RESUMEN
Importance: It is uncertain whether intravenous methylprednisolone improves outcomes for patients with acute ischemic stroke due to large-vessel occlusion (LVO) undergoing endovascular thrombectomy. Objective: To assess the efficacy and adverse events of adjunctive intravenous low-dose methylprednisolone to endovascular thrombectomy for acute ischemic stroke secondary to LVO. Design, Setting, and Participants: This investigator-initiated, randomized, double-blind, placebo-controlled trial was implemented at 82 hospitals in China, enrolling 1680 patients with stroke and proximal intracranial LVO presenting within 24 hours of time last known to be well. Recruitment took place between February 9, 2022, and June 30, 2023, with a final follow-up on September 30, 2023. Interventions: Eligible patients were randomly assigned to intravenous methylprednisolone (n = 839) at 2 mg/kg/d or placebo (n = 841) for 3 days adjunctive to endovascular thrombectomy. Main Outcomes and Measures: The primary efficacy outcome was disability level at 90 days as measured by the overall distribution of the modified Rankin Scale scores (range, 0 [no symptoms] to 6 [death]). The primary safety outcomes included mortality at 90 days and the incidence of symptomatic intracranial hemorrhage within 48 hours. Results: Among 1680 patients randomized (median age, 69 years; 727 female [43.3%]), 1673 (99.6%) completed the trial. The median 90-day modified Rankin Scale score was 3 (IQR, 1-5) in the methylprednisolone group vs 3 (IQR, 1-6) in the placebo group (adjusted generalized odds ratio for a lower level of disability, 1.10 [95% CI, 0.96-1.25]; P = .17). In the methylprednisolone group, there was a lower mortality rate (23.2% vs 28.5%; adjusted risk ratio, 0.84 [95% CI, 0.71-0.98]; P = .03) and a lower rate of symptomatic intracranial hemorrhage (8.6% vs 11.7%; adjusted risk ratio, 0.74 [95% CI, 0.55-0.99]; P = .04) compared with placebo. Conclusions and Relevance: Among patients with acute ischemic stroke due to LVO undergoing endovascular thrombectomy, adjunctive methylprednisolone added to endovascular thrombectomy did not significantly improve the degree of overall disability. Trial Registration: ChiCTR.org.cn Identifier: ChiCTR2100051729.
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Accidente Cerebrovascular Isquémico , Accidente Cerebrovascular , Femenino , Humanos , Anciano , Método Doble Ciego , Trombectomía/efectos adversos , Hemorragias Intracraneales , Metilprednisolona/efectos adversosRESUMEN
BACKGROUND: Wallerian degeneration (WD) can occur in different projecting systems, such as corticospinal tract, dentate-rubro-olivary pathway, and corticopontocerebellar tract. However, the co-occurrence of hypertrophic olivary degeneration (HOD) and middle cerebellar peduncles (MCPs) degeneration secondary to unilateral pontine infarction in a single patient is extremely rare. CASE PRESENTATION: A 71-year-old man presented with acute onset of dizzness, slurred speech, and right-sided weakness. On the next day, his previous neurologic deficits deteriorated. Brain magnetic resonance imaging (MRI) revealed acute ischemic stroke of the left pons. After treatment with thrombolysis, antiplatelets, and rehabilitation training, his speaking and motor function improved moderately. At the 3-month follow-up, the MRI showed hyperintensity in the left medulla oblongata and bilateral MCPs on T2-weighted and FLAIR images, suggesting HOD as well as MCPs degeneration. CONCLUSIONS: It is of great importance for us to know the anatomic knowledge of dentate-rubro-olivary and corticopontocerebellar pathways.
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Accidente Cerebrovascular Isquémico/patología , Pedúnculo Cerebeloso Medio/patología , Degeneración Walleriana/patología , Anciano , Infartos del Tronco Encefálico/patología , Humanos , Hipertrofia/patología , Imagen por Resonancia Magnética/métodos , Masculino , Núcleo Olivar/patología , Paresia/etiología , Puente/patología , Tractos Piramidales/patologíaRESUMEN
Rheumatoid arthritis (RA) is a chronic inflammation mediated by autoimmune responses. MEG3, a kind of long noncoding RNA (lncRNA), participates in cell proliferation in cancer tissues. However, the correlation between MEG3 and RA is yet unclear. Therefore, to clarify how MEG3 works in RA, we performed a series of experiments using RA samples. We found that MEG3 was downregulated in the fibroblast-like synoviocytes of RA patients (RA-FLS), in comparison with healthy subjects. MEG3 was also down-regulated evidently in lipopolysaccharide (LPS)-treated chondrocyte. As part of our experiments, MEG3 was overexpressed in chondrocyte by transfection with lentivirus containing sequences encoding MEG3. In addition, in presence of LPS, reductions were identified not only in the cell proliferation, but also in the generation of interleukin-23 (IL-23), which, however were reversed in the lentivirus (containing MEG3-encoding sequences)-transfected chondrocytes. Up-regulated MEG3 resulted in an increase the level of Ki67. Moreover, MEG3 was negatively correlated with miR-141, and miR-141 was up-regulated in LPS-treated chondrocyte. Inhibitory effects of MEG3 overexpression, mentioned above, were partially abolished by overexpressed miR-141. Further, animal experiment also showed the inhibitory effect of MEG3 in overexpression on the AKT/mTOR signaling pathway. In-vivoexperiments also showed that cell proliferation was facilitated by MEG3 overexpression with inhibited inflammation. In summary, the protective role of MEG3 in RA was proved to be exerted by the increase in the rate of proliferation, which might correlate to the regulatory role of miR-141 and AKT/mTOR signal pathway, suggesting that MEG3 holds great promise as a therapeutic strategy for RA.
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Artritis Reumatoide/genética , MicroARNs/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , ARN Largo no Codificante/metabolismo , Transducción de Señal , Serina-Treonina Quinasas TOR/metabolismo , Animales , Secuencia de Bases , Proliferación Celular/genética , Condrocitos/metabolismo , Condrocitos/patología , Humanos , Inflamación/genética , Lipopolisacáridos , MicroARNs/metabolismo , ARN Largo no Codificante/genética , Ratas , Regulación hacia Arriba/genéticaRESUMEN
BACKGROUND: Microvascular changes play a decisive role in systemic sclerosis (SSc) and occur early in the course of the disease. Pulmonary arterial hypertension (PAH) represents one of the main clinical expressions of the vascular changes in SSc, and the abnormal changes, especially capillary density and capillary width, are detectable at nailfold videocapillaroscopy (NVC). AIMS: To investigate the differences in capillary nailfold changes in SSc patients with and without PAH and to estimate the early diagnostic value of NVC in SSc secondary PAH (SSc-PAH). METHODS: A comprehensive literature search of MEDLINE and PUBMED was performed to identify published studies without language restrictions. The methodological quality of the included studies was evaluated. The pooled specificity, sensitivity, positive likelihood rate, negative likelihood rate, diagnostic odds ratio, area under the curve and Q value were found using Meta-Disc version 1.4 software packages. Finally, seven studies were included in this meta-analysis. RESULTS: The meta-analysis demonstrated that the diagnostic odds ratio, area under the curve and Q value were 5.84 (95% confidence interval: 1.95-17.54), 0.79 and 0.72 respectively. It indicated that the microvascular changes detected at NVC were significant in SSc-PAH and especially showed significantly lower capillary density and higher capillary width. CONCLUSION: The NVC may be a valuable tool for the early diagnosis of SSc-PAH. It can detect the early microvascular changes associated with the risk of PAH and has a significant role in the early prediction of SSc-PAH.
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Hipertensión Pulmonar/diagnóstico , Angioscopía Microscópica , Esclerodermia Sistémica/diagnóstico , Área Bajo la Curva , Estudios de Casos y Controles , Progresión de la Enfermedad , Femenino , Humanos , Hipertensión Pulmonar/etiología , Masculino , Oportunidad Relativa , Valor Predictivo de las Pruebas , Estudios Retrospectivos , Esclerodermia Sistémica/complicacionesRESUMEN
BACKGROUND: Systemic lupus erythematosus (SLE) and atopic dermatitis (AD) are common diseases in human populations. Previous studies have suggested a potential association between SLE and AD. However, the causal relationship and direction between the two conditions remain unclear. OBJECTIVE: The aim of this study is to evaluate the causal relationship between SLE and AD. METHODS: In this study, we employed Mendelian randomization (MR) analysis to investigate the causal relationship between SLE and AD. MR analysis has the advantage of reducing confounding factors, determining the direction of causality, and providing quantitative effect estimates. We obtained summary data from genome-wide association studies (GWAS) on SLE and AD from publicly available databases. Five MR methods, namely MR Egger, weighted median, inverse variance weighted, simple mode, and weighted mode, were used to assess the causal relationship between SLE and AD. Several techniques, including MR-Egger intercept, MR-PRESSO, and Cochran's Q test, were utilized to evaluate heterogeneity and pleiotropy. RESULTS: Our study demonstrated a causal relationship between the prevalence of SLE and an increased risk of AD (MR Egger OR: 1.567, 95% CI: [1.041, 1.285], P = 0.009; IVW OR: 1.085, 95% CI: [1.005, 1.143], P = 0.035). Furthermore, sensitivity analyses did not detect heterogeneity or pleiotropy. CONCLUSION: Our research finds that SLE is a contributing factor to the development of AD, providing valuable insights into the pathogenesis and prevention of both diseases. Key Points ⢠Currently, there is no research that clearly indicates a causal relationship between SLE and AD. This study, for the first time, identified a positive causal relationship between SLE and AD. ⢠The results of this study contribute to our understanding of the pathogenesis and treatment strategies for SLE and AD, providing some guidance for future clinical practice.
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Dermatitis Atópica , Lupus Eritematoso Sistémico , Humanos , Dermatitis Atópica/epidemiología , Dermatitis Atópica/genética , Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , Lupus Eritematoso Sistémico/complicaciones , Lupus Eritematoso Sistémico/epidemiología , Lupus Eritematoso Sistémico/genética , Bases de Datos FactualesRESUMEN
To investigate the potential causal relationship between ulcerative colitis and nephrotic syndrome. We obtained the whole-genome association study data of ulcerative colitis in the European population from the GWAS database. Relevant single nucleotide polymorphisms (SNPs) were selected for analysis. We employed the inverse variance-weighted meta-analysis of multiplicative random effects models to obtain SNP-specific Wald ratio estimates, which assume horizontal pleiotropy. In addition, we performed sensitivity analyses using MR-Egger, weighted median, and IVW. Our findings suggest a strong association between ulcerative colitis and nephrotic syndrome (P < 0.05). After conducting sensitivity analyses, we found no evidence of horizontal pleiotropy or heterogeneity (P > 0.05). This study provides evidence for an association between ulcerative colitis and nephrotic syndrome, which may help us better understand the conditions of ulcerative colitis and nephropathy.
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Colitis Ulcerosa , Análisis de la Aleatorización Mendeliana , Síndrome Nefrótico , Polimorfismo de Nucleótido Simple , Humanos , Colitis Ulcerosa/genética , Colitis Ulcerosa/complicaciones , Colitis Ulcerosa/epidemiología , Síndrome Nefrótico/genética , Síndrome Nefrótico/fisiopatología , Análisis de la Aleatorización Mendeliana/métodos , Estudio de Asociación del Genoma CompletoRESUMEN
Kawasaki disease (KD) is an acute autoimmune vascular disease featured with a long stage of febrile. It predominantly afflicts children under 5 years old and causes an increased risk of cardiovascular combinations. The onset and progression of KD are impacted by many aspects, including genetic susceptibility, infection, and immunity. In recent years, many studies revealed that miRNAs, a novel class of small non-coding RNAs, may play an indispensable role in the development of KD via differential expression and participation in the central pathogenesis of KD comprise of the modulation of immunity, inflammatory response and vascular dysregulation. Although specific diagnose criteria remains unclear up to date, accumulating clinical evidence indicated that miRNAs, as small molecules, could serve as potential diagnostic biomarkers and exhibit extraordinary specificity and sensitivity. Besides, miRNAs have gained attention in affecting therapies for Kawasaki disease and providing new insights into personalized treatment. Through consanguineous coordination with classical therapies, miRNAs could overcome the inevitable drug-resistance and poor prognosis problem in a novel point of view. In this review, we systematically reviewed the existing literature and summarized those findings to analyze the latest mechanism to explore the role of miRNAs in the treatment of KD from basic and clinical aspects retrospectively. Our discussion helps to better understand the pathogenesis of KD and may offer profound inspiration on KD diagnosis, treatment, and prognosis.
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MicroARNs , Síndrome Mucocutáneo Linfonodular , Niño , Humanos , Preescolar , Síndrome Mucocutáneo Linfonodular/diagnóstico , Síndrome Mucocutáneo Linfonodular/genética , Síndrome Mucocutáneo Linfonodular/terapia , MicroARNs/metabolismo , Estudios Retrospectivos , Predisposición Genética a la EnfermedadRESUMEN
BACKGROUND: Systemic lupus erythematosus (SLE) is a chronic, systemic autoimmune disease that commonly causes kidney damage. Therefore, we measured plasma levels of cytokines that may be related to renal dysfunction in SLE patients. METHODS: To explore the differences between SLE patients with renal dysfunction and healthy volunteers, the levels of cytokines in plasma were screened using a human cytokine antibody array. Then, we chose fourteen of the elevated cytokines for verification with an expanded sample size by a human magnetic Luminex assay. Plasma samples were isolated from SLE patients (n = 72) and healthy volunteers (n = 8). RESULTS: Cytokine antibody array data showed elevated plasma cytokines in SLE patients with renal dysfunction compared with healthy volunteers. By using the human magnetic Luminex assay, we found that plasma levels of CHI3L1, GDF-15, IGFBP-2, MIF, ST2, TFF3, and uPAR were significantly higher in SLE patients than in healthy volunteers. Plasma levels of CXCL4 were significantly lower in the active group than in the inactive group, and plasma levels of CHI3L1, IGFBP-2, MIF, and MPO were significantly higher in the active group than in the inactive group. We also analyzed the correlation between plasma cytokine levels and the SLEDAI-2K, and our results showed that the plasma levels of the fourteen selected cytokines were weakly correlated or not correlated with the SLEDAI-2K. We further analyzed the correlation between cytokines and renal dysfunction. Plasma levels of GDF-15 and TFF3 were highly positively correlated with serum creatinine levels and 24-hour urine protein levels. CONCLUSION: Our data suggest that plasma levels of GDF-15 and TFF3 are potential renal dysfunction markers in SLE patients, but plasma levels of these cytokines are not correlated with the SLEDAI-2K. Further study is warranted to determine how these cytokines regulate inflammatory responses and renal dysfunction in SLE.
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Biomarcadores/sangre , Citocinas/sangre , Factor 15 de Diferenciación de Crecimiento/sangre , Enfermedades Renales/inmunología , Lupus Eritematoso Sistémico/inmunología , Factor Plaquetario 4/sangre , Factor Trefoil-3/sangre , Adulto , China , Femenino , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Humanos , Masculino , Factor Plaquetario 4/genética , Índice de Severidad de la EnfermedadRESUMEN
Rheumatoid arthritis (RA) is a common chronic autoimmune joint disease characteristic of elevated proliferation and infiltration of fibroblast-like synoviocytes (FLS). Here, we aimed to explore the mechanisms of the Tanshinone IIA (Tan IIA)-induced apoptosis of FLS from patients with RA (termed RAFLS). Cell Counting Kit-8 (CCK-8) assay and Annexin V staining revealed that RAFLS viability decreased and apoptosis increased after Tan IIA treatment. Long non-coding RNA (lncRNA) GAS5 expression was significantly decreased in the synovial tissues and RAFLS, while Tan IIA treatment resulted in an up-regulation of GAS5. Consistently, knockdown of GAS5 using siRNA inhibited RAFLS apoptosis. Mechanistically, GAS5 knockdown down-regulated the expression of cleaved caspase-3 and caspase-9 in the RAFLS cells and activated the phosphoinositide 3-kinase (PI3K)/AKT signaling pathway. These data indicate that Tan IIA promotes RAFLS apoptosis by up-regulating lncRNA GAS5, with enhanced expression of cleaved caspase-3/caspase-9 and inhibited PI3K/AKT signaling.
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Abietanos/farmacología , Artritis Reumatoide/tratamiento farmacológico , ARN Largo no Codificante/genética , Sinoviocitos/efectos de los fármacos , Adulto , Anciano , Apoptosis/efectos de los fármacos , Artritis Reumatoide/genética , Artritis Reumatoide/patología , Caspasa 3/genética , Caspasa 9/genética , Proliferación Celular/efectos de los fármacos , Femenino , Fibroblastos/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Masculino , Persona de Mediana Edad , Fosfatidilinositol 3-Quinasas/genética , Proteínas Proto-Oncogénicas c-akt/genética , Salvia miltiorrhiza/química , Membrana Sinovial/efectos de los fármacos , Sinoviocitos/metabolismo , Sinoviocitos/patología , TransfecciónRESUMEN
Cerebrovascular injury is the most prevalent human cerebrovascular disease and frequently results in ischemic stroke. Simvastatin may be a potential therapeutic agent for the treatment of patients with cerebrovascular injury. The present study aimed to investigate the efficacy of and the potential mechanisms regulated by simvastatin in a rat model of ischemiareperfusion (I/R)induced cerebrovascular injury. Cerebrovascular injury model rats were established and were subsequently treated with simvastatin or a vehicle control following I/R injury. Cell damage, neurological functions and neuronal apoptosis were examined, as well as the nuclear factor (NF)κBmediated myeloid differentiation primary response protein 88 (MyD88)/tollinterleukin1 receptor domaincontaining adapter molecule 1 (TRIF) signaling pathway following simvastatin treatment. The results of the present study demonstrated that simvastatin treatment led to a reduction in cell damage, improvement of neurological functions and decreased neuronal apoptosis compared with vehicletreated I/R model rats, 14 days posttreatment. In addition, simvastatin treatment reduced cerebral water content and bloodbrain barrier disruption in cerebrovascular injury induced by I/R. The results also revealed that simvastatin treatment inhibited neuronal apoptosis via the NFκBmediated MyD88/TRIF signaling pathway. In conclusion, simvastatin treatment may reduce I/Rinduced neuronal apoptosis via inhibition of the NFκBmediated MyD88/TRIF signaling pathway.
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Anticolesterolemiantes/uso terapéutico , Traumatismos Cerebrovasculares/tratamiento farmacológico , Traumatismos Cerebrovasculares/etiología , FN-kappa B/inmunología , Fármacos Neuroprotectores/uso terapéutico , Daño por Reperfusión/complicaciones , Simvastatina/uso terapéutico , Proteínas Adaptadoras del Transporte Vesicular/inmunología , Animales , Apoptosis/efectos de los fármacos , Barrera Hematoencefálica/efectos de los fármacos , Barrera Hematoencefálica/inmunología , Barrera Hematoencefálica/patología , Células Cultivadas , Traumatismos Cerebrovasculares/inmunología , Traumatismos Cerebrovasculares/patología , Masculino , Ratones , Factor 88 de Diferenciación Mieloide/inmunología , Ratas , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacosRESUMEN
Background: Rheumatoid arthritis (RA) is a inflammatory disease that characterized with the destruction of synovial joint, which could induce disability. Inflammatory response mediated the RA. It has been reported that MiR-128-3p is significantly increased in RA, while the potential role was still unclear.Methods: T cells in peripheral blood mononuclear cell (PBMC) were isolated from the peripheral blood from people of RA and normal person were used. Real-time PCR was performed to detect the expression of MiR-128-3p, while the protein expression of tumor necrosis factor-α-induced protein 3 (TNFAIP3) was determined using Western blot. The levels of IL-6 and IL-17 were measured using enzyme-linked immunosorbent assay (ELISA). The expression of CD69 and CD25 was detected using flow cytometry. The RA mouse model was constructed for verification of the role of MiR-128-3p.Results: The expression of MiR-128-3p was significantly increased, while TNFAIP3 was decreased, the levels of IL-6 and IL-17 were also increased in the T cells of RA patients. Down-regulated MiR-128-3p significantly suppressed the expression of p-IkBα and CD69, and CD25in T cells. MiR-128-3p targets TNFAIP3 to regulate its expression. MiR-128-3p knockdown significantly suppressed the activity of nuclear factor κB (NF-κB) and T cells by up-regulating TNFAIP3, while cells co-transfected with si-TNFAIP3 abolished the effects of MiR-128-3p knockdown. The in vivo experiments verified the potential role of MiR-128-3p on RA.Conclusion: Down-regulated MiR-128-3p significantly suppressed the inflammation response of RA through suppressing the activity of NF-κB pathway, which was mediated by TNFAIP3.
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Artritis Reumatoide/genética , Artritis Reumatoide/patología , MicroARNs/genética , Proteína 3 Inducida por el Factor de Necrosis Tumoral alfa/genética , Adulto , Anciano , Animales , Progresión de la Enfermedad , Femenino , Regulación de la Expresión Génica , Técnicas de Silenciamiento del Gen , Humanos , Interleucina-17/análisis , Interleucina-6/análisis , Masculino , Ratones Endogámicos C57BL , Persona de Mediana Edad , Linfocitos T/metabolismo , Linfocitos T/patología , Proteína 3 Inducida por el Factor de Necrosis Tumoral alfa/análisis , Regulación hacia ArribaRESUMEN
BACKGROUND: Rheumatoid arthritis (RA) is the most common inflammatory arthritis and is a major cause of disability. The nuclear factor-kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway has been reported to be involved in the pathogenesis of RA with unclear mechanisms. Therefore, this study aims to explore the effect of NF-κB pathway on proliferation, apoptosis, and angiogenesis of human fibroblast-like synovial cells (HFLS) in RA. METHODS: Normal HFLS and RA-HFLS were selected as the normal and control groups, respectively. RA-HFLS were treated by BAY11-7082 (an inhibitor of NF-κB) in different concentrations, namely 2.5âµmol/L BAY11-7082, 5âµmol/LBAY11-7082 and 10âµmol/L BAY11-7082. MTT assay was employed to detect cell proliferation. Cell apoptosis was determined by flow cytometry at 24, 48, and 72âhours after culture. Western blot analysis was employed to detect the expressions of NF-κB, angiogenesis-related factors (VEGF, Ang1, and Ang2). RESULTS: Initially, we found that BAY11-7082 inhibited NF-κB expression in a concentration-dependent manner. According to the findings of MTT assay and flow cytometry, we understood that RA-HFLS treated by BAY11-7082 (an inhibitor of NF-κB), the inhibition of NF-κB pathway, suppressed RA-HFLS proliferation and induced RA-HFLS apoptosis in a concentration and time-dependent manner. Furthermore, RA-HFLS treated by BAY11-7082 presented decreased VEGF, Ang1 and Ang2 expressions in a concentration-dependent manner. CONCLUSION: The study concluded that inhibition of NF-κB pathway induced cell apoptosis and suppressed proliferation and angiogenesis of RA-HFLS, which could serve as a novel target in the treatment of RA.