RESUMEN
Triosephosphate isomerase deficiency (TPI Df) is a rare multisystem disorder with severe neuromuscular symptoms which arises exclusively from mutations within the TPI1 gene. Studies of TPI Df have been limited due to the absence of mammalian disease models and difficulties obtaining patient samples. Recently, we developed a novel murine model of TPI Df which models the most common disease-causing mutation in humans, TPI1E105D. Using our model in the present study, the underlying pathogenesis of neuromuscular symptoms has been elucidated. This is the first report detailing studies of neuromuscular pathology within a murine model of TPI Df. We identified several contributors to neuromuscular symptoms, including neurodegeneration in the brain, alterations in neurotransmission at the neuromuscular junction, and reduced muscle fiber size. TPI Df mice also exhibited signs of cardiac pathology and displayed a deficit in vascular smooth muscle functionality. Together, these findings provide insight into pathogenesis of the neuromuscular symptoms in TPI Df and can guide the future development of therapeutics.
Asunto(s)
Modelos Animales de Enfermedad , Unión Neuromuscular , Triosa-Fosfato Isomerasa , Animales , Triosa-Fosfato Isomerasa/deficiencia , Triosa-Fosfato Isomerasa/genética , Triosa-Fosfato Isomerasa/metabolismo , Ratones , Unión Neuromuscular/patología , Unión Neuromuscular/metabolismo , Anemia Hemolítica Congénita no Esferocítica/genética , Anemia Hemolítica Congénita no Esferocítica/patología , Enfermedades Neuromusculares/genética , Enfermedades Neuromusculares/patología , Enfermedades Neuromusculares/etiología , Errores Innatos del Metabolismo de los Carbohidratos/genética , Mutación , HumanosRESUMEN
OBJECTIVES: To investigate the differences in clinical characteristics among children on prolonged mechanical ventilation (PMV) due to different primary diseases. METHODS: A retrospective analysis was performed on the clinical data of 59 pediatric patients requiring PMV from July 2017 to September 2022. According to the primary disease, they were divided into respiratory disease (RD) group, central nervous system (CNS) group, neuromuscular disease (NMD) group, and other disease group. The four groups were compared in terms of general information, treatment, and outcome. RESULTS: There were significant differences among the four groups in age, body weight, Pediatric Logistic Organ Dysfunction-2 (PELOD-2) score, Pediatric Risk of Mortality III (PRISM â ¢) score, analgesic and sedative treatment, nutrition supply, rehabilitation treatment, tracheotomy, successful ventilator weaning, and outcomes (P<0.05). Compared with the RD group, the CNS group and the other disease group had a significantly higher age and a significantly higher proportion of children receiving rehabilitation treatment, and the CNS group had a significantly higher proportion of children receiving tracheotomy (P<0.008). Compared with the other disease group, the CNS group and the NMD group had significantly lower PELOD-2 and PRISM III scores, and the CNS group had a significantly higher proportion of children with successful ventilator weaning and a significantly higher proportion of children who were improved and discharged (P<0.008). CONCLUSIONS: There are differences in clinical characteristics among children receiving PMV due to different etiologies. Most children in the RD group have a younger age, and children in the CNS group have a relatively good prognosis.
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Enfermedades Neuromusculares , Respiración Artificial , Humanos , Masculino , Femenino , Estudios Retrospectivos , Preescolar , Lactante , Enfermedades Neuromusculares/terapia , Enfermedades Neuromusculares/etiología , Niño , Enfermedades del Sistema Nervioso Central/etiología , Enfermedades del Sistema Nervioso Central/terapia , Enfermedades Respiratorias/terapia , Enfermedades Respiratorias/etiologíaRESUMEN
Pulmonary complications continue to be the most common adverse event after surgery. The main objective was to carry out two independent predictive models, both for early pulmonary complications in the Post-Anesthesia Care Unit and late-onset pulmonary complications after 30 postoperative days. The secondary objective was to determine whether presenting early complications subsequently causes patients to have other late-onset events. This is a secondary analysis of a cohort study. 714 patients were divided into four groups depending on the neuromuscular blocking agent, and spontaneous or pharmacological reversal. Incidence of late-onset complications if we have not previously had any early complications was 4.96%. If the patient has previously had early complications the incidence of late-onset complications was 22.02%. If airway obstruction occurs, the risk of atelectasis increased from 6.88 to 22.58% (p = 0.002). If hypoxemia occurs, the incidence increased from 5.82 to 21.79% (p < 0.001). Based on our predictive models, we conclude that diabetes mellitus and preoperative anemia are two risk factors for early and late-onset postoperative pulmonary complications, respectively. Hypoxemia and airway obstruction in Post-Anesthesia Care Unit increased four times the risk of the development of pneumonia and atelectasis at 30 postoperative days.
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Obstrucción de las Vías Aéreas , Anestésicos , Bloqueo Neuromuscular , Enfermedades Neuromusculares , Atelectasia Pulmonar , Trastornos Respiratorios , Humanos , Bloqueo Neuromuscular/efectos adversos , Estudios de Cohortes , Atelectasia Pulmonar/epidemiología , Atelectasia Pulmonar/etiología , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/etiología , Trastornos Respiratorios/etiología , Enfermedades Neuromusculares/etiología , Hipoxia/etiología , Obstrucción de las Vías Aéreas/etiologíaRESUMEN
BACKGROUND: Spine abnormalities are a common manifestation of Neurofibromatosis Type 1 (NF1); however, the outcomes of surgical treatment for NF1-associated spinal deformity are not well explored. The purpose of this study was to investigate the outcome and risk profiles of multilevel fusion surgery for NF1 patients. METHODS: The National Inpatient Sample was queried for NF1 and non-NF1 patient populations with neuromuscular scoliosis who underwent multilevel fusion surgery involving eight or more vertebral levels between 2004 and 2017. Multivariate regression modeling was used to explore the relationship between perioperative variables and pertinent outcomes. RESULTS: Of the 55,485 patients with scoliosis, 533 patients (0.96%) had NF1. Patients with NF1 were more likely to have comorbid solid tumors (P < 0.0001), clinical depression (P < 0.0001), peripheral vascular disease (P < 0.0001), and hypertension (P < 0.001). Following surgery, NF1 patients had a higher incidence of hydrocephalus (0.6% vs. 1.9% P = 0.002), seizures (4.9% vs. 5.7% P = 0.006), and accidental vessel laceration (0.3% vs.1.9% P = 0.011). Although there were no differences in overall complication rates or in-hospital mortality, multivariate regression revealed NF1 patients had an increased probability of pulmonary (OR 0.5, 95%CI 0.3-0.8, P = 0.004) complications. There were no significant differences in utilization, including nonhome discharge or extended hospitalization; however, patients with NF1 had higher total hospital charges (mean -$18739, SE 3384, P < 0.0001). CONCLUSIONS: These findings indicate that NF1 is associated with certain complications following multilevel fusion surgery but does not appear to be associated with differences in quality or cost outcomes. These results provide some guidance to surgeons and other healthcare professionals in their perioperative decision making by raising awareness about risk factors for NF1 patients undergoing multilevel fusion surgery. We intend for this study to set the national baseline for complications after multilevel fusion in the NF1 population.
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Neurofibromatosis 1 , Enfermedades Neuromusculares , Escoliosis , Fusión Vertebral , Humanos , Escoliosis/cirugía , Neurofibromatosis 1/complicaciones , Complicaciones Posoperatorias/epidemiología , Hospitalización , Alta del Paciente , Fusión Vertebral/métodos , Enfermedades Neuromusculares/etiología , Estudios RetrospectivosRESUMEN
INTRODUCTION: Coronavirus disease 2019 patients hospitalized in intensive care units develop neuromuscular manifestations. However, to our knowledge, a study describing the neurophysiological findings in these patients has not been reported. The objective of this study was to diagnose the cause of neuromuscular deficit in severe coronavirus disease 2019 patients, through neurophysiological examination. METHODS: This is a retrospective, observational case series. Data were collected from April 13, 2020, to May 31, 2020. Twenty-two coronavirus disease 2019 patients with generalized neuromuscular deficit during intensive care unit hospitalization were studied. Neurophysiological examinations included motor and sensory peripheral nerve conductions, needle electromyography, F waves, and repetitive nerve stimulation. RESULTS: The subjects were 14 men (63.6%) and eight women, ranged from 35 to 74 years old (58.0, interquartile ranges 50.7-66.2). Intensive care unit hospitalization time ranged from 14 to 82 days (median 37.5, interquartile ranges 22.7-55.0). Through neurophysiological examination, myopathy was diagnosed in 17 patients (77.3%) and polyneuropathy in four (18.2%). Focal neuropathies were diagnosed in 12 patients (54.6%), with a total of 19 affected nerves. Common peroneal nerve lesions at the fibular head (68.4%) and ulnar nerve lesions at the elbow level (21.1%) were the most frequent locations. No significant differences were established between neurophysiological findings and clinical or analytical data. CONCLUSIONS: In critical coronavirus disease 2019 patients with neuromuscular complaints, neurophysiological examination provides an accurate diagnosis-useful to select treatment measures and establish the prognosis of recovery. Neurophysiological findings are similar to those described for critical illness neuromuscular disease, with myopathy being the most frequent diagnosis.
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COVID-19 , Enfermedades Musculares , Enfermedades Neuromusculares , Masculino , Humanos , Femenino , Adulto , Persona de Mediana Edad , Anciano , COVID-19/diagnóstico , Enfermedades Neuromusculares/etiología , Electromiografía/efectos adversos , Enfermedad Crítica , Nervio PeroneoRESUMEN
Although the references warn about the adverse effects of adding O2 without ventilatory assistance in patients with neuromuscular diseases (NMD), patients are still to be admitted to intensive care units with severe hypercapnia and CO2 narcosis. It seems that the problem is rediscovered as the years and generations go by. Unfortunately, many patients and their network of formal and informal caregivers are unaware of this risk, leading to significant worsening of symptoms, acute events, hospital admissions, and, in some cases, cause death. This article focuses on the dangers of O2 administration as well as its precise indications in people with NMD. The central problem is that the administration of O2 can remove the hypoxic impulse to ventilate, however, other mechanisms could be involved, but. The complete withdrawal of oxygen therapy is an even greater mistake if it is not supported by ventilatory assistance. It is possible to supply O2 and control CO2 safely. Oxygen should never be administered without constantly monitoring the CO2 level. Bi-level non-invasive ventilation (BiPAP) through a buccal, nasal interface or mouthpiece is the primary measure to reverse hypoventilation and achieve a decrease in PaCO2. The indications for oxygen therapy in people with NMD have been agreed upon and are reserved for specific situations. To improve the care of those with NMD and avoid iatrogenic interventions, education of the health team and support in the patient's environment is required.
A pesar de las referencias que advierten sobre los efectos adversos de la utilización de O2 suplementario sin asistencia ventilatoria en pacientes con enfermedades neuromusculares (ENM), aún hoy continúan ingresando pacientes en unidades de cuidados intensivos con hipercapnia grave y narcosis por CO2. Parecería que el problema es redescubierto según pasan los años y las generaciones. Muchos pacientes y su red de cuidadores formales e informales no son conscientes de este riesgo que puede llevar a un empeoramiento significativo de los síntomas, eventos agudos, ingresos hospitalarios y, en algunos casos, causar la muerte. Este artículo está centrado en los riesgos de la administración de O2, así como en sus indicaciones puntuales en personas con ENM. El problema central es que la administración de O2 puede quitar el impulso hipóxico para ventilar, aunque otros mecanismos podrían estar involucrados. El retiro completo de la oxigenoterapia sin apoyo de asistencia ventilatoria, es un error aún mayor. Es posible administrar O2 y controlar el CO2 de forma segura. Nunca se debe administrar O2 sin monitorear constantemente el nivel de CO2. La ventilación no invasiva binivelada (BiPAP) mediante interfaz nasal, bucal o boquilla, es la principal medida para revertir la hipoventilación y lograr el descenso de la PaCO2. Las indicaciones de oxigenoterapia en personas con ENM han sido consensuadas y están reservadas a situaciones específicas. Para mejorar la atención de aquellos enfermos con ENM y evitar intervenciones iatrogénicas, se requiere educación al equipo de salud y contención en el entorno del paciente.
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Enfermedades Neuromusculares , Oxígeno , Dióxido de Carbono , Humanos , Hipercapnia/etiología , Hipercapnia/terapia , Enfermedades Neuromusculares/etiología , Enfermedades Neuromusculares/terapia , Terapia por Inhalación de Oxígeno/efectos adversosRESUMEN
It is known that resistance exercise using one limb can affect motor function of both the exercised limb and the unexercised contralateral limb, a phenomenon termed cross-education. It has been suggested that cross-education has clinical implications, e.g. in rehabilitation for orthopaedic conditions or post-stroke paresis. Much of the research on the contralateral effect of unilateral intervention on motor output is based on voluntary exercise. This scoping review aimed to map the characteristics of current literature on the cross-education caused by three most frequently utilised peripheral neuromuscular stimulation modalities in this context: electrical stimulation, mechanical vibration and percutaneous needling, that may direct future research and translate to clinical practice. A systematic search of relevant databases (Ebsco, ProQuest, PubMed, Scopus, Web of Science) through to the end of 2020 was conducted following the PRISMA Extension for Scoping Review. Empirical studies on human participants that applied a unilateral peripheral neuromuscular stimulation and assessed neuromuscular function of the stimulated and/or the unstimulated side were selected. By reading the full text, the demographic characteristics, context, design, methods and major findings of the studies were synthesised. The results found that 83 studies were eligible for the review, with the majority (53) utilised electrical stimulation whilst those applied vibration (18) or needling (12) were emerging. Although the contralateral effects appeared to be robust, only 31 studies claimed to be in the context of cross-education, and 25 investigated on clinical patients. The underlying mechanism for the contralateral effects induced by unilateral peripheral stimulation remains unclear. The findings suggest a need to enhance the awareness of cross-education caused by peripheral stimulation, to help improve the translation of theoretical concepts to clinical practice, and aid in developing well-designed clinical trials to determine the efficacy of cross-education therapies.
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Terapia por Estimulación Eléctrica , Fenómenos Fisiológicos Musculoesqueléticos , Rehabilitación de Accidente Cerebrovascular/métodos , Terapia por Estimulación Eléctrica/métodos , Humanos , Enfermedades Neuromusculares/etiología , Enfermedades Neuromusculares/fisiopatología , Enfermedades Neuromusculares/terapia , Paresia/etiología , Paresia/fisiopatología , Paresia/terapia , Nervios Periféricos/fisiopatología , Modalidades de Fisioterapia , Accidente Cerebrovascular/complicaciones , Accidente Cerebrovascular/fisiopatología , Accidente Cerebrovascular/terapiaRESUMEN
BACKGROUND: The purpose of this study was to report mortality and associated risk factors in neuromuscular early onset scoliosis following spinal deformity surgery. METHODS: This is a multicenter retrospective cohort study of patients with cerebral palsy (CP), spinal muscular atrophy, myelodysplasia, muscular dystrophy, or myopathy undergoing index spine surgery from 1994 to 2020. Mortality risk was calculated up to 10 years postoperatively. Proportional hazard modeling was utilized to investigate associations between risk factors and mortality rate. RESULTS: A total of 808 patients [mean age 7.7 y; 439 (54.3%) female] were identified. Postoperative 30-day, 90-day, and 120-day mortality was 0%, 0.001%, and 0.01%, respectively. 1-year, 2-year, 5-year, and 10-year mortality was 0.5%, 1.1%, 5.4%, and 17.4%, respectively. Factors associated with increased mortality rate: CP diagnosis [hazard ratio (HR): 3.14, 95% confidence interval (CI): 1.71; 5.79, P<0.001]; nonambulatory status (HR: 3.01, 95% CI: 1.06; 8.5, P=0.04)]; need for respiratory assistance (HR: 2.17, 95% CI: 1.00; 4.69, P=0.05). CONCLUSIONS: In neuromuscular patients with early onset scoliosis, mortality risk at 10 years following spine surgery was 17.4%. As mortality was 1.1% at 2 years, premature death was unlikely a direct result of spine surgery. Diagnosis (CP) and markers of disease severity (nonambulatory status, respiratory assistance) were associated with increased mortality rate. LEVEL OF EVIDENCE: Prognostic level II.
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Parálisis Cerebral , Enfermedades Neuromusculares , Escoliosis , Fusión Vertebral , Niño , Femenino , Humanos , Enfermedades Neuromusculares/epidemiología , Enfermedades Neuromusculares/etiología , Estudios Retrospectivos , Escoliosis/cirugíaRESUMEN
Peripheral facial paralysis (PFP) has been shown to be a neurological manifestation of COVID-19. The current study presents two cases of PFP after COVID-19, along with a rapid review of known cases in the literature. Both case reports were conducted following CARE guidelines. We also performed a systematic review of PFP cases temporally related to COVID-19 using PubMed, Embase, and Cochrane Library databases on August 30, 2021, using a rapid review methodology. The two patients experienced PFP 102 and 110 days after COVID-19 symptom onset. SARS-CoV-2 RNA was detected in nasal samples through reverse-transcription real-time polymerase chain reaction (RT-qPCR) testing. Anosmia was the only other neurological manifestation. PFP was treated with steroids in both cases, with complete subsequent recovery. In the rapid review, we identified 764 articles and included 43 studies. From those, 128 patients with PFP were analyzed, of whom 42.1% (54/128) were male, 39.06% (50/128) female, and in 23 cases the gender was not reported. The age range was 18 to 59 (54.68%). The median time between COVID-19 and PFP was three days (ranging from the first symptom of COVID-19 to 40 days after the acute phase of infection). Late PFP associated with COVID-19 presents mild symptoms and improves with time, with no identified predictors. Late PFP should be added to the spectrum of neurological manifestations associated with the long-term effects of SARS-CoV-2 infection as a post COVID-19 condition.
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Humanos , Parálisis Facial/etiología , COVID-19/complicaciones , Enfermedades Neuromusculares/etiologíaAsunto(s)
Enfermedades Musculares , Enfermedades Desatendidas , Enfermedades Neuromusculares , Enfermedades Raras , Francia , Humanos , Investigación Interdisciplinaria , Enfermedades Musculares/diagnóstico , Enfermedades Musculares/etiología , Enfermedades Desatendidas/diagnóstico , Enfermedades Desatendidas/etiología , Enfermedades Neuromusculares/diagnóstico , Enfermedades Neuromusculares/etiología , Enfermedades Neuromusculares/genética , Enfermedades Raras/diagnóstico , Enfermedades Raras/etiología , Sociedades MédicasRESUMEN
Lipodystrophy syndromes are rare complex multisystem disorders caused by generalized or partial lack of adipose tissue. Adipose tissue dysfunction in lipodystrophy is associated with leptin deficiency. Lipodystrophy leads to severe metabolic problems. These abnormalities include, but are not limited to, insulin-resistant diabetes, severe hypertriglyceridemia, and lipid accumulation in ectopic organs such as the liver, and are associated with end-organ complications. Metabolic abnormalities can be present at the time of diagnosis or may develop over time as the disease progresses. In addition to metabolic abnormalities, subtype-specific presentations due to underlying molecular etiology in genetic forms and autoimmunity in acquired forms contribute to severe morbidity in lipodystrophy.
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Leptina/deficiencia , Lipodistrofia/complicaciones , Enfermedades Autoinmunes/etiología , Diabetes Mellitus/etiología , Cardiopatías/genética , Humanos , Hipertrigliceridemia/etiología , Resistencia a la Insulina , Enfermedades Renales/complicaciones , Metabolismo de los Lípidos , Lipodistrofia/genética , Lipodistrofia/metabolismo , Lipodistrofia/mortalidad , Hígado/metabolismo , Síndrome Metabólico/etiología , Enfermedades Neuromusculares/etiología , Enfermedad del Hígado Graso no Alcohólico/etiología , Pancreatitis/etiología , SíndromeRESUMEN
The complement cascade is a key arm of the immune system that protects the host from exogenous and endogenous toxic stimuli through its ability to potently regulate inflammation, phagocytosis, and cell lysis. Due to recent clinical trial successes and drug approvals for complement inhibitors, there is a resurgence in targeting complement as a therapeutic approach to prevent ongoing tissue destruction in several diseases. In particular, neuromuscular diseases are undergoing a recent focus, with demonstrated links between complement activation and disease pathology. This review aims to provide a comprehensive overview of complement activation and its role during the initiation and progression of neuromuscular disorders including myasthenia gravis, amyotrophic lateral sclerosis, and Duchenne muscular dystrophy. We will review the preclinical and clinical evidence for complement in these diseases, with an emphasis on the complement-targeting drugs in clinical trials for these indications.
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Miastenia Gravis , Enfermedades Neuromusculares , Activación de Complemento , Inactivadores del Complemento/uso terapéutico , Proteínas del Sistema Complemento , Humanos , Miastenia Gravis/tratamiento farmacológico , Enfermedades Neuromusculares/tratamiento farmacológico , Enfermedades Neuromusculares/etiologíaRESUMEN
Inflammasomes are molecular hubs that are assembled and activated by a host in response to various microbial and non-microbial stimuli and play a pivotal role in maintaining tissue homeostasis. The NLRP3 is a highly promiscuous inflammasome that is activated by a wide variety of sterile triggers, including misfolded protein aggregates, and drives chronic inflammation via caspase-1-mediated proteolytic cleavage and secretion of proinflammatory cytokines, interleukin-1ß and interleukin-18. These cytokines further amplify inflammatory responses by activating various signaling cascades, leading to the recruitment of immune cells and overproduction of proinflammatory cytokines and chemokines, resulting in a vicious cycle of chronic inflammation and tissue damage. Neuromuscular diseases are a heterogeneous group of muscle disorders that involve injury or dysfunction of peripheral nerves, neuromuscular junctions and muscles. A growing body of evidence suggests that dysregulation, impairment or aberrant NLRP3 inflammasome signaling leads to the initiation and exacerbation of pathological processes associated with neuromuscular diseases. In this review, we summarize the available knowledge about the NLRP3 inflammasome in neuromuscular diseases that affect the peripheral nervous system and amyotrophic lateral sclerosis, which affects the central nervous system. In addition, we also examine whether therapeutic targeting of the NLRP3 inflammasome components is a viable approach to alleviating the detrimental phenotype of neuromuscular diseases and improving clinical outcomes.
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Inflamasomas/metabolismo , Inflamación/patología , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Enfermedades Neuromusculares/patología , Animales , Humanos , Inflamación/complicaciones , Inflamación/metabolismo , Enfermedades Neuromusculares/etiología , Enfermedades Neuromusculares/metabolismoRESUMEN
Stonefish are regarded as one of the most venomous fish in the world. Research on stonefish venom has chiefly focused on the in vitro and in vivo neurological, cardiovascular, cytotoxic and nociceptive effects of the venom. The last literature review on stonefish venom was published over a decade ago, and much has changed in the field since. In this review, we have generated a global map of the current distribution of all stonefish (Synanceia) species, presented a table of clinical case reports and provided up-to-date information about the development of polyspecific stonefish antivenom. We have also presented an overview of recent advancements in the biomolecular composition of stonefish venom, including the analysis of transcriptomic and proteomic data from Synanceia horrida venom gland. Moreover, this review highlights the need for further research on the composition and properties of stonefish venom, which may reveal novel molecules for drug discovery, development or other novel physiological uses.
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Mordeduras y Picaduras/epidemiología , Mordeduras y Picaduras/terapia , Venenos de los Peces/envenenamiento , Peces Venenosos , Animales , Mordeduras y Picaduras/complicaciones , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/etiología , Enfermedades Cardiovasculares/terapia , Venenos de los Peces/análisis , Venenos de los Peces/química , Peces Venenosos/fisiología , Geografía , Humanos , Océano Índico/epidemiología , Enfermedades Neuromusculares/epidemiología , Enfermedades Neuromusculares/etiología , Enfermedades Neuromusculares/terapia , Océano Pacífico/epidemiologíaRESUMEN
The neuromuscular junction (NMJ) is the peripheral synapse formed between a motor neuron axon terminal and a muscle fibre. NMJs are thought to be the primary site of peripheral pathology in many neuromuscular diseases, but innervation/denervation status is often assessed qualitatively with poor systematic criteria across studies, and separately from 3D morphological structure. Here, we describe the development of 'NMJ-Analyser', to comprehensively screen the morphology of NMJs and their corresponding innervation status automatically. NMJ-Analyser generates 29 biologically relevant features to quantitatively define healthy and aberrant neuromuscular synapses and applies machine learning to diagnose NMJ degeneration. We validated this framework in longitudinal analyses of wildtype mice, as well as in four different neuromuscular disease models: three for amyotrophic lateral sclerosis (ALS) and one for peripheral neuropathy. We showed that structural changes at the NMJ initially occur in the nerve terminal of mutant TDP43 and FUS ALS models. Using a machine learning algorithm, healthy and aberrant neuromuscular synapses are identified with 95% accuracy, with 88% sensitivity and 97% specificity. Our results validate NMJ-Analyser as a robust platform for systematic and structural screening of NMJs, and pave the way for transferrable, and cross-comparison and high-throughput studies in neuromuscular diseases.
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Enfermedades Neuromusculares/etiología , Enfermedades Neuromusculares/metabolismo , Unión Neuromuscular/metabolismo , Animales , Biomarcadores , Estudios de Casos y Controles , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades , Técnica del Anticuerpo Fluorescente , Aprendizaje Automático , Ratones , Ratones Noqueados , Enfermedades Neuromusculares/diagnóstico , Unión Neuromuscular/patología , Proteína FUS de Unión a ARN/genética , Proteína FUS de Unión a ARN/metabolismo , Curva ROCRESUMEN
The advent of modern critical care medicine has revolutionized care of the critically ill patient in the last 50 years. The Society of Critical Care Medicine (was formed in recognition of the challenges and need for specialized treatment for these fragile patients. As the specialty has grown, it has achieved impressive scientific advances that have reduced mortality and saved lives. With those advances, however, came growing recognition that the burden of critical illness did not end at the doorstep of the hospital. Delirium, once thought to be a mere by-product of critical illness, was found to be an independent predictor of mortality, prolonged mechanical ventilation, and long-lasting cognitive impairment. Similarly, deep sedation and immobility, so often used to keep patients "comfortable" and to facilitate mechanical ventilation and recovery, worsen mortality and lead to the development of ICU-acquired weakness. The realization that these outcomes are inextricably linked to one another and how we manage our patients has helped us recognize the need for culture change. We, as a specialty, now understand that although celebrating the successes of survival, we now also have a duty to focus on those who survive their diseases. Led by initiatives such as the ICU Liberation Campaign of the Society of Critical Care Medicine, the natural progression of the field is now focused on getting patients back to their homes and lives unencumbered by disability and impairment. Much work remains to be done, but the futures of our most critically ill patients will continue to benefit if we leverage and build on the history of our first 50 years.
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Enfermedad Crítica/terapia , Delirio/etiología , Demencia/etiología , Fragilidad/etiología , Supervivencia , Astenia/etiología , Cuidados Críticos/métodos , Humanos , Enfermedad Iatrogénica/prevención & control , Unidades de Cuidados Intensivos , Enfermedades Neuromusculares/etiología , Factores de RiesgoRESUMEN
Diabetic sensorimotor peripheral neuropathy (DSPN) is a serious complication of diabetes mellitus and is associated with increased mortality, lower-limb amputations and distressing painful neuropathic symptoms (painful DSPN). Our understanding of the pathophysiology of the disease has largely been derived from animal models, which have identified key potential mechanisms. However, effective therapies in preclinical models have not translated into clinical trials and we have no universally accepted disease-modifying treatments. Moreover, the condition is generally diagnosed late when irreversible nerve damage has already taken place. Innovative point-of-care devices have great potential to enable the early diagnosis of DSPN when the condition might be more amenable to treatment. The management of painful DSPN remains less than optimal; however, studies suggest that a mechanism-based approach might offer an enhanced benefit in certain pain phenotypes. The management of patients with DSPN involves the control of individualized cardiometabolic targets, a multidisciplinary approach aimed at the prevention and management of foot complications, and the timely diagnosis and management of neuropathic pain. Here, we discuss the latest advances in the mechanisms of DSPN and painful DSPN, originating both from the periphery and the central nervous system, as well as the emerging diagnostics and treatments.
Asunto(s)
Neuropatías Diabéticas/diagnóstico , Neuropatías Diabéticas/etiología , Neuropatías Diabéticas/terapia , Amputación Quirúrgica/mortalidad , Amputación Quirúrgica/estadística & datos numéricos , Animales , Neuropatías Diabéticas/mortalidad , Humanos , Neuralgia/diagnóstico , Neuralgia/etiología , Neuralgia/mortalidad , Neuralgia/terapia , Enfermedades Neuromusculares/diagnóstico , Enfermedades Neuromusculares/etiología , Enfermedades Neuromusculares/mortalidad , Enfermedades Neuromusculares/terapia , Enfermedades del Sistema Nervioso Periférico/diagnóstico , Enfermedades del Sistema Nervioso Periférico/etiología , Enfermedades del Sistema Nervioso Periférico/mortalidad , Enfermedades del Sistema Nervioso Periférico/terapiaRESUMEN
The diagnosis of neuromuscular diseases (NMDs) has been progressively evolving from the grouping of clinical symptoms and signs towards the molecular definition. Optimal clinical, biochemical, electrophysiological, electrophysiological, and histopathological characterization is very helpful to achieve molecular diagnosis, which is essential for establishing prognosis, treatment and genetic counselling. Currently, the genetic approach includes both the gene-targeted analysis in specific clinically recognizable diseases, as well as genomic analysis based on next-generation sequencing, analyzing either the clinical exome/genome or the whole exome or genome. However, as of today, there are still many patients in whom the causative genetic variant cannot be definitely established and variants of uncertain significance are often found. In this review, we address these drawbacks by incorporating two additional biological omics approaches into the molecular diagnostic process of NMDs. First, functional genomics by introducing experimental cell and molecular biology to analyze and validate the variant for its biological effect in an in-house translational diagnostic program, and second, incorporating a multi-omics approach including RNA-seq, metabolomics, and proteomics in the molecular diagnosis of neuromuscular disease. Both translational diagnostics programs and omics are being implemented as part of the diagnostic process in academic centers and referral hospitals and, therefore, an increase in the proportion of neuromuscular patients with a molecular diagnosis is expected. This improvement in the process and diagnostic performance of patients will allow solving aspects of their health problems in a precise way and will allow them and their families to take a step forward in their lives.
Asunto(s)
Biomarcadores , Técnicas de Diagnóstico Molecular , Enfermedades Neuromusculares/diagnóstico , Alelos , Animales , Susceptibilidad a Enfermedades , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Genómica/métodos , Humanos , Metabolómica/métodos , Técnicas de Diagnóstico Molecular/métodos , Enfermedades Neuromusculares/etiología , Fenotipo , Proteómica/métodos , Investigación Biomédica TraslacionalAsunto(s)
Insuficiencia Cardíaca/terapia , Enfermedades Neuromusculares/terapia , Insuficiencia Renal/terapia , Apnea Central del Sueño/complicaciones , Apnea Central del Sueño/diagnóstico , Apnea Central del Sueño/fisiopatología , Apnea Central del Sueño/terapia , Accidente Cerebrovascular/terapia , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Insuficiencia Cardíaca/etiología , Humanos , Masculino , Persona de Mediana Edad , Enfermedades Neuromusculares/etiología , Polisomnografía/métodos , Insuficiencia Renal/etiología , Factores de Riesgo , Accidente Cerebrovascular/etiologíaRESUMEN
OBJECTIVE: We report the findings from the Spanish Society of Neurology's NeuroCOVID-19 Registry. METHODS: We performed a multicentre study of patients with neurological manifestations of COVID-19. Participating physicians reported demographic, clinical, and paraclinical data and judged the involvement of COVID-19 in causing neurological symptoms. RESULTS: A total of 233 cases were submitted, including 74 different combinations of manifestations. The most frequently reported were stroke (27%), neuromuscular symptoms (23.6%), altered mental status (23.6%), anosmia (17.6%), headache (12.9%), and seizures (11.6%). The mean age of patients was 61.1 years, with 42.1% being women; a higher proportion of women was recorded among patients with altered mental status, anosmia, and headache. The onset of symptoms differed within categories. Onset of anosmia occurred a mean (standard deviation) of 2.9 (2.5) days after the first general symptom, whereas neuromuscular symptoms appeared after 13.9 (10.1) days. Neurological symptoms were persistent in 33% of patients. General symptoms were present in 97.7% of patients, and results from general laboratory studies were abnormal in 99.4% of patients. Cerebrospinal fluid analysis findings were abnormal in 62.7% of the cases in which this test was performed (n = 51), but positive results for SARS-CoV-2 were only found in one case. CONCLUSIONS: The neurological manifestations of COVID-19 are diverse. Anosmia, myalgia, and headache occur earlier in the course of the disease. Altered mental status, neuromuscular symptoms, and stroke are associated with greater severity. COVID-19 must be incorporated into most clinical and radiological differential diagnoses. COVID-19 may cause persistent and disabling neurological symptoms.