CAPTURE ALS: The comprehensive analysis platform to understand, remedy and eliminate ALS

The absence of disease modifying treatments for amyotrophic lateral sclerosis (ALS) is in large part a consequence of its complexity and heterogeneity. Deep clinical and biological phenotyping of people living with ALS would assist in the development of effective treatments and target specific biomarkers to monitor disease progression and inform on treatment efficacy. The objective of this paper is to present the Comprehensive Analysis Platform To Understand Remedy and Eliminate ALS (CAPTURE ALS), an open and translational platform for the scientific community currently in development. CAPTURE ALS is a Canadian-based platform designed to include participants\u27 voices in its development and through execution. Standardized methods will be used to longitudinally characterize ALS patients and healthy controls through deep clinical phenotyping, neuroimaging, neurocognitive and speech assessments, genotyping and multisource biospecimen collection. This effort plugs into complementary Canadian and international initiatives to share common resources. Here, we describe in detail the infrastructure, operating procedures, and long-term vision of CAPTURE ALS to facilitate and accelerate translational ALS research in Canada and beyond

Epiregulin and EGFR interactions are involved in pain processing

The EGFR belongs to the well-studied ErbB family of receptor tyrosine kinases. EGFR is activated by numerous endogenous ligands that promote cellular growth, proliferation, and tissue regeneration. In the present study, we have demonstrated a role for EGFR and its natural ligand, epiregulin (EREG), in pain processing. We show that inhibition of EGFR with clinically available compounds strongly reduced nocifensive behavior in mouse models of inflammatory and chronic pain. EREG-mediated activation of EGFR enhanced nociception through a mechanism involving the PI3K/AKT/mTOR pathway and matrix metalloproteinase-9. Moreover, EREG application potentiated capsaicin-induced calcium influx in a subset of sensory neurons. Both the EGFR and EREG genes displayed a genetic association with the development of chronic pain in several clinical cohorts of temporomandibular disorder. Thus, EGFR and EREG may be suitable therapeutic targets for persistent pain conditions

MuscleMap: An Open-Source, Community-Supported Consortium for Whole-Body Quantitative MRI of Muscle

Disorders affecting the neurological and musculoskeletal systems represent international health priorities. A significant impediment to progress in trials of new therapies is the absence of responsive, objective, and valid outcome measures sensitive to early disease changes. A key finding in individuals with neuromuscular and musculoskeletal disorders is the compositional changes to muscles, evinced by the expression of fatty infiltrates. Quantification of skeletal muscle composition by MRI has emerged as a sensitive marker for the severity of these disorders; however, little is known about the composition of healthy muscles across the lifespan. Knowledge of what is ‘typical’ age-related muscle composition is essential to accurately identify and evaluate what is ‘atypical’. This innovative project, known as the MuscleMap, will achieve the first important steps towards establishing a world-first, normative reference MRI dataset of skeletal muscle composition with the potential to provide valuable insights into various diseases and disorders, ultimately improving patient care and advancing research in the field

The evolving SARS-CoV-2 epidemic in Africa: Insights from rapidly expanding genomic surveillance

INTRODUCTION Investment in Africa over the past year with regard to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sequencing has led to a massive increase in the number of sequences, which, to date, exceeds 100,000 sequences generated to track the pandemic on the continent. These sequences have profoundly affected how public health officials in Africa have navigated the COVID-19 pandemic. RATIONALE We demonstrate how the first 100,000 SARS-CoV-2 sequences from Africa have helped monitor the epidemic on the continent, how genomic surveillance expanded over the course of the pandemic, and how we adapted our sequencing methods to deal with an evolving virus. Finally, we also examine how viral lineages have spread across the continent in a phylogeographic framework to gain insights into the underlying temporal and spatial transmission dynamics for several variants of concern (VOCs). RESULTS Our results indicate that the number of countries in Africa that can sequence the virus within their own borders is growing and that this is coupled with a shorter turnaround time from the time of sampling to sequence submission. Ongoing evolution necessitated the continual updating of primer sets, and, as a result, eight primer sets were designed in tandem with viral evolution and used to ensure effective sequencing of the virus. The pandemic unfolded through multiple waves of infection that were each driven by distinct genetic lineages, with B.1-like ancestral strains associated with the first pandemic wave of infections in 2020. Successive waves on the continent were fueled by different VOCs, with Alpha and Beta cocirculating in distinct spatial patterns during the second wave and Delta and Omicron affecting the whole continent during the third and fourth waves, respectively. Phylogeographic reconstruction points toward distinct differences in viral importation and exportation patterns associated with the Alpha, Beta, Delta, and Omicron variants and subvariants, when considering both Africa versus the rest of the world and viral dissemination within the continent. Our epidemiological and phylogenetic inferences therefore underscore the heterogeneous nature of the pandemic on the continent and highlight key insights and challenges, for instance, recognizing the limitations of low testing proportions. We also highlight the early warning capacity that genomic surveillance in Africa has had for the rest of the world with the detection of new lineages and variants, the most recent being the characterization of various Omicron subvariants. CONCLUSION Sustained investment for diagnostics and genomic surveillance in Africa is needed as the virus continues to evolve. This is important not only to help combat SARS-CoV-2 on the continent but also because it can be used as a platform to help address the many emerging and reemerging infectious disease threats in Africa. In particular, capacity building for local sequencing within countries or within the continent should be prioritized because this is generally associated with shorter turnaround times, providing the most benefit to local public health authorities tasked with pandemic response and mitigation and allowing for the fastest reaction to localized outbreaks. These investments are crucial for pandemic preparedness and response and will serve the health of the continent well into the 21st century

Peripheral mechanisms of neuropathic pain

Neuropathic pain is a complex chronic pain state which can be caused by damage to primary afferent sensory neurons. When pain is present in the orofacial territory it is termed trigeminal neuropathic pain. Due to the severity of pain, and to its unrelenting nature, neuropathic pain is an extremely troubling and disabling condition. In addition to being poorly managed in the clinic, it is a great scientific challenge as the pain does not reflect the amount of tissue damage. A comprehensive understanding of the mechanisms underlying these conditions is required in order to improve treatment outcomes. The skin is the largest sensory organ in the body. It receives innervation from various populations of primary afferents which together transduce innocuous and nociceptive stimuli encountered in the environment. The skin also contains autonomic efferents including sympathetic fibers that release norepinephrine and neuropeptide Y (NPY), known pain modulators. Because nerve injuries which precipitate neuropathic pain typically occur in the periphery, changes in the peripheral nervous system are especially relevant in driving this abnormal pain response. Therefore, the overall objective of this thesis was to investigate peripheral nervous system changes in various rat models of neuropathic and trigeminal neuropathic pain. We found that the pattern of sensory innervation was significantly altered by nerve injury, with an early loss and later re-innervation of the skin by primary afferents. Sensory neuron phenotype was also changed, and a de novo upregulation of NPY was described in the cell bodies, axons and terminals of myelinated fibers. These findings provide a possible mechanism to account for the abnormal encoding of sensory information after nerve injury. Sympathetic fibers sprouted into the upper dermis of the skin in constriction and transection models of neuropathic pain and pharmacological studies pointed to their involvement in mediating pain-behaviours at later stages after nerve injury. Interestingly, these sympathetic fibers appeared to contribute to unique sensory symptoms in a model specific manner. Ectopic sympathetic fibers were also found to be a major source of de novo NPY in the skin, suggesting a way in which they might influence the activity of adjacent sensory fibers. Sympathetic fiber sprouting and pain are thought to be driven in part by the aberrant expression of nerve growth factor (NGF) in the skin after nerve injury. Modulating NGF levels thus represents an attractive therapeutic intervention for the treatment of neuropathic pain. Chronic administration of α2-antiplasmin, known to prevent the maturation of NGF in the central nervous system, completely attenuated pain-like behaviour after nerve injury, and significantly increased the expression of proNGF, suggesting that this approach did indeed act through preventing the conversion of proNGF to NGF. Collectively these results highlight the incredible plasticity of the peripheral nervous system after nerve injury. Alterations in sensory but especially sympathetic skin innervation, as well as changes in primary afferent phenotype and aberrations in the levels of NGF have been identified as peripheral mechanisms involved in driving neuropathic and trigeminal neuropathic pain.La douleur neuropathique est une douleur complexe pouvant être causée par une atteinte des afférences sensorielles primaires. Elle est appelée douleur neuropathique trigéminale lorsque présente dans le territoire oro-facial. De par sa sévérité et sa nature implacable, la douleur neuropathique est une affection extrêmement inconfortable et invalidante. Peu efficacement gérée en clinique, elle reste un gros défi scientifique étant donné que son intensité ne se reflète pas dans la quantité de lésion tissulaire. La compréhension des mécanismes sous-jacents à cette affection est nécessaire à l'amélioration de l'efficacité des traitements.La peau, organe sensoriel le plus vaste du corps, est innervé par une variété d'afférences primaires transmettant les stimuli environnementaux non-nociceptifs et nociceptifs. Elle contient aussi des efférences autonomes, notamment les fibres sympathiques libérant la noradrénaline et le neuropeptide Y (NPY), modulateurs connus de la douleur. Les lésions nerveuses qui engendrent la douleur neuropathique se produisant dans la périphérie, les changements du système nerveux périphérique apparaissent alors particulièrement importants pour la mise en place de réponses nociceptives anormales. Ainsi, l'objectif principal de ce travail de thèse fut d'étudier les modifications du système nerveux périphérique dans différents modèles de douleur neuropathique et de douleur neuropathique trigéminale, chez le rat. Nous avons montré que le patron d'innervation des fibres sensorielles est altéré significativement par une lésion nerveuse, avec une perte d'innervation précoce suivie d'une ré-innervation cutanée par les afférences primaires. Le phénotype des neurones sensoriels est également modifié et nous avons mis en évidence une surexpression de novo du NPY dans les corps cellulaires, les axones et les terminaisons des fibres myélinisées. Ces données proposent un mécanisme d'action éventuel pouvant expliquer le codage anormal de l'information sensorielle après une lésion nerveuse. Le bourgeonnement des fibres sympathiques dans le derme supérieur de la peau, dans des modèles de douleurs neuropathiques induits par constriction ou par transsection de nerfs, associé à des études pharmacologiques nous ont permis de montrer l'implication de ces fibres dans les comportements nociceptifs associés aux stades avancés consécutifs d'une lésion nerveuse. De façon intéressante, ces fibres sympathiques semblent avoir des effets différentiels selon la modalité sensorielle considérée et dépendamment du modèle considéré. Les fibres sympathiques ectopiques s'avèrent également une source de NPY exprimé de novo dans la peau, suggérant ainsi une manière pour elles d'influencer l'activité des fibres sensorielles adjacentes.Dans la peau, suite à une lésion nerveuse, le bourgeonnement sympathique et la douleur semblent être engendrés en partie par l'expression aberrante du facteur de croissance neurale (NGF). La modulation des taux de NGF ouvre alors une voie prometteuse quant au traitement de la douleur neuropathique. L'administration chronique d'α2-antiplasmine, connue pour prévenir la maturation du NGF dans le système nerveux central, réduit complètement la douleur consécutive à une lésion nerveuse, et augmente significativement l'expression du proNGF, suggérant ainsi que l'efficacité de ce traitement passe par la prévention de la conversion du proNGF en NGF. Pour conclure, ces résultats montrent l'incroyable plasticité du système nerveux périphérique suite à une lésion nerveuse. Des changements dans l'innervation sensorielle, plus particulièrement dans l'innervation sympathique cutanée, des modifications phénotypiques des afférences primaires, ainsi que des irrégularités dans les niveaux de NGF, ont été identifiés comme des mécanismes périphériques impliqués dans le développement de la douleur neuropathique et de la douleur neuropathique trigéminale

Novel expression pattern of neuropeptide Y immunoreactivity in the peripheral nervous system in a rat model of neuropathic pain

Background: Neuropeptide Y (NPY) has been implicated in the modulation of pain. Under normal conditions, NPY is found in interneurons in the dorsal horn of the spinal cord and in sympathetic postganglionic neurons but is absent from the cell bodies of sensory neurons. Following peripheral nerve injury NPY is dramatically upregulated in the sensory ganglia. How NPY expression is altered in the peripheral nervous system, distal to a site of nerve lesion, remains unknown. To address this question, NPY expression was investigated using immunohistochemistry at the level of the trigeminal ganglion, the mental nerve and in the skin of the lower lip in relation to markers of sensory and sympathetic fibers in a rat model of trigeminal neuropathic pain. [...

Sympathetic fibre sprouting in the skin contributes to pain-related behaviour in spared nerve injury and cuff models of neuropathic pain

Background: Cuff and spared nerve injury (SNI) in the sciatic territory are widely used to model neuropathic pain. Because nociceptive information is first detected in skin, it is important to understand how alterations in peripheral innervation contribute to pain in each model. Over 16 weeks in male rats, changes in sensory and autonomic innervation of the skin were described after cuff and SNI using immunohistochemistry to label myelinated (neurofilament 200 positive—NF200+) and peptidergic (calcitonin gene-related peptide positive—CGRP+) primary afferents and sympathetic fibres (dopamine β-hydroxylase positive—DBH+). [...

Changes in morphine reward in a model of neuropathic pain.

In addition to sensory disturbances, neuropathic pain is associated with an ongoing and persistent negative affective state. This condition may be reflected as altered sensitivity to rewarding stimuli. We examined this hypothesis by testing whether the rewarding properties of morphine are altered in a rat model of neuropathic pain. Neuropathic pain was induced by chronic constriction of the common sciatic nerve. Drug reward was assessed using an unbiased, three-compartment conditioned place preference (CPP) paradigm. The rats underwent two habituation sessions beginning 6 days after surgery. Over the next 8 days, they were injected with drug or vehicle and were confined to one CPP compartment for 30 min. On the following test day, the rats had access to all three compartments for 30 min. Consistent with the literature, systemic administration of morphine dose-dependently increased the CPP in pain-naive animals. In rats with neuropathic pain, however, the dose-dependent effects of morphine were in a bell-shaped curve, with a low dose of morphine (2 mg/kg) producing a greater CPP than a higher dose of morphine (8 mg/kg). In a separate group of animals, acute administration of morphine reversed mechanical allodynia in animals with neuropathic pain at the same doses that produced a CPP. The increased potency of systemic morphine to produce a CPP in animals with neuropathic pain suggests that the motivation for opioid-induced reward is different in the two states

Changes in morphine reward in a model of neuropathic pain.

In addition to sensory disturbances, neuropathic pain is associated with an ongoing and persistent negative affective state. This condition may be reflected as altered sensitivity to rewarding stimuli. We examined this hypothesis by testing whether the rewarding properties of morphine are altered in a rat model of neuropathic pain. Neuropathic pain was induced by chronic constriction of the common sciatic nerve. Drug reward was assessed using an unbiased, three-compartment conditioned place preference (CPP) paradigm. The rats underwent two habituation sessions beginning 6 days after surgery. Over the next 8 days, they were injected with drug or vehicle and were confined to one CPP compartment for 30 min. On the following test day, the rats had access to all three compartments for 30 min. Consistent with the literature, systemic administration of morphine dose-dependently increased the CPP in pain-naive animals. In rats with neuropathic pain, however, the dose-dependent effects of morphine were in a bell-shaped curve, with a low dose of morphine (2 mg/kg) producing a greater CPP than a higher dose of morphine (8 mg/kg). In a separate group of animals, acute administration of morphine reversed mechanical allodynia in animals with neuropathic pain at the same doses that produced a CPP. The increased potency of systemic morphine to produce a CPP in animals with neuropathic pain suggests that the motivation for opioid-induced reward is different in the two states