Background: Despite evidence supporting interventions that improve outcomes for patients with stroke, their implementation remains suboptimal. Facilitation can support implementation of research into clinical practice by helping people develop the strategies to implement change. However, variability in the amount (dose) and type of facilitation activities/facilitator roles that make up the facilitation strategies (content), may affect the effectiveness of facilitation.
View Article and Find Full Text PDFBackground: The Quality in Acute Stroke Care (QASC) Trial demonstrated that assistance to implement protocols to manage Fever, hyperglycaemia (Sugar) and Swallowing (FeSS) post-stroke reduced death and disability. In 2017, a 'Strong Recommendation' for use of FeSS Protocols was included in the Australian Clinical Guidelines for Stroke Management. We aimed to: i) compare adherence to FeSS Protocols pre- and post-guideline inclusion; ii) determine if adherence varied with prior participation in a treatment arm of a FeSS Intervention study, or receiving treatment in a stroke unit; and compare findings with our previous studies.
View Article and Find Full Text PDFIsolated methylmalonic acidemia/aciduria (MMA) due to MMUT enzyme deficiency is an ultra-rare pediatric disease with high morbidity and mortality, with no approved disease-altering therapies. Previous publications showed that systemic treatment with a codon-optimized mRNA encoding wild-type human MMUT (MMUT) is a promising strategy for treatment of MMA. We developed a second-generation drug product, mRNA-3705, comprised of an mRNA encoding the MMUT enzyme formulated in a lipid nanoparticle (LNP) with incorporation of enhancements over the previous clinical candidate mRNA-3704.
View Article and Find Full Text PDFCommercially produced cyanobacteria preparations sold under the name spirulina are widely consumed, due to their traditional use as a nutrient-rich foodstuff and subsequent marketing as a superfood. Despite their popularity, the microbial composition of ponds used to cultivate these bacteria is understudied. A total of 19 pond samples were obtained from small-scale spirulina farms and subjected to metagenome and/or virome sequencing, and the results were analysed.
View Article and Find Full Text PDFMessenger RNA (mRNA) therapeutics delivered via lipid nanoparticles hold the potential to treat metabolic diseases caused by protein deficiency, including propionic acidemia (PA), methylmalonic acidemia (MMA), and phenylketonuria (PKU). Herein we report results from multiple independent preclinical studies of mRNA-3927 (an investigational treatment for PA), mRNA-3705 (an investigational treatment for MMA), and mRNA-3210 (an investigational treatment for PKU) in murine models of each disease. All 3 mRNA therapeutics exhibited pharmacokinetic/pharmacodynamic (PK/PD) responses in their respective murine model by driving mRNA, protein, and/or protein activity responses, as well as by decreasing levels of the relevant biomarker(s) when compared to control-treated animals.
View Article and Find Full Text PDFBACKGROUND: Stroke unit care reduces patient morbidity and mortality. The Quality in Acute Stroke Care Europe Study achieved significant large-scale translation of nurse-initiated protocols to manage Fever, hyperglycemia (Sugar), and Swallowing (FeSS) in 64 hospitals across 17 European countries. However, not all hospitals had stroke units.
View Article and Find Full Text PDFTraditional models of oxidative stress predict accumulation of damage caused by reactive oxygen species (ROS) production as highly correlated with aerobic metabolism, a prediction under increasing scrutiny. Here, we repeat sampled female great tits (Parus major) at two opposite levels of energy use during the period of maximum food provisioning to nestlings, once at rest and once during activity. Our results were in contrast to the above prediction, namely significantly higher levels of oxidative damage during rest opposed to active phase.
View Article and Find Full Text PDFMedium-chain acyl-CoA dehydrogenase (MCAD) deficiency is the most common inherited disorder of mitochondrial fatty acid β-oxidation (FAO) in humans. Patients exhibit clinical episodes often associated with fasting. Symptoms include hypoketotic hypoglycemia and Reye-like episodes.
View Article and Find Full Text PDFCrigler-Najjar syndrome is a rare disorder of bilirubin metabolism caused by uridine diphosphate glucuronosyl transferase 1A1 () mutations characterized by hyperbilirubinemia and jaundice. No cure currently exists; treatment options are limited to phototherapy, whose effectiveness diminishes over time, and liver transplantation. Here, we evaluated the therapeutic potential of systemically administered, lipid nanoparticle-encapsulated human (h) mRNA therapy in a Crigler-Najjar mouse model.
View Article and Find Full Text PDFBackground: Facilitated implementation of nurse-initiated protocols to manage fever, hyperglycaemia (sugar) and swallowing difficulties (FeSS Protocols) in 19 Australian stroke units resulted in reduced death and dependency for stroke patients. However, a significant gap remains in translating this evidence-based care bundle protocol into standard practice in Australia and New Zealand. Facilitation is a key component for increasing implementation.
View Article and Find Full Text PDFVery long-chain acyl-CoA dehydrogenase (VLCAD) deficiency is an inborn error of long chain fatty acid β-oxidation (FAO) with limited treatment options. Patients present with heterogeneous clinical phenotypes affecting predominantly heart, liver, and skeletal muscle. While VLCAD deficiency is a systemic disease, restoration of liver FAO has the potential to improve symptoms more broadly due to increased total body ATP production and reduced accumulation of potentially toxic metabolites.
View Article and Find Full Text PDFRecent evidence indicates that activation of adenosine monophosphate-activated protein kinase (AMPK), a highly conserved sensor and modulator of cellular energy and redox, regulates cell mitosis. However, the underlying molecular mechanisms for AMPKα subunit regulation of chromosome segregation remain poorly understood. This study aimed to ascertain if AMPKα1 deletion contributes to chromosome missegregation by elevating Polo-like kinase 4 (PLK4) expression.
View Article and Find Full Text PDFAmyotrophic lateral sclerosis (ALS) presents a poorly understood pathogenesis. Evidence from patients and mutant SOD1 mouse models suggests vascular damage may precede or aggravate motor dysfunction in ALS. We have previously shown angiogenin (ANG) treatment enhances motor neuron survival, delays motor dysfunction and prevents vascular regression in the SOD1 ALS model.
View Article and Find Full Text PDFCitrin deficiency is an autosomal recessive disorder caused by loss-of-function mutations in SLC25A13, encoding the liver-specific mitochondrial aspartate/glutamate transporter. It has a broad spectrum of clinical phenotypes, including life-threatening neurological complications. Conventional protein replacement therapy is not an option for these patients because of drug delivery hurdles, and current gene therapy approaches (e.
View Article and Find Full Text PDFLoss-of-function mutations in the angiogenin (ANG) gene have been identified in familial and sporadic ALS patients. Previous work from our group identified human ANG (huANG) to protect motoneurons in vitro, and provided proof-of-concept that daily intraperitoneal (i.p.
View Article and Find Full Text PDFAmyotroph Lateral Scler Frontotemporal Degener
August 2018
Background: Riluzole is the most widespread therapeutic for treatment of the progressive degenerative disease amyotrophic lateral sclerosis (ALS). Riluzole gained FDA approval in 1995 before the development of ALS mouse models. We assessed riluzole in three transgenic ALS mouse models: the SOD1 model, the TDP-43 model, and the recently developed FUS (1-359) model.
View Article and Find Full Text PDFAMP-activated protein kinase (AMPK) is an enzyme crucial in cellular metabolism found to be inhibited in many metabolic diseases including type 2 diabetes. Thiazolidinediones (TZDs) are a class of anti-diabetic drug known to activate AMPK through increased phosphorylation at Thr, however there has been no research to date on whether they have any effect on inhibition of AMPK's lesser known site of inhibition, Ser. HepG2 cells were treated with troglitazone and phosphorylation of AMPK was found to increase at both Thr and Ser in a dose- and time-dependent manner.
View Article and Find Full Text PDFBackground And Purpose: Implementation of nurse-initiated protocols to manage fever, hyperglycemia, and swallowing dysfunction decreased death and disability 90 days poststroke in the QASC trial (Quality in Acute Stroke Care) conducted in 19 Australian acute stroke units (2005-2010). We now examine long-term all-cause mortality.
Methods: Mortality was ascertained using Australia's National Death Index.