A peer-volunteer led active ageing programme to prevent decline in physical function in older people at risk of mobility disability (Active, Connected, Engaged [ACE]): study protocol for a randomised controlled trial.

Background: The Active Connected Engaged [ACE] study is a multi-centre, pragmatic, two-arm, parallel-group randomised controlled trial [RCT] with an internal pilot phase. The ACE study incorporates a multi-level mixed methods process evaluation including a systems mapping approach and an economic evaluation. ACE aims to test the effectiveness and cost-effectiveness of a peer-volunteer led active ageing intervention designed to support older adults at risk of mobility disability to become more physically and socially active within their communities and to reduce or reverse, the progression of functional limitations associated with ageing.

Keeping kin close? Geographies of family networks by race and income, 1981–2017.

Objective:: This study examined changes in geographic proximity to family members among race and income groups in the United States from 1981 to 2017.

Background:: Close geographic proximity to family members can facilitate mutual support and strengthen family bonds. Some scholars argue that institutional sources of support have replaced many core family functions, which might mean that households are likely to live increasingly farther away from family.

Childhood neighborhoods and health: Census-based neighborhood measures versus residential lived experiences.

This study examines the impact of neighborhood disadvantage and neighborhood social connectedness during childhood on subsequent health status during early adulthood. We link longitudinal data from the Panel Study of Income Dynamics with Census data on children's surrounding neighborhoods. We estimate results with conventional linear regression and novel methods that better adjust for neighborhood selection processes.

Prevalence Rates of Primary Headache Disorders and Evaluation and Treatment Patterns Among Korean Neurologists.

Background And Purpose: Several studies have found that the prevalence of migraine is higher among healthcare professionals than in the general population. Furthermore, several investigations have suggested that the personal experiences of neurologists with migraine can influence their perception and treatment of the disease. This study assessed these relationships in Korea.

Migraine-attributed burden, impact and disability, and migraine-impacted quality of life: Expert consensus on definitions from a Delphi process.

Background: Migraine-attributed burden, impact, disability and migraine-impacted quality of life are important concepts in clinical management, clinical and epidemiological research, and health policy, requiring clear and agreed definitions. We aimed to formulate concise and precise definitions of these concepts by expert consensus.

Methods: We searched the terms migraine-attributed burden, impact, disability and migraine-impacted quality of life in Embase and Medline from 1974 and 1946 respectively.

Glycaemic variability in patients with type 2 diabetes mellitus treated with dulaglutide, with and without concomitant insulin: Post hoc analyses of randomized clinical trials.

Aim: To investigate the association between treatment with dulaglutide and glycaemic variability (GV) in adult patients with type 2 diabetes mellitus (T2D).

Materials And Methods: Post hoc analyses of six randomized, phase 3 studies were conducted to investigate the association between treatment with dulaglutide 1.5 mg once weekly and GV in adult patients with T2D.

Rod Photoreceptor Neuroprotection in Dark-Reared Pde6brd10 Mice.

Purpose: The purpose of this study was to test the hypothesis that anti-oxidant and / or anti-inflammation drugs that suppress rod death in cyclic light-reared Pde6brd10 mice are also effective in dark-reared Pde6brd10 mice.

Methods: In untreated dark-reared Pde6brd10 mice at post-natal (P) days 23 to 24, we measured the outer nuclear layer (ONL) thickness (histology) and dark-light thickness difference in external limiting membrane-retinal pigment epithelium (ELM-RPE) (optical coherence tomography [OCT]), retina layer oxidative stress (QUEnch-assiSTed [QUEST] magnetic resonance imaging [MRI]); and microglia/macrophage-driven inflammation (immunohistology). In dark-reared P50 Pde6brd10 mice, ONL thickness was measured (OCT) in groups given normal chow or chow admixed with methylene blue (MB) + Norgestrel (anti-oxidant, anti-inflammatory), or MB or Norgestrel separately.

Selective Histone Deacetylase 6 Inhibitors Restore Cone Photoreceptor Vision or Outer Segment Morphology in Zebrafish and Mouse Models of Retinal Blindness.

Blindness arising from retinal or macular degeneration results in significant social, health and economic burden. While approved treatments exist for neovascular (') age-related macular degeneration, new therapeutic targets/interventions are needed for the more prevalent atrophic (') form of age-related macular degeneration. Similarly, in inherited retinal diseases, most patients have no access to an effective treatment.

Norgestrel, a Progesterone Analogue, Promotes Significant Long-Term Neuroprotection of Cone Photoreceptors in a Mouse Model of Retinal Disease.

Purpose: Retinitis pigmentosa (RP) refers to a group of inherited blinding retinal diseases, whereby the death of mutated rod photoreceptors is followed closely by the death of cone photoreceptors. Cone cell death can be hugely debilitating as color/daytime vision becomes impaired. Thus, treatments that are effective against cone cell death are urgently needed.

Cell Death Analysis in Retinal Cultures.

Evaluating cell death is essential when investigating neurodegeneration and neuroprotection in the retina. Cell death assays provide us with a means to identify and quantify dying cells in a population. Terminal dUTP nick end-labeling (TUNEL) is one method used for the identification of dying cells.

Nuclear membrane-localised NOX4D generates pro-survival ROS in FLT3-ITD-expressing AML.

Internal tandem duplication of the juxtamembrane domain of FMS-like tyrosine kinase 3 (FLT3-ITD) is the most prevalent genetic aberration present in 20-30% of acute myeloid leukaemia (AML) cases and is associated with a poor prognosis. FLT3-ITD expressing cells express elevated levels of NADPH oxidase 4 (NOX4)-generated pro-survival hydrogen peroxide (HO) contributing to increased levels of DNA oxidation and double strand breaks. NOX4 is constitutively active and has been found to have various isoforms expressed at multiple locations within a cell.

Microglial-induced Müller cell gliosis is attenuated by progesterone in a mouse model of retinitis pigmentosa.

Norgestrel, a progesterone analogue, has demonstrated neuroprotective effects in a mouse model of retinitis pigmentosa. Neuroprotection is achieved in part through Norgestrels anti-inflammatory properties, alleviating detrimental microglial activity. Gliosis is a feature of many neurodegenerative diseases of the retina, including retinitis pigmentosa.

Pro-survival redox signalling in progesterone-mediated retinal neuroprotection.

Retinitis pigmentosa (RP) is a group of hereditary retinal diseases, characterised by photoreceptor cell loss. Despite a substantial understanding of the mechanisms leading to cell death, an effective therapeutic strategy is sought. Our laboratory has previously demonstrated the neuroprotective properties of Norgestrel, a progesterone analogue, in the degenerating retina, mediated in part by the neurotrophic factor basic fibroblast growth factor (bFGF).

Fractalkine-CX3CR1 signaling is critical for progesterone-mediated neuroprotection in the retina.

Retinitis pigmentosa (RP) encompasses a group of retinal diseases resulting in photoreceptor loss and blindness. We have previously shown in the rd10 mouse model of RP, that rd10 microglia drive degeneration of viable neurons. Norgestrel, a progesterone analogue, primes viable neurons against potential microglial damage.

Progesterone Attenuates Microglial-Driven Retinal Degeneration and Stimulates Protective Fractalkine-CX3CR1 Signaling.

Retinitis pigmentosa (RP) is a degenerative disease leading to photoreceptor cell loss. Mouse models of RP, such as the rd10 mouse (B6.CXBl-Pde6brd10/J), have enhanced our understanding of the disease, allowing for development of potential therapeutics.

Progesterone analogue protects stressed photoreceptors via bFGF-mediated calcium influx.

Retinitis pigmentosa (RP) is a degenerative retinal disease leading to photoreceptor cell loss. In 2011, our group identified the synthetic progesterone 'Norgestrel' as a potential treatment for RP. Subsequent research showed Norgestrel to work through progesterone receptor membrane component 1 (PGRMC1) activation and upregulation of neuroprotective basic fibroblast growth factor (bFGF).

The synthetic progestin norgestrel modulates Nrf2 signaling and acts as an antioxidant in a model of retinal degeneration.

Retinitis pigmentosa (RP) is one of the most common retinal degenerative conditions affecting people worldwide, and is currently incurable. It is characterized by the progressive loss of photoreceptors, in which the death of rod cells leads to the secondary death of cone cells; the cause of eventual blindness. As rod cells die, retinal-oxygen metabolism becomes perturbed, leading to increased levels of reactive oxygen species (ROS) and thus oxidative stress; a key factor in the secondary death of cones.

Alterations to retinal architecture prior to photoreceptor loss in a mouse model of retinitis pigmentosa.

Mouse models of retinitis pigmentosa (RP) are essential tools in the pursuit to understand fully what cell types and processes underlie the degeneration observed in RP. Knowledge of these processes is required if we are to develop successful therapies to treat this currently incurable disease. We have used the rd10 mouse model of RP to study retinal morphology prior to photoreceptor loss, using immunohistochemistry and confocal microscopy on cryosections, since little is known about how the mutation affects the retina during this period.

The synthetic progestin norgestrel acts to increase LIF levels in the rd10 mouse model of retinitis pigmentosa.

Purpose: Retinal degenerative conditions affect thousands of people worldwide. Retinitis pigmentosa (RP) is among the most common, but it is currently incurable. It is characterized by the progressive death of photoreceptor cells, eventually leading to blindness.

Progesterone receptor signalling in retinal photoreceptor neuroprotection.

'Norgestrel', a synthetic form of the female hormone progesterone has been identified as potential drug candidate for the treatment of the degenerative eye disease retinitis pigmentosa. However, to date, no work has looked at the compound's specific cellular target. Therefore, this study aimed to identify the receptor target of Norgestrel and begin to examine its potential mechanism of action in the retina.

Loss of glial neurofascin155 delays developmental synapse elimination at the neuromuscular junction.

Postnatal synapse elimination plays a critical role in sculpting and refining neural connectivity throughout the central and peripheral nervous systems, including the removal of supernumerary axonal inputs from neuromuscular junctions (NMJs). Here, we reveal a novel and important role for myelinating glia in regulating synapse elimination at the mouse NMJ, where loss of a single glial cell protein, the glial isoform of neurofascin (Nfasc155), was sufficient to disrupt postnatal remodeling of synaptic circuitry. Neuromuscular synapses were formed normally in mice lacking Nfasc155, including the establishment of robust neuromuscular synaptic transmission.

The influence of storage parameters on measurement of survival motor neuron (SMN) protein levels: implications for pre-clinical studies and clinical trials for spinal muscular atrophy.

Spinal muscular atrophy (SMA) is caused by low levels of survival motor neuron (SMN) protein. A growing number of potential therapeutic strategies for SMA are entering pre-clinical and clinical testing, including gene therapy and antisense oligonucleotide-based approaches. For many such studies SMN protein levels are used as one major readout of treatment efficacy, often necessitating comparisons between samples obtained at different times and/or using different protocols.

A novel mouse model of Warburg Micro syndrome reveals roles for RAB18 in eye development and organisation of the neuronal cytoskeleton.

Mutations in RAB18 have been shown to cause the heterogeneous autosomal recessive disorder Warburg Micro syndrome (WARBM). Individuals with WARBM present with a range of clinical symptoms, including ocular and neurological abnormalities. However, the underlying cellular and molecular pathogenesis of the disorder remains unclear, largely owing to the lack of any robust animal models that phenocopy both the ocular and neurological features of the disease.

Canonical BMP-Smad signalling promotes neurite growth in rat midbrain dopaminergic neurons.

Ventral midbrain (VM) dopaminergic (DA) neurons project to the dorsal striatum via the nigrostriatal pathway to regulate voluntary movements, and their loss leads to the motor dysfunction seen in Parkinson's disease (PD). Despite recent progress in the understanding of VM DA neurogenesis, the factors regulating nigrostriatal pathway development remain largely unknown. The bone morphogenetic protein (BMP) family regulates neurite growth in the developing nervous system and may contribute to nigrostriatal pathway development.

Dysregulation of ubiquitin homeostasis and β-catenin signaling promote spinal muscular atrophy.

The autosomal recessive neurodegenerative disease spinal muscular atrophy (SMA) results from low levels of survival motor neuron (SMN) protein; however, it is unclear how reduced SMN promotes SMA development. Here, we determined that ubiquitin-dependent pathways regulate neuromuscular pathology in SMA. Using mouse models of SMA, we observed widespread perturbations in ubiquitin homeostasis, including reduced levels of ubiquitin-like modifier activating enzyme 1 (UBA1).