate engineering model-based approaches, including concepts related to circuits, systems, modeling, electrophysiology, programming, and software tutorials that enhance learning in undergraduate neuroscience courses. These modules can also be integrated into other neuroscience courses.

Background: Educators in biological and physical sciences urge incorporation of computation and engineering approaches into biology.

Students' Motivation and Engagement Predict Reading Achievement Differently by Ethnic Group.

The authors examined Grade 3 and Grade 5 teacher-rated classroom engagement and student self-reported motivation for reading as predictors of reading achievement. They investigated the patterns of prediction of achievement for three racial/ethnic groups (White, Black, and Hispanic) and five levels of socioeconomic status (SES) in a combined within-group model. Groups were created by crossing race/ethnicity with SES to form 15 independent groups for each grade level.

Open Source Software Tools for Teaching Neuroscience.

We developed an interdisciplinary course in computational neuroscience to address the need for students trained in both biological/psychological and quantitative sciences. Increasingly, exposure to advanced math and physics is important to stay on the cutting edge of developments and research in neuroscience. Additionally, the ability to work in multidisciplinary teams will continue to be an asset as the field develops.

Asthma referrals: a key component of asthma management that needs to be addressed.

Heterogeneity of asthma and difficulty in achieving optimal control are the major challenges in the management of asthma. To help attain the best possible clinical outcomes in patients with asthma, several guidelines provide recommendations for patients who will require a referral to a specialist. Such referrals can help in clearing the uncertainty from the initial diagnosis, provide tailored treatment options to patients with persistent symptoms and offer the patients access to health care providers with expertise in the management of the asthma; thus, specialist referrals have a substantial impact on disease prognosis and the patient's health status.

Activation of Neutrophils via IP3 Pathway Following Exposure to Demodex-Associated Bacterial Proteins.

Rosacea is a chronic inflammatory condition that predominantly affects the skin of the face. Sera from rosacea patients display elevated reactivity to proteins from a bacterium (Bacillus oleronius) originally isolated from a Demodex mite from a rosacea patient suggesting a possible role for bacteria in the induction and persistence of this condition. This work investigated the ability of B.

The effect of the decoy molecule PA401 on CXCL8 levels in bronchoalveolar lavage fluid of patients with cystic fibrosis.

Background: The chemokine interleukin-8 (CXCL8) is a key mediator of inflammation in airways of patients with cystic fibrosis (CF). Glycosaminoglycans (GAGs) possess the ability to influence the chemokine profile of the CF lung by binding CXCL8 and protecting it from proteolytic degradation. CXCL8 is maintained in an active state by this glycan interaction thus increasing infiltration of immune cells such as neutrophils into the lungs.

Alpha-1 antitrypsin augmentation therapy corrects accelerated neutrophil apoptosis in deficient individuals.

Alpha-1 antitrypsin (AAT) deficiency (AATD) is characterized by neutrophil-driven lung destruction and early emphysema in a low AAT, and high neutrophil elastase environment in the lungs of affected individuals. In this study, we examined peripheral blood neutrophil apoptosis and showed it to be accelerated in individuals with AATD by a mechanism involving endoplasmic reticulum stress and aberrant TNF-α signaling. We reveal that neutrophil apoptosis in individuals homozygous for the Z allele (PiZZ) is increased nearly 2-fold compared with healthy controls and is associated with activation of the external death pathway.

A neutrophil intrinsic impairment affecting Rab27a and degranulation in cystic fibrosis is corrected by CFTR potentiator therapy.

Studies have endeavored to reconcile whether dysfunction of neutrophils in people with cystic fibrosis (CF) is a result of the genetic defect or is secondary due to infection and inflammation. In this study, we illustrate that disrupted function of the CF transmembrane conductance regulator (CFTR), such as that which occurs in patients with ∆F508 and/or G551D mutations, correlates with impaired degranulation of antimicrobial proteins. We demonstrate that CF blood neutrophils release less secondary and tertiary granule components compared with control cells and that activation of the low-molecular-mass GTP-binding protein Rab27a, involved in the regulation of granule trafficking, is defective.

The acoustic features of inhalation can be used to quantify aerosol delivery from a Diskus™ dry powder inhaler.

Purpose: Some patients are unable to generate the peak inspiratory flow rate (PIFR) necessary to de-agglomerate drug particles from dry powder inhalers (DPIs). In this study we tested the hypothesis that the acoustic parameters of an inhalation are related to the PIFR and hence reflect drug delivery.

Methods: A sensitivity analysis of the relationship of the acoustics of inhalation to simultaneously recorded airflow, in a cohort of volunteers (n = 92) was performed.

Measuring engagement in fourth to twelfth grade classrooms: the Classroom Engagement Inventory.

Research on factors that may promote engagement is hampered by the absence of a measure of classroom-level engagement. Literature has suggested that engagement may have 3 dimensions--affective, behavioral, and cognitive. No existing engagement scales measure all 3 dimensions at the classroom level.

Galectin-9 signaling through TIM-3 is involved in neutrophil-mediated Gram-negative bacterial killing: an effect abrogated within the cystic fibrosis lung.

The T cell Ig and mucin domain-containing molecule (TIM) family of receptors have emerged as potential therapeutic targets to correct abnormal immune function in chronic inflammatory conditions. TIM-3 serves as a functional receptor in structural cells of the airways and via the ligand galectin-9 (Gal-9) can modulate the inflammatory response. The aim of this study was to investigate TIM-3 expression and function in neutrophils, focusing on its potential role in cystic fibrosis (CF) lung disease.

The circulating proteinase inhibitor α-1 antitrypsin regulates neutrophil degranulation and autoimmunity.

Pathological inflammation and autoimmune disease frequently involve elevated neutrophil activity in the absence of infectious agents. Tumor necrosis factor-α (TNF-α) contributes to many of the problems associated with autoimmune diseases. We investigated the ability of serum α-1 antitrypsin (AAT) to control TNF-α biosynthesis and signaling in neutrophils and assessed whether AAT deficiency (AATD) is a TNF-α-related disease.

Increased outer arm and core fucose residues on the N-glycans of mutated alpha-1 antitrypsin protein from alpha-1 antitrypsin deficient individuals.

Alpha-1 antitrypsin (AAT) is the major physiological inhibitor of a range of serine proteases, and in the lung, it maintains a protease-antiprotease balance. AAT deficiency (AATD) is an autosomal co-dominant condition with the Z mutation being the most common cause. Individuals homozygous for Z (PiZZ) have low levels of circulating mutant Z-AAT protein leading to premature emphysematous lung disease.

Intracellular secretory leukoprotease inhibitor modulates inositol 1,4,5-triphosphate generation and exerts an anti-inflammatory effect on neutrophils of individuals with cystic fibrosis and chronic obstructive pulmonary disease.

Secretory leukoprotease inhibitor (SLPI) is an anti-inflammatory protein present in respiratory secretions. Whilst epithelial cell SLPI is extensively studied, neutrophil associated SLPI is poorly characterised. Neutrophil function including chemotaxis and degranulation of proteolytic enzymes involves changes in cytosolic calcium (Ca(2+)) levels which is mediated by production of inositol 1,4,5-triphosphate (IP3) in response to G-protein-coupled receptor (GPCR) stimuli.

Airway inflammatory markers in individuals with cystic fibrosis and non-cystic fibrosis bronchiectasis.

Bronchiectasis is an airway disease characterized by thickening of the bronchial wall, chronic inflammation , and destruction of affected bronchi. Underlying etiologies include severe pulmonary infection and cystic fibrosis (CF); however, in a substantial number of patients with non-CF-related bronchiectasis (NCFB), no cause is found. The increasing armamentarium of therapies now available to combat disease in CF is in stark contrast to the limited tools employed in NCFB.

Endothelial progenitor cells in mothers of low-birthweight infants: a link between defective placental vascularization and increased cardiovascular risk?

Context: Offspring birthweight is inversely associated with future maternal cardiovascular mortality, a relationship that has yet to be fully elucidated. Endothelial progenitor cells (EPCs) are thought to play a key role in vasculogenesis, and EPC numbers reflect cardiovascular risk.

Objective: Our objective was to ascertain whether EPC number or function was reduced in mothers of low-birthweight infants.

Alpha-1 antitrypsin: a potent anti-inflammatory and potential novel therapeutic agent.

Alpha-1 antitrypsin (AAT) has long been thought of as an important anti-protease in the lung where it is known to decrease the destructive effects of major proteases such as neutrophil elastase. In recent years, the perception of this protein in this simple one dimensional capacity as an anti-protease has evolved and it is now recognised that AAT has significant anti-inflammatory properties affecting a wide range of inflammatory cells, leading to its potential therapeutic use in a number of important diseases. This present review aims to discuss the described anti-inflammatory actions of AAT in modulating key immune cell functions, delineate known signalling pathways and specifically to identify the models of disease in which AAT has been shown to be effective as a therapy.

A novel neutrophil derived inflammatory biomarker of pulmonary exacerbation in cystic fibrosis.

Background: The focus of this study was to characterize a novel biomarker for cystic fibrosis (CF) that could reflect exacerbations of the disease and could be useful for therapeutic stratification of patients, or for testing of potential drug treatments. This study focused exclusively on a protein complex containing alpha-1 antitrypsin and CD16b (AAT:CD16b) which is released into the bloodstream from membranes of pro-inflammatory primed neutrophils.

Methods: Neutrophil membrane expression and extracellular levels of AAT and CD16b were quantified by flow cytometry, Western blot analysis and by 2D-PAGE.