SMA Identified: Clinical and Molecular Findings From a Sponsored Testing Program for Spinal Muscular Atrophy in More Than 2,000 Individuals.

Spinal muscular atrophy (SMA) linked to chromosome 5q is an inherited progressive neuromuscular disorder with a narrow therapeutic window for optimal treatment. Although genetic testing provides a definitive molecular diagnosis that can facilitate access to effective treatments, limited awareness and other barriers may prohibit widespread testing. In this study, the clinical and molecular findings of SMA Identified-a no-charge sponsored next-generation sequencing (NGS)-based genetic testing program for SMA diagnosis-are reported.

Accurate prediction of clinical stroke scales and improved biomarkers of motor impairment from robotic measurements.

Objective: One of the greatest challenges in clinical trial design is dealing with the subjectivity and variability introduced by human raters when measuring clinical end-points. We hypothesized that robotic measures that capture the kinematics of human movements collected longitudinally in patients after stroke would bear a significant relationship to the ordinal clinical scales and potentially lead to the development of more sensitive motor biomarkers that could improve the efficiency and cost of clinical trials.

Materials And Methods: We used clinical scales and a robotic assay to measure arm movement in 208 patients 7, 14, 21, 30 and 90 days after acute ischemic stroke at two separate clinical sites.

Citrullinated vimentin and biglycan protein fingerprints as candidate serological biomarkers for disease activity in systemic sclerosis: a pilot study.

Extracellular matrix (ECM) deposition and remodelling in skin and lungs of systemic sclerosis (SSc) subjects lead to release of metabolites/biomarkers into circulation. We investigated if biomarkers of ECM degradation (biglycan and elastin) and macrophage activation (citrullinated vimentin) could identify diffuse SSc (dSSc) subjects from controls and the biomarkers discriminative power. DSSc subjects ( = 40) fulfilling the 2013 EULAR/ACR classification criteria were divided in early (<2years of symptoms) and late (≥10 years of symptoms).

The implementation of the Plan Esperanza and response to the imPACT Review.

Following the implementation of the National Cancer Prevention and Control Results-based Budget Programme (PpR Cancer-024) in 2011, the Peruvian Government approved the Plan Esperanza-a population-based national cancer control plan-in 2012. Legislation that ensured full government-supported funding for people who were otherwise unable to access or afford care and treatment accompanied the Plan. In 2013, the Ministry of Health requested an integrated mission of the Programme of Action for Cancer Therapy (imPACT) report to strengthen cancer control in Peru.

Robotic measurement of arm movements after stroke establishes biomarkers of motor recovery.

Background And Purpose: Because robotic devices record the kinematics and kinetics of human movements with high resolution, we hypothesized that robotic measures collected longitudinally in patients after stroke would bear a significant relationship to standard clinical outcome measures and, therefore, might provide superior biomarkers.

Methods: In patients with moderate-to-severe acute ischemic stroke, we used clinical scales and robotic devices to measure arm movement 7, 14, 21, 30, and 90 days after the event at 2 clinical sites. The robots are interactive devices that measure speed, position, and force so that calculated kinematic and kinetic parameters could be compared with clinical assessments.

O2 regulates stem cells through Wnt/β-catenin signalling.

Stem cells reside in specialized microenvironments or 'niches' that regulate their function. In vitro studies using hypoxic culture conditions (<5% O2) have revealed strong regulatory links between O2 availability and functions of stem and precursor cells. Although some stem cells are perivascular, others may occupy hypoxic niches and be regulated by O2 gradients.

Pharmacologic interventions for stroke: looking beyond the thrombolysis time window into the penumbra with biomarkers, not a stopwatch.

Background And Purpose: The majority of pharmacological agents for stroke were developed based on the assumption that neurological deficits will be reduced upon the successful interruption of biochemical mechanisms leading to neuronal death. Despite significant evidence of preclinical efficacy, none of these agents succeeded. They either failed to demonstrate efficacy in the clinic or their development was halted for safety, strategic, or commercial reasons.

Increased prolyl 4-hydroxylase expression and differential regulation of hypoxia-inducible factors in the aged rat brain.

Hypoxia-inducible factors (HIFs) are heterodimeric transcription factors that mediate the adaptive response of mammalian cells and tissues to changes in tissue oxygenation. In the present study, we show an age-dependent decline in cortical HIF-1alpha accumulation and activation of HIF target genes in response to hypoxia. This inducible response is significantly attenuated in the cerebral cortex of 18-mo-old Fischer 344 rat yet virtually absent in the cerebral cortex of 24-mo-old Fischer 344 rat.

Mitochondria and hypoxia-induced gene expression mediated by hypoxia-inducible factors.

The influence of mitochondrial activity on gene expression programs, particularly those involved in neuroprotection and repair, is likely to play an important role in the pathophysiology of neurodegenerative diseases. One such gene expression program is activated by the cellular pathway that senses a decrease in optimal oxygen levels and leads to activation of a family of transcriptional activators called hypoxia-inducible factors (HIFs). HIFs are members of the bHLH-PAS family of transcription factors and are heterodimers composed of HIF-alpha and HIF-beta (also known as aryl hydrocarbon receptor nuclear translocator) subunits that bind to canonical DNA sequences (hypoxia-regulated elements) in the promoters or enhancers of target genes.

Multimodal magnetic resonance imaging for assessing evolution of ischemic penumbra: a key translational medicine strategy to manage the risk of developing novel therapies for acute ischemic stroke.

The implicit aim of neuroprotection is to rescue neurons within distressed but still viable tissue, thereby promoting functional recovery upon neuronal salvage. The clinical failure of this approach suggests that previous efforts to develop stroke therapies lacked means to predict success or futility in pre-clinical and early clinical studies. A key translational medicine strategy that can improve predictability relies on imaging methodologies to map the spatiotemporal evolution of the ischemic penumbra.

ATF4 is an oxidative stress-inducible, prodeath transcription factor in neurons in vitro and in vivo.

Oxidative stress is pathogenic in neurological diseases, including stroke. The identity of oxidative stress-inducible transcription factors and their role in propagating the death cascade are not well known. In an in vitro model of oxidative stress, the expression of the bZip transcription factor activating transcription factor 4 (ATF4) was induced by glutathione depletion and localized to the promoter of a putative death gene in neurons.

Hypoxia-inducible factor-1 mediates neuronal expression of the receptor for advanced glycation end products following hypoxia/ischemia.

Activation of the receptor for advanced glycation endproducts (RAGE) by its multiple ligands can trigger diverse signaling pathways with injurious or pro-survival consequences. In this study, we show that Rage mRNA and protein levels were stimulated in the mouse brain after experimental stroke and systemic hypoxia. In both cases, RAGE expression was primarily associated with neurons.

The lipophilic metal chelators DP-109 and DP-460 are neuroprotective in a transgenic mouse model of amyotrophic lateral sclerosis.

One of the hypotheses for the development of familial amyotrophic lateral sclerosis (ALS) is that mutations in the superoxide dismutase 1 enzyme lead to aberrant properties of the copper within the active site of the enzyme which then causes increased oxidative damage. The lipophilic metal chelators DP-109 and DP-460 which chelate calcium, copper, and zinc were tested in the G93A-transgenic ALS mouse model. Both compounds significantly extended survival, DP-109 (5 mg/kg/day) by 10%, DP-460 (10 mg/kg/day) by 9%.

Neuron-specific inactivation of the hypoxia inducible factor 1 alpha increases brain injury in a mouse model of transient focal cerebral ischemia.

In the present study, we show a biphasic activation of hypoxia inducible factor 1alpha (HIF-1) after stroke that lasts for up to 10 d, suggesting the involvement of the HIF pathway in several aspects of the pathophysiology of cerebral ischemia. We provide evidence that HIF-1-mediated responses have an overall beneficial role in the ischemic brain as indicated by increased tissue damage and reduced survival rate of mice with neuron-specific knockdown of HIF-1alpha that were subjected to transient focal cerebral ischemia. In addition, we demonstrated that drugs known to activate HIF-1 in cultured cells as well as in vivo had neuroprotective properties in this model of cerebral ischemia.

The transcriptional activator hypoxia inducible factor 2 (HIF-2/EPAS-1) regulates the oxygen-dependent expression of erythropoietin in cortical astrocytes.

In the ischemic or hypoxic brain, astrocytes appear to be one of the main sources of erythropoietin (EPO). In this study, we investigated the differential contribution of hypoxia inducible factor (HIF) isoforms to the regulation of hypoxic EPO expression in cultured astrocytes. In addition, using an in vitro model of oxygen-glucose deprivation (OGD), we studied the role of HIF-1alpha and HIF-2alpha in the generation of paracrine protective signals by astrocytes that modulate the survival of neurons exposed to OGD.

Hypoxia-inducible factor prolyl 4-hydroxylase inhibition. A target for neuroprotection in the central nervous system.

Hypoxia-inducible factor (HIF) prolyl 4-hydroxylases are a family of iron- and 2-oxoglutarate-dependent dioxygenases that negatively regulate the stability of several proteins that have established roles in adaptation to hypoxic or oxidative stress. These proteins include the transcriptional activators HIF-1alpha and HIF-2alpha. The ability of the inhibitors of HIF prolyl 4-hydroxylases to stabilize proteins involved in adaptation in neurons and to prevent neuronal injury remains unclear.

Transient expression of hypoxia-inducible factor-1 alpha and target genes in peripheral nerves from diabetic rats.

Decreased blood flow is one of the earliest physiological changes observed after the onset of either clinical or experimental diabetes. The reduction in blood flow is believed to lead to nerve hypoxia, which in conjunction with other metabolic alterations and degenerative processes in different nerve compartments, results in the dysfunction known as diabetic neuropathy. The transcriptional regulator hypoxia-inducible factor-1 alpha (HIF-1alpha) accumulates rapidly under hypoxic conditions and modulates the expression of several target genes that protect tissues against ischemia and infarction.

Prosurvival and prodeath effects of hypoxia-inducible factor-1alpha stabilization in a murine hippocampal cell line.

Hypoxia-inducible factor-1 (HIF-1) is a transcriptional activator involved in adaptation to hypoxic stress. Previous studies from our laboratory demonstrated that pharmacological activators of HIF-1 (e.g.

Structural and functional adaptation to hypoxia in the rat brain.

Chronic exposure to a hypoxic environment leads to structural and functional adaptations in the rat brain. One significant adaptation is a decrease in intercapillary distances through a near doubling of the capillary density, which begins after about 1 week of hypoxic exposure and is completed by 3 weeks. Hypoxic angiogenesis is controlled by activation of downstream genes by Hypoxia Inducible Factor-1 and Angiopoietin-2.

The third signal in T cell-mediated autoimmune disease?

The initial event in the pathogenesis of autoimmune disease is thought to be the priming of naive autoreactive T cells by an infection with a cross-reactive microorganism. Although such cross-reactive priming should be a common event, autoimmune disease does not frequently develop. This situation is reflected after the immunization of C57BL/6 mice with the neuroantigen myelin oligodendrocyte glycoprotein (MOG) with CFA, which primes a type 1 T cell response but does not lead to clinical or histological manifestation of experimental allergic encephalomyelitis unless pertussis toxin is injected in addition.

Hypoxic regulation of angiopoietin-2 expression in endothelial cells.

Exposure of endothelial cells to hypoxia-induced angiopoietin-2 (Ang2) expression. The increase in Ang2 mRNA levels occurred by transcriptional regulation and by post-transcriptional increase in mRNA stability. Induction of Ang2 mRNA resulted in an increase of intracellular and secreted Ang2 protein levels.

HIF-1 alpha and VEGF expression after transient global cerebral ischemia.

Hypoxia inducible factor-1 alpha (HIF-1 alpha) and vascular endothelial growth factor (VEGF) expression were studied in rat cerebral cortex after reversible global cerebral ischemia produced by cardiac arrest and resuscitation. Immunoblot analysis showed a significant induction of HIF-1 alpha protein after 1 hour of recovery from cardiac arrest which remained elevated for at least 12 hours. Upregulation of VEGF mRNA and protein were also observed but this was delayed in comparison to the HIF-1 alpha response.