Betamethasone improved near-term neonatal lamb lung maturation in experimental maternal asthma.

Maternal asthma is associated with increased rates of neonatal lung disease, and fetuses from asthmatic ewes have fewer surfactant-producing cells and lower surfactant-protein B gene (SFTPB) expression than controls. Antenatal betamethasone increases lung surfactant production in preterm babies, and we therefore tested this therapy in experimental maternal asthma. Ewes were sensitised to house dust mite allergen, and an asthmatic phenotype induced by fortnightly allergen lung challenges; controls received saline.

Aerosol Delivery of Palivizumab in a Neonatal Lamb Model of Respiratory Syncytial Virus Infection.

(1) Background: Palivizumab has been an approved preventative monoclonal antibody for respiratory syncytial virus (RSV) infection for over two decades. However, due to its high cost and requirement for multiple intramuscular injections, its use has been limited mostly to high-income countries. Following our previous study showing the successful lung deposition of aerosolised palivizumab in lambs, this current study evaluated the "proof-of-principle" effect of aerosolised palivizumab delivered as a therapeutic to neonatal lambs following RSV infection.

Single-dose pharmacokinetics and lung function of nebulized niclosamide ethanolamine in sheep.

Purpose: Niclosamide is approved as an oral anthelminthic, but its low oral bioavailability hinders its medical use requiring high drug exposure outside the gastrointestinal tract. An optimized solution of niclosamide for nebulization and intranasal administration using the ethanolamine salt has been developed and tested in a Phase 1 trial. In this study we investigate the pulmonary exposure of niclosamide following administration via intravenous injection, oral administration or nebulization.

From liquid to solid-state, solvent-free oxidative ammonolysis of lignins - an easy, alternative approach to generate "N-lignins".

A new chemical modification protocol to generate N-lignins is presented, based on Indulin AT and Mg-lignosulfonate. The already known ammonoxidation reaction in liquid phase was used as a starting point and stepwise optimised towards a full solid-state approach. The "classical" liquid ammonoxidation products, the transition products from the optimization trials, as well as the "solid-state" products were comprehensively analysed and compared to the literature.

Liposomes are Poorly Absorbed Lung Lymph After Inhaled Administration in Sheep.

Enhancing the delivery of therapeutic agents to the lung lymph, including drugs, transfection agents, vaccine antigens and vectors, has the potential to significantly improve the treatment and prevention of a range of lung-related illnesses. One way in which lymphatic delivery can be optimized is the use of nanomaterial-based carriers, such as liposomes. After inhaled delivery however, there is conflicting information in the literature regarding whether nanomaterials can sufficiently access the lung lymphatics to have a therapeutic benefit, in large part due to a lack of reliable quantitative pharmacokinetic data.

A general solvent system for the analysis of lignosulfonates by P NMR.

P nuclear magnetic resonance (NMR) spectroscopy is the most common and most accurate analytical method to quantitatively determine the hydroxy group contents of technical lignins. However, for lignosulfonates, liquid-state NMR analysis is often limited due to solubility problems in commonly used solvent systems, which may arise from the broad range of lignosulfonates from different wood sources, pulping conditions, and purification procedures used in biorefineries. Finding a suitable solvent system is even more difficult for chemically modified or fractionated lignosulfonates.

Intermolecular Interactions in the Membrane Filtration of Highly Alkaline Steeping Lye.

The reuse of steeping lye is crucial for the sustainable production of viscose fibers. Steeping lye contains hemicellulose and many alkaline degradation products, such as organic acids, so that its purification can be evaluated in terms of total organic carbon removal. When considering purification by membrane filtration, intermolecular interactions between hemicellulose and organic acids can strongly affect their retention efficiency.

Identification of placental androgen receptor isoforms in a sheep model of maternal allergic asthma.

Maternal asthma is known to impact intrauterine growth outcomes, which may be mediated, in part, by altered androgen signalling. Our aim was to explore whether the sheep placenta expresses androgen receptor (AR) isoforms and determine if the differential expression of AR protein isoforms is altered by maternal asthma. Four known AR isoforms were detected (AR-FL, AR-v1, AR-v7, and AR-45), and their expression and subcellular distribution was altered in the presence of maternal allergic asthma.

Pulmonary Deposition of Radionucleotide-Labeled Palivizumab: Proof-of-Concept Study.

Objective: Current prevention and/or treatment options for respiratory syncytial virus (RSV) infections are limited as no vaccine is available. Prophylaxis with palivizumab is very expensive and requires multiple intramuscular injections over the RSV season. Here we present proof-of-concept data using nebulized palivizumab delivery as a promising new approach for the prevention or treatment of severe RSV infections, documenting both aerosol characteristics and pulmonary deposition patterns in the lungs of lambs.

Blood and saliva-derived exomes from healthy Caucasian subjects do not display overt evidence of somatic mosaicism.

Somatic mosaicism is a normal occurrence during development in the tissues and organs. As part of establishing a "healthy population "(HP) background or base-line, we investigated whether such mosaicism can be routinely detected in the circulating DNA secured from a rigorously designed healthy human liquid biopsy clinical trial (saliva, blood). We deployed next generation (NG) whole exome sequencing (WES) at median exome coverage rates of 97.

Aerosol Pirfenidone Pharmacokinetics after Inhaled Delivery in Sheep: a Viable Approach to Treating Idiopathic Pulmonary Fibrosis.

Purpose: Inhaled delivery of pirfenidone to the lungs of patients with idiopathic pulmonary fibrosis holds promise to eliminate oral-observed side effects while enhancing efficacy. This study aimed to comprehensively describe the pulmonary pharmacokinetics of inhaled aerosol pirfenidone in healthy adult sheep.

Methods: Pirfenidone concentrations were evaluated in plasma, lung-derived lymph and epithelial lining fluid (ELF) with data subjected to non-compartmental pharmacokinetic analysis.

Placental glucocorticoid receptor isoforms in a sheep model of maternal allergic asthma.

Maternal asthma increases the risk of adverse pregnancy outcomes and may affect fetal growth and placental function by differential effects on the expression of glucocorticoid receptor (GR) isoforms, leading to altered glucocorticoid signalling. Our aim was to examine the effect of maternal asthma on placental GR profiles using a pregnant sheep model of asthma. Nine known GR isoforms were detected.

Maternal allergic asthma during pregnancy alters fetal lung and immune development in sheep: potential mechanisms for programming asthma and allergy.

Key Points: Experimental maternal allergic asthma in sheep provides an experimental model in which to test impacts on progeny. Fetuses from allergic asthmatic ewes had fewer surfactant-producing cells in lungs. A greater proportion of lymphocytes from thymus were CD44 positive in fetuses from allergic asthmatic ewes than in controls.

Umbilical cord blood versus mesenchymal stem cells for inflammation-induced preterm brain injury in fetal sheep.

Background: Chorioamnionitis and fetal inflammation are principal causes of neuropathology detected after birth, particularly in very preterm infants. Preclinical studies show that umbilical cord blood (UCB) cells are neuroprotective, but it is uncertain if allogeneic UCB cells are a feasible early intervention for preterm infants. In contrast, mesenchymal stem cells (MSCs) are more readily accessible and show strong anti-inflammatory benefits.

Human Umbilical Cord Blood Therapy Protects Cerebral White Matter from Systemic LPS Exposure in Preterm Fetal Sheep.

Background: Infants born preterm following exposure to in utero inflammation/chorioamnionitis are at high risk of brain injury and life-long neurological deficits. In this study, we assessed the efficacy of early intervention umbilical cord blood (UCB) cell therapy in a large animal model of preterm brain inflammation and injury. We hypothesised that UCB treatment would be neuroprotective for the preterm brain following subclinical fetal inflammation.

Exacerbation of Ventilation-Induced Lung Injury and Inflammation in Preterm Lambs by High-Dose Nanoparticles.

Mechanical ventilation of preterm neonates causes lung inflammation and injury, with potential life-long consequences. Inert 50-nm polystyrene nanoparticles (PS50G) reduce allergic inflammation in the lungs of adult mice. We aimed to confirm the anti-inflammatory effects of PS50G in a sheep asthma model, and investigate the effects of prophylactic administration of PS50G on ventilation-induced lung injury (VILI) in preterm lambs.

Late-gestation maternal dietary methyl donor and cofactor supplementation in sheep partially reverses protection against allergic sensitization by IUGR.

Perinatal exposures are associated with altered risks of childhood allergy. Human studies and our previous work suggest that restricted growth in utero (IUGR) is protective against allergic disease. The mechanisms are not clearly defined, but reduced fetal abundance and altered metabolism of methyl donors are hypothesized as possible underlying mechanisms.

Term vs. preterm cord blood cells for the prevention of preterm brain injury.

BACKGROUNDWhite matter brain injury in preterm infants can induce neurodevelopmental deficits. Umbilical cord blood (UCB) cells demonstrate neuroprotective properties, but it is unknown whether cells obtained from preterm cord blood (PCB) vs. term cord blood (TCB) have similar efficacy.

Human amnion epithelial cells modulate the inflammatory response to ventilation in preterm lambs.

Ventilation of preterm neonates causes pulmonary inflammation that can contribute to lung injury, propagate systemically and result in long-term disease. Modulation of this initial response may reduce lung injury and its sequelae. We aimed to determine the effect of human amnion epithelial cells (hAECs) on immune activation and lung injury in preterm neonatal lambs.

Substantial Targeting Advantage Achieved by Pulmonary Administration of Colistin Methanesulfonate in a Large-Animal Model.

Colistin, administered as its inactive prodrug colistin methanesulfonate (CMS), is often used in multidrug-resistant Gram-negative pulmonary infections. The CMS and colistin pharmacokinetics in plasma and epithelial lining fluid (ELF) following intravenous and pulmonary dosing have not been evaluated in a large-animal model with pulmonary architecture similar to that of humans. Six merino sheep (34 to 43 kg body weight) received an intravenous or pulmonary dose of 4 to 8 mg/kg CMS (sodium) or 2 to 3 mg/kg colistin (sulfate) in a 4-way crossover study.

Preterm white matter brain injury is prevented by early administration of umbilical cord blood cells.

Infants born very preterm are at high risk for neurological deficits including cerebral palsy. In this study we assessed the neuroprotective effects of umbilical cord blood cells (UCBCs) and optimal administration timing in a fetal sheep model of preterm brain injury. 50 million allogeneic UCBCs were intravenously administered to fetal sheep (0.

Cellulases and beyond: the first 70 years of the enzyme producer Trichoderma reesei.

More than 70 years ago, the filamentous ascomycete Trichoderma reesei was isolated on the Solomon Islands due to its ability to degrade and thrive on cellulose containing fabrics. This trait that relies on its secreted cellulases is nowadays exploited by several industries. Most prominently in biorefineries which use T.

A Comparison of the Pharmacokinetics and Pulmonary Lymphatic Exposure of a Generation 4 PEGylated Dendrimer Following Intravenous and Aerosol Administration to Rats and Sheep.

Purpose: Cancer metastasis to pulmonary lymph nodes dictates the need to deliver chemotherapeutic and diagnostic agents to the lung and associated lymph nodes. Drug conjugation to dendrimer-based delivery systems has the potential to reduce toxicity, enhance lung retention and promote lymphatic distribution in rats. The current study therefore evaluated the pharmacokinetics and lung lymphatic exposure of a PEGylated dendrimer following inhaled administration.

Dynamics of IL-4 and IL-13 expression in the airways of sheep following allergen challenge.

Background: IL-4 and IL-13 play a critical yet poorly understood role in orchestrating the recruitment and activation of effector cells of the asthmatic response and driving the pathophysiology of allergic asthma. The house dust mite (HDM) sheep asthma model displays many features of the human condition and is an ideal model to further elucidate the involvement of these critical Th2 cytokines. We hypothesized that airway exposure to HDM allergen would induce or elevate the expression profile of IL-4 and IL-13 during the allergic airway response in this large animal model of asthma.

L-Methionine repressible promoters for tuneable gene expression in Trichoderma reesei.

Background: Trichoderma reesei is the main producer of lignocellulolytic enzymes that are required for plant biomass hydrolysis in the biorefinery industry. Although the molecular toolbox for T. reesei is already well developed, repressible promoters for strain engineering and functional genomics studies are still lacking.