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Increased intestinal permeability is a manifestation of cystic fibrosis (CF) in people with CF (pwCF) and in CF mouse models. CF transmembrane conductance regulator knockout (Cftr KO) mouse intestine exhibits increased proliferation and Wnt/ß-catenin signaling relative to wild-type mice (WT). Since the Rho GTPase Cdc42 plays a central role in intestinal epithelial proliferation and tight junction remodeling, we hypothesized that Cdc42 may be altered in the Cftr KO crypts. Immunofluorescence showed distinct tight junction localization of Cdc42 in Cftr KO fresh crypts and enteroids, the latter indicating an epithelial-autonomous feature. Quantitative PCR and immunoblots revealed similar expression of Cdc42 in the Cftr KO crypts/enteroids relative to WT, whereas pull-down assays showed increased GTP-bound (active) Cdc42 in proportion to total Cdc42 in Cftr KO enteroids. Cdc42 activity in the Cftr KO and WT enteroids could be reduced by inhibition of the Wnt transducer Disheveled 2. Using a dye permeability assay, Cftr KO enteroids exhibited increased paracellular permeability to 3kD dextran relative to WT. In Cftr KO relative to WT enteroids, leak permeability and Cdc42 tight junction localization were reduced to a greater extent by inhibition of Wnt/ß-catenin signaling with Endo-IWR1. Increased proliferation or inhibition of Cdc42 activity with ML141 had no effect on WT enteroid permeability. In contrast, inhibition of Cdc42 with ML141 increased permeability to both 3kD dextran and tight-junction impermeant 500 kD dextran in Cftr KO enteroids. These data suggest that increased constitutive Cdc42 activity may alter the stability of paracellular permeability in Cftr KO crypt epithelium.
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BACKGROUND: The effectiveness of percutaneous coronary intervention (PCI) for chronic total occlusion (CTO) is still uncertain, especially for patients with ischemic left ventricular dysfunction. This study aimed to assess hibernating myocardium (HM), as determined by single-photon emission computed tomography (SPECT) and 18F-FDG positron emission tomography (PET), and to compare the benefits of PCI and optimal medical therapy (OMT). METHODS: A retrospective study collected data from 332 patients with CTO and ischemic left ventricular dysfunction. The study compared patients who underwent PCI or OMT via propensity score matching (PSM) analysis which was performed with a 1:2 matching protocol using the nearest neighbour matching algorithm. The primary endpoint of the study was the occurrence of major adverse cardiac events (MACE), defined as a composite of cardiac death, readmission for worsening heart failure (WHF), revascularization and myocardial infarction (MI). RESULTS: After PSM, there were a total of 246 individuals in the PCI and OMT groups. Following Cox regression, hibernating myocardium/total perfusion defect (HM/TPD) was identified as an independent risk factor (hazard ratio (HR): 1.03, 95% confidence interval (CI): 1.008-1.052, p = .007). The cut-off value of HM/TPD was 38%. The results of the subgroup analysis suggest that for patients with HM/TPD >38%, the OMT group had a greater risk of MACE (p = .035). A sensitivity analysis restricting patients with single-vessel CTO lesions, HM/TPD remained an independent predictor (HR 1.025, 95% CI 1.008-1.043, p = .005). CONCLUSION: HM/TPD is an independent predictor of MACE, and for patients with HM/TPD > 38%, CTO-PCI had a lower risk of MACE compared with OMT. However, further validation is still needed through large-scale studies.
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Oclusión Coronaria , Aturdimiento Miocárdico , Intervención Coronaria Percutánea , Tomografía Computarizada de Emisión de Fotón Único , Humanos , Masculino , Femenino , Intervención Coronaria Percutánea/métodos , Oclusión Coronaria/cirugía , Oclusión Coronaria/terapia , Oclusión Coronaria/diagnóstico por imagen , Estudios Retrospectivos , Persona de Mediana Edad , Anciano , Tomografía de Emisión de Positrones , Disfunción Ventricular Izquierda/diagnóstico por imagen , Fluorodesoxiglucosa F18 , Enfermedad Crónica , Puntaje de Propensión , Infarto del Miocardio/terapia , Resultado del Tratamiento , Modelos de Riesgos Proporcionales , Insuficiencia Cardíaca/terapia , Insuficiencia Cardíaca/fisiopatología , Revascularización Miocárdica , RadiofármacosRESUMEN
PURPOSE: Benzalkonium chloride (BAC) is commonly used as a preservative in ophthalmic medications, despite its potential to induce chemical injury. Extensive research has demonstrated that BAC can lead to adverse effects, including injuries to the ocular surface. Our study aimed to elucidate the underlying mechanism of necroptosis induced by BAC. METHODS: Human corneal epithelial (HCE) cells and mouse corneas were subjected to chemical injury, and the necrostatin-1 (Nec1) group was compared to the dimethylsulfoxide (DMSO) group. The extent of damage to HCE cells was assessed using CCK-8 and flow cytometry. Hematoxylin and eosin staining, as well as fluorescein sodium staining, were used to detect and characterize corneal injury. The activation of inflammatory cytokines and necroptosis-related proteins and genes was evaluated using Western blotting, immunofluorescence staining, and quantitative RTâPCR. RESULTS: In our study, the induction of necroptosis by a hypertonic solution was not observed. However, necroptosis was observed in HCE cells exposed to NaOH and BAC, which activated the receptor-interacting protein kinase 1 (RIPK1) - receptor-interacting protein kinase 3 (RIPK3) - mixed lineage kinase domain-like protein (MLKL) signaling pathway. In mouse corneal tissues, BAC could induce necroptosis and inflammation. The administration of Nec1 mitigated the inflammatory response and ocular surface damage caused by BAC-induced necroptosis in our experimental models. Furthermore, our in vivo experiments revealed that the severity of necroptosis was greater in the 3-day group than in the 7-day group. CONCLUSIONS: Necroptosis plays a role in the pathological development of ocular surface injury caused by exposure to BAC. Furthermore, our study demonstrated that the administration of Nec1 could mitigate the pathological effects of necroptosis induced by BAC in clinical settings.
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A novel enrofloxacin-degrading fungus was isolated from a rhizosphere sediment of the submerged macrophyte Vallisneria spiralis L.. The isolate, designated KC0924g, was identified as a member of the genus Humicola based on morphological characteristics and tandem conserved sequence analysis. The optimal temperature and pH for enrofloxacin degradation by strain KC0924g were 28 °C and 9.0, respectively. Under such condition, 98.2% of enrofloxacin with an initial concentration of 1 mg L-1 was degraded after 72 h of incubation, with nine possible degradation products identified. Four different metabolic pathways were proposed, which were initiated by cleavage of the piperazine moiety, hydroxylation of the aromatic ring, oxidative decarboxylation, or defluorination. In addition to enrofloxacin, strain KC0924g also degraded other fluoroquinolone antibiotics (ciprofloxacin, norfloxacin, and ofloxacin), malachite green (an illegal additive in aquaculture), and leucomalachite green. Pretreatment of cells of strain KC0924g with Cu2+ accelerated ENR degradation. Furthermore, it was speculated that a flavin-dependent monooxygenase was involved in ENR degradation, based on the increased transcriptional levels of these two genes after Cu2+ induction. This work enriches strain resources for enrofloxacin remediation and, more importantly, would facilitate studies on the molecular mechanism of ENR degradation with degradation-related transcriptome available.
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OBJECTIVES: Utilising readily available clinical variables, we aimed to develop and validate a novel machine learning (ML) model to predict severe coronary calcification, and further assessed its prognostic significance. METHODS: This retrospective study enrolled patients who underwent coronary CT angiography and subsequent invasive coronary angiography. Multiple ML algorithms were used to train the models for predicting severe coronary calcification (cardiac CT-measured coronary artery calcium [CT-CAC] score ≥ 400). The ML-based CAC (ML-CAC) score derived from the ML predictive probability was stratified into quartiles for prognostic analysis. The primary endpoint was a composite of all-cause death, nonfatal myocardial infarction, or nonfatal stroke. RESULTS: Overall, 5785 patients were divided into training (80%) and test sets (20%). For clinical practicability, we selected the nine-feature support vector machine model with good and satisfactory performance regarding both discrimination and calibration based on five repetitions of the 10-fold cross-validation in the training set (mean AUC = 0.715, Brier score = 0.202), and based on the test in the test set (AUC = 0.753, Brier score = 0.191). In the test set cohort (n = 1137), the primary endpoint was observed in 50 (4.4%) patients during a median 2.8 years' follow-up. The ML-CAC system was significantly associated with an increased risk of the primary endpoint (adjusted hazard ratio for trend 2.26, 95% CI 1.35-3.79, p = 0.002). There was no significant difference in the prognostic value between the ML-CAC and CT-CAC systems (C-index, 0.67 vs. 0.69; p = 0.618). CONCLUSION: ML-CAC score predicted from clinical variables can serve as a novel prognostic indicator in patients referred for invasive coronary angiography. CLINICAL RELEVANCE STATEMENT: In patients referred for invasive coronary angiography who have not undergone preoperative CT-measured coronary artery calcium scoring, machine learning-based coronary artery calcium score assessment can serve as an alternative for predicting the prognosis. KEY POINTS: ⢠The coronary artery calcium (CAC) score, a solid prognostic indicator, can be predicted using non-CT methods. ⢠We developed a machine learning (ML)-CAC model utilising nine clinical variables to predict severe coronary calcification. ⢠The ML-CAC system offers significant prognostic value in patients referred for invasive coronary angiography.
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BACKGROUND: Calcified lesions are one of the most challenging cases for PCI, where optimal angiographic results and satisfying outcomes are hard to achieve. METHODS: We evaluated the baseline clinical, procedures characteristics and outcomes of patients with severe coronary artery calcification (CAC) who underwent coronary intravascular lithotripsy (IVL) and rotational atherectomy (RA). RESULTS: Respectively 152 and 238 patients who underwent IVL and RA are enrolled from January 2023 to November 2023. Regarding demographic characteristics, the gender proportion, medical history of PCI and smoke history among groups reach statistical significance. Left anterior descending and right coronary artery were the main vessels treated in both groups. The 2.5 and 3.0 mm IVL balloons and 1.5 mm burr were the most commonly used. 99.3% cases were successfully implanted drug-eluting stents after IVL balloon pre-treatment, which was higher than in the group treated with RA. During hospitalization, there were no serious adverse events in the IVL group, but there were two adverse events in the RA group. Procedural complications were higher in the RA group than the IVL group (5.5% vs. 0.7%, P = 0.027). CONCLUSIONS: IVL appears to be safe and effective for the treatment of severe CAC lesions compared to RA.
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Aterectomía Coronaria , Enfermedad de la Arteria Coronaria , Litotricia , Índice de Severidad de la Enfermedad , Calcificación Vascular , Humanos , Aterectomía Coronaria/efectos adversos , Masculino , Femenino , Calcificación Vascular/terapia , Calcificación Vascular/diagnóstico por imagen , Enfermedad de la Arteria Coronaria/terapia , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Anciano , Resultado del Tratamiento , Persona de Mediana Edad , Estudios Retrospectivos , Factores de Riesgo , Factores de Tiempo , Stents Liberadores de Fármacos , Angiografía Coronaria , Angioplastia Coronaria con Balón/instrumentación , Angioplastia Coronaria con Balón/efectos adversos , Anciano de 80 o más AñosRESUMEN
BACKGROUND: With advancements in chronic total coronary occlusion (CTO) recanalization techniques and concepts, the success rate of recanalization has been steadily increasing. However, the current data are too limited to draw any reliable conclusions about the efficacy and safety of drug-coated balloons (DCBs) in CTO percutaneous coronary intervention (PCI). Herein, we conducted a meta-analysis to confirm the efficacy of DCB in CTO PCI. METHODS: We systematically searched PubMed, Web of Science and Embase from inception to July 25, 2023. The primary outcome was major advent cardiovascular events (MACE), including cardiac death, nonfatal myocardial infarction (MI), target lesion revascularization (TLR), and target vessel revascularization (TVR). The follow-up angiographic endpoints were late lumen enlargement (LLE), reocclusion and restenosis. RESULTS: Five studies with a total of 511 patients were included in the meta-analysis. Across studies, patients were predominantly male (72.9-85.7%) and over fifty years old. The summary estimate rate of MACE was 13.0% (95% CI 10.1%-15.9%, I2 = 0%, p = 0.428). The summary estimate rates of cardiac death and MI were 2.2% (95% CI 0.7%-3.7%, I2 = 0%, p = 0.873) and 1.2% (95% CI -0.2-2.6%, I2 = 13.7%, p = 0.314), respectively. Finally, the pooled incidences of TLR and TVR were 10.1% (95% CI 5.7%-14.5%, I2 = 51.7%, p = 0.082) and 7.1% (95% CI 3.0%-11.2%, I2 = 57.6%, p = 0.070), respectively. Finally, the summary estimate rates of LLE, reocclusion and restenosis were 59.4% (95% CI 53.5-65.3%, I2 = 0%, p = 0.742), 3.3% (95% CI 1.1-5.4%, I2 = 0%, p = 0.865) and 17.5% (95% CI 12.9-22.0%, I2 = 0%, p = 0.623), respectively. CONCLUSION: Accordingly, DCB has the potential to be used as a treatment for CTO in suitable patients.
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Angioplastia Coronaria con Balón , Catéteres Cardíacos , Materiales Biocompatibles Revestidos , Oclusión Coronaria , Humanos , Oclusión Coronaria/diagnóstico por imagen , Oclusión Coronaria/mortalidad , Oclusión Coronaria/terapia , Resultado del Tratamiento , Enfermedad Crónica , Angioplastia Coronaria con Balón/instrumentación , Angioplastia Coronaria con Balón/efectos adversos , Angioplastia Coronaria con Balón/mortalidad , Factores de Riesgo , Anciano , Femenino , Persona de Mediana Edad , Masculino , Fármacos Cardiovasculares/administración & dosificación , Fármacos Cardiovasculares/efectos adversos , Anciano de 80 o más Años , Medición de Riesgo , Factores de Tiempo , Diseño de Equipo , Reestenosis Coronaria/etiología , Reestenosis Coronaria/diagnóstico por imagen , Reestenosis Coronaria/mortalidadRESUMEN
Objectives: To create a nomogram using single photon emission computed tomography (SPECT) myocardial perfusion imaging and 18F-FDG positron emissions tomography (PET) gated myocardial metabolism imaging to forecast major adverse cardiovascular events (MACE) in chronic total occlusion (CTO) patients treated with optimal medical therapy (OMT). Methods: A total of 257 patients who received OMT between January 2016 and December 2021 were included in this retrospective study. Patients were randomly divided into development (n=179) and validation (n=78) cohorts. A thorough evaluation was conducted, encompassing clinical features and imaging analysis, which involved assessing myocardial perfusion and metabolism. Independent risk factors were identified using least absolute shrinkage and selection operator (LASSO) and multivariate Cox regression analyses. Calibration curves and decision curve analysis (DCA) were used to evaluate the clinical usefulness. Results: In the development cohort, 53 patients (29.6%) experienced MACE out of 179 patients, while in the validation cohort, MACE occurred in 23 (29.5%) patients out of 78. The PET-left ventricular end-systolic volume (P-ESV) (HR 1.01; 95% CI 1.003-1.017; p=0.003), hibernating myocardium / total perfusion defect (HM/TPD) (HR 1.053; 95% CI 1.038-1.069; p<0.001), PET-left ventricular ejection fraction (P-LVEF) (HR 0.862; 95% CI 0.788-0.943; p=0.001), and left anterior descending branch (LAD) (HR 2.303; 95% CI 1.086-4.884; p=0.03) were significantly associated with MACE and were used to develop the nomogram. The nomogram demonstrated excellent discrimination with C-indexes of 0.931 and 0.911 in the development and validation cohorts. DCA determined that the model exhibited a considerably superior net advantage in predicting MACE. Conclusion: A new nomogram integrating clinical factors and imaging features was created to predict the risk of MACE in patients with CTO.
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Oclusión Coronaria , Imagen de Perfusión Miocárdica , Nomogramas , Humanos , Masculino , Femenino , Persona de Mediana Edad , Anciano , Oclusión Coronaria/diagnóstico por imagen , Oclusión Coronaria/diagnóstico , Estudios Retrospectivos , Imagen de Perfusión Miocárdica/métodos , Enfermedad Crónica , Tomografía de Emisión de Positrones , Tomografía Computarizada de Emisión de Fotón Único , Factores de Riesgo , Fluorodesoxiglucosa F18/administración & dosificación , Medición de Riesgo/estadística & datos numéricos , Medición de Riesgo/métodosRESUMEN
OBJECTIVE: The preoperative prediction of the overall survival (OS) status of patients with head and neck cancer (HNC) is significant value for their individualized treatment and prognosis. This study aims to evaluate the impact of adding 3D deep learning features to radiomics models for predicting 5-year OS status. METHODS: Two hundred twenty cases from The Cancer Imaging Archive public dataset were included in this study; 2212 radiomics features and 304 deep features were extracted from each case. The features were selected by univariate analysis and the least absolute shrinkage and selection operator, and then grouped into a radiomics model containing Positron Emission Tomography /Computed Tomography (PET/CT) radiomics features score, a deep model containing deep features score, and a combined model containing PET/CT radiomics features score +3D deep features score. TumorStage model was also constructed using initial patient tumor node metastasis stage to compare the performance of the combined model. A nomogram was constructed to analyze the influence of deep features on the performance of the model. The 10-fold cross-validation of the average area under the receiver operating characteristic curve and calibration curve were used to evaluate performance, and Shapley Additive exPlanations (SHAP) was developed for interpretation. RESULTS: The TumorStage model, radiomics model, deep model, and the combined model achieved areas under the receiver operating characteristic curve of 0.604, 0.851, 0.840, and 0.895 on the train set and 0.571, 0.849, 0.832, and 0.900 on the test set. The combined model showed better performance of predicting the 5-year OS status of HNC patients than the radiomics model and deep model. The combined model was shown to provide a favorable fit in calibration curves and be clinically useful in decision curve analysis. SHAP summary plot and SHAP The SHAP summary plot and SHAP force plot visually interpreted the influence of deep features and radiomics features on the model results. CONCLUSIONS: In predicting 5-year OS status in patients with HNC, 3D deep features could provide richer features for combined model, which showed outperformance compared with the radiomics model and deep model.
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Aprendizaje Profundo , Neoplasias de Cabeza y Cuello , Nomogramas , Tomografía Computarizada por Tomografía de Emisión de Positrones , Humanos , Neoplasias de Cabeza y Cuello/diagnóstico por imagen , Masculino , Femenino , Persona de Mediana Edad , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Pronóstico , Anciano , Imagenología Tridimensional/métodos , Adulto , Estudios Retrospectivos , RadiómicaRESUMEN
PURPOSE: To evaluate the long-term safety and efficacy of adjuvant intravitreal anti-VEGF therapy in juvenile Coats disease. METHODS: This retrospective, observational study included a total of 62 eyes in 62 pediatric patients with juvenile Coats disease treated with intravitreal anti-VEGF agents followed for a mean of 67.08 months (ranged from 60 to 93 months). All affected eyes were managed initially with one session of ablative treatment plus adjuvant intravitreal anti-VEGF agent (0.5 mg/0.05 ml ranibizumab or conbercept). Ablative treatment was repeated if telangiectatic retinal vessels were not completely regressed or recurred. Anti-VEGF therapy was repeated if subretinal fluid or macular edema still existed. Treatments above were repeated every 2 to 3 months. We reviewed clinical and photographic records of patients including the demographics, clinical characteristics and interventions. RESULTS: At final visit, all 62 affected eyes had partially or completely disease resolution; none progressed to advanced stage namely neovascular glaucoma or phthisis bulbi, respectively. No ocular or systemic side effects related to intravitreal injections were observed during follow-up. In terms of 42 affected eyes that could cooperate with visual examination, best corrected visual acuity improved in 14 (14/42, 33.3%) eyes, stabled in 25 (25/42, 59.5%) eyes, and worsened in 3 (3/42, 7.1%) eyes. In the field of complications, 22 (22/62, 35.5%) eyes developed cataracts; 33 (33/62, 53.2%) eyes developed vitreoretinal fibrosis, of whom 14 (14/33, 42.4%) eyes in the subgroup of stage 3B developed progressive TRD; 40 (40/62, 64.5%) eyes developed subretinal fibrosis. Multivariate regression analysis showed increased clinical stage may be associated with the development of vitreo- and subretinal fibrosis (adjusted odds ratio:16.77,17.59; 95% CI:4.50-62.53, 3.98-77.86, respectively, all P < 0.001). CONCLUSION: Adjuvant intravitreal ranibizumab or conbercept combined with ablative therapies may be a long-term safe and effective treatment for juvenile Coats disease.
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Ranibizumab , Telangiectasia Retiniana , Niño , Humanos , Inhibidores de la Angiogénesis , Bevacizumab/uso terapéutico , Fibrosis , Estudios de Seguimiento , Inyecciones Intravítreas , Estudios Observacionales como Asunto , Ranibizumab/uso terapéutico , Telangiectasia Retiniana/diagnóstico , Telangiectasia Retiniana/tratamiento farmacológico , Estudios Retrospectivos , Factor A de Crecimiento Endotelial Vascular , Factores de Crecimiento Endotelial Vascular , PreescolarRESUMEN
BACKGROUND: Two main subclasses of macrophages are found in almost all solid tissues: embryo-derived resident tissue macrophages and bone marrow-derived infiltrated macrophages. These macrophage subtypes show transcriptional and functional divergence, and the programs that have shaped the evolution of renal macrophages and related signaling pathways remain poorly understood. To clarify these processes, we performed data analysis based on single-cell transcriptional profiling of renal tissue-resident and infiltrated macrophages in human, mouse and rat. RESULTS: In this study, we (i) characterized the transcriptional divergence among species and (ii) illustrated variability in expression among cells of each subtype and (iii) compared the gene regulation network and (iv) ligand-receptor pairs in human and mouse. Using single-cell transcriptomics, we mapped the promoter architecture during homeostasis. CONCLUSIONS: Transcriptionally divergent genes, such as the differentially TF-encoding genes expressed in resident and infiltrated macrophages across the three species, vary among cells and include distinct promoter structures. The gene regulatory network in infiltrated macrophages shows comparatively better species-wide consistency than resident macrophages. The conserved transcriptional gene regulatory network in infiltrated macrophages among species is uniquely enriched in pathways related to kinases, and TFs associated with largely conserved regulons among species are uniquely enriched in kinase-related pathways.
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Análisis de Datos , Macrófagos , Humanos , Animales , Ratones , Ratas , Embrión de Mamíferos , Perfilación de la Expresión Génica , Expresión GénicaRESUMEN
Vascular calcification is very common in clinical. Severe vascular calcification is related to the occurrence of adverse events. Oxidative stress (OS) plays a pathophysiological role in the formation of vascular calcification. Previous studies have demonstrated that fibroblast growth factor 21(FGF21) could inhibit vascular calcification both in vivo and in vitro. FGF21 has also been proved to promote the recovery of superoxide dismutase (SOD) and thereby alleviate OS. Thus, our assumption was that FGF21 inhibit vascular calcification partly by restoring the level of antioxidant SOD and reducing OS. In this study, we established the vascular calcification by 5/6 nephrectomy plus high phosphate diet chronic kidney disease (CKD) model. The results showed the receptor of FGF21, fibroblast growth factor receptor 1 (FGFR1) and ßKlotho in the aorta increased in CKD group, and mainly located in the media of the artery. Ulteriorly, immunofluorescence (IF) and IHC staining showed that FGFR1 and ßKlotho mainly existed in arterial vascular smooth muscle cells (VSMCs). When FGF21 was knock out, the calcification was more severe in FGF21 KO + CKD mice, compared to wild type (WT)+ CKD mice. The transcriptional level of vascular calcification-related genes was significantly higher in FGF21 KO mice than control group. The dihydroethidium (DHE) staining reactive oxygen species (ROS) level in the CKD group was higher compared to the control group, but lower in FGF21 KO + CKD group, and the transcriptional level of SOD1 and SOD2 in FGF21 KO + CKD group was significantly higher than that in CKD group. In conclusion, FGF21 could inhibit vascular calcification, partly by restoring the level of antioxidant SOD and reducing vascular oxidative stress. This study provides further evidence for FGF21 as a candidate drug for cardiovascular protective agents.
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Insuficiencia Renal Crónica , Calcificación Vascular , Animales , Ratones , Antioxidantes/metabolismo , Factores de Crecimiento de Fibroblastos/metabolismo , Músculo Liso Vascular/metabolismo , Miocitos del Músculo Liso/metabolismo , Estrés Oxidativo , Insuficiencia Renal Crónica/metabolismo , Superóxido Dismutasa/metabolismo , Calcificación Vascular/metabolismoRESUMEN
Irritable bowel syndrome (IBS) is a common disorder of gut-brain interaction with an increasing prevalence, and its precise aetiology remains unclear. Gut microbiota dysbiosis has been found to be associated with IBS pathogenesis. In addition, a high incidence of bile acid diarrhoea and disturbed bile acid metabolism has been observed in IBS patients. The abundant microorganisms inhabited in human gut have essential functions in bile acid biotransformation, and can immensely affect the size and constitution of bile acid pool. Meanwhile, the alterations of bile acid profile can inversely interfere with the gut microbiota. This review discussed the role of intricate correlations between bile acids and gut microbiota in IBS pathogenesis and delineated the possible molecular mechanisms, mainly the signalling induced by farnesoid X receptor and transmembrane G protein-coupled receptor 5. Besides, some biomarkers for identifying bile acid diarrhoea in IBS population were listed, assisting the diagnosis and classification of IBS. Moreover, it also assessed some therapeutic strategies for IBS that regulate the bile acid-gut microbiota axis, such as dietary modulation, probiotics/prebiotics, faecal microbiota transplantation, and antibiotics. Collectively, this article illustrated the relationship between bile acids and gut microbiota in IBS pathophysiology and might offer some novel therapeutic options for IBS.
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Microbioma Gastrointestinal , Síndrome del Colon Irritable , Probióticos , Humanos , Síndrome del Colon Irritable/tratamiento farmacológico , Ácidos y Sales Biliares/uso terapéutico , DiarreaRESUMEN
Background: Owing to advances in procedural techniques and the training of interventional staff in catheterization labs, recent work has demonstrated the safety of percutaneous coronary intervention (PCI) as a treatment for patients suffering from chronic total occlusion (CTO). However, there has been little research focused on systematic comparisons of PCI outcomes in CTO patients that did or did not exhibit a history of previous coronary artery bypass grafting (CABG). Methods: Electronic databases were systematically searched for all studies comparing CTO-PCI outcomes for patients with and without a history of CABG, with event rates subsequently being compared via random-effects models with forest plots and odds ratios with 95% confidence intervals (CI), owing to the assumption of between-studies heterogeneity. Results: In total, 8 observational studies enrolling 13,509 CTO patients were identified, including 3389 and 10,120 patients with and without a history of prior CABG, respectively. Patients were enrolled in these studies from 1999-2018. Pooled analyses indicated that CABG history was not linked to a lower proportion of radial access 24 (95% CI 0.52-1.03, p = 0.08), and a prior CABG history was linked to a greater contrast volume (95% CI 0.12-0.44, p < 0.001), higher radiation dose (95% CI 0.27-0.40, p < 0.001), longer fluoroscopy time (95% CI 0.42-0.61, p < 0.001), longer procedural time (95% CI 0.38-0.64, p < 0.001), a higher number of implanted stents (95% CI 0.41-0.60, p < 0.001), longer total stent length (95% CI 0.21-0.60, p < 0.001), higher technical failure rates (95% CI 1.46-1.85, p < 0.001), and higher rates of procedural failure (95% CI 1.42-1.79, p < 0.001). The in-hospital mortality (95% CI 1.50-4.03, p < 0.001) and periprocedural mortality (95% CI 1.63-3.73, p < 0.001) of patients with a history of CABG were also higher. While stroke incidence was comparable in both groups (95% CI 0.80-4.47, p = 0.15), periprocedural major adverse cardiovascular and cerebrovascular events (MACCE) rates were significantly higher among patients exhibiting a history of CABG (95% CI 1.66-2.94, p < 0.001). Conclusions: These results suggest that CTO-PCI procedures may be more challenging and associated with lower rates of success in CABG patients relative to procedures performed in patients without any history of CABG. Moreover, in-hospital outcomes including MACCE and mortality were worse for patients that had undergone prior CABG.
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Background: The risk of sudden cardiac death (SCD) after coronary revascularization in patients with left ventricular (LV) systolic dysfunction has not been characterized completely. This study aims to evaluate the incidence and time course of SCD after revascularization in such patients. The determinants of SCD within 3 months after revascularization were also assessed. Methods: A cohort study of patients with reduced ejection fraction (EF ≤ 40%), who underwent revascularization was performed. The incidence of SCD was estimated to account for the competing risk of deaths due to other causes. Results: 2317 patients were enrolled. With a median follow-up of 3.5 years, 162 (32.1%) of the 504 deaths were due to SCD. The risk of SCD was highest in the first 3 months after revascularization, with an incidence rate of 0.37%/month. The event rate decreased to 0.12%/month, 0.08%/month, 0.09%/month, 0.14%/month, and 0.19%/month at 3-6 months, 6-12 months, 1-3 years, 3-5 years, and 5-10 years, respectively. A history of ventricular tachycardia/ventricular fibrillation (hazard ratio [HR], 5.55; 95% confidence interval [CI], 1.33-23.19; p = 0.019) and triple vessel disease (HR, 3.90; 95% CI, 1.38-11.05; p = 0.010) were associated with the risk of SCD within 3 months. However, preoperative EF (in 5% increments) was not predictive (HR per 5% increase, 0.98; 95% CI, 0.62-1.55; p = 0.935). Conclusions: For patients with LV dysfunction, the risk of SCD was the highest during the first 3 months after revascularization. Further risk classification and treatment strategy are warranted. Clinical Trial Registration: The name of the registry: Coronary Revascularization in Patients with Ischemic Heart Failure and Prevention of Sudden Cardiac Death. Registration number: ChiCTR2100044378.
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The Mpemba effect and its inverse can be understood as a result of nonequilibrium thermodynamics. In polymers, changes of state are generally non-equilibrium processes. However, the Mpemba effect has been rarely reported in the crystallization of polymers. In the melt, polybutene-1 (PB-1) has the lowest critical cooling rate in polyolefins and tends to maintain its original structure and properties with thermal history. A nascent PB-1 sample was prepared by using metallocene catalysis at low temperature, and the crystallization behavior and crystalline structure of the PB-1 were characterized by DSC and WAXS. Experimentally, a clear Mpemba effect is observed not only in the crystallization of the nascent PB-1 melt in form II but also in form I obtained from the nascent PB-1 at low melting temperature. It is proposed that this is due to the differences in the chain conformational entropy in the lattice which influence conformational relaxation times. The entropy and the relaxation time can be predicted using the Adam-Gibbs equations, whereas non-equilibrium thermodynamics is required to describe the crystallization with the Mpemba effect.
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Herein, we propose a label-free chemiresistive sensor for the highly sensitive and selective detection of microcystin (MC)-LR in water samples. The sensor uses a layer-by-layer (LBL) assembled conductive film consisting of Ti3C2Tx nanosheets as the sensing channel. It is further modified by using an aptamer for the specific recognition of MC-LR. The response signal is based on the change in resistance of the conductive channel upon binding of MC-LR with the aptamer. Our novel strategy is the first concept proposed for immobilizing the aptamer containing -SH on the channel surface through a Ti-S bond under weakly alkaline condition. The resulting sensor is highly sensitive and stable for the detection of MC-LR, with a detection limit of 0.18 ng L-1 and a wide linear range from 1 to 104 ng L-1. We used the sensor to continuously monitor MC-LR released by cultivated Microcystis aeruginosa, showing a strong relationship between MC-LR and cell density. Furthermore, the sensor was successfully used to measure MC-LR in freshwater lakes with moderate algal blooms, and the results agreed well with those obtained by liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis. The present study provides a reliable method for highly sensitive and selective detection of MC-LR in environmental waters.
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Microcistinas , Espectrometría de Masas en Tándem , Microcistinas/análisis , Microcistinas/química , Cromatografía Liquida , Titanio , Lagos/análisis , Agua/químicaRESUMEN
Dominant infiltration of neutrophils is a hallmark of many inflammatory diseases, especially in septic shock. IL-1ß as one of the most early released proinflammatory cytokine in neutrophil, plays a pivotal role in the progress of sepsis. In this study, we built a high-throughput-compatible drug screen assay platform based on our newly constructed reporter C57BL/6 mice, pIL1-DsRed, expressing the DsRed gene under the control of the IL-1ß promoter. After screening 1200 U.S. Food and Drug Administration-approved compounds, we found that pinaverium bromide (PVB) significantly suppressed the DsRed expression of primed neutrophil and improved the survival rate of mice given LPS in an endotoxin challenge analogous to sepsis, regardless of whether PVB was administered before or after LPS. PVB also protected the liver and lung from LPS-induced damage and reduced organ-specific inflammatory responses. PVB decreased the production of IL-1ß, IL-6, and CXCL1 mRNA in the lungs of LPS-treated mice and decreased the serum levels of liver transaminases (alanine aminotransferase and aspartate aminotransferase) at multiple time points and doses tested. PVB can significantly suppress primed neutrophil-specific respiratory bursts and migration as well. Lastly, PVB affected neutrophils' gene expression and phenotypic changes during neutrophil priming. PVB downregulated GM-CSF-induced expression of CD54 and dectin-2 (markers of fully primed neutrophils) at both mRNA and protein levels during late-phase neutrophil priming. In summary, we demonstrated that PVB can be used as a potential therapeutic agent for sepsis by inhibiting neutrophil priming.
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Lipopolisacáridos , Neutrófilos , Animales , Inflamación , Ratones , Ratones Endogámicos C57BL , MorfolinasRESUMEN
AIMS: In-stent chronic total occlusion (IS-CTO) represents a unique challenge for percutaneous coronary intervention. Whether the optimal treatment for IS-CTO is angioplasty with paclitaxel-coated balloons (PCBs) or repeat stenting with drug-eluting stents (DESs) is unclear. We aimed to evaluate the long-term clinical outcome of PCB angioplasty and DES repeat stenting for DES IS-CTO. METHODS: We retrospectively included patients with DES IS-CTO who underwent successful PCB angioplasty or DES repeat stenting from January 2016 to December 2019. The primary endpoints were major adverse cardiac events (MACEs), including cardiac death, myocardial infarction, and target lesion revascularization (TLR). Cox proportional hazards model was performed to compare the risk of MACEs between PCB angioplasty and DES repeat stenting, and to further explore the prognostic factors of patients with DES IS-CTO. RESULTS: A total of 214 patients with DES IS-CTO were enrolled: 78 patients (36.4%) treated with PCB and 136 patients (63.6%) treated with DES respectively. The median follow-up was 1160 days, and MACEs were observed in 28.2% of patients with PCB angioplasty versus 26.5% of patients with DES repeat stenting (P = 0.784), mainly driven by TLR (21.8% vs. 19.9%, P = 0.735). There was no significant difference in the risk of MACEs between the PCB group and the DES group (hazard ratio [HR] 1.25, 95% confidence interval [CI] 0.64-2.46, P = 0.512). Multivariate Cox analysis revealed that chronic kidney disease and ≥ 3 stent layers in the lesion were independent predictors of MACEs, while switching to another antiproliferative drug was an independent protective factor (all P < 0.05). CONCLUSIONS: PCB angioplasty was an effective alternative treatment strategy for DES IS-CTO, which had similar long-term outcomes to DES repeat stenting in contemporary practice, but both were accompanied by a high rate of long-term MACEs. Improving the poor prognosis of patients with DES IS-CTO remains a challenge.
Asunto(s)
Angioplastia Coronaria con Balón , Reestenosis Coronaria , Stents Liberadores de Fármacos , Humanos , Stents Liberadores de Fármacos/efectos adversos , Paclitaxel/efectos adversos , Estudios Retrospectivos , Factores de Riesgo , Reestenosis Coronaria/etiología , Angioplastia Coronaria con Balón/efectos adversos , Resultado del Tratamiento , Stents , Angiografía CoronariaRESUMEN
In the context of diabetes mellitus (DM), the circulating cathepsin S (CTSS) level is significantly higher in the cardiovascular disease group. Therefore, this study was designed to investigate the role of CTSS in restenosis following carotid injury in diabetic rats. To induce DM, 60 mg/kg of streptozotocin (STZ) in citrate buffer was injected intraperitoneally into Sprague-Dawley rats. After successful modeling of DM, wire injury of the rat carotid artery was performed, followed by adenovirus transduction. Levels of blood glucose and Th17 cell surface antigens including ROR-γt, IL-17A, IL-17F, IL-22, and IL-23 in perivascular adipose tissues (PVAT) were evaluated. For in vitro analysis, human dendritic cells (DCs) were treated with 5.6-25 mM glucose for 24 h. The morphology of DCs was observed using an optical microscope. CD4+ T cells derived from human peripheral blood mononuclear cells were cocultured with DCs for 5 days. Levels of IL-6, CTSS, ROR-γt, IL-17A, IL-17F, IL-22 and IL-23 were measured. Flow cytometry was conducted to detect DC surface biomarkers (CD1a, CD83, and CD86) and Th17 cell differentiation. The collected DCs presented a treelike shape and were positive for CD1a, CD83, and CD86. Glucose impaired DC viability at the dose of 35 mM. Glucose treatment led to an increase in CTSS and IL-6 expression in DCs. Glucose-treated DCs promoted the differentiation of Th17 cells. CTSS depletion downregulated IL-6 expression and inhibited Th17 cell differentiation in vitro and in vivo. CTSS inhibition in DCs inhibits Th17 cell differentiation in PVAT tissues from diabetic rats following vascular injury.