RESUMEN
A 46-year-old man with neck pain and impaired physical mobility called for emergency medical services. The patient was able to communicate with the emergency medical team upon their arrival. However, he went into cardiopulmonary arrest 5 minutes later. Cardiopulmonary resuscitation was immediately performed, and the patient was admitted to our hospital with a Glasgow Coma Scale score of E1V1M1. His respiratory rate was 5 breaths/minute and his partial pressure of carbon dioxide in arterial blood (PaCO2) was 127â |mmHg, necessitating intubation and ventilation. His consciousness improved as the PaCO2 level decreased. However, he was unable to be weaned off the ventilator and breathe independently. Neurological examination revealed flaccid quadriplegia, pain sensation up to the C5 level, absence of deep tendon reflexes, indifferent plantar responses, and absence of the rectoanal inhibitory reflex. Magnetic resonance imaging showed a hyperintense lesion with slight enlargement of the anterior two-thirds of the spinal cord at the C2-C4 level on both T2-weighted and diffusion-weighted images, consistent with a diagnosis of spinal cord infarction. Although the quadriplegia and sensory loss partially improved, the patient was unable to be weaned from the ventilator. Cervical cord infarction of the anterior spinal artery can cause rapid respiratory failure leading to cardiopulmonary arrest. Therefore, cervical cord infarction should be included as a differential diagnosis when examining patients after cardiopulmonary resuscitation.
Asunto(s)
Paro Cardíaco , Infarto , Humanos , Masculino , Persona de Mediana Edad , Paro Cardíaco/etiología , Paro Cardíaco/terapia , Infarto/etiología , Infarto/diagnóstico , Médula Cervical/diagnóstico por imagen , Reanimación Cardiopulmonar , Insuficiencia Respiratoria/etiología , Insuficiencia Respiratoria/terapia , Imagen por Resonancia MagnéticaRESUMEN
According to previous reports, most cases of inflammatory myopathy following messenger RNA (mRNA) vaccination can be classified as idiopathic inflammatory myopathy, particularly dermatomyositis, owing to their similar clinical features and courses. However, some patients have different clinical features and courses. We report a rare case of transient inflammatory myopathy involving the masseter muscle following the third dose of coronavirus disease 2019 (COVID-19) mRNA vaccination. An 80-year-old woman presented with a history of fever and fatigue for 3 months soon after receiving the third COVID-19 mRNA vaccination. Her symptoms progressed to jaw pain and inability to open her mouth. She also experienced mild proximal muscle weakness in the lower limbs but no skin manifestations or daily difficulties. Fat-saturated T2-weighted magnetic resonance imaging showed bilateral high-intensity signals for the masseter and quadriceps muscles. The patient experienced spontaneous resolution of fever and improvement of symptoms 5 months after onset. The timing of the onset of symptoms, the lack of detectable autoantibodies, and the atypical presentation of myopathy in the masseter muscles, in addition to the spontaneous mild course of the disease, all indicate the substantial role of mRNA vaccination in this myopathy. Since then, the patient has been followed up for 4 months without any recurrence of symptoms or any additional treatment. It is important to recognise that the course of myopathy after COVID-19 mRNA vaccination could be different from that of typical idiopathic inflammatory myopathies.
Asunto(s)
COVID-19 , Enfermedades Musculares , Miositis , Femenino , Humanos , Anciano de 80 o más Años , Músculo Masetero , COVID-19/diagnóstico , COVID-19/prevención & control , Miositis/diagnóstico , Enfermedades Musculares/diagnóstico , AutoanticuerposRESUMEN
Lipid interaction with α-synuclein (αSyn) has been long implicated in the pathogenesis of Parkinson's disease (PD). However, it has not been fully determined which lipids are involved in the initiation of αSyn aggregation in PD. Here exploiting genetic understanding associating the loss-of-function mutation in Synaptojanin 1 (SYNJ1), a phosphoinositide phosphatase, with familial PD and analysis of postmortem PD brains, we identified a novel lipid molecule involved in the toxic conversion of αSyn and its relation to PD. We first established a SYNJ1 knockout cell model and found SYNJ1 depletion increases the accumulation of pathological αSyn. Lipidomic analysis revealed SYNJ1 depletion elevates the level of its substrate phosphatidylinositol-3,4,5-trisphosphate (PIP3). We then employed Caenorhabditis elegans model to examine the effect of SYNJ1 defect on the neurotoxicity of αSyn. Mutations in SYNJ1 accelerated the accumulation of αSyn aggregation and induced locomotory defects in the nematodes. These results indicate that functional loss of SYNJ1 promotes the pathological aggregation of αSyn via the dysregulation of its substrate PIP3, leading to the aggravation of αSyn-mediated neurodegeneration. Treatment of cultured cell line and primary neurons with PIP3 itself or with PIP3 phosphatase inhibitor resulted in intracellular formation of αSyn inclusions. Indeed, in vitro protein-lipid overlay assay validated that phosphoinositides, especially PIP3, strongly interact with αSyn. Furthermore, the aggregation assay revealed that PIP3 not only accelerates the fibrillation of αSyn, but also induces the formation of fibrils sharing conformational and biochemical characteristics similar to the fibrils amplified from the brains of PD patients. Notably, the immunohistochemical and lipidomic analyses on postmortem brain of patients with sporadic PD showed increased PIP3 level and its colocalization with αSyn. Taken together, PIP3 dysregulation promotes the pathological aggregation of αSyn and increases the risk of developing PD, and PIP3 represents a potent target for intervention in PD.
Asunto(s)
Enfermedad de Parkinson , Humanos , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismo , Encéfalo/patología , Lípidos , Neuronas/patología , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/metabolismo , Fosfatos de Fosfatidilinositol/metabolismoRESUMEN
Parkinson's disease is a neurodegenerative disease characterized by the formation of neuronal inclusions of α-synuclein in patient brains. As the disease progresses, toxic α-synuclein aggregates transmit throughout the nervous system. No effective disease-modifying therapy has been established, and preventing α-synuclein aggregation is thought to be one of the most promising approaches to ameliorate the disease. In this study, we performed a two-step screening using the thioflavin T assay and a cell-based assay to identify α-synuclein aggregation inhibitors. The first screening, thioflavin T assay, allowed the identification of 30 molecules, among a total of 1262 FDA-approved small compounds, which showed inhibitory effects on α-synuclein fibrilization. In the second screening, a cell-based aggregation assay, seven out of these 30 candidates were found to prevent α-synuclein aggregation without causing substantial toxicity. Of the seven final candidates, tannic acid was the most promising compound. The robustness of our screening method was validated by a primary neuronal cell model and a Caenorhabditis elegans model, which demonstrated the effect of tannic acid against α-synuclein aggregation. In conclusion, our two-step screening system is a powerful method for the identification of α-synuclein aggregation inhibitors, and tannic acid is a promising candidate as a disease-modifying drug for Parkinson's disease.
Asunto(s)
Antiparkinsonianos/farmacología , Ensayos Analíticos de Alto Rendimiento , Neuronas/efectos de los fármacos , Enfermedad de Parkinson/tratamiento farmacológico , Agregación Patológica de Proteínas , Taninos/farmacología , alfa-Sinucleína/metabolismo , Animales , Animales Modificados Genéticamente , Antiparkinsonianos/toxicidad , Benzotiazoles/química , Bioensayo , Caenorhabditis elegans/efectos de los fármacos , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Modelos Animales de Enfermedad , Reposicionamiento de Medicamentos , Células HeLa , Humanos , Ratones Endogámicos C57BL , Neuronas/metabolismo , Neuronas/patología , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/patología , Agregado de Proteínas , Espectrometría de Fluorescencia , Taninos/toxicidad , alfa-Sinucleína/genética , alfa-Sinucleína/ultraestructuraRESUMEN
We report an autopsy case of amyotrophic lateral sclerosis with L126S mutation in the superoxide dismutase 1 (SOD1) gene (SOD1). The patient was a 69-year-old Japanese man without relevant family history, who initially presented with slow progressive muscle weakness of the lower extremities without upper motor neuron signs, and died of respiratory failure 6 years after the onset. Neuropathological examination revealed a loss of lower motor neurons and degeneration of Clarke's column commensurate with that of the posterior spinocerebellar tract and the middle root zone of the posterior column. The primary motor area was minimally affected. Characteristic SOD1-immunopositive neuronal intracytoplasmic inclusions, mixed with neurofilament accumulation, were present in the affected areas. Isolated inferior olivary hypertrophy was observed, but did not involve the contralateral dentate nucleus, or the ipsilateral red nucleus and central tegmental tract, where no neuronal inclusions were found. In combination with data from a previous autopsy case, this study suggests that the L126S mutation may cause focal neuronal degeneration in the brainstem.
Asunto(s)
Esclerosis Amiotrófica Lateral/genética , Esclerosis Amiotrófica Lateral/patología , Núcleo Olivar/patología , Superóxido Dismutasa-1/genética , Anciano , Autopsia , Humanos , Hipertrofia , Masculino , MutaciónRESUMEN
We analyzed 14 patients in our hospital, who underwent levodopa-carbidopa intestinal gel (LCIG) treatment through a percutaneous endoscopic gastrojejunostomy (PEG-J). The PEG-J related complications were observed in 10 patients (71.4%). Detailed complications are as followings: J-tube related complications such as kinking (3 cases, 21.4%), pump malfunctions (3 cases, 21.4%), skin troubles in the gastrostoma (7 cases, 50.0%), duodenal perforation, peritonitis, and ulcers (2 cases, 14.3%). These results indicated that the sufficient care for PEG-J associated complications are important in LCIG treatment.
Asunto(s)
Antiparkinsonianos/administración & dosificación , Carbidopa/administración & dosificación , Endoscopía Gastrointestinal/efectos adversos , Gastrostomía/efectos adversos , Yeyunostomía/efectos adversos , Levodopa/administración & dosificación , Enfermedad de Parkinson/tratamiento farmacológico , Adulto , Anciano , Combinación de Medicamentos , Enfermedades Duodenales/epidemiología , Enfermedades Duodenales/etiología , Úlcera Duodenal/epidemiología , Úlcera Duodenal/etiología , Endoscopía Gastrointestinal/instrumentación , Endoscopía Gastrointestinal/métodos , Femenino , Gastrostomía/instrumentación , Gastrostomía/métodos , Geles , Humanos , Perforación Intestinal/epidemiología , Perforación Intestinal/etiología , Yeyunostomía/instrumentación , Yeyunostomía/métodos , Masculino , Persona de Mediana Edad , Peritonitis/epidemiología , Peritonitis/etiología , Estudios Retrospectivos , Enfermedades de la Piel/epidemiología , Enfermedades de la Piel/etiología , Estomas QuirúrgicosRESUMEN
The ubiquitin-proteasome system (UPS) plays a fundamental role in regulating various biological activities. Ubiquitin C-terminal hydrolase L1 (UCH-L1) is a deubiquitinating enzyme, belonging to the UPS. To date, it has been reported that UCH-L1 is highly and restrictedly expressed in neural and reproductive tissues and plays significant roles in these organs. Although the expression of UCH-L1 in the anterior pituitary gland has been reported, the detailed localization and the role of UCH-L1 remain obscure. In the present study, we detected UCH-L1 protein exclusively in hormone-producing cells, but not non-hormone producing folliculostellate cells in the anterior pituitary lobe. In addition, the cytoplasmic expression of UCH-L1 varied and was limited to gonadotropes and mammotropes. To investigate the role of UCH-L1 in anterior pituitary cells, we performed a comparative analysis using genetically UCH-L1-deficient gad mice. Significant decreases in the numbers of gonadotropes and mammotropes were observed in gad mice, suggesting a close involvement of UCH-L1 in these cells. Moreover, we also determined the expression of UCH-L1 in cultured gonadotropes. Taken together, this is the first report to definitely demonstrate the presence of UCH-L1 in mouse anterior pituitary gland, and our results might provide a novel insight for better understanding the role of UCH-L1 in the hypothalamic-pituitary-gonadal axis and in the reproduction.
Asunto(s)
Gonadotrofos/enzimología , Ubiquitina Tiolesterasa/metabolismo , Ubiquitina Tiolesterasa/fisiología , Animales , Línea Celular , Gónadas/fisiología , Hipotálamo/fisiología , Masculino , Ratones , Ratones Endogámicos ICR , Hipófisis/fisiología , Adenohipófisis/citología , Adenohipófisis/enzimología , Reproducción/genéticaRESUMEN
Atherosclerosis is thought to be associated with endoplasmic reticulum (ER) dysfunction and the accumulation of unfolded proteins. In this study, we examined the relationship between atherosclerosis and ER stress and the effect of sodium 4-phenylbutyrate (4-PBA), a kind of chemical chaperone, on atherosclerosis in streptozotocin-induced diabetic APA hamsters. Male, 8-week-old, APA hamsters were injected with streptozotocin (30 mg/kg body weight) to induce diabetes mellitus, and ER stress was evaluated immunohistochemically or by semi-quantitative RT-PCR analysis using ER stress markers such as calreticulin and GPR78. Control hamsters were injected with citrate buffer and were similarly analyzed. In the aorta of control animals, a weak ER stress was detected, and 4-PBA treatment decreased the calreticulin- and GRP78-positive areas and also reduced the mRNA levels of calreticulin and GRP78. On the other hand, strong ER stress was detected at the lesser curvature of the aortic arch of streptozotocin-induced diabetic APA hamsters. However, 4-PBA treatment failed to lessen the ER stress in the aorta and had no effect on improvement of the atherosclerotic lesions. These results may provide an explanation for the complex etiology of atherosclerosis accompanied by diabetes mellitus and various other clinical phenotypes of atherosclerosis.
Asunto(s)
Aorta Abdominal/metabolismo , Aterosclerosis/metabolismo , Diabetes Mellitus Experimental/metabolismo , Retículo Endoplásmico/metabolismo , Estrés Oxidativo/fisiología , Animales , Antineoplásicos/farmacología , Aorta Abdominal/efectos de los fármacos , Aorta Abdominal/patología , Aterosclerosis/genética , Aterosclerosis/patología , Calreticulina/genética , Calreticulina/metabolismo , Cricetinae , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/patología , Retículo Endoplásmico/efectos de los fármacos , Técnica del Anticuerpo Fluorescente Indirecta , Procesamiento de Imagen Asistido por Computador , Masculino , Estrés Oxidativo/efectos de los fármacos , Fenilbutiratos/farmacología , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , EstreptozocinaRESUMEN
Protein degradation is essential for oogenesis and embryogenesis. The ubiquitin-proteasome system regulates many cellular processes via the rapid degradation of specific proteins. Ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1) is exclusively expressed in neurons, testis, ovary, and placenta, each of which has unique biological activities. However, the functional role of UCH-L1 in mouse oocytes remains unknown. Here, we report the expression pattern of UCH-L1 and its isozyme UCH-L3 in mouse ovaries and embryos. Using immunocytochemistry, UCH-L1 was selectively detected on the plasma membrane, whereas UCH-L3 was mainly detected in the cytoplasm, suggesting that these isozymes have distinct functions in mouse eggs. To further investigate the functional role of UCH-L1 in mouse eggs, we analyzed the fertilization rate of UCH-L1-deficient ova of gad female mice. Female gad mice had a significantly increased rate of polyspermy in in vitro fertilization assays, although the rate of fertilization did not differ significantly from wild-type mice. In addition, the litter size of gad female mice was significantly reduced compared with wild-type mice. These results may identify UCH-L1 as a candidate for a sperm-oocyte interactive binding or fusion protein on the plasma membrane that functions during the block to polyspermy in mouse oocytes.