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Hemorrhagic stroke and brain microbleeds are caused by cerebrovascular ruptures. Fast repair of such ruptures is the most promising therapeutic approach. Due to a lack of high-resolution in vivo real-time studies, the dynamic cellular events involved in cerebrovascular repair remain unknown. Here, we have developed a cerebrovascular rupture system in zebrafish by using multi-photon laser, which generates a lesion with two endothelial ends. In vivo time-lapse imaging showed that a macrophage arrived at the lesion and extended filopodia or lamellipodia to physically adhere to both endothelial ends. This macrophage generated mechanical traction forces to pull the endothelial ends and facilitate their ligation, thus mediating the repair of the rupture. Both depolymerization of microfilaments and inhibition of phosphatidylinositide 3-kinase or Rac1 activity disrupted macrophage-endothelial adhesion and impaired cerebrovascular repair. Our study reveals a hitherto unexpected role for macrophages in mediating repair of cerebrovascular ruptures through direct physical adhesion and mechanical traction.
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Aneurisma Roto/imunologia , Traumatismo Cerebrovascular/imunologia , Endotélio Vascular/fisiologia , Macrófagos/imunologia , Fenômenos Mecânicos , Remodelação Vascular , Peixe-Zebra/imunologia , Citoesqueleto de Actina/metabolismo , Animais , Adesão Celular , Células Cultivadas , Fosfatidilinositol 3-Quinases/metabolismo , Tração , Cicatrização , Proteínas rac1 de Ligação ao GTP/metabolismoRESUMO
Neurovascular coupling serves as an essential neurophysiological mechanism in functional neuroimaging, which is generally presumed to be robust and invariant across different physiological states, encompassing both task engagement and resting state. Nevertheless, emerging evidence suggests that neurovascular coupling may exhibit state dependency, even in normal human participants. To investigate this premise, we analyzed the cross-frequency spectral correspondence between concurrently recorded electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) data, utilizing them as proxies for neurovascular coupling during the two conditions: an eye-open-eye-close (EOEC) task and a resting state. We hypothesized that given the state dependency of neurovascular coupling, EEG-fMRI spectral correspondences would change between the two conditions in the visual system. During the EOEC task, we observed a negative phase-amplitude-coupling (PAC) between EEG alpha-band and fMRI visual activity. Conversely, in the resting state, a pronounced amplitude-amplitude-coupling (AAC) emerged between EEG and fMRI signals, as evidenced by the spectral correspondence between the EEG gamma-band of the midline occipital channel (Oz) and the high-frequency fMRI signals (0.15-0.25 Hz) in the visual network. This study reveals distinct scenarios of EEG-fMRI spectral correspondence in healthy participants, corroborating the state-dependent nature of neurovascular coupling.
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Imageamento por Ressonância Magnética , Acoplamento Neurovascular , Humanos , Imageamento por Ressonância Magnética/métodos , Acoplamento Neurovascular/fisiologia , Mapeamento Encefálico/métodos , Eletroencefalografia/métodos , Olho , Encéfalo/diagnóstico por imagem , Encéfalo/fisiologiaRESUMO
The adsorption behaviors and electronic properties of five gas molecules (CO, H2O, NH3, NO, and C2H6O) on the intrinsic Ti2CO2 and Fe-doped Ti2CO2 were calculated and studied based on first principles. The adsorption height, bond length change, adsorption energy, charge transfer, band structure, differential charge, work function, and recovery time of the two gas adsorption systems were discussed, and their sensing performance was evaluated. The results show that the CO gas molecules have the best adsorption energy and charge transfer on Ti2CO2 modified by the Fe atom (Ti2CO2-Fe). The electrical conductivity obviously increases with the decrease of the band gap, which changes from semiconductor to conductor behavior. The reduction of the work function in the Ti2CO2-Fe system weakens the binding of the electron, which improves the electron flow between the substrate and the gas molecules. In addition, the Ti2CO2-Fe system with H2O molecule participation remained the best adsorption effect on CO gas, and the fast recovery time was 625 s at 398 K. Therefore, Ti2CO2-Fe is a prospective material for the advancement of CO gas-sensitive sensors.
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Cadmium poisoning is a chronic accumulation process, and long-term drinking of even low cadmium content water will cause kidney damage, so an ultra-low detection limit is particularly important. However, at the present stage, the traditional detection method cannot reach a sufficiently low detection limit, the response time is too long, and the cost of detection is very high, so that real-time measurement cannot be realized. Therefore, the traditional cadmium ion detection method has a slow response and an insufficient detection limit. This paper presents a fiber optic cadmium ion sensor functionalized based on an Fe3O4@SiO2@CS magnetic ion imprinting polymer (M-IIP). The sensor is based on the coupling characteristics of the optical microfiber coupler (OMC) cone region to achieve a highly sensitive response to the change in the cadmium ion concentration. M-IIP materials were prepared by surface imprinting polymerization to achieve low cross-sensitivity and thus improve the detection limit of the sensor. The results show that the developed fiber sensor has high specificity and a rapid response to cadmium ions. The experimental limit of detection (LOD) reached 0.051 nM within 0-1 µM with a response time of less than 50 s. Moreover, the proposed fiber cadmium ion sensor exhibits excellent performance in terms of sensitivity, stability, repeatability and biocompatibility.
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INTRODUCTION: The prevalence of type 2 diabetes (T2D) has increased dramatically in recent decades, and there are increasing indications that dementia is related to T2D. Previous attempts to analyze such relationships principally relied on traditional multiple linear regression (MLR). However, recently developed machine learning methods (Mach-L) outperform MLR in capturing non-linear relationships. The present study applied four different Mach-L methods to analyze the relationships between risk factors and cognitive function in older T2D patients, seeking to compare the accuracy between MLR and Mach-L in predicting cognitive function and to rank the importance of risks factors for impaired cognitive function in T2D. METHODS: We recruited older T2D between 60-95 years old without other major comorbidities. Demographic factors and biochemistry data were used as independent variables and cognitive function assessment (CFA) was conducted using the Montreal Cognitive Assessment as an independent variable. In addition to traditional MLR, we applied random forest (RF), stochastic gradient boosting (SGB), Naïve Byer's classifier (NB) and eXtreme gradient boosting (XGBoost). RESULTS: Totally, the test cohort consisted of 197 T2D (98 men and 99 women). Results showed that all ML methods outperformed MLR, with symmetric mean absolute percentage errors for MLR, RF, SGB, NB and XGBoost respectively of 0.61, 0.599, 0.606, 0.599 and 0.2139. Education level, age, frailty score, fasting plasma glucose and body mass index were identified as key factors in descending order of importance. CONCLUSION: In conclusion, our study demonstrated that RF, SGB, NB and XGBoost are more accurate than MLR for predicting CFA score, and identify education level, age, frailty score, fasting plasma glucose, body fat and body mass index as important risk factors in an older Chinese T2D cohort.
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Diabetes Mellitus Tipo 2 , Fragilidade , Masculino , Humanos , Feminino , Idoso , Pessoa de Meia-Idade , Idoso de 80 Anos ou mais , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/epidemiologia , Modelos Lineares , Glicemia , Cognição , Aprendizado de Máquina , China/epidemiologiaRESUMO
This study investigated the potential role of the mouse homolog of bombesin receptor-activated protein (BRAP) in imiquimod (IMQ) induced psoriasis - like skin inflammation. The expression of both human BRAP, encoded by C6orf89, and its mouse homolog, encoded by BC004004, has been found to be expressed abundantly in the keratinocytes. BC004004 knockout mice (BC004004-/-) were topically treated with IMQ daily for 7 days to test whether they were more vulnerable to psoriasis - like inflammation. We found that those mice exhibited an altered pattern of inflammation process compared to isogenic wild type control mice (BC004004+/+). BC004004-/- mice developed skin lesions with earlier and more acute onset, as well as a quicker remission. The cytokines related to pathogenesis of psoriasis also exhibited different expression patterns in IMQ treated BC004004-/- mice. On day 4 of IMQ treatment, BC004004-/- mice exhibited a higher expression level of IL-17A compared to BC004004+/+ mice, suggesting a more robust activation of Th17 cells in the knockout mice. The serum level of thymic stromal lymphopoietin (TSLP), one of the keratinocyte derived cytokines, was also increased in BC004004-/- mice and reached its peak on day 4. Knockdown of BRAP in cultured human keratinocyte-derived HaCaT cells by siRNA silencing led to increased release of TSLP. Our data suggest that the elevated of level of TSLP released from keratinocytes due to BRAP deficiency might mediate the crosstalk between the epidermal cells and immune cells and thereby contributing to the altered pathological changes observed in psoriasis - like skin lesion in knockout mice.
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Psoríase , Receptores da Bombesina , Camundongos , Humanos , Animais , Receptores da Bombesina/genética , Receptores da Bombesina/metabolismo , Queratinócitos/metabolismo , Imiquimode/metabolismo , Inflamação/patologia , Citocinas/metabolismo , Camundongos Knockout , Modelos Animais de Doenças , Pele/patologia , Camundongos Endogâmicos BALB CRESUMO
OBJECTIVE: Various prediction scores have been developed to predict mortality in trauma patients, such as the shock index (SI), modified SI (mSI), age-adjusted SI (aSI), and the shock index (SI) multiplied by the alert/verbal/painful/unresponsive (AVPU) score (SIAVPU). The SIAVPU is a novel scoring system but its prediction accuracy for trauma outcomes remains in need of further validation. Therefore, we investigated the accuracy of four scoring systems, including SI, mSI, aSI, and SIAVPU, in predicting mortality, admission to the intensive care unit (ICU), and prolonged hospital length of stay ≥ 30 days (LOS). METHODS: This retrospective multicenter study used data from the Tzu Chi Hospital trauma database. The area under the receiver operating characteristic curve (AUROC) was determined for each outcome to assess their discrimination capabilities and comparing by Delong's test. Subgroup analyses were conducted to investigate the prediction accuracy of the SIAVPU in different patient populations. RESULTS: In total, 5355 patients were included in the analysis. The median of SIAVPU were significantly higher among patients at those with major injury (1.47 vs 0.63), those admitted to the ICU (0.73 vs 0.62), those with prolonged hospital LOS≥ 30 days (0.83 vs 0.64), and those with mortality (1.08 vs 0.64). The AUROC of the SIAVPU was significantly higher than that of the SI, mSI, and aSI for 24-h mortality (AUROC: 0.845 vs 0.533, 0.540, and 0.678), 3-day mortality (AUROC: 0.803 vs 0.513, 0.524, and 0.688), 7-day mortality (AUROC: 0.755 vs 0.494, 0.505, and 0.648), in-hospital mortality (AUROC: 0.722 vs 0.510, 0.524, and 0.667), ICU admission (AUROC: 0.635 vs 0.547, 0.551, and 0.563). At the optimal cutoff value of 0.9, the SIAVPU had an accuracy of 82.2% for predicting 24-h mortality, 82.8% for predicting 3-day mortality, of 82.8% for predicting 7-day mortality, of 82.5% for predicting in-hospital mortality, of 73.9% for predicting Intensive Care Unit (ICU) admission, and of 81.7% for predicting prolonged hospital LOS ≥30 days. CONCLUSIONS: Our results reveal that SIAVPU has better accuracy than the SI, mSI, and aSI for predicting 24-h, 3-day, 7-day, and in-hospital mortality; ICU admission; and prolonged hospital LOS ≥30 days among patients with traumatic injury.
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Ferimentos e Lesões , Humanos , Estudos Retrospectivos , Masculino , Feminino , Ferimentos e Lesões/mortalidade , Pessoa de Meia-Idade , Adulto , Serviços Médicos de Emergência , Tempo de Internação/estatística & dados numéricos , Valor Preditivo dos Testes , Idoso , Unidades de Terapia Intensiva/estatística & dados numéricos , Choque/mortalidade , Curva ROC , Escala de Gravidade do Ferimento , Mortalidade HospitalarRESUMO
The incidence and related death of hepatocellular carcinoma (HCC) have increased over the past decades. However, the molecular mechanisms underlying HCC pathogenesis are not fully understood. Long noncoding RNA (lncRNA) RP11-495P10.1 has been proven to be closely associated with the progression of prostate cancer, but its role and specific mechanism in HCC are still unknown. Here, we identify that RP11-495P10.1 is highly expressed in HCC tissues and cells and contributes to the proliferation of HCC cells. Moreover, this study demonstrates that RP11-495P10.1 affects the proliferation of HCC by negatively regulating the expression of nuclear receptor subfamily 4 group a member 3 (NR4A3). Glycometabolism reprogramming is one of the main characteristics of tumor cells. In this study, we discover that RP11-495P10.1 regulates glycometabolism reprogramming by changing the expression of pyruvate dehydrogenase kinase 1 (PDK1) and pyruvate dehydrogenase (PDH), thus contributing to the proliferation of HCC cells. Furthermore, knockdown of RP11-495P10.1 increases enrichment of H3K27Ac in the promoter of NR4A3 by promoting the activity of PDH and the production of acetyl-CoA, which leads to the increased transcription of NR4A3. Altogether, RP11-495P10.1 promotes HCC cell proliferation by regulating the reprogramming of glucose metabolism and acetylation of the NR4A3 promoter via the PDK1/PDH axis, which provides an lncRNA-oriented therapeutic strategy for the diagnosis and treatment of HCC.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , RNA Longo não Codificante , Receptores de Esteroides , Humanos , Masculino , Acetilação , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Proliferação de Células/genética , Proteínas de Ligação a DNA/genética , Regulação Neoplásica da Expressão Gênica , Glucose , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Receptores de Esteroides/genética , Receptores de Esteroides/metabolismo , Receptores dos Hormônios Tireóideos/genética , Receptores dos Hormônios Tireóideos/metabolismo , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Piruvato Desidrogenase Quinase de Transferência de Acetil/metabolismo , Complexo Piruvato Desidrogenase/metabolismoRESUMO
Adhesion molecules play critical roles in maintaining the structural integrity of the airway epithelium in airways under stress. Previously, we reported that catenin alpha-like 1 (CTNNAL1) is downregulated in an asthma animal model and upregulated at the edge of human bronchial epithelial cells (HBECs) after ozone stress. In this work, we explore the potential role of CTNNAL1 in the structural adhesion of HBECs and its possible mechanism. We construct a CTNNAL1 â/â mouse model with CTNNAL1-RNAi recombinant adeno-associated virus (AAV) in the lung and a CTNNAL1-silencing cell line stably transfected with CTNNAL1-siRNA recombinant plasmids. Hematoxylin and eosin (HE) staining reveals that CTNNAL1 â/â mice have denuded epithelial cells and structural damage to the airway. Silencing of CTNNAL1 in HBECs inhibits cell proliferation and weakens extracellular matrix adhesion and intercellular adhesion, possibly through the action of the cytoskeleton. We also find that the expressions of the structural adhesion-related molecules E-cadherin, integrin ß1, and integrin ß4 are significantly decreased in ozone-treated cells than in vector control cells. In addition, our results show that the expression levels of RhoA/ROCK1 are decreased after CTNNAL1 silencing. Treatment with Y27632, a ROCK inhibitor, abolished the expressions of adhesion molecules induced by ozone in CTNNAL1-overexpressing HBECs. Overall, the findings of the present study suggest that CTNNAL1 plays a critical role in maintaining the structural integrity of the airway epithelium under ozone challenge, and is associated with epithelial cytoskeleton dynamics and the expressions of adhesion-related molecules via the RhoA/ROCK1 pathway.
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Brônquios , Células Epiteliais , Transdução de Sinais , Quinases Associadas a rho , Proteína rhoA de Ligação ao GTP , Animais , Humanos , Camundongos , alfa Catenina/metabolismo , alfa Catenina/genética , Brônquios/citologia , Brônquios/metabolismo , Adesão Celular , Linhagem Celular , Proliferação de Células , Células Epiteliais/metabolismo , Ozônio , Quinases Associadas a rho/metabolismo , Quinases Associadas a rho/genética , Proteína rhoA de Ligação ao GTP/metabolismoRESUMO
BACKGROUND: Current guidelines advocate for maintaining BP level below 180/105 mmHg during EVT, determining the safe lower boundary remains primarily consensus-driven by experts. This study aims to delve into the correlation between various targets of lower boundary for systolic and diastolic BP (SBP and DBP) during EVT and 3-month functional outcomes. METHODS: A cohort study was conducted across two EVT-capable centers, enrolling patients with large artery occlusion undergoing EVT within 8 h of stroke onset. Mean BP values during EVT were meticulously recorded, and logistic regression models were utilized to evaluate the correlation between outcomes and diverse lower boundary targets for SBP and DBP. Additionally, logistic regression models investigated the relationship between periprocedural BP variability and subsequent outcomes. RESULTS: Among the 201 patients included, having a SBP higher than 130 or 140 mmHg showed an independent association with increased good functional outcomes at 3 months (adjusted odds ratio, aOR 2.80, 95% Cis, 1.26-6.39 for 140 mmHg; aOR 2.34, 95% Cis, 1.03-5.56 for 130 mmHg). Additionally, an SBP exceeding 130 mmHg was correlated with decreased 3-month mortality (aOR, 0.24, 95% CI 0.07-0.74). No significant relationship was observed between DBP and functional outcomes. Patients with higher periprocedural SBP coefficient variance exhibited a decreased rate of good functional outcomes at 3 months (aOR, 0.42, 95% CI, 0.18-0.96). CONCLUSIONS: A SBP range above 130-140 mmHg could potentially serve as a safe lower boundary during EVT, while minimizing BP fluctuations may correlate with improved post-EVT functional outcomes.
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BACKGROUND: Airway epithelial cells (AECs) with impaired barrier function contribute to airway remodeling through the activation of epithelial-mesenchymal trophic units (EMTUs). Although the decreased expression of ITGB4 in AECs is implicated in the pathogenesis of asthma, how ITGB4 deficiency impacts airway remodeling remains obscure. OBJECTIVE: This study aims to determine the effect of epithelial ITGB4 deficiency on the barrier function of AECs, asthma susceptibility, airway remodeling, and EMTU activation. METHODS: AEC-specific ITGB4 conditional knockout mice (ITGB4-/-) were generated and an asthma model was employed by the sensitization and challenge of house dust mite (HDM). EMTU activation-related growth factors were examined in ITGB4-silenced primary human bronchial epithelial cells of healthy subjects after HDM stimulation. Dexamethasone, the inhibitors of JNK phosphorylation or FGF2 were administered for the identification of the molecular mechanisms of airway remodeling in HDM-exposed ITGB4-/- mice. RESULTS: ITGB4 deficiency in AECs enhanced asthma susceptibility and airway remodeling by disrupting airway epithelial barrier function. Aggravated airway remodeling in HDM-exposed ITGB4-/- mice was induced through the enhanced activation of EMTU mediated by Src homology domain 2-containing protein tyrosine phosphatase 2/c-Jun N-terminal kinase/Jun N-terminal kinase-dependent transcription factor/FGF2 (SHP2/JNK/c-Jun/FGF2) signaling pathway, which was partially independent of airway inflammation. Both JNK and FGF2 inhibitors significantly inhibited the aggravated airway remodeling and EMTU activation in HDM-exposed ITGB4-/- mice. CONCLUSIONS: Airway epithelial ITGB4 deficiency induces airway remodeling in a mouse model of asthma through enhanced EMTU activation that is regulated by the SHP2/JNK/c-Jun/FGF2 pathway.
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Remodelação das Vias Aéreas , Asma , Humanos , Camundongos , Animais , Remodelação das Vias Aéreas/fisiologia , Fator 2 de Crescimento de Fibroblastos/metabolismo , Sistema Respiratório/metabolismo , Asma/patologia , Pyroglyphidae , Dermatophagoides pteronyssinus , Células Epiteliais/metabolismo , Camundongos Knockout , Modelos Animais de Doenças , Integrina beta4/genética , Integrina beta4/metabolismoRESUMO
BACKGROUND: The fat retention rate is associated with postoperative inflammation. However, fat survival is still unpredictable even when supplemented with adipose-derived stem cells (ADSCs). Beige adipocytes play a role in regulating pathological inflammation. Thus, we assumed that exosomes may promote macrophage polarization to regulate inflammation when we simulated postgrafted inflammation by lipopolysaccharide (LPS) induction. METHODS: 3T3-L1 preadipocytes were used to differentiate into beige adipocytes, which were stimulated by special culture media, and then, exosomes were isolated from the supernatant. We identified them by morphology, protein and gene expression, or size distribution. Next, we utilized exosomes to stimulate LPS-induced macrophages and evaluated the changes in inflammatory cytokines and macrophage polarization. RESULTS: The induced cells contained multilocular lipid droplets and expressed uncoupling protein 1 (UCP1) and beige adipocyte-specific gene. The exosomes, which were approximately 111.5 nm and cup-like, were positive for surface markers. Additionally, the levels of proinflammatory-related indicators in the LPS+exosomes (LPS+Exos) group were increased after inflammation was activated for 6 h. When inflammation lasted 16 h, exosomes decreased the expression of proinflammatory-related indicators and increased the expression of anti-inflammatory-related indicators compared with the group without exosomes. CONCLUSION: The method described in this article can successfully obtain beige adipocytes and exosomes. The results suggest that beige adipocyte exosomes can promote inflammatory infiltration and polarize more macrophages to the M1 type in the early period of inflammation, accelerating the occurrence of the inflammation endpoint and the progression of macrophage switching from M1 to M2, while inflammation develops continuously. NO LEVEL ASSIGNED: This journal requires that authors assign a level of evidence to each submission to which Evidence-Based Medicine rankings are applicable. This excludes Review Articles, Book Reviews, and manuscripts that concern Basic Science, Animal Studies, Cadaver Studies, and Experimental Studies. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .
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Adipócitos Bege , Exossomos , Animais , Lipopolissacarídeos/farmacologia , Macrófagos , InflamaçãoRESUMO
Isoliquiritigenin (ISL) is a chalcone that has shown great potential in the treatment of cancer. However, its relatively weak activity and low water solubility limit its clinical application. In this study, we designed and synthesized 21 amino acid ester derivatives of ISL and characterized the compounds using 1H NMR and 13C NMR. Among them, compound 9 (IC50 = 14.36 µM) had a better inhibitory effect on human cervical cancer (Hela) than ISL (IC50 = 126.5 µM), and it was superior to the positive drug 5-FU (IC50 = 33.59 µM). The mechanism of the action experiment showed that compound 9 could induce Hela cell apoptosis and autophagy through the PI3K/Akt/mTOR pathway.
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Aminoácidos , Antineoplásicos , Apoptose , Chalconas , Desenho de Fármacos , Ésteres , Chalconas/farmacologia , Chalconas/química , Chalconas/síntese química , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Células HeLa , Aminoácidos/química , Aminoácidos/farmacologia , Ésteres/química , Ésteres/farmacologia , Ésteres/síntese química , Apoptose/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Relação Estrutura-Atividade , Fosfatidilinositol 3-Quinases/metabolismo , Autofagia/efeitos dos fármacos , Estrutura MolecularRESUMO
Background and Objectives: The Taiwan Triage and Acuity Scale (TTAS) is reliable for triaging patients in emergency departments in Taiwan; however, most triage decisions are still based on chief complaints. The reverse-shock index (SI) multiplied by the simplified motor score (rSI-sMS) is a more comprehensive approach to triage that combines the SI and a modified consciousness assessment. We investigated the combination of the TTAS and rSI-sMS for triage compared with either parameter alone as well as the SI and modified SI. Materials and Methods: We analyzed 13,144 patients with trauma from the Taipei Tzu Chi Trauma Database. We investigated the prioritization performance of the TTAS, rSI-sMS, and their combination. A subgroup analysis was performed to evaluate the trends in all clinical outcomes for different rSI-sMS values. The sensitivity and specificity of rSI-sMS were investigated at a cutoff value of 4 (based on previous study and the highest score of the Youden Index) in predicting injury severity clinical outcomes under the TTAS system were also investigated. Results: Compared with patients in triage level III, those in triage levels I and II had higher odds ratios for major injury (as indicated by revised trauma score < 7 and injury severity score [ISS] ≥ 16), intensive care unit (ICU) admission, prolonged ICU stay (≥14 days), prolonged hospital stay (≥30 days), and mortality. In all three triage levels, the rSI-sMS < 4 group had severe injury and worse outcomes than the rSI-sMS ≥ 4 group. The TTAS and rSI-sMS had higher area under the receiver operating characteristic curves (AUROCs) for mortality, ICU admission, prolonged ICU stay, and prolonged hospital stay than the SI and modified SI. The combination of the TTAS and rSI-sMS had the highest AUROC for all clinical outcomes. The prediction performance of rSI-sMS < 4 for major injury (ISS ≥ 16) exhibited 81.49% specificity in triage levels I and II and 87.6% specificity in triage level III. The specificity for mortality was 79.2% in triage levels I and II and 87.4% in triage level III. Conclusions: The combination of rSI-sMS and the TTAS yielded superior prioritization performance to TTAS alone. The integration of rSI-sMS and TTAS effectively enhances the efficiency and accuracy of identifying trauma patients at a high risk of mortality.
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Triagem , Ferimentos e Lesões , Humanos , Triagem/métodos , Triagem/normas , Masculino , Feminino , Taiwan/epidemiologia , Pessoa de Meia-Idade , Adulto , Ferimentos e Lesões/mortalidade , Idoso , Serviço Hospitalar de Emergência/organização & administração , Serviço Hospitalar de Emergência/estatística & dados numéricos , Escala de Gravidade do Ferimento , Sensibilidade e Especificidade , Índices de Gravidade do Trauma , Choque/mortalidade , Choque/diagnóstico , Tempo de Internação/estatística & dados numéricosRESUMO
Background: Research on the impact of reduced time to emergent surgery in trauma patients has yielded inconsistent results. Therefore, this study investigated the relationship between waiting emergent surgery time (WEST) and outcomes in trauma patients. Methods: This retrospective, multicenter study used data from the Tzu Chi Hospital trauma database. The primary clinical outcomes were in-hospital mortality, intensive care unit (ICU) admission, and prolonged hospital length of stay (LOS) of ≥30 days. Results: A total of 15,164 patients were analyzed. The median WEST was 444 min, with an interquartile range (IQR) of 248-848 min for all patients. Patients who died in the hospital had a shorter median WEST than did those who survived (240 vs. 446 min, p < 0.001). Among the trauma patients with a WEST of <2 h, the median time was 79 min (IQR = 50-100 min). No significant difference in WEST was observed between the survival and mortality groups for patients with a WEST of <120 min (median WEST: 85 vs. 78 min, p < 0.001). Multivariable logistic regression analysis revealed that WEST was not associated with an increased risk of in-hospital mortality (adjusted odds ratio [aOR] = 1.05, 95% confidence interval [CI] = 0.17-6.35 for 30 min ≤ WEST < 60 min; aOR = 1.12, 95% CI = 0.22-5.70 for 60 min ≤ WEST < 90 min; and aOR = 0.60, 95% CI = 0.13-2.74 for WEST ≥ 90 min). Conclusions: Our findings do not support the "golden hour" concept because no association was identified between the time to definitive care and in-hospital mortality, ICU admission, and prolonged hospital stay of ≥30 days.
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Mortalidade Hospitalar , Tempo de Internação , Ferimentos e Lesões , Humanos , Feminino , Masculino , Estudos Retrospectivos , Pessoa de Meia-Idade , Adulto , Tempo de Internação/estatística & dados numéricos , Ferimentos e Lesões/mortalidade , Ferimentos e Lesões/cirurgia , Idoso , Unidades de Terapia Intensiva/estatística & dados numéricos , Fatores de Tempo , Tempo para o Tratamento/estatística & dados numéricos , Modelos LogísticosRESUMO
Neonatal respiratory system disease is closely associated with embryonic lung development. Our group found that integrin ß4 (ITGB4) is downregulated in the airway epithelium of asthma patients. Asthma is the most common chronic respiratory illness in childhood. Therefore, we suspect whether the deletion of ITGB4 would affect fetal lung development. In this study, we characterized the role of ITGB4 deficiency in bronchopulmonary dysplasia (BPD). ITGB4 was conditionally knocked out in CCSP-rtTA, Tet-O-Cre and ITGB4f/f triple transgenic mice. Lung tissues at different developmental stages were collected for experimental detection and transcriptome sequencing. The effects of ITGB4 deficiency on lung branching morphogenesis were observed by fetal mouse lung explant culture. Deleting ITGB4 from the airway epithelial cells results in enlargement of alveolar airspaces, inhibition of branching, the abnormal structure of epithelium cells and the impairment of cilia growth during lung development. Scanning electron microscopy showed that the airway epithelial cilia of the ß4ccsp.cre group appear to be sparse, shortened and lodging. Lung-development-relevant factors such as SftpC and SOX2 significantly decreased both mRNA and protein levels. KEGG pathway analysis indicated that multiple ontogenesis-regulating-relevant pathways converge to FAK. Accordingly, ITGB4 deletion decreased phospho-FAK, phospho-GSK3ß and SOX2 levels, and the correspondingly contrary consequence was detected after treatment with GSK3ß agonist (wortmannin). Airway branching defect of ß4ccsp.cre mice lung explants was also partly recovered after wortmannin treatment. Airway epithelial-specific deletion of ITGB4 contributes to lung developmental defect, which could be achieved through the FAK/GSK3ß/SOX2 signal pathway.
Assuntos
Asma , Displasia Broncopulmonar , Integrina beta4 , Animais , Humanos , Recém-Nascido , Camundongos , Asma/metabolismo , Displasia Broncopulmonar/genética , Displasia Broncopulmonar/metabolismo , Células Epiteliais/metabolismo , Glicogênio Sintase Quinase 3 beta/metabolismo , Integrina beta4/genética , Integrina beta4/metabolismo , Pulmão/metabolismo , Camundongos Transgênicos , Wortmanina/metabolismoRESUMO
BACKGROUND: The appropriate timing of resuming antithrombotic therapy after intracerebral hemorrhage (ICH) remains unclear. The aim of this study was to compare the risks of major bleeding between early and late antiplatelet resumption in ICH survivors. METHODS: Between 2008 and 2017, ICH patients were available in the National Health Insurance Research Database. Patients with a medication possession ratio of antiplatelet treatment ≥50% before ICH and after antiplatelet resumption were screened. We excluded patients with atrial fibrillation, heart failure, under anticoagulant or hemodialysis treatment, and developed cerebrovascular events or died before antiplatelet resumption. Finally, 1584 eligible patients were divided into EARLY (≤30 days) and LATE groups (31-365 days after the index ICH) based on the timing of antiplatelet resumption. Patients were followed until the occurrence of a clinical outcome, end of 1-year follow-up, death, or until December 31, 2018. The primary outcome was recurrent ICH. The secondary outcomes included all-cause mortality, major hemorrhagic events, major occlusive vascular events, and ischemic stroke. Cox proportional hazard model after matching was used for comparison between the 2 groups. RESULTS: Both the EARLY and LATE groups had a similar risk of 1-year recurrent ICH (EARLY versus LATE: 3.12% versus 3.27%; adjusted hazard ratio [AHR], 0.967 [95% CI, 0.522-1.791]) after matching. Both groups also had a similar risk of each secondary outcome at 1-year follow-up. Subgroup analyses disclosed early antiplatelet resumption in the patients without prior cerebrovascular disease were associated with lower risks of all-cause mortality (AHR, 0.199 [95% CI, 0.054-0.739]) and major hemorrhagic events (AHR, 0.090 [95% CI, 0.010-0.797]), while early antiplatelet resumption in the patients with chronic kidney disease were associated with a lower risk of ischemic stroke (AHR, 0.065 [95% CI, 0.012-0.364]). CONCLUSIONS: Early resumption of antiplatelet was as safe as delayed antiplatelet resumption in ICH patients. Besides, those without prior cerebrovascular disease or with chronic kidney disease may benefit more from early antiplatelet resumption.
Assuntos
Fibrilação Atrial , AVC Isquêmico , Acidente Vascular Cerebral , Humanos , Hemorragia Cerebral/epidemiologia , Anticoagulantes/uso terapêutico , Fibrilação Atrial/complicações , AVC Isquêmico/tratamento farmacológico , Acidente Vascular Cerebral/epidemiologia , Fatores de RiscoRESUMO
Accumulating evidence highlights mitochondrial dysfunction as a crucial factor in the pathogenesis of acute kidney injury (AKI); thus, novel therapeutic strategies maintaining mitochondrial homeostasis are highly anticipated. Recent studies have shown that cobaltosic oxide has peroxidase-like catalytic activities, although its role and mechanism remain elusive in AKI. In the present study, we synthesized and identified cobaltosic oxide-polyethylene glycol-triphenylphosphine (COPT) nanoparticles by conjugating cobaltosic oxide with polyethylene glycol and triphenylphosphine, to improve its biocompatibility and mitochondria-targeting property. We found that COPT preferentially accumulated in the kidney proximal tubule cells, and significantly alleviated ischemic AKI in mouse models and gentamicin induced-AKI in the zebrafish model. COPT also inhibited the transition from AKI to chronic kidney disease (CKD), with few side effects. Further studies demonstrated that COPT localized in the mitochondria, and ameliorated hypoxia-reoxygenation-mediated mitochondrial damage through enhancing mitophagy in vitro and in vivo. Mechanistically, COPT dose-dependently induced the expression of Bcl-2/adenovirus E1B 19-kDa interacting protein (BNIP3), while knockdown of BNIP3 attenuated COPT-induced mitophagic flux and mitochondrial protection. Thus, our findings suggest that COPT nanoparticles ameliorate AKI and its progression to CKD through inducing BNIP3-mediated mitophagy, indicating that COPT may serve as a promising mitochondria-targeting therapeutic agent against AKI.
Assuntos
Injúria Renal Aguda , Insuficiência Renal Crônica , Camundongos , Animais , Mitofagia , Peixe-Zebra/metabolismo , Insuficiência Renal Crônica/tratamento farmacológico , Injúria Renal Aguda/patologia , Proteínas Mitocondriais/metabolismo , Proteínas de Membrana/metabolismoRESUMO
Background: Estimated glucose disposal rate (eGDR) is highly associated with all-cause mortality in type 2 diabetes mellitus (T2DM) cases undergoing coronary artery bypass grafting (CABG). Nevertheless, eGDR's prognostic value in non-ST-segment elevation acute coronary syndrome (NSTE-ACS) following percutaneous coronary intervention (PCI) remains unknown. Methods: The population of this retrospective cohort study comprised NSTE-ACS patients administered PCI in Beijing Anzhen Hospital between January and December 2015. The primary endpoint was major adverse cardiac and cerebral events (MACCEs). eGDR was calculated based on waist circumference (WC) ( eGDR WC ) or body mass index (BMI) ( eGDR BMI ). Results: Totally 2308 participants were included, and the mean follow-up time was 41.06 months. The incidence of MACCEs was markedly increased with decreasing eGDR. Multivariable analysis showed hazard ratios (HRs) for eGDR WC and eGDR BMI of 1.152 (95% confidence interval [CI] 1.088-1.219; p < 0.001) and 0.998 (95% CI 0.936-1.064; p = 0.957), respectively. Addition of eGDR WC to a model that included currently recognized cardiovascular risk factors markedly enhanced its predictive power compared with the baseline model (Harrell's C-index, eGDR WC versus Baseline model, 0.778 versus 0.768, p = 0.003; continuous net reclassification improvement (continuous-NRI) of 0.125, p < 0.001; integrated discrimination improvement (IDI) of 0.016, p < 0.001). Conclusions: Low eGDR independently predicts low survival of NSTE-ACS cases who underwent PCI.
RESUMO
Bombesin receptor-activated protein (BRAP) and its homologous protein in mice, which is encoded by bc004004 gene, were expressed abundantly in brain tissues with unknown functions. We treated bc004004-/- mice with chronic unpredictable mild stress (CUMS) to test whether those mice were more vulnerable to stress-related disorders. The results of forced swimming test, sucrose preference test, and open field test showed that after being treated with CUMS for 28 days or 35 days both bc004004-/- and bc004004+/+ mice exhibited behavioural changes and there was no significant difference between bc004004+/+ and bc004004-/-. However, behavioural changes were observed only in bc004004-/- mice after being exposed to CUMS for 21 days, but not in bc004004+/+ after 21-day CUMS exposure, indicating that lack of BRAP homologous protein may cause vulnerability to stress-related disorders in mice. In addition, bc004004-/- mice showed a reduction in recognition memory as revealed by novel object recognition test. Since memory changes and stress related behavioural changes are all closely related to the hippocampus function we further analyzed the changes of dendrites and synapses of hippocampal neurons as well as expression levels of some proteins closely related to synaptic function. bc004004-/- mice exhibited decreased dendritic lengths and increased amount of immature spines, as well as altered expression pattern of synaptic related proteins including GluN2A, synaptophysin and BDNF in the hippocampus. Those findings suggest that BRAP homologous protein may have a protective effect on the behavioural response to stress via regulating dendritic spine formation and synaptic plasticity in the hippocampus.