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BACKGROUND: Heat stroke (HS) is a critical illness that can cause multiple organ dysfunction, including damage to the central nervous system (CNS), which can be life-threatening in severe cases. Brain lesions in patients with HS who present with CNS damage have been rarely reported before, and they usually vary in different cases, hence, patients with such lesions may present a clinical challenge in terms of diagnosis and management. Cerebral venous thrombosis (CVT) is a rare cause of stroke that mostly affects young individuals and children. The pathogenesis of brain damage caused by HS is complex, and CVT may be involved in the pathogenesis of HS with CNS damage. In this manuscript, we have reported a case of a patient with HS having CVT with symmetrical lesions in the bilateral putamen, posterior limb of the internal capsule, external capsule, insular lobe, and subcortical white matter in the brain. CASE PRESENTATION: We encountered a 48-year-old man who presented with HS in the summer season. During admission, he had a high body temperature and was in coma and shock. Then, he developed rhabdomyolysis syndrome, acute kidney and liver damage, electrolyte imbalance, and acid-base balance disorders, and his D-dimer level was elevated. After several days of anti-shock treatment, the patient's level of consciousness improved. However, he experienced a decline in vision. Cerebral magnetic resonance imaging (MRI) showed symmetrical lesions in the bilateral posterior limb of the internal capsule, putamen, external capsule, insula, and subcortical white matter, and cerebral magnetic resonance venography (MRV) showed the development of CVT. Therefore, anti-coagulation treatment was provided. After timely clinical intervention, the symptoms of the patient gradually improved. CONCLUSIONS: This case showed that HS can cause CVT. Therefore, cerebral MRI findings in HS must be assessed; in addition, early MRV can help in the diagnosis of the disease, which can effectively improve prognosis.
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Golpe de Calor/complicaciones , Golpe de Calor/diagnóstico por imagen , Golpe de Calor/patología , Trombosis Intracraneal/diagnóstico por imagen , Trombosis Intracraneal/etiología , Trombosis Intracraneal/patología , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Humanos , Imagen por Resonancia Magnética/métodos , Masculino , Persona de Mediana Edad , Flebografía/métodosRESUMEN
Parkinson's disease (PD) is one of the most common nervous system degenerative diseases. However, the etiology of this disease remains elusive. Here, a proteasome inhibitor (PSI)-induced undifferentiated SH-SY5Y PD model was established to analyze protein alterations through proteomic study. METHODS: Cultured undifferentiated SH-SY5Y cells were divided into a control group and a group treated with 2.5 µM PSI (PSI-treated group). An methyl thiazolyl tetrazolium (MTT) assay was applied to detect cell viability. Acridine orange/ethidium bromide (AO/EB), α-synuclein immunofluorescence and hematoxylin and eosin (H&E) staining were applied to evaluate apoptosis and cytoplasmic inclusions, respectively. The protein spots that were significantly changed were separated, analyzed by 2D gel electrophoresis and DIGE De Cyder software, and subsequently identified by MALDI-TOF mass spectrometry and database searching. RESULTS: The results of the MTT assay showed that there was a time and dose dependent change in cell viability following incubation with PSI. After 24 h incubation, PSI resulted in early apoptosis, and cytoplasmic inclusions were found in the PSI-treated group through H&E staining and α-synuclein immunofluorescence. Thus, undifferentiated SH-SY5Y cells could be used as PD model following PSI-induced inhibition of proteasomal function. In total, 18 proteins were differentially expressed between the groups, 7 of which were up-regulated and 11 of which were down-regulated. Among them, 5 protein spots were identified as being involved in the ubiquitin proteasome pathway-induced PD process. CONCLUSIONS: Mitochondrial heat shock protein 75 (MTHSP75), phosphoglycerate dehydrogenase (PHGDH), laminin binding protein (LBP), tyrosine 3/tryptophan 5-monooxygenase activation protein (14-3-3ε) and YWHAZ protein (14-3-3ζ) are involved in mitochondrial dysfunction, serine synthesis, amyloid clearance, apoptosis process and neuroprotection. These findings may provide new clues to deepen our understanding of PD pathogenesis.
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Enfermedad de Parkinson/metabolismo , Inhibidores de Proteasoma/farmacología , Proteómica , Proteínas 14-3-3/metabolismo , Apoptosis/efectos de los fármacos , Proteínas Portadoras/metabolismo , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Regulación hacia Abajo , Proteínas de Choque Térmico/metabolismo , Humanos , Cuerpos de Inclusión/efectos de los fármacos , Laminina/metabolismo , Enfermedad de Parkinson Secundaria/metabolismo , Fosfoglicerato-Deshidrogenasa/metabolismo , Complejo de la Endopetidasa Proteasomal/metabolismo , Ubiquitina/metabolismoRESUMEN
Cortical spreading depression (CSD), based on its similarities with peri-infarct depolarization, is an ideal model for investigating transformation from the ischemic penumbra to infarct core. However, the underlying mechanisms remain unclear. To our knowledge, this is the first study to use a middle cerebral artery occlusion ischemic-reperfusion (I/R) injury model to determine whether AMP-activated protein kinase (AMPK)-dependent autophagy contributes to the neuroprotection of CSD preconditioning in rat cortex. In this study, we topically applied a pledget soaked in 1 mol/L KCl solution on rat cortex for 2 h to elicite CSD or 1 mol/L NaCl solution as a control. The results demonstrated that CSD preconditioning significantly decreased the infarct volume, neurological deficits and neuronal apoptosis in the cortical penumbra of middle cerebral artery occlusion rats, which was inhibited by the autophagy inhibitor 3-methyladenine (3-MA, 200 nmol). Furthermore, CSD increased the protein levels of the autophagy markers LC3-II, Beclin-1 and the p-AMPK (Thr172 )/AMPK ratio at 12 h and decreased P62 and p-P70S6K (Thr389 ). Moreover, the AMPK inhibitor Compound C (20 mg/kg) down-regulated the LC3-II, p-AMPK (Thr172 )/AMPK and ULK1 levels, up-regulated the P62 and p-P70S6K (Thr389 ) levels induced by CSD. The neuroprotection of CSD is likely a result of AMPK-mediated autophagy activity and autophagy-induced neuronal cells apoptosis inhibition. These novel findings support a central role for AMPK and autophagy in CSD-induced ischemic tolerance. AMPK-mediated autophagy may represent a new target for stroke.
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Proteínas Quinasas Activadas por AMP/metabolismo , Autofagia , Isquemia Encefálica/patología , Depresión de Propagación Cortical/fisiología , Precondicionamiento Isquémico , Neuroprotección , Daño por Reperfusión/prevención & control , Accidente Cerebrovascular/patología , Proteínas Quinasas Activadas por AMP/antagonistas & inhibidores , Adenina/análogos & derivados , Adenina/farmacología , Animales , Conducta Animal , Isquemia Encefálica/metabolismo , Isquemia Encefálica/psicología , Infarto Cerebral/patología , Depresión de Propagación Cortical/efectos de los fármacos , Infarto de la Arteria Cerebral Media/patología , Masculino , Enfermedades del Sistema Nervioso/etiología , Enfermedades del Sistema Nervioso/patología , Enfermedades del Sistema Nervioso/psicología , Cloruro de Potasio/farmacología , Ratas , Ratas Wistar , Daño por Reperfusión/metabolismo , Daño por Reperfusión/patología , Accidente Cerebrovascular/metabolismoRESUMEN
BACKGROUND: Hashimoto's encephalitis (HE) is a rare neurological complication of Hashimoto's thyroiditis (HT), while limbic encephalitis (LE) is an autoimmune inflammatory disorder frequently associated with anti-neuronal antibodies. The glutamate receptor α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor (AMPAR) is important for synaptic transmission, memory, and learning. The etiology of HE remains unclear. We present a case of HE with antibodies to AMPAR2 both in the serum and cerebrospinal fluid. CASE PRESENTATION: The patient presented with progressive memory loss and subsequently went into a coma. Magnetic resonance imaging revealed temporal lobe and hippocampal lesions, while the electrocardiogram showed paroxysmal delta waves. Elevated serum levels of antibodies against thyroid globulin, thyroid peroxidase, and thyroid stimulating receptor were also noted. Ultrasonography showed enlargement of the thyroid gland. Therefore, the diagnosis was established as HE. Both the CSF and serum samples of the patient tested positive for antibodies to the cell-surface antigen AMPAR2. Intravenous injection of immunoglobulin followed by dexamethasone treatment resulted in recovery from the coma. Follow-up examination three months later showed some improvement of memory. To our knowledge, this is the first report on the detection of AMPAR2 antibodies in HE. CONCLUSIONS: Our findings suggest that antibodies to AMPAR2 may be involved in the pathogenesis of HE. Elevated levels of thyroid antibodies possibly cause immune dysfunction, leading to the production of anti-AMPAR2 antibodies that are detrimental to the neurons. We believe that encephalitis patients with thyroid abnormalities should undergo screening for anti-neuronal antibodies, and early immune therapy may improve prognosis.
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Autoanticuerpos/inmunología , Encefalitis/inmunología , Enfermedad de Hashimoto/inmunología , Receptores AMPA/inmunología , Autoanticuerpos/sangre , Autoanticuerpos/líquido cefalorraquídeo , Autoantígenos/inmunología , Encefalitis/sangre , Encefalitis/líquido cefalorraquídeo , Encefalitis/diagnóstico por imagen , Femenino , Enfermedad de Hashimoto/sangre , Enfermedad de Hashimoto/líquido cefalorraquídeo , Enfermedad de Hashimoto/diagnóstico por imagen , Humanos , Yoduro Peroxidasa/inmunología , Proteínas de Unión a Hierro/inmunología , Encefalitis Límbica/complicaciones , Imagen por Resonancia Magnética , Persona de Mediana Edad , Neuronas/inmunología , Receptores de Tirotropina/inmunología , Tiroglobulina/inmunologíaRESUMEN
Although plasma levels of lysophosphatidylglycerol (LPG) are increased in hypertension, its role in the pathogenesis of vascular defects is not clear. In view of the importance of Ca2+ overload in causing vascular smooth muscle (VSM) dysfunction, the action of LPG on [Ca2+]i in cultured A10 VSM cell line was examined by using Fura 2-AM acetoxymethyl ester technique. LPG was found to induce a concentration-dependent increase in [Ca2+]i in VSM cells. This change was dependent both on the extracellular and intracellular Ca2+ sources, as it was reduced by 30% by EGTA, an extracellular Ca2+ chelator, and 70% by thapsigargin, a sarcoplasmic reticulum (SR) Ca2+-pump inhibitor. However the increase in [Ca2+]i due to LPG was not altered by caffeine or ryanodine, which affect Ca2+-release through the ryanodine receptors in the SR. On the other hand, LPG-induced change in [Ca2+]i was suppressed by 2-nitro-4-carboxyphenyl N,N-diphenylcarbamate, a phospholipase C (PLC) inhibitor, as well as by xestospongin and 2-aminoethoxydiphenyl borate, two inositol trisphosphate (IP3) receptor inhibitors in the SR. These observations support the view that LPG-induced increase in [Ca2+]i in VSM cells is mainly a result of Ca2+ release from Ca2+ pool in the SR through PLC/IP3-sensitive signal transduction mechanism. Furthermore, it is suggested that the elevated level of LPG may induce intracellular Ca2+ overload and thus play a critical role in the development of vascular abnormalities.
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Calcio/metabolismo , Lisofosfolípidos/farmacología , Músculo Liso Vascular/efectos de los fármacos , Miocitos del Músculo Liso/efectos de los fármacos , Animales , Señalización del Calcio/efectos de los fármacos , Línea Celular , Relación Dosis-Respuesta a Droga , Receptores de Inositol 1,4,5-Trifosfato/metabolismo , Músculo Liso Vascular/metabolismo , Miocitos del Músculo Liso/metabolismo , Ratas , ATPasas Transportadoras de Calcio del Retículo Sarcoplásmico/metabolismo , Fosfolipasas de Tipo C/metabolismoRESUMEN
BACKGROUND: Resolution is the final stage of the inflammatory response, when restoration of tissue occurs. Failure may lead to chronic inflammation, which is known as part of the pathology in the brain of individuals with Alzheimer's disease (AD). METHODS: Specialized pro-resolving mediators (SPMs), receptors, biosynthetic enzyme, and downstream effectors involved in resolution were analyzed in postmortem hippocampal tissue from AD patients and non-AD subjects. SPMs were analyzed in cerebrospinal fluid (CSF). RESULTS: SPMs and SPM receptors were detected in the human brain. Levels of the SPM lipoxin A4 (LXA4) were reduced in AD, both in the CSF and hippocampus. An enzyme involved in LXA4 synthesis and two SPM receptors were elevated in AD brains. LXA4 and RvD1 levels in CSF correlated with Mini-Mental State Examination (MMSE) scores. CONCLUSIONS: A resolution pathway exists in the brain and the alterations described herein strongly suggest a dysfunction of this pathway in AD. MMSE correlations suggest a connection with cognitive function in AD.
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Enfermedad de Alzheimer/metabolismo , Hipocampo/metabolismo , Mediadores de Inflamación/metabolismo , Anciano , Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/enzimología , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/líquido cefalorraquídeo , Biomarcadores/líquido cefalorraquídeo , Estudios de Casos y Controles , Disfunción Cognitiva/líquido cefalorraquídeo , Disfunción Cognitiva/enzimología , Disfunción Cognitiva/patología , Ácidos Docosahexaenoicos/líquido cefalorraquídeo , Femenino , Hipocampo/enzimología , Hipocampo/patología , Humanos , Inflamación/líquido cefalorraquídeo , Inflamación/enzimología , Inflamación/metabolismo , Inflamación/patología , Mediadores de Inflamación/líquido cefalorraquídeo , Lipoxinas/líquido cefalorraquídeo , Lipooxigenasa/líquido cefalorraquídeo , Masculino , Persona de Mediana Edad , Receptores de Formil Péptido/análisis , Receptores de Lipoxina/análisis , Proteínas tau/líquido cefalorraquídeoRESUMEN
ABSTRACT: Multiple sclerosis is an inflammatory disorder characterized by inflammation, demyelination, and neurodegeneration in the central nervous system. Although current first-line therapies can help manage symptoms and slow down disease progression, there is no cure for multiple sclerosis. The gut-brain axis refers to complex communications between the gut flora and the immune, nervous, and endocrine systems, which bridges the functions of the gut and the brain. Disruptions in the gut flora, termed dysbiosis, can lead to systemic inflammation, leaky gut syndrome, and increased susceptibility to infections. The pathogenesis of multiple sclerosis involves a combination of genetic and environmental factors, and gut flora may play a pivotal role in regulating immune responses related to multiple sclerosis. To develop more effective therapies for multiple sclerosis, we should further uncover the disease processes involved in multiple sclerosis and gain a better understanding of the gut-brain axis. This review provides an overview of the role of the gut flora in multiple sclerosis.
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BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) is an anti-aquaporin 4 (anti-AQP4) autoantibodies-mediated idiopathic inflammatory demyelinating disease of the central nervous system. While intravenous pulse methylprednisolone (IVMP) is the recommended initial treatment option for acute onset NMOSD, its therapeutic mechanism remains unclear. We hypothesized that IVMP would reduce the expression of pro-inflammatory factors and increase the resolution of inflammation in patients with NMOSD. METHODS: Mendelian randomization (MR) analysis was used to screen meaningful inflammatory and resolution factors for inclusion. Three MR methods with inverse variance weighting (IVW) were primarily used to identify positive results. Interleukin (IL)-10, IL-1ß, IL-6, C-X-C motif chemokine ligand 12 (CXCL12), and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) were screened from 41 inflammatory factors, and resolvin D1 (RvD1), maresin 1 (MaR1), and lipoxin A4 (LXA4) were screened from 6 resolution markers for inclusion. Subsequently, 12 patients with NMOSD were enrolled and treated with IVMP. Serum levels of the aforementioned inflammatory and resolution markers were measured by enzyme-linked immunosorbent assay before and after IVMP treatment. RESULTS: High levels of TRAIL, CXCL12, and IL-1ß were associated with an increased risk of NMOSD (TRAIL: odds ratio [OR], 1.582; 95% confidence interval [CI], 1.003-2.495; CXCL12: OR, 3.610; 95% CI, 1.011-12.889; IL-1ß: OR, 4.500; 95% CI, 1.129-17.927). High levels of RvD1, MaR1, and LXA4 were associated with a reduced risk of NMOSD (RvD1: OR, 0.725; 95% CI, 0.538-0.976; MaR1: OR, 0.985; 95% CI, 0.970-0.999; LXA4: OR, 0.849; 95% CI, 0.727-0.993). Among patients with NMOSD, serum levels of IL-6, CXCL12, and TRAIL significantly decreased following IVMP treatment, compared with pretreatment levels, while levels of IL-1ß, LXA4, and MaR1 significantly increased after IVMP treatment (p < 0.05). A significant positive correlation was observed between CXCL12 levels and Expanded Disability Status Scale (EDSS) scores (r = 0.451, p < 0.05). CONCLUSION: Several systemic inflammatory regulators associated with the pathogenesis of NMOSD were identified. The protective roles of LXA4 and MaR1 may be indispensable components of glucocorticoid treatment. Therefore, the use of resolution markers may be a potential strategy for improving central nervous system injury in individuals with NMOSD.
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Experimental neural cell therapies, including donor neural stem/progenitor cells (NPCs) have been reported to offer beneficial effects on the recovery after an injury and to counteract inflammatory and degenerative processes in the central nervous system (CNS). The interplay between donor neural cells and the host CNS still to a large degree remains unclear, in particular in human allogeneic conditions. Here, we focused our studies on the interaction of human NPCs and microglia utilizing a co-culture model. In co-cultures, both NPCs and microglia showed increased survival and proliferation compared with mono-cultures. In the presence of microglia, a larger subpopulation of NPCs expressed the progenitor cell marker nestin, whereas a smaller group of NPCs expressed the neural markers polysialylated neural cell adhesion molecule, A2B5 and glial fibrillary acidic protein compared with NPC mono-cultures. Microglia thus hindered differentiation of NPCs. The presence of human NPCs increased microglial phagocytosis of latex beads. Furthermore, we observed that the expression of CD200 molecules on NPCs and the CD200 receptor protein on microglia was enhanced in co-cultures, whereas the release of transforming growth factor-ß was increased suggesting anti-inflammatory features of the co-cultures. To conclude, the interplay between human allogeneic NPCs and microglia, significantly affected their respective proliferation and phenotype. Neural cell therapy including human donor NPCs may in addition to offering cell replacement, modulate host microglial phenotypes and functions to benefit neuroprotection and repair.
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Microglía/fisiología , Células-Madre Neurales/fisiología , Aloinjertos , Antígenos CD/metabolismo , Antígenos de Superficie/metabolismo , Comunicación Celular , Diferenciación Celular , Proliferación Celular , Supervivencia Celular , Células Cultivadas , Técnicas de Cocultivo , Humanos , Interleucina-6/metabolismo , Receptores de Orexina , Fagocitosis , Fenotipo , Receptores de Superficie Celular/metabolismo , Medicina Regenerativa , Factor de Crecimiento Transformador beta1/metabolismoRESUMEN
Background: Neurological disorders can be caused by viral infections. The association between viral infections and neuromyelitis optica spectrum disorder (NMOSD) has been well-documented for a long time, and this connection has recently come to attention with the occurrence of SARS-CoV-2 infection. However, the precise nature of the causal connection between NMOSD and COVID-19 infection remains uncertain. Methods: To investigate the causal relationship between COVID-19 and NMOSD, we utilized a two-sample Mendelian randomization (MR) approach. This analysis was based on the most extensive and recent genome-wide association study (GWAS) that included SARS-CoV-2 infection data (122616 cases and 2475240 controls), hospitalized COVID-19 data (32519 cases and 2062805 controls), and data on severe respiratory confirmed COVID-19 cases (13769 cases and 1072442 controls). Additionally, we incorporated a GWAS meta-analysis comprising 132 cases of AQP4-IgG-seropositive NMOSD (NMO-IgG+), 83 cases of AQP4-IgG-seronegative NMOSD (NMO-IgG-), and 1244 controls. Results: The findings of our study indicate that the risk of developing NMO-IgG+ is elevated when there is a genetic predisposition to SARS-CoV-2 infection (OR = 5.512, 95% CI = 1.403-21.657, P = 0.014). Furthermore, patients with genetically predicted NMOSD did not exhibit any heightened susceptibility to SARS-CoV2 infection, COVID-19 hospitalization, or severity. Conclusion: our study using Mendelian randomization (MR) revealed, for the first time, that the presence of genetically predicted SARS-CoV2 infection was identified as a contributing factor for NMO-IgG+ relapses.
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COVID-19 , Neuromielitis Óptica , Humanos , Acuaporina 4 , Autoanticuerpos , COVID-19/genética , COVID-19/complicaciones , Estudio de Asociación del Genoma Completo , Inmunoglobulina G , Neuromielitis Óptica/genética , Ensayos Clínicos Controlados Aleatorios como Asunto , ARN Viral , SARS-CoV-2RESUMEN
BACKGROUND: Anti-aquaporin-4 (AQP-4) immunoglobulin G (IgG) is a major autoimmune antibody that contributes to the pathogenesis of neuromyelitis optica spectrum disorder (NMOSD). NMOSD often presents as disability, severe sensory impairment, and sleep disorders, which can cause anxiety and depression and further affect the quality of life. The age of onset is a key factor influencing the prognosis of NMOSD. However, this result was based on studies involving only anti-aquaporin-4 (AQP4) immunoglobulin G (IgG)-seropositive NMOSD patients or studies using the 2006 NMOSD diagnosis criteria. Therefore, further study of the age of onset of NMOSD is valuable. This study aimed to describe the clinical and magnetic resonance imaging (MRI) differences between early-onset neuromyelitis optica spectrum disorder (EO-NMOSD) and late-onset (LO)-NMOSD patients. METHODS: Fifty patients were enrolled, their anti-AQP4-IgG titers were measured, and brain and spinal cord MRIs were obtained. Additionally, several questionnaires related to disease severity, anxiety, depression, cognition, sleep, pain, and fatigue were collected. RESULTS: Higher AQP4-IgG seropositivity, higher AQP4-IgG titer, frequency of thoracic myelitis, and white matter hyperintensities (WMH), as well as greater severity of disability, greater severity of sleep disorders, higher anxiety, poorer cognitive function, and higher clinical dementia rating (CDR)-community affairs scores were observed in late-onset (LO)-NMOSD patients than those in early-onset (EO)-NMOSD. AQP4-IgG titer positively correlated with age, annual relapse rate, Expanded Disability Status Scale (EDSS) sensory scores, Activity of Daily Living Scale (ADL) scores, and Pittsburgh Sleep Quality Index (PSQI) scores. The EDSS-sensory scores positively correlated with age, relapse time, Hamilton Depression Rating Scale, Hamilton Anxiety Rating Scale, PSQI, ADL, and CDR. WMH was positively correlated with age, EDSS-sensory scores, PSQI scores, and CDR scores and negatively correlated with the California Verbal Learning Test scores. CONCLUSION: LO-NMOSD patients have worse prognoses than those of EO-NMOSD patients. Higher AQP4-IgG titers, more WMHs, thoracic myelitis, and severe sensory symptoms are associated with cognition, depression, anxiety, and sleep disorders.
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Mielitis , Neuromielitis Óptica , Humanos , Neuromielitis Óptica/complicaciones , Calidad de Vida , Acuaporina 4 , Autoanticuerpos , Inmunoglobulina G , Estudios RetrospectivosRESUMEN
Background: Generalized convulsive epilepsy (GCE), an important subtype of epilepsy, is a syndrome of neuronal dysfunction characterized by diffuse abnormal discharge of neurons within the brain. Compounding evidence suggests a correlation between epilepsy and inflammatory factors, for instance, cyclooxygenase-2, interleukin-1ß, and interleukin-6. Elevated levels of inflammatory factors have been observed in patients with epilepsy and several animal models. Therefore, inflammation may be closely associated with the pathogenesis and progression of GCE. However, the cause-and-effect relationship between the two is difficult to determine because of small sample sizes and confounding factors. Methods: To test for causality of the 41 cytokines on GCE, we conducted a two-sample Mendelian randomization (MR) based on the largest and latest genome-wide association study (GWAS) involving 290 cases and 453,521 European controls and a GWAS meta-analysis consisting of 41 cytokines from 8,293 individuals. Results: R confirmed a bidirectional causal link between cytokines and GCE. Genetically predicted increased levels of hepatocyte growth factor and decreased levels of eotaxin and interleukin-18 are associated with an increased risk of GCE (OR = 1.904, 95% CI = 1.019-3.561, p = 0.044; OR = 0.641, 95% CI = 0.417-0.984, p = 0.042; OR = 0.482, 95% CI = 0.251-0.927, p = 0.046). Furthermore, the presence of GCE is related to an increase in levels of multiple cytokines, such as macrophage inflammatory protein-1α, interleukin-12p70, interleukin-17, interleukin-1 receptor antagonist, and basic fibroblast growth factor (OR = 1.038, 95% CI = 1.005-1.073, p = 0.024; OR = 1.031, 95% CI = 1.009-1.054, p = 0.006; OR = 1.027, 95% CI = 1.002-1.053, p = 0.037; OR = 1.037, 95% CI = 1.003-1.072, p = 0.032; OR = 1.032, 95% CI = 1.000-1.066, p = 0.048; OR = 1.025, 95% CI = 1.003-1.048, p = 0026). Conclusion: A bidirectional causal link existed between inflammation and GCE. Detecting significantly altered factor concentrations may be of great significance for screening GCE and predicting their occurrence. Moreover, available pharmacological treatments for GCE are focused primarily on suppressing seizures. In future, altering the concentration of these cytokines in the body through targeted anti-inflammatory therapy to modify the epileptogenic mechanism and prevent the recurrence and refractoriness of GCE may become the key to new treatments.
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Introduction: Cognitive dysfunction has frequently been found in patients with migraine. The so-called contingent negative variation (CNV) and EEG power spectral densities may be the best choices to explore the underlining pathophysiology, such as cortical inhibition and habituation. Methods: Thirty migraine patients without aura and healthy controls matched for sex, age, and education were recruited separately for CNV recording. The amplitudes, latencies, and squares of different CNV components, such as oCNV, iCNV, tCNV, and PINV, were selected and analyzed. Behavioral data, such as manual reaction time (RT), were analyzed. We used the Person correlation coefficient R to analyze different ERP components in relation to clinical characteristics. A multiple regression analysis was conducted for the migraine group. Spectral analysis of EEG data from all channels using the fast Fourier transform (FFT). Results: The migraine group had longer A-latency, C-latency, and iCNV-latency than the control group. The migraine group had higher iCNV-amplitude, oCNV-amplitude, and tCNV-amplitude than the control group, especially those located in the occipital area. The iCNV-square, oCNV-square, tCNV-square, or PINV-square in the migraine group was significantly larger than the control group. Different correlations were found between clinical characteristics and ERP components. The delta or theta activity in the migraine group was statistically lower than in the control group. Discussion: Our study has revealed that migraine attacks may influence responsivity, pre-activation, habituation, and cortical inhibition not only on the behavioral level but also on the electrophysiological level. Abnormal changes in cortical habituation and inhibition can be interpreted as CNV components. Additionally, analyses have revealed correlations between CNV components and various factors, including age, the clinical course of the condition, attack frequency, pain intensity, and duration. Thus, repetitive migraine attacks can lead to a reduction in cortical inhibition and subsequent impairment in executive function.
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Inflammation plays a role in the pathogenesis of acute-on-chronic liver failure (ACLF), however, whether there is a causal relationship between inflammation and ACLF remains unclear. A two-sample Mendelian randomization (MR) approach was used to investigate the causal relationship between systemic inflammatory regulators and ACLF. The study analyzed 41 cytokines and growth factors from 8,293 individuals extracted from a genome-wide association study (GWAS) meta-analysis database involving 253 ACLF cases and 456,095 controls. Our results showed that lower stem cell factor (SCF) levels, lower basic fibroblast growth factor (bFGF) levels and higher Interleukin-13 (IL-13) levels were associated with an increased risk of ACLF (OR = 0.486, 95% CI = 0.264-0.892, p = 0.020; OR = 0.323, 95% CI = 0.107-0.972, p = 0.044; OR = 1.492, 95% CI = 1.111-2.004, p = 0.008, respectively). In addition, genetically predicted ACLF did not affect the expression of systemic inflammatory regulators. Our results indicate that cytokines play a crucial role in the pathogenesis of ACLF. Further studies are needed to determine whether these biomarkers can be used to prevent and treat ACLF.
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Leptomeningeal metastasis (LM) has a high degree of malignancy and high mortality. We describe a patient admitted to hospital with acute lower extremity weakness, dysuria, and high intracranial pressure. Enhanced magnetic resonance imaging (MRI) showed extensive enhancement of the leptomeningeal and spinal meninges with multiple nodular changes and extensive fusion. His cerebrospinal fluid (CSF) was yellow and cloudy, the Pandy test was strongly positive (++++), the protein was 46 g/L (normal range 0.15-0.45 g/L), which attracted our attention. Initially, miliary TB with associated tuberculous meningitis (TBM) was diagnosed, and neurosarcoidosis cannot be ruled out. After poor therapeutic effect of standard antituberculosis (anti-TB) therapy, further inspection found that malignant cells were detected by cerebrospinal fluid (CSF) cytology. PET/CT suggested the diagnosis of LM. The purpose of this paper is to describe the characteristics of atypical diffuse LM. In conclusion, when patient with unexplained high levels of CSF protein, it is necessary to be alert to the diagnosis of LM. Multiple examinations of fresh CSF are helpful to increase the positive detection rate of tumor cells. Early diagnosis and active treatment are conducive to improving survival rate.
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Neuromyelitis optica spectrum disorders (NMOSD) are severe inflammatory disorders of the central nervous system targeting aquaporin-4 (AQP4). The risk factors for NMOSD remain to be determined, though they may be related to diet and nutrition. This study aimed to explore the possibility of a causal relationship between specific food intake and AQP4-positive NMOSD risk. The study followed a two-sample Mendelian randomization (MR) design. Genetic instruments and self-reported information on the intake of 29 types of food were obtained from a genome-wide association study (GWAS) on 445,779 UK Biobank participants. A total of 132 individuals with AQP4-positive NMOSD and 784 controls from this GWAS were included in our study. The associations were evaluated using inverse-variance-weighted meta-analysis, weighted-median analysis, and MR-Egger regression. A high consumption of oily fish and raw vegetables was associated with a decreased risk of AQP4-positive NMOSD (odds ratio [OR] = 1.78 × 10-16, 95% confidence interval [CI] = 2.60 × 10-25-1.22 × 10-7, p = 0.001; OR = 5.28 × 10-6, 95% CI = 4.67 × 10-11-0.598, p = 0.041, respectively). The results were consistent in the sensitivity analyses, and no evidence of directional pleiotropy was observed. Our study provides useful implications for the development of AQP4-positive NMOSD prevention strategies. Further research is needed to determine the exact causal relationship and mechanisms underlying the association between specific food intake and AQP4-positive NMOSD.
Asunto(s)
Neuromielitis Óptica , Animales , Neuromielitis Óptica/epidemiología , Neuromielitis Óptica/genética , Neuromielitis Óptica/complicaciones , Verduras/genética , Estudio de Asociación del Genoma Completo , Distribución Aleatoria , Acuaporina 4/genética , Autoanticuerpos/genéticaRESUMEN
Background: As a result of the COVID-19 pandemic, patients with glioblastoma (GBM) are considered a highly vulnerable population. Despite this, the extent of the causative relationship between GBM and COVID-19 infection is uncertain. Methods: Genetic instruments for SARS-CoV-2 infection (38,984 cases and 1,644,784 control individuals), COVID-19 hospitalization (8,316 cases and 1,549,095 control individuals), and COVID-19 severity (4,792 cases and 1,054,664 control individuals) were obtained from a genome-wide association study (GWAS) from European populations. A total of 6,183 GBM cases and 18,169 controls from GWAS were enrolled in our study. Their associations were evaluated by applying Mendelian randomization (MR) including IVW meta-analysis, MR-Egger regression, and weighted-median analysis. To make the conclusions more robust and reliable, sensitivity analyses were performed. Results: Our results showed that genetically predicted COVID-19 hospitalization increases the risk of GBM (OR = 1.202, 95% CI = 1.035-1.395, p = 0.016). In addition, no increased risk of SARS-CoV-2 infection, COVID-19 hospitalization and severity were observed in patients with any type of genetically predicted GBM. Conclusion: Our MR study indicated for the first time that genetically predicted COVID-19 hospitalization was demonstrated as a risk factor for the development of GBM.
RESUMEN
Methylmalonic acidemia is a severe heterogeneous disorder of methylmalonate and cobalamin (Cbl; vitamin B12) metabolism with poor prognosis. Around 90% of reported patients with methylmalonic acidemia (MMA) are severe infantile early onset, while cases with late-onset MMA have been rarely reported. Few reported late-onset MMA patients presented with atypical clinical symptoms, therefore, often misdiagnosed if without family history. Herein, we report a 29-year-old female who was admitted to our hospital due to symptoms manifested as encephalitis. The brain MRI showed symmetrical bilateral cerebellar lesions with Gd enhancement. Laboratory tests showed significantly elevated levels of homocysteine and methylmalonic acid. A genetic analysis identified a novel homozygous mutation (c.484G>A; p.Gly162 Arg) in the MMACHC gene. The patient was diagnosed with MMA, and her symptoms improved dramatically with intramuscular adenosine cobalamin treatment. In conclusion, for patients with symmetrical lesions in the brain, the possibility of metabolic diseases should be considered, detailed medical and family history should be collected, and metabolic screening tests as well as gene tests are necessary for correct diagnosis. The mutation diversity in MMACHC gene is an important factor leading to the heterogeneity of clinical manifestations of patients with MMA.
RESUMEN
China experienced another widespread Coronavirus disease 2019 (COVID-19) outbreak recently caused by the Omicron variant, which is less severe but far more contagious than the other COVID-19 variants, leading local governments to focus efforts on eliminating the spread of the disease. Previous studies showed that after "recovering" from the virus, some patients could re-test positive for COVID-19 with nucleic acid tests, challenging the control of disease spread. In this study, we aimed to analyze the clinical and laboratory characteristics of re-positive COVID-19 patients in Northeast China. We retrospectively analyzed data from confirmed reverse transcription polymerase chain reaction (RT-PCR) re-positive COVID-19 patients who were admitted to the First Hospital of Jilin University, Jilin Province, China, from March to June 2022. Detailed clinical symptoms, medical history, anti-Corona Virus (CoV) IgG and IgM levels, and CoV nucleic acid cycle threshold (Ct) values during the re-positive period were collected and analyzed. A total of 180 patients were included in this study, including 62 asymptomatic cases and 118 mild cases. The cohort included 113 men and 67 women, with an average age of 45.73 years. The median time between recovery from the virus and re-positivity was 13 days. Our results showed that the proportion of re-positive patients with symptoms was lower, and the nucleic acid test-positive duration was shorter during the re-positive period. Furthermore, in patients with underlying disease, the proportion of patients with symptoms was higher, anti-CoV IgG levels were lower, and the total disease duration was longer. In conclusion, during the re-positive period, the symptoms were milder, and the CoV nucleic acid test-positive course was shorter. The concomitant underlying disease is an important factor associated with clinical symptoms, and the overall course of COVID-19 re-positive patients may be associated with lower anti-CoV IgG levels. Large-scale and multicenter studies are recommended to better understand the pathophysiology of recurrence in patients with COVID-19.
RESUMEN
Neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory demyelinating disease of the central nervous system (CNS) associated with autoantibody (ab) to aquaporin-4 (AQP4). There is obvious variation between regions and countries in the epidemiology, clinical features and management in NMOSD. Based on published population-based observation and cohort studies, the different clinical pattern of NMOSD has been seen in several geographical regions and some of these patients with NMOSD-like features do not fully meet the current diagnostic criteria, which is needed to consider the value of recently revised diagnostic criteria. At present, all treatments applied in NMOSD have made great progress, however, these treatments failed in AQP4 ab negative and refractory patients. Therefore, it is necessary to turn into an innovative idea and to open a new era of NMOSD treatment to develop novel and diverse targets and effective therapeutic drugs in NMOSD and to conduct the trails in large clinical samples and case-control studies to confirm their therapeutic effects on NMOSD in the future, which still remain a challenge.