Passive Immunotherapy Targeting Tau Oligomeric Strains Reverses Tauopathy Phenotypes in Aged Human-Tau Mice in a Mouse Model-Specific Manner.

Background: Tau oligomers are one of the most toxic species, displaying prion-like strains which have different conformations resulting in different tauopathies. Passive immunotherapy targeting different tau species is a promising therapeutic approach. Age is one of the greatest risk factors; however, most immunotherapy studies are done in young to middle-aged mice tauopathy models, which is not representative of the many clinical trials done with older humans with established tauopathies.

Tau Modulates mRNA Transcription, Alternative Polyadenylation Profiles of hnRNPs, Chromatin Remodeling and Spliceosome Complexes.

Tau protein is a known contributor in several neurodegenerative diseases, including Alzheimer's disease (AD) and frontotemporal dementia (FTD). It is well-established that tau forms pathological aggregates and fibrils in these diseases. Tau has been observed within the nuclei of neurons, but there is a gap in understanding regarding the mechanism by which tau modulates transcription.

TDP-43 and Tau Oligomers in Alzheimer's Disease, Amyotrophic Lateral Sclerosis, and Frontotemporal Dementia.

Proteinaceous aggregates are major hallmarks of several neurodegenerative diseases. Aggregates of post-translationally modified transactive response (TAR)-DNA binding protein 43 (TDP-43) in cytoplasmic inclusion bodies are characteristic features in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Recent studies have also reported TDP-43 aggregation in Alzheimer's disease (AD).

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Internalization mechanisms of brain-derived tau oligomers from patients with Alzheimer's disease, progressive supranuclear palsy and dementia with Lewy bodies.

Tau aggregates propagate in brain cells and transmit to neighboring cells as well as anatomically connected brain regions by prion-like mechanisms. Soluble tau aggregates (tau oligomers) are the most toxic species that initiate neurodegeneration in tauopathies, such as Alzheimer's disease (AD), progressive supranuclear palsy (PSP), and dementia with Lewy bodies (DLB). Exogenous tau aggregates have been shown to be internalized by brain cells; however, the precise cellular and molecular mechanisms that underlie the internalization of tau oligomers (TauO) remain elusive.

Toxic Tau Oligomers Modulated by Novel Curcumin Derivatives.

The pathological aggregation and accumulation of tau, a microtubule-associated protein, is a common feature amongst more than 18 different neurodegenerative diseases that are collectively known as tauopathies. Recently, it has been demonstrated that the soluble and hydrophobic tau oligomers are highly toxic in vitro due to their capacity towards seeding tau misfolding, thereby propagating the tau pathology seen across different neurodegenerative diseases. Modulating the aggregation state of tau oligomers through the use of small molecules could be a useful therapeutic strategy to target their toxicity, regardless of other factors involved in their formation.

Neurotoxic tau oligomers after single versus repetitive mild traumatic brain injury.

Mild traumatic brain injury accounts for the majority of head injuries and has been correlated with neurodegeneration and dementia. While repetitive mild traumatic brain injury is highly correlated to neurodegeneration, the correlation of a single mild traumatic brain injury with neurodegeneration is still unclear. Because tau aggregates are the main form of mild traumatic brain injury induced pathology, toxic forms of tau protein most likely play a role in the development of post-mild traumatic brain injury neurodegeneration.

Tau oligomers mediate aggregation of RNA-binding proteins Musashi1 and Musashi2 inducing Lamin alteration.

The exact mechanisms leading to neurodegeneration in Alzheimer's disease (AD) and other tauopathies are not yet entirely understood. However, it is known that several RNA-binding proteins (RBPs) form toxic aggregates and also interact with tau in such granules in tauopathies, including AD. The Musashi (MSI) family of RBPs, consisting of two homologues: Musashi1 and Musashi2, have not been extensively investigated in neurodegenerative diseases.

Soluble tau aggregates, not large fibrils, are the toxic species that display seeding and cross-seeding behavior.

Several studies have proposed that fibrillary aggregates of tau and other amyloidogenic proteins are neurotoxic and result in numerous neurodegenerative diseases. However, these studies usually involve sonication or extrusion through needles before experimentation. As a consequence, these methods may fragment large aggregates producing a mixture of aggregated species rather than intact fibrils.

Growth velocity reduced with once-daily fluticasone furoate nasal spray in prepubescent children with perennial allergic rhinitis.

Background: The effect of fluticasone furoate nasal spray (FFNS) on growth in prepubescent children has not been evaluated.

Objective: To characterize the difference in mean prepubescent growth velocities, as determined by stadiometry, between patients treated continuously for 1 year with FFNS 110 mcg once daily and placebo nasal spray.

Methods: This was a multicenter, randomized, double-blind, placebo-controlled, parallel-group 76-week safety study.

Efficacy and safety of fluticasone furoate 100 μg and 200 μg once daily in the treatment of moderate-severe asthma in adults and adolescents: a 24-week randomised study.

Background: Inhaled corticosteroids are a mainstay of therapy for persistent asthma, but suboptimal adherence with twice-daily use is widespread. Fluticasone furoate (FF) is a new inhaled corticosteroid (ICS) suitable for once-daily dosing in asthma. This study was performed to descriptively assess the efficacy and safety of two doses of FF, with no planned formal statistical hypothesis testing.

Efficacy and safety of fluticasone furoate/vilanterol compared with fluticasone propionate/salmeterol combination in adult and adolescent patients with persistent asthma: a randomized trial.

Background: The combination of fluticasone furoate (FF), a novel inhaled corticosteroid (ICS), and vilanterol (VI), a long-acting β2 agonist, is under development as a once-daily treatment of asthma and COPD. The aim of this study was to compare the efficacy of FF/VI with fluticasone propionate (FP)/salmeterol (SAL) in patients with persistent asthma uncontrolled on a medium dose of ICS.

Methods: In a randomized, double-blind, double-dummy, parallel group study, 806 patients received FF/VI (100/25 μg, n = 403) once daily in the evening delivered through ELLIPTA (GlaxoSmithKline) dry powder inhaler, or FP/SAL (250/50 μg, n = 403) bid through DISKUS/ACCUHALER (GlaxoSmithKline).

Repeat dosing of albuterol via metered-dose inhaler in infants with acute obstructive airway disease: a randomized controlled safety trial.

Background: Airway obstruction and bronchial hyperactivity often times lead to emergency department visits in infants. Inhaled short-acting beta2-agonist bronchodilators have traditionally been dispensed to young children via nebulizers in the emergency department. Delivery of bronchodilators via metered-dose inhalers (MDIs) in conjunction with holding chambers (spacers) has been shown to be effective.

Effectiveness of fluticasone furoate 110 microg once daily in the treatment of nasal and ocular symptoms of seasonal allergic rhinitis in adults and adolescents sensitized to mountain cedar pollen.

Background: Fluticasone furoate (FF) is a novel enhanced-affinity corticosteroid for the treatment of allergic rhinitis, delivered by a unique side-actuated device. This study was designed to investigate the efficacy and safety of FF nasal spray (FFNS) 110 microg once daily compared with placebo in adults and adolescents (aged > or =12 years) with seasonal allergic rhinitis (SAR) symptoms caused by mountain cedar (Juniperus ashei) pollen.

Methods: This was a randomized, double-blind, placebo-controlled, parallel-group, phase III study conducted over a 2-week period (between 10 December 2004 and 19 January 2005) at seven study sites, in Austin, Texas, USA, and San Antonio, Texas, two metropolitan cities in the central Texas Hill Country located approximately 80 miles apart.

Efficacy and safety of once-daily fluticasone furoate nasal spray in children with seasonal allergic rhinitis treated for 2 wk.

The objective of this study was to evaluate the efficacy and safety of fluticasone furoate (FF) nasal spray 55 and 110 microg once daily in children with seasonal allergic rhinitis (SAR). Patients (n = 554) received placebo nasal spray or FF, administered using a unique side-actuated device, in a 2-wk, randomized, double-blind study. Symptoms were evaluated by patients using a 4-point categorical scale.

Fluticasone furoate nasal spray: a single treatment option for the symptoms of seasonal allergic rhinitis.

Background: Fluticasone furoate (USAN-approved name) is a novel, enhanced-affinity glucocorticoid administered in a unique side-actuated device for the management of seasonal allergic rhinitis (SAR).

Objective: We sought to evaluate the efficacy and safety of once-daily fluticasone furoate nasal spray, 110 microg, in patients aged 12 years or older with fall SAR.

Methods: Patients (n = 299) received fluticasone furoate or placebo for 2 weeks in this double-blind, parallel-group randomized study.

Efficacy and tolerability of fluticasone propionate/salmeterol administered twice daily via hydrofluoroalkane 134a metered-dose inhaler in adolescent and adult patients with persistent asthma: a randomized, double-blind, placebo-controlled, 12-week study.

Objective: This study compared the efficacy and tolerability of the combination of fluticasone propionate (FP) and salmeterol (SAL) delivered via a single hydrofluoroalkane (HFA) 134a metered-dose inhaler (MDI) with those of its 2 components alone delivered via a chlorofluorocarbon (CFC) MDI and placebo (PLA) delivered via HFA MDI in adolescent and adult patients with persistent asthma that was not controlled by medium doses (equivalent to FP 440-660 microg/d) of inhaled corticosteroids (ICSs).

Methods: This was a randomized, double-blind,placebo-controlled, parallel-group study consisting of a 2-week, single-blind, placebo run-in period followed by a 12-week, double-blind treatment period. Participants had to be > or =12 years of age and have a diagnosis of asthma requiring pharmacotherapy for at least 6 months before the study.

The safety of twice-daily treatment with fluticasone propionate and salmeterol in pediatric patients with persistent asthma.

Background: For children older than 5 years with asthma who remain symptomatic despite inhaled corticosteroid (ICS) therapy, the preferred treatment is to add an inhaled long-acting beta2-agonist vs increasing the ICS dose.

Objective: To compare the safety of twice-daily treatment with inhaled fluticasone propionate plus the inhaled long-acting beta2-agonist salmeterol with that of fluticasone propionate used alone in children aged 4 to 11 years with persistent asthma.

Methods: A randomized, multicenter, double-blind, active-controlled, parallel-group study in 203 children with persistent asthma who were symptomatic during ICS therapy.