RESUMEN
Pain experiences are common during childhood (eg, "everyday" pain, vaccine injections) and are powerful opportunities for children to learn about pain and injury. These experiences likely inform fundamental and life-long beliefs about pain. There is scant research investigating the sociocultural contexts in which children learn about pain and injury. One unexplored context is the shared reading of picture books (eg, between parents/caregivers and children). In this study, we investigated whether shared reading of picture books that included depictions of pain and/or injury prompted parent/caregiver-child interactions. If interactions were observed, we explored what those interactions entailed. Twenty parents/caregivers (8 men, 12 women) and their children (n = 27; 10 boys, 17 girls) were recruited from libraries in South Australia. Parent/caregiver-child families chose from 8 books (7 fiction, 1 nonfiction) with varying amounts of pain/injury-related content. Shared reading interactions were video recorded, transcribed, and analyzed alongside analysis of the picture books using reflexive thematic analysis. Pain/injury-related interactions were observed between parents/caregivers and children during shared reading of picture books. Qualitative analyses generated 1 main theme and 3 subthemes. Findings identified that shared reading presented an opportunity for children's understanding of pain and injury to be socialized through discussion of characters' experiences. This included teaching children about pain and injury, as well as promoting empathy and emotional attunement toward characters who were depicted as being in pain. Finally, parents/caregivers often responded with observable/expressed amusement if pain/injury was depicted in a light-hearted or unrealistic way. Overall, shared reading of picture books presents an untapped opportunity to socialize children about pain and injury. PERSPECTIVE: Shared reading of picture books that have depictions of pain and/or injury can prompt parent/caregiver-child interactions about pain and injury. These interactions present critical opportunities that can be harnessed to promote children's learning of adaptive pain-related concepts and behaviors during a critical developmental period.
Asunto(s)
Libros , Dolor , Relaciones Padres-Hijo , Investigación Cualitativa , Humanos , Masculino , Femenino , Niño , Dolor/psicología , Dolor/etiología , Adulto , Heridas y Lesiones/psicología , Adolescente , Lectura , PreescolarRESUMEN
Background: The Sensation and Pain Rating Scale (SPARS) allows rating of non-painful as well as painful percepts. While it performs well in the experimental context, its clinical utility is untested. This prospective, repeated-measures study mixed qualitative and quantitative methods to examine the utility and performance of the SPARS in a clinical context, and to compare it with the widely used 11-point NRS for pain. Methods: People presenting for outpatient physiotherapy (n = 121) provided ratings on the SPARS and NRS at first consultation, before and after sham and active clinical interventions, and at follow-up consultation. Clinicians (n = 9) reported each scale's usability and interpretability using Likert-type scales and free text, and answered additional questions with free text. Each data type was initially analysed separately: quantitative data were visualised and the ES II metric was used to estimate SPARS internal responsiveness; qualitative data were analysed with a reflexive inductive thematic approach. Data types were then integrated for triangulation and complementarity. Results: The SPARS was well received and considered easy to use, after initial familiarisation. Clinicians favoured the SPARS over the NRS for clarity of interpretation and inter-rater reliability. SPARS sensitivity to change was good (ESII=0.9; 95%CI: 0.75-1.10). The greater perceptual range of the SPARS was deemed especially relevant in the later phases of recovery, when pain may recede into discomfort that still warrants clinical attention. Conclusion: The SPARS is a promising tool for assessing patient percept, with strong endorsement from clinicians for its clarity and superior perceptual scope.
RESUMEN
Background and Objectives: Knee osteoarthritis is one of the primary causes of chronic pain among older adults and because of the aging population, the number of total knee arthroplasties (TKAs) performed is exponentially increasing. While pain reduction is a goal of TKA, movement-evoked pain is rarely assessed pre- and post-TKA. We characterized the distributions of change in pain, function, and situational catastrophizing in patients from presurgery to 3 months postsurgery and explored associations among these pre-post changes. Research Design and Methods: This prospective study longitudinally assessed movement-evoked pain, function, and situational catastrophizing in patients with knee osteoarthritis (N = 92) using in-person performance-based tests (6-min walk test [6MWT], stair-climb test [SCT]) prior to and 3 months after TKA. Patients also completed the Western Ontario McMaster Universities Scales (WOMAC) pain and function subscales, and Pain Catastrophizing Scale, presurgery and 3- and 6-months postsurgery. Results: Movement-evoked pain and function on performance tests significantly improved from pre- to post-TKA. Improved SCT function was associated with reduced SCT pain and catastrophizing. Similarly, reduced pain during the SCT was associated with reduced catastrophizing during the SCT. However, 6MWT function was not associated with 6MWT pain or catastrophizing; yet reduced pain during the 6MWT was associated with reduced catastrophizing during the 6MWT. Reduced movement-evoked pain during both performance tests was consistently associated with improved WOMAC function and pain, whereas improved function on performance tests was inconsistently associated with WOMAC function and pain. Notably, greater movement-evoked pain on both performance tests at 3-month post-TKA was associated with worse WOMAC function and pain at 6 months, whereas better function on performance tests at 3 months was associated with better WOMAC function, but not related to WOMAC pain at 6 months. Discussion and Implications: Findings highlight the importance of situation-specific and in vivo assessments of pain and catastrophizing during physical activity.
RESUMEN
This systematic review and meta-analysis investigated the effects of non-pharmacological manipulations on experimentally induced secondary hypersensitivity in pain-free humans. We investigated the magnitude (change/difference in follow-up ratings from pre-manipulation ratings) of secondary hypersensitivity (primary outcome), and surface area of secondary hypersensitivity (secondary outcome), in 27 studies representing 847 participants. Risk of bias assessment concluded most studies (23 of 27) had an unclear or high risk of performance and detection bias. Further, 2 (of 27) studies had a high risk of measurement bias. Datasets were pooled by the method of manipulation and outcome. The magnitude of secondary hypersensitivity was decreased by diverting attention, anodal transcranial direct current stimulation, or emotional disclosure; increased by directing attention toward the induction site, nicotine deprivation, or negative suggestion; and unaffected by cathodal transcranial direct current stimulation or thermal change. Area of secondary hypersensitivity was decreased by anodal transcranial direct current stimulation, emotional disclosure, cognitive behavioral therapy, hyperbaric oxygen therapy, placebo analgesia, or spinal manipulation; increased by directing attention to the induction site, nicotine deprivation, or sleep disruption (in males only); and unaffected by cathodal transcranial direct current stimulation, thermal change, acupuncture, or electroacupuncture. Meta-analytical pooling was only appropriate for studies that used transcranial direct current stimulation or hyperbaric oxygen therapy, given the high clinical heterogeneity among the studies and unavailability of data. The evidence base for this question remains small. We discuss opportunities to improve methodological rigor including manipulation checks, structured blinding strategies, control conditions or time points, and public sharing of raw data. PERSPECTIVE: We described the effects of several non-pharmacological manipulations on experimentally induced secondary hypersensitivity in humans. By shedding light on the potential for non-pharmacological therapies to influence secondary hypersensitivity, it provides a foundation for the development and testing of targeted therapies for secondary hypersensitivity.
RESUMEN
We report on how the endoplasmic reticulum (ER)-associated-autophagy pathway (ERAA) delivers P23H-rhodopsin (P23H-R) to the lysosome. P23H-R accumulates in an ERAD-resistant conformation that is stabilized in a detergent-soluble state by DNAJB12 and Hsp70. P23H-R, DNAJB12, and FIP200 colocalize in discrete foci that punctuate the rim of omegasome rings coated by WIPI1. Loss of DNAJB12 function prevents the association of P23H-R containing ER tubules with omegasomes. P23H-R tubules thread through the wall of WIPI1 rings into their central cavity. Transfer of P23H-R from ER-connected phagophores to lysosomes requires GABARAP and is associated with the transient docking of lysosomes to WIPI1 rings. After departure from WIPI1 rings, new patches of P23H-R are seen in the membranes of lysosomes. The absence of GABARAP prevents transfer of P23H-R from phagophores to lysosomes without interfering with docking. These data identify lysosome docking to omegasomes as an important step in the DNAJB12- and GABARAP-dependent autophagic disposal of dominantly toxic P23H-R.
Asunto(s)
Autofagosomas , Rodopsina , Autofagosomas/metabolismo , Autofagia , Retículo Endoplásmico/metabolismo , Lisosomas/metabolismo , Rodopsina/metabolismoRESUMEN
Pain is thought to be influenced by the threat value of the particular context in which it occurs. However, the mechanisms by which a threat achieves this influence on pain are unclear. Here, we explore how threat influences experimentally-induced secondary hyperalgesia, which is thought to be a manifestation of central sensitization. We developed an experimental study to investigate the effect of a manipulation of threat on experimentally-induced secondary hyperalgesia in 26 healthy human adults (16 identifying as female; 10 as male). We induced secondary hyperalgesia at both forearms using high-frequency electrical stimulation. Prior to the induction, we used a previously successful method to manipulate threat of tissue damage at one forearm (threat site). The effect of the threat manipulation was determined by comparing participant-rated anxiety, perceived threat, and pain during the experimental induction of secondary hyperalgesia, between the threat and control sites. We hypothesized that the threat site would show greater secondary hyperalgesia (primary outcome) and greater surface area (secondary outcome) of induced secondary hyperalgesia than the control site. Despite a thorough piloting procedure to test the threat manipulation, our data showed no main effect of site on pain, anxiety, or threat ratings during high-frequency electrical stimulation. In the light of no difference in threat between sites, the primary and secondary hypotheses cannot be tested. We discuss reasons why we were unable to replicate the efficacy of this established threat manipulation in our sample, including: (1) competition between threats, (2) generalization of learned threat value, (3) safety cues, (4) trust, and requirements for participant safety, (5) sampling bias, (6) sample-specific habituation to threat, and (7) implausibility of (sham) skin examination and report. Better strategies to manipulate threat are required for further research on the mechanisms by which threat influences pain.
Asunto(s)
Hiperalgesia , Dolor , Adulto , Humanos , Masculino , Femenino , Hiperalgesia/terapia , Dimensión del Dolor , Estimulación EléctricaRESUMEN
Innocuous cues that become associated with pain can enhance pain. This is termed classically conditioned hyperalgesia. The size of this effect varies under different conditions. We aimed to test whether the sensitising effect of pain-associated cues depends on the intensity of the paired test stimulus. To do this, two virtual reality environments were paired with either painful or non-painful vibrotactile stimuli in a counterbalanced fashion. The differential effect of the two environments was evaluated using pain intensity ratings of paired electrocutaneous test stimuli at three different intensity levels. Forty healthy participants were included in the study; 30 participants experienced sufficient pain during the learning phase and were included in the main analysis. An effect of environment (p = 0.014) and interaction between environment and test stimulus intensity was found (p = 0.046). Only the most intense test stimulus was modulated by environment. While the effect was small, the results are consistent with the proposition that pain-associated cues may induce hyperalgesia to some degree, under certain conditions. In particular, results highlight the potential relevance of stimulus intensity during and after the initial painful experience. Further attention is needed to comprehensively understand the variables that impact classically conditioned hyperalgesia.
Asunto(s)
Condicionamiento Clásico , Hiperalgesia , Señales (Psicología) , Humanos , Dolor , Dimensión del Dolor/métodosRESUMEN
INTRODUCTION: Many people with HIV report both distress and pain. The relationship between distress and pain is bidirectional, but the mechanisms by which distress exacerbates pain are unclear. The inflammatory response to challenge (inflammatory reactivity, IR) may be a partial mediator, given that neuroimmune interactions provide a substrate for IR to also influence neurological reactivity and, thus, pain-related neural signalling. This prospective, observational, case-control study will characterise the relationships between distress, IR, pain-related signalling as captured by induced secondary hyperalgesia (SH), and pain, in people with HIV who report persistent pain (PP) (cases) or no pain (controls). METHODS AND ANALYSIS: One hundred people with suppressed HIV, reporting either PP or no pain, will be assessed two or four times over 6 months. The primary outcomes are distress (Hopkins 25-item symptom checklist), IR (multiplex assay after LPS challenge), and PP (Brief Pain Inventory), assessed at the baseline timepoint, although each will also be assessed at follow-up time points. Induced SH will be assessed in a subsample of 60 participants (baseline timepoint only). To test the hypothesis that IR partly mediates the relationship between distress and pain, mediation analysis will use the baseline data from the PP group to estimate direct and indirect contributions of distress and IR to pain. To test the hypothesis that IR is positively associated with SH, data from the subsample will be analysed with generalised mixed effects models to estimate the association between IR and group membership, with SH as the dependent variable. ETHICS AND DISSEMINATION: Information obtained from this study will be published in peer-reviewed journals and presented at scientific meetings. The study has been approved by the Human Research Ethics Committee of the University of Cape Town (approval number: 764/2019) and the City of Cape Town (ref: 24699). TRIAL REGISTRATION NUMBER: NCT04757987.
Asunto(s)
Infecciones por VIH , Dolor de la Región Lumbar , Humanos , Estudios Prospectivos , Estudios de Casos y Controles , Sudáfrica , Inmunidad , Estudios Observacionales como AsuntoRESUMEN
We tested the hypotheses that rendering sensory input about hand location imprecise increases a classically conditioned pain expectancy effect, increases generalization of the effect to novel locations and reduces extinction of the effect. Forty healthy volunteers performed movements with their right hand along predefined paths. Each path passed through 2 locations that were defined as either i) the conditioned stimulus (CS+; paired with a painful unconditioned stimulus), or ii) unpaired (CS-). During acquisition phase, participants watched their hand as they moved it. Participants were randomly allocated to an Imprecise group, for whom visual feedback of the hand was offset 30 to 50 mm from its true location, or a Precise group, for whom vision was not disrupted. In the test phase, participants moved their hands to 5 locations-the CS+, CS-, and 3 locations that lay between the 2 ("generalization stimuli"). Our primary hypothesis was supported-pain expectancy was greater at the CS+ location in the Imprecise group than in the Precise group (6.9 [SDâ¯=â¯1.9] vs 5.4 [SDâ¯=â¯2.5], P= .02). Pain expectancies generalized to novel locations similarly in both groups and there was no difference in extinction between groups. Our primary hypothesis was supported but our subsequent hypotheses were not. PERSPECTIVE: We conditioned pain expectancy at a certain location of one hand, even though most participants were unaware of the contingency. Conditioned pain expectancy was greater when sensory information about location was less precise. This adds support to the possibility that associative learning may play a role in the progression of an acute pain episode to a more generalized pain disorder.
Asunto(s)
Anticipación Psicológica/fisiología , Aprendizaje por Asociación/fisiología , Condicionamiento Clásico/fisiología , Retroalimentación Sensorial/fisiología , Mano/fisiología , Ilusiones/fisiología , Dolor Nociceptivo/fisiopatología , Adulto , Femenino , Humanos , Masculino , Percepción Espacial/fisiología , Percepción Visual/fisiología , Adulto JovenRESUMEN
All coronaviruses known to have recently emerged as human pathogens probably originated in bats1. Here we use a single experimental platform based on immunodeficient mice implanted with human lung tissue (hereafter, human lung-only mice (LoM)) to demonstrate the efficient in vivo replication of severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), as well as two endogenous SARS-like bat coronaviruses that show potential for emergence as human pathogens. Virus replication in this model occurs in bona fide human lung tissue and does not require any type of adaptation of the virus or the host. Our results indicate that bats contain endogenous coronaviruses that are capable of direct transmission to humans. Our detailed analysis of in vivo infection with SARS-CoV-2 in human lung tissue from LoM showed a predominant infection of human lung epithelial cells, including type-2 pneumocytes that are present in alveoli and ciliated airway cells. Acute infection with SARS-CoV-2 was highly cytopathic and induced a robust and sustained type-I interferon and inflammatory cytokine and chemokine response. Finally, we evaluated a therapeutic and pre-exposure prophylaxis strategy for SARS-CoV-2 infection. Our results show that therapeutic and prophylactic administration of EIDD-2801-an oral broad-spectrum antiviral agent that is currently in phase II/III clinical trials-markedly inhibited SARS-CoV-2 replication in vivo, and thus has considerable potential for the prevention and treatment of COVID-19.
Asunto(s)
Tratamiento Farmacológico de COVID-19 , COVID-19/prevención & control , Citidina/análogos & derivados , Hidroxilaminas/administración & dosificación , Hidroxilaminas/uso terapéutico , Administración Oral , Células Epiteliales Alveolares/inmunología , Células Epiteliales Alveolares/patología , Células Epiteliales Alveolares/virología , Animales , COVID-19/inmunología , Quimioprevención , Quirópteros/virología , Ensayos Clínicos Fase II como Asunto , Ensayos Clínicos Fase III como Asunto , Citidina/administración & dosificación , Citidina/uso terapéutico , Citocinas/inmunología , Células Epiteliales/virología , Femenino , Xenoinjertos , Humanos , Inmunidad Innata , Interferón Tipo I/inmunología , Pulmón/inmunología , Pulmón/patología , Pulmón/virología , Trasplante de Pulmón , Masculino , Ratones , Profilaxis Posexposición , Profilaxis Pre-Exposición , SARS-CoV-2/inmunología , SARS-CoV-2/patogenicidad , Replicación ViralRESUMEN
BACKGROUND: Phantom limb pain (PLP)-pain felt in the amputated limb-is often accompanied by significant suffering. Estimates of the burden of PLP have provided conflicting data. To obtain a robust estimate of the burden of PLP, we gathered and critically appraised the literature on the prevalence and risk factors associated with PLP in people with limb amputations. METHODS: Articles published between 1980 and July 2019 were identified through a systematic search of the following electronic databases: MEDLINE/PubMed, PsycINFO, PsycArticles, Cumulative Index to Nursing and Allied Health Literature, Africa-Wide Information, Health Source: Nursing/Academic Edition, SCOPUS, Web of Science and Academic Search Premier. Grey literature was searched on databases for preprints. Two reviewers independently conducted the screening of articles, data extraction and risk of bias assessment. The meta-analyses were conducted using the random effects model. A statistically significant level for the analyses was set at p<0.05. RESULTS: The pooling of all studies demonstrated a prevalence estimate of 64% [95% CI: 60.01-68.05] with high heterogeneity [I2 = 95.95% (95% CI: 95.10-96.60)]. The prevalence of PLP was significantly lower in developing countries compared to developed countries [53.98% vs 66.55%; p = 0.03]. Persistent pre-operative pain, proximal site of amputation, stump pain, lower limb amputation and phantom sensations were identified as risk factors for PLP. CONCLUSION: This systematic review and meta-analysis estimates that six of every 10 people with an amputation report PLP-a high and important prevalence of PLP. Healthcare professionals ought to be aware of the high rates of PLP and implement strategies to reduce PLP by addressing known risk factors, specifically those identified by the current study.
Asunto(s)
Amputación Quirúrgica/efectos adversos , Miembro Fantasma/epidemiología , Toma de Decisiones Clínicas , Humanos , Miembro Fantasma/etiología , Prevalencia , Factores de RiesgoRESUMEN
Autophagy is a conserved process that recycles cellular contents to promote survival. Although nitrogen limitation is the canonical inducer of autophagy, recent studies have revealed several other nutrients important to this process. In this study, we used a quantitative, high-throughput assay to identify potassium starvation as a new and potent inducer of autophagy in the yeast Saccharomyces cerevisiae We found that potassium-dependent autophagy requires the core pathway kinases Atg1, Atg5, and Vps34, and other components of the phosphatidylinositol 3-kinase complex. Transmission EM revealed abundant autophagosome formation in response to both stimuli. RNA-Seq indicated distinct transcriptional responses: nitrogen affects transport of ions such as copper, whereas potassium targets the organization of other cellular components. Thus, nitrogen and potassium share the ability to influence molecular supply and demand but do so in different ways. Both inputs promote catabolism through bulk autophagy, but result in distinct mechanisms of cellular remodeling and synthesis.
Asunto(s)
Autofagia , Potasio/metabolismo , Saccharomyces cerevisiae/metabolismo , Proteína 5 Relacionada con la Autofagia/genética , Proteína 5 Relacionada con la Autofagia/metabolismo , Proteínas Relacionadas con la Autofagia/genética , Proteínas Relacionadas con la Autofagia/metabolismo , Fosfatidilinositol 3-Quinasas Clase III/genética , Fosfatidilinositol 3-Quinasas Clase III/metabolismo , Fosfatidilinositol 3-Quinasas/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Quinasas/genética , Proteínas Quinasas/metabolismo , Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismoRESUMEN
Evidence indicates that over half of all people with HIV (PWH) will experience nonmalignant chronic pain throughout their lifetimes, with increasing prevalence as they age. Peripheral neuropathy resulting from the neurotoxic effects of HIV itself and the medications used to treat HIV were widely considered the primary cause of acute and chronic pain early on in the antiretroviral treatment era. However, recent studies suggest a predominance of non-neuropathic (e.g., musculoskeletal) pain in PWH with uncertain etiology. Chronic pain is often widespread in PWH, affecting multiple body locations. Additional research is needed to better understand contributors to chronic pain in PWH, which is likely to include biological (e.g., immune dysregulation), psychological (e.g., substance abuse) and social (e.g., stigma) factors.
Asunto(s)
Dolor Crónico/epidemiología , Infecciones por VIH/epidemiología , Dolor Musculoesquelético/epidemiología , Calidad de Vida , Adulto , Dolor Crónico/etiología , Dolor Crónico/psicología , Dolor Crónico/terapia , Comorbilidad , Infecciones por VIH/tratamiento farmacológico , Accesibilidad a los Servicios de Salud , Humanos , Dolor Musculoesquelético/etiología , Dolor Musculoesquelético/psicología , Dolor Musculoesquelético/terapia , Prevalencia , Calidad de Vida/psicología , Estigma Social , Apoyo SocialRESUMEN
BACKGROUND: Pain is the most common reason for patients to seek help from a health care professional. In the past few decades, research has yielded gains in the Pain Sciences - multiple fields of scientific research that, when integrated, help to clarify what causes and influences human pain. OBJECTIVES: In this article, we discuss the key areas in which the Pain Sciences have shifted the physiotherapy profession. METHOD: A narrative review of the Pain Sciences literature was conducted. The review analyses how the Pain Sciences have influenced physiotherapy in several categories: assessment; clinical reasoning; treatment; research rigor and building the profile of the profession. RESULTS: Scientific research on pain has largely converged in support of three 'game-changing' concepts that have shifted the physiotherapy profession's understanding and treatment of pain: (1) pain is not a signal originating from bodily tissues, (2) pain is not an accurate measure of tissue damage and (3) the plasticity of the nervous system means the nervous system itself is a viable target of treatment. These three concepts have influenced physiotherapy assessment and treatment approaches, and research design to consider pain mechanisms using patient-centred models. CONCLUSION: The Pain Sciences have shifted physiotherapists' assessment and treatment approaches and shifted the status of the physiotherapy profession. Ultimately the Pain Sciences have embedded interdisciplinary teams and expanded physiotherapy practice. CLINICAL IMPLICATIONS: We believe that the pain sciences should be embedded in undergraduate and postgraduate education and training of physiotherapists (including the three key concepts regarding pain) to benefit physiotherapists and their patients.
RESUMEN
OBJECTIVE: To investigate whether graded motor imagery (GMI) is effective for reducing phantom limb pain (PLP) in people who have undergone limb amputations. DESIGN: A single-blinded randomised, controlled trial. SETTING: Physiotherapy out-patient departments in three secondary level hospitals in Cape Town, South Africa. PARTICIPANTS: Twenty-one adults (≥18 years) who had undergone unilateral upper or lower limb amputations and had self-reported PLP persisting beyond three months. INTERVENTIONS: A 6-week GMI programme was compared to routine physiotherapy. The study outcomes were evaluated at baseline, 6 weeks, 3 months and 6 months. OUTCOME MEASURES: The pain severity scale of the Brief Pain Inventory (BPI) was used to assess the primary outcome - PLP. The pain interference scale of the BPI and the EuroQol EQ-5D-5L were used to assess the secondary outcomes - pain interference with function and health-related quality of life (HRQoL) respectively. RESULTS: The participants in the experimental group had significantly greater improvements in pain than the control group at 6 weeks and 6 months. Further, the participants in the experimental group had significantly greater improvements than the control group in pain interference at all follow-up points. There was no between-group difference in HRQoL. CONCLUSION: The results of the current study suggest that GMI is better than routine physiotherapy for reducing PLP. Based on the significant reduction in PLP and pain interference within the participants who received GMI, and the ease of application, GMI may be a viable treatment for treating PLP in people who have undergone limb amputations. CLINICAL TRIAL REGISTRATION NUMBER: (PACTR201701001979279).
Asunto(s)
Imágenes en Psicoterapia/métodos , Manejo del Dolor/métodos , Miembro Fantasma/terapia , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Dimensión del Dolor , Modalidades de Fisioterapia , Calidad de Vida , Método Simple Ciego , SudáfricaRESUMEN
Alexander disease (AxD) is a fatal neurodegenerative disorder caused by mutations in glial fibrillary acidic protein (GFAP), which supports the structural integrity of astrocytes. Over 70 GFAP missense mutations cause AxD, but the mechanism linking different mutations to disease-relevant phenotypes remains unknown. We used AxD patient brain tissue and induced pluripotent stem cell (iPSC)-derived astrocytes to investigate the hypothesis that AxD-causing mutations perturb key post-translational modifications (PTMs) on GFAP. Our findings reveal selective phosphorylation of GFAP-Ser13 in patients who died young, independently of the mutation they carried. AxD iPSC-astrocytes accumulated pSer13-GFAP in cytoplasmic aggregates within deep nuclear invaginations, resembling the hallmark Rosenthal fibers observed in vivo. Ser13 phosphorylation facilitated GFAP aggregation and was associated with increased GFAP proteolysis by caspase-6. Furthermore, caspase-6 was selectively expressed in young AxD patients, and correlated with the presence of cleaved GFAP. We reveal a novel PTM signature linking different GFAP mutations in infantile AxD.
Asunto(s)
Enfermedad de Alexander/metabolismo , Biomarcadores/metabolismo , Caspasas/metabolismo , Proteína Ácida Fibrilar de la Glía/metabolismo , Adulto , Enfermedad de Alexander/diagnóstico , Enfermedad de Alexander/genética , Astrocitos/metabolismo , Sitios de Unión/genética , Encéfalo/metabolismo , Encéfalo/patología , Línea Celular , Proteína Ácida Fibrilar de la Glía/genética , Humanos , Células Madre Pluripotentes Inducidas/metabolismo , Lactante , Filamentos Intermedios/metabolismo , Mutación , Fosforilación , Proteolisis , Índice de Severidad de la EnfermedadRESUMEN
BACKGROUND: Neuropathic pain affects 7-10% of people, but responds poorly to pharmacotherapy, indicating a need for better treatments. Mechanistic research on neuropathic pain frequently uses human surrogate models of the secondary hyperalgesia that is a common feature of neuropathic pain. Experimentally induced secondary hyperalgesia has been manipulated with pharmacological and non-pharmacological methods to clarify the relative contributions of different mechanisms to secondary hyperalgesia. However, this literature has not been systematically synthesised. The aim of this systematic review is to identify, describe, and compare methods that have been used to manipulate experimentally induced secondary hyperalgesia in healthy humans. METHODS: A systematic search strategy will be supplemented by reference list checks and direct contact with identified laboratories to maximise the identification of data reporting the experimental manipulation of experimentally induced secondary hyperalgesia in healthy humans. Duplicated screening, risk of bias assessment, and data extraction procedures will be used. Authors will be asked to provide data as necessary. Data will be pooled and meta-analyses conducted where possible, with subgrouping according to manipulation method. Manipulation methods will be ranked for potency and risk. DISCUSSION: The results of this review will provide a useful reference for researchers interested in using experimental methods to manipulate secondary hyperalgesia in humans and will help to clarify the relative contributions of different mechanisms to secondary hyperalgesia. SYSTEMATIC REVIEW REGISTRATION: This protocol will be registered on PROSPERO before the review begins. Review records will be updated on PROSPERO once the review is complete. This review is intended for publication in a peer-reviewed journal. Analyses and scripts will be made publicly available.