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Sepsis-associated encephalopathy (SAE) is a significant cause of mortality in patients with sepsis. Despite extensive research, its exact cause remains unclear. Our previous research indicated a relationship between non-hepatic hyperammonemia (NHH) and SAE. This study aimed to investigate the relationship between NHH and SAE and the potential mechanisms causing cognitive impairment. In the in vivo experimental results, there were no significant abnormalities in the livers of mice with moderate cecal ligation and perforation (CLP); however, ammonia levels were elevated in the hippocampal tissue and serum. The ELISA study suggest that fecal microbiota transplantation in CLP mice can reduce ammonia levels. Reduction in ammonia levels improved cognitive dysfunction and neurological impairment in CLP mice through behavioral, neuroimaging, and molecular biology studies. Further studies have shown that ammonia enters the brain to regulate the expression of aquaporins-4 (AQP4) in astrocytes, which may be the mechanism underlying brain dysfunction in CLP mice. The results of the in vitro experiments showed that ammonia up-regulated AQP4 expression in astrocytes, resulting in astrocyte damage. The results of this study suggest that ammonia up-regulates astrocyte AQP4 expression through the gut-brain axis, which may be a potential mechanism for the occurrence of SAE.
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Acuaporina 4 , Astrocitos , Eje Cerebro-Intestino , Hiperamonemia , Encefalopatía Asociada a la Sepsis , Animales , Ratones , Acuaporina 4/metabolismo , Acuaporina 4/genética , Acuaporina 4/biosíntesis , Astrocitos/metabolismo , Hiperamonemia/metabolismo , Encefalopatía Asociada a la Sepsis/metabolismo , Masculino , Eje Cerebro-Intestino/fisiología , Ratones Endogámicos C57BL , Amoníaco/metabolismo , Amoníaco/sangre , Encéfalo/metabolismo , Trasplante de Microbiota FecalRESUMEN
BACKGROUND: Relapsed childhood polymicrobial osteomyelitis associated with dermatophytosis has not been reported in the literature. CASE PRESENTATION: Here we report on a case of a 45-year-old man who had left tibial osteomyelitis for 29 years, accompanied by skin fungal infection of the ipsilateral heel for 20 years, and underwent a second operation due to recurrence of polymicrobial infection 6 years ago. The patient had a history of injury from a rusty object, which penetrated the anterior skin of the left tibia middle segment causing subsequent bone infection, but was asymptomatic after receiving treatments in 1983. The patient was physically normal until dermatophytosis occurred on the ipsilateral heel skin in 1998. The patient complained that the dermatophytosis was gradually getting worse, and the tibial wound site became itchy, red, and swollen. The left tibial infection resurged in May 2012, leading to the patient receiving debridement and antibiotic treatment. H&E and Gram-stained histology was performed on biopsy specimens of sequestrum and surrounding inflammatory tissue. Tissue culture and microbiology examination confirmed polymicrobial infection with Staphylococcus aureus (S. aureus) and Corynebacterium and a fungus. Additionally, the patient also received potassium permanganate for dermatophytosis when he was admitted into the hospital. CONCLUSIONS: Together with longitudinal follow-up of medical history, surgical findings, histopathological and microbiology culture evidence, we conclude that boyhood tibia polymicrobial osteomyelitis with S. aureus and Corynebacterium occurred in this patient, and the fungal activation of dermatophytosis may have led to osteomyelitis relapse.
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Coinfección , Osteomielitis , Infecciones Estafilocócicas , Tiña , Antibacterianos , Niño , Coinfección/complicaciones , Coinfección/diagnóstico , Desbridamiento , Humanos , Masculino , Persona de Mediana Edad , Osteomielitis/complicaciones , Osteomielitis/diagnóstico , Infecciones Estafilocócicas/complicaciones , Staphylococcus aureus , Tibia/cirugía , Tiña/complicacionesRESUMEN
INTRODUCTION: High mobility group box 1 (HMGB1) is an important "late" inflammatory mediator in bacterial sepsis. Ethyl pyruvate (EP), an inhibitor of HMGB1, can prevent bacterial sepsis by decreasing HMGB1 levels. However, the role of HMGB1 in fungal sepsis is still unclear. Therefore, we investigated the role of HMGB1 and EP in invasive C. albicans infection. METHODS: We measured serum HMGB1 levels in patients with sepsis with C. albicans infection and without fungal infection, and control subjects. We collected clinical indices to estimate correlations between HMGB1 levels and disease severity. Furthermore, we experimentally stimulated mice with C. albicans and C. albicans + EP. Then, we examined HMGB1 levels from serum and tissue, investigated serum levels of tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6), determined pathological changes in tissues, and assessed mortality. RESULTS: Serum HMGB1 levels in patients with severe sepsis with C. albicans infection were elevated. Increased HMGB1 levels were correlated with procalcitonin (PCT), C-reactive protein (CRP), 1,3-ß-D-Glucan (BDG) and C. albicans sepsis severity. HMGB1 levels in serum and tissues were significantly increased within 7 days after mice were infected with C. albicans. The administration of EP inhibited HMGB1 levels, decreased tissue damage, increased survival rates and inhibited the release of TNF-α and IL-6. CONCLUSIONS: HMGB1 levels were significantly increased in invasive C. albicans infections. EP prevented C. albicans lethality by decreasing HMGB1 expression and release. HMGB1 may provide an effective diagnostic and therapeutic target for invasive C. albicans infections.
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Proteína HMGB1 , Sepsis , Animales , Proteína C-Reactiva , Candida albicans , Humanos , Ratones , Factor de Necrosis Tumoral alfaRESUMEN
Mitochondria are important sites for the production of ATP and the generation of ROS in cells. However, whether acute hypoxia increases ROS generation in cells or affects ATP production remains unclear, and therefore, monitoring the changes in ATP and ROS in living cells in real time is important. In this study, cardiomyocytes were transfected with RoGFP for ROS detection and MitGO-Ateam2 for ATP detection, whereby ROS and ATP production in cardiomyocytes were respectively monitored in real time. Furthermore, the oxygen consumption rate (OCR) of cardiomyocytes was measured. Similar results were produced for adult and neonatal rat cardiomyocytes. Hypoxia (1% O2) reduced the basal OCR, ATP-linked OCR, and maximal OCR in cardiomyocytes compared with these OCR levels in the cardiomyocytes in the normoxic group (21% O2). However, ATP-linked OCR, normalized to maximal OCR, was increased during hypoxia, indicating that the electron leakage of complex III exacerbated the increase of ATP-linked oxygen consumption during hypoxia and vice versa. Combined with the result that cardiomyocytes expressing MitGO-Ateam2 showed a significant decrease in ATP production during hypoxia compared with that of normoxic group, acute hypoxia might depress the mitochondrial oxygen utilization efficiency of the cardiomyocytes. Moreover, cardiomyocytes expressing Cyto-RoGFP or IMS-RoGFP showed an increase in ROS generation in the cytosol and the mitochondrial intermembrane space (IMS) during hypoxia. All of these results indicate that acute hypoxia generated more ROS in complex III and increased mitochondrial oxygen consumption, leading to less ATP production. In conclusion, acute hypoxia depresses the mitochondrial oxygen utilization efficiency by decreasing ATP production and increasing oxygen consumption as a result of the enhanced ROS generation at mitochondrial complex III.
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Hipoxia de la Célula , Mitocondrias Cardíacas/metabolismo , Miocitos Cardíacos/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Adenosina Trifosfato/metabolismo , Animales , Células Cultivadas , Complejo III de Transporte de Electrones/metabolismo , Ratas , Ratas Sprague-DawleyRESUMEN
OBJECTIVES: The clinical symptoms of the patients with intracellular bacterial bloodstream infections (Intra-bac BSIs) are atypical, and no early and accurate diagnostic biomarkers exist, which can easily lead to misdiagnosis, inappropriate and delayed treatment. Therefore, it is imperative to find novel biomarkers to help clinical diagnosis of Intra-bac BSIs. The present study was initiated to evaluate the diagnostic values of traditional inflammatory biomarkers (PCT, WBC and NEU% in identifying the patients with Intra-bac BSIs, and to further explore into the possibility of using suPAR and sCD14-ST as novel biomarkers for Intra-bac BSIs. METHODS: A multi-center retrospective study was conducted in three teaching hospitals in Chongqing. A total of 146 cases with BSIs, including 73 cases with Intra-bac BSIs and 73 cases with extracellular bacterial BSIs (Extra-bac BSIs) were enrolled in the retrospective study. We then prospectively enrolled 34 patients with Intra-bac BSIs, 34 patients with Extra-bac BSIs, 34 patients with viral infection and with normal medical examination results as a control group for further detection of sCD14-ST and suPAR by ELISA. RESULTS: PCT levels, WBC counts and NEU% in patients with Intra-bac BSIs were not increased or minimally increased, they were significantly lower than that with Extra-bac BSIs (P < 0.05), especially those with the Brucella bacterial BSIs, demonstrated a respective negative rate of 84% and 92% for PCT and WBC counts. In the prospective study, the levels of suPAR and sCD14-ST in both the Intra-bac BSIs and the Extra-bac BSIs groups were significantly higher than those in the viral infection group and normal control group (P < 0.05). The areas under the curve (AUC) of Intra-bac BSIs were 0.830 for suPAR, and 0.855 for sCD14-ST. The sensitivity, specificity, Youden's index for suPAR and sCD14-ST were respectively 76.5%, 88.2%, 0.647 and 94.1%, 64.7%, 0.588. CONCLUSIONS: Our multi-center study demonstrated that while the traditional inflammatory markers such as PCT, WBC counts, NEU% could not be served as promising diagnostic markers for Intra-bac BSIs; CRP can help guide the diagnosis of Intra-bac BSIs; Both suPAR and sCD14-ST could be considered as novel diagnostic biomarkers for Intra-bac BSIs as they showed good diagnostic accuracies in Intra-bac BSIs, especially suPAR.
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Receptores de Lipopolisacáridos/sangre , Sepsis/sangre , Sepsis/diagnóstico , Adulto , Biomarcadores/sangre , Femenino , Humanos , Recuento de Leucocitos , Masculino , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
Mucus hypersecretion and plugging of lower respiratory tract airways due to mucus plugs have long been recognized as the leading cause of the morbidity and mortality in asthma. MUC5AC protein is a major component of airway mucus. Here, we showed that interleukin (IL)-13 induced MUC5AC production and secretion, and leptin expression in the human bronchial epithelial cell line-16 (HBE16) cells in a concentration-dependent manner. Leptin knockdown suppressed MUC5AC production and secretion induced by IL-13. We further investigated the molecular mechanism by which leptin functioned, and found that leptin regulated IL-13-induced MUC5AC production and secretion via the JAK2-STAT3 pathway. Subsequently, Munc18b, a limiting component of the exocytic machinery of airway epithelial and mast cells, was found that when knockdown, MUC5AC secretion was significantly inhibited. SABiosciences ChIP search tool identified three STAT3 binding sites with Munc18b promoter. Chromatin immunoprecipitation analysis further confirmed that Stat3 upregulated Munc18b expression by directly binding to its promoter. These data suggested that leptin promotes MUC5AC secretion via JAK2-STAT3-MUNC18b regulatory network. Taken together, our data highlight a positive feedback role and molecular mechanism for leptin in the control of MUC5AC production and secretion from airway epithelial cells stimulated by IL-13, which encourage further exploration of the therapeutic potentials of manipulating leptin in the treatment of mucus hypersecretion in chronic inflammation lung diseases.
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Bronquios/inmunología , Interleucina-13/inmunología , Leptina/inmunología , Mucina 5AC/inmunología , Mucosa Respiratoria/inmunología , Asma/inmunología , Bronquios/citología , Línea Celular , Humanos , Janus Quinasa 2/inmunología , Moco/inmunología , Mucosa Respiratoria/citología , Factor de Transcripción STAT3/inmunología , Transducción de SeñalRESUMEN
Oceanic turbulence is described by the oceanic refractive-index spectrum (ORIS), which considers several important hydrodynamic parameters. Based on ORIS, many optical oceanic quantities can be calculated using numerical integration. However, it is difficult to calculate the analytical solutions. In this paper, an approximate oceanic temperature spectrum is obtained by multiplying the non-Kolmogorov spectrum with a correction factor. By analogy with the obtained temperature spectrum, an approximate salinity spectrum and an approximate coupling spectrum are obtained. A linear summation of these three approximate spectra forms the approximate form of ORIS. The approximate form of ORIS we obtained helps calculate the analytical solutions of the relevant oceanic optical quantities.
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Activated protein kinase Cδ (PKCδ) associated with cardiac hypertrophy moves from the cytoplasm to the mitochondria and subsequently triggers the apoptotic signalling pathway. The underlying mechanisms remain unknown. The aim of the present study was to investigate whether mitochondrial translocation of PKCδ phosphorylates multiple sites of Bcl-2, resulting in an imbalance between Bcl-2 and Bak or Bax, thus enhancing the susceptibility of hypertrophic cardiomyocytes to angiotensin II (AngII)-induced apoptosis. Chronic pressure overload was induced by transverse aortic constriction (TAC) in rats. The apoptotic rate increased in hypertrophied cardiomyocytes. In AngII-treated hearts (10 nmol/L, 60 min), there was an increase in the number of TERMINAL deoxyribonucleotidyl transferase-mediated dUTP-digoxigenin nick end-labelling (TUNEL)-positive cells; PKCδ inhibition with 500 nmol/L δV1-1 for 60 min prevented the AngII-induced increase in apoptosis. In the hypertrophied myocardium, PKCδ expression increased, whereas that of Bcl-2 decreased compared with the synchronous control. Treatment of hearts with 10 nmol/L AngII for 60 min activated PKCδ and induced translocation of PKCδ to the mitochondria, where activated PKCδ facilitated the phosphorylation of Bcl-2 at serine-87 and serine-70 sites. The multisite phosphorylated Bcl-2 was released from the mitochondria, and exhibited reduced affinity for Bak and Bax. The imbalance between Bcl-2 and Bak/Bax induced the release of mitochondrial cytochrome c and then activated the caspase 3 apoptotic pathway during AngII stimulation (10 nmol/L, 60 min) of hypertrophied cardiomyocytes. Inhibition of PKCδ reduced these effects of AngII. The results suggest that PKCδ can counteract the anti-apoptotic effect of Bcl-2 and may promote cardiomyocyte apoptosis through multisite phosphorylation of Bcl-2 in hypertrophied cardiomyocytes.
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Apoptosis , Cardiomegalia/patología , Mitocondrias Cardíacas/metabolismo , Miocitos Cardíacos/patología , Proteína Quinasa C-delta/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Animales , Cardiomegalia/enzimología , Cardiomegalia/metabolismo , Modelos Animales de Enfermedad , Etiquetado Corte-Fin in Situ , Masculino , Mitocondrias Cardíacas/enzimología , Miocitos Cardíacos/enzimología , Miocitos Cardíacos/metabolismo , Fosforilación , Proteína Quinasa C-delta/genética , Transporte de Proteínas , Proteínas Proto-Oncogénicas c-bcl-2/genética , Ratas Sprague-DawleyRESUMEN
BACKGROUND: Accurate identification of delirium in sepsis patients is crucial for guiding clinical diagnosis and treatment. However, there are no accurate biomarkers and indicators at present. We aimed to identify which combinations of cognitive impairment-related biomarkers and other easily accessible assessments best predict delirium in sepsis patients. METHODS: One hundred and one sepsis patients were enrolled in a prospective study cohort. S100B, NSE, and BNIP3 L biomarkers were detected in plasma and cerebrospinal fluid and patients' optic nerve sheath diameter (ONSD). The optimal biomarkers identified by Logistic regression are combined with other factors such as ONSD to filter out the perfect model to predict delirium in sepsis patients through Logistic regression, Naïve Bayes, decision tree, and neural network models. MAIN RESULTS: Among all biomarkers, compared with BNIP3 L (AUC = .706, 95% CI = .597-.815) and NSE (AUC = .711, 95% CI = .609-.813) in cerebrospinal fluid, plasma S100B (AUC = .729, 95% CI = .626-.832) had the best discrimination performance for delirium in sepsis patients. Logistic regression analysis showed that the combination of cerebrospinal fluid BNIP3 L with plasma S100B, ONSD, neutrophils, and age provided the best discrimination to cognitive impairment in sepsis patients (accuracy = .901, specificity = .923, sensitivity = .911), which was better than Naïve Bayes, decision tree, and neural network models. Neutrophils, ONSD, and cerebrospinal fluid BNIP3 L were consistently the major contributors in a few models. CONCLUSIONS: The logistic regression showed that the combination model was strongly correlated with cognitive dysfunction in sepsis patients.
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Delirio , Encefalopatía Asociada a la Sepsis , Sepsis , Humanos , Encefalopatía Asociada a la Sepsis/diagnóstico , Estudios Prospectivos , Pronóstico , Teorema de Bayes , Biomarcadores , Sepsis/complicaciones , Sepsis/diagnóstico , Proteínas de la Membrana , Proteínas Proto-Oncogénicas , Subunidad beta de la Proteína de Unión al Calcio S100RESUMEN
Clarifying the responses of human activities and climate change to the water cycle under variable environments is crucial for accurately assessing regional water balance. An analysis of the changes in actual evapotranspiration and its driving factors was conducted in the global high-elevation mountains during the period from 2001 to 2022. Utilizing 18 formulas for calculating evapotranspiration, which are based on comprehensive, temperature, radiation, and mass transfer, and then simulated the variations in reference evapotranspiration. Furthermore, we optimized the ET simulation model based on the most effective simulation results and projected future changes using scenario simulation data. Our findings reveal that: 1) ET at high-elevation mountains has significantly decreased at an average rate of 3.923 %/a, with monthly values ranging from 31.179 to 33.652 mm and an average of 32.646 mm; 2) The radiation-based model of Irmark-Allen is particularly well-suited for simulating ET at high-elevation mountains, with precision analysis and the Taylor diagram confirming its superior simulation performance. After optimizing the model using the method of least squares, the value of R2 before and after the optimization were 0.633 and 0.853, respectively. 3) An upward trend in ET under both SSP245 and SSP585 scenario in future simulation projections. Attribution analysis has identified Vapor Pressure Deficit as the key positive driver influencing the change of ET in global high-elevation mountains. Structural equation modeling further reveals that variations in net radiation and precipitation play a significant role in altering evapotranspiration rates. Meanwhileï¼The water balance analysis reveals that ET has been declining from 2001 to 2022. This phenomenon can be largely attributed to the substantial decline in vapor pressure deficit, the rise in the Normalized Difference Vegetation Index signifying increased vegetation cover, and the reduction in shallow soil moisture during the same period. These factors collectively explain the notable decrease in ET observed in high-elevation mountains.
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Long-term exposure to microgravity is considered to cause liver lipid accumulation, thereby increasing the risk of non-alcoholic fatty liver disease (NAFLD) among astronauts. However, the reasons for this persistence of symptoms remain insufficiently investigated. In this study, we used tandem mass tag (TMT)-based quantitative proteomics techniques, as well as non-targeted metabolomics techniques based on liquid chromatography-tandem mass spectrometry (LC-MS/MS), to comprehensively analyse the relative expression levels of proteins and the abundance of metabolites associated with lipid accumulation in rat liver tissues under simulated microgravity conditions. The differential analysis revealed 63 proteins and 150 metabolites between the simulated microgravity group and the control group. By integrating differentially expressed proteins and metabolites and performing pathway enrichment analysis, we revealed the dysregulation of major metabolic pathways under simulated microgravity conditions, including the biosynthesis of unsaturated fatty acids, linoleic acid metabolism, steroid hormone biosynthesis and butanoate metabolism, indicating disrupted liver metabolism in rats due to weightlessness. Finally, we examined differentially expressed proteins associated with lipid metabolism in the liver of rats exposed to stimulated microgravity. These findings contribute to identifying the key molecules affected by microgravity and could guide the design of rational nutritional or pharmacological countermeasures for astronauts.
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Metabolismo de los Lípidos , Hígado , Metabolómica , Proteómica , Simulación de Ingravidez , Animales , Ratas , Hígado/metabolismo , Proteómica/métodos , Masculino , Metabolómica/métodos , Ratas Sprague-Dawley , Espectrometría de Masas en Tándem , Cromatografía Liquida , Trastornos del Metabolismo de los Lípidos/metabolismoRESUMEN
Psoriasis and rosacea are both chronic inflammatory skin disorders resulted from aberrant keratinocyte-immune cell crosstalk, but the common molecular foundations for these 2 conditions are poorly understood. In this study, we reveal that both patients with psoriasis and those with rosacea as well as their mouse models have significantly elevated expressions of SERPINB3/B4 (members of serine protease inhibitor) in the lesional skin. Skin inflammation in mice that resembles both psoriasis and rosacea is prevented by SERPINB3/B4 deficiency. Mechanistically, we demonstrate that SERPINB3/B4 positively induces NF-κB signaling activation, thereby stimulating disease-characteristic inflammatory chemokines and cytokines production in keratinocytes and promoting the chemotaxis of CD4+ T cells. Our results suggest that in keratinocytes, SERPINB3/B4 may be involved in the pathogenesis of both psoriasis and rosacea by stimulating NF-κB signaling, and they indicate a possible treatment overlap between these 2 diseases.
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Transmissible gastroenteritis virus (TGEV) could cause diarrhea, vomiting, dehydration and even death in piglets, miRNA played an important role in the interaction between virus and cell. The study aimed to investigate the impact of miR-17 on the polysaccharide of Polygonum Cillinerve (PCP) in combating TGEV. miR-17 was screened and transfection validation was performed by Real-time PCR. The function of miR-17 on PK15 cells infected with TGEV and treated with PCP was investigated by DCFH-DA loading probe, JC-1 staining and Hoechst fluorescence staining. Furthermore, the effect of miR-17 on PCP inhibiting TGEV replication and apoptosis signaling pathways during PCP against TGEV infection was measured through Real-time PCR and Western blot. The results showed that miR-17 mimic and inhibitor could be transferred into PK15 cells and the expression of miR-17 significantly increased and decreased respectively compared with miR-17 mimic and inhibitor (P < 0.05). A total 250 µg/mL of PCP could inhibit cells apoptosis after transfection with miR-17. PCP (250 µg/mL and 125 µg/mL) significantly inhibited the decrease in mitochondrial membrane potential induced by TGEV after transfection with miR-17 (P < 0.05). After transfection of miR-17 mimic, PCP at concentrations of 250 µg/mL and 125 µg/mL significantly promoted the mRNA expression of P53, cyt C and caspase 9 (P < 0.05). Compared with the control group, the replication of TGEV gRNA and gene N was significantly inhibited by PCP at concentrations of 250 µg/mL and 125 µg/mL after transfection of both miR-17 mimic and inhibitor (P < 0.05). PCP at 62.5 µg/mL significantly inhibited the replication of gene S following transfection with miR-17 inhibitor (P < 0.05). These results suggested that PCP could inhibit the replication of TGEV and apoptosis induced by TGEV by regulating miR-17.
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Hypoxic preconditioning (HPC) has been shown to improve organ tolerance to subsequent severe hypoxia or ischemia. However, its impact on intestinal ischemic injury has not been well studied. In this study, we evaluated the effects of HPC on intestinal ischemia in rats. Intestinal rehabilitation, levels of fatty acid oxidation (FAO) by-products, intestinal stem cells (ISCs), levels of hypoxia-inducible factor 1 subunit α (HIF-1α) and its downstream genes such as peroxisome proliferator-activated receptor α (PPARα), and carnitine palmitoyltransferase 1a (CPT1A) were assessed at distinct time intervals following intestinal ischemia with or without the interference of HIF-1α. Our data showed that HPC facilitates the restoration of the intestinal structure and enhances the FAO, by boosting intestinal stem cells. Additionally, HIF-1α, PPARα, and CPT1A mRNA and their protein levels were generally up-regulated in the small intestine of HPC rats as compared to the control group. Our vitro experiment also shows low-oxygen induces highly levels of HIF-1α and its downstream genes, with a concurrent increase in FAO products in IEC-6 cells. Furthermore, the above phenomenon could be reversed by silencing HIF-1α. In conclusion, we hypothesize that HPC can stimulate the activation of intestinal stem cells via HIF-1α/PPARα pathway-mediated FAO, thereby accelerating the healing process post ischemic intestinal injury.
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STUDY OBJECTIVE: This study aimed to compare the time to emergence from general anesthesia with remimazolam versus propofol in patients undergoing cerebral endovascular procedures. DESIGN: A prospective, double-blind, randomized controlled, non-inferiority trial. SETTING: An academic hospital. PATIENTS: Adult patients scheduled for cerebral endovascular procedures. INTERVENTIONS: Patients were randomized at a 1:1 ratio to undergo surgery under general anesthesia with remimazolam (0.1 mg kg-1 for induction and 0.3-0.7 mg kg-1 h-1 for maintenance) or propofol (1-1.5 mg kg-1 for induction and 4-10 mg kg-1 h-1 for maintenance). MEASUREMENTS: The primary outcome was the time to emergence from anesthesia. The non-inferiority margin was -2.55 min in group difference. Major secondary outcomes included hypotension during induction, incidence of postoperative delirium and Modified Rankin Scale (mRs) at 30 days and 90 days after surgery. MAIN RESULTS: Of the 142 randomized patients, 129 completed the trial. In the modified intention-to-treat analysis, the mean time to emergence from anesthesia was 16.1 [10.4] min in the remimazolam group vs. 19.0 [11.2] min in the propofol group. The group difference was -2.9 min [95% CI -6.5, 0.7] (P = 0.003 for non-inferiority). The remimazolam group had lower rate of hypotension during induction (11.3% vs 25.4%, P = 0.03) and use of vasopressors during surgery (29.6% vs 62.0%, P < 0.001). The two groups did not differ in postoperative delirium and mRs at 30 and 90 days after surgery. CONCLUSIONS: In patients undergoing cerebral endovascular procedures, remimazolam did not increase the time from anesthesia vs propofol.
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Delirio del Despertar , Hipotensión , Propofol , Adulto , Humanos , Propofol/efectos adversos , Estudios Prospectivos , Anestesia General/efectos adversos , Benzodiazepinas , Hipotensión/inducido químicamente , Hipotensión/epidemiologíaRESUMEN
Cardiac autophagy dramatically increases in heart failure induced by sustained pressure overload. However, it has not yet been addressed if enhanced autophagy plays a role in protecting myocardium or mediating progression from compensative hypertrophy to heart failure. The aim of the present study was to detect autophagic flux of cardiomyocytes from 20-week transverse abdominal aortic constriction (TAC) rats. Fasting rats were used as the positive control for detecting cardiac autophagy. Echocardiography was applied to find the changes of cardiac structure and function. Immunofluorescent histochemistry and Western blot were used to analyze the related biomolecular indexes reflecting cardiac autophagic flux. After the previous methods for detecting cardiac autophagy were confirmed, the autophagic flux in cardiomyocytes of rats subjected to 20-week TAC was examined. The results showed that fasting had no obvious influence on parameters of cardiac structure in rats, including interventricular septal wall thickness and left ventricle posterior wall thickness, but heart rate, diastolic left ventricle internal dimension, fractional shortening of left ventricle dimension, ejection fraction and mitral inflow velocity decreased in rats after fasting for 3 d. Meanwhile, positively stained particles of LC3 and cathepsin D, but not ubiquitin and complement 9, distributed within cardiomyocytes of 3-day fasting rats, indicating augmented autophagic flux. Compared with sham rats, 20-week TAC rats did not show any changes of LC3, cathepsin D, ubiquitin and complement 9 in myocardium detected by immunofluorescent histochemistry. In addition, protein levels of LC3, cathepsin D and p62 in myocardium of TAC rats did not changed. These results reveal the unchanged autophagic flux in cardiomyocytes at middle or late phase of cardiac hypertrophy in TAC rats, implying a balance between inhibition of hypertrophy and activation of pressure load stress on autophagy.
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Autofagia , Corazón/fisiopatología , Miocardio/patología , Miocitos Cardíacos/citología , Animales , Aorta/patología , Cardiomegalia/fisiopatología , Constricción , RatasRESUMEN
Rosacea is a common inflammatory skin disorder mediated by the dysregulation of both keratinocytes and T cells. Here, we report that aquaporin 3 (AQP3), a channel protein that mediates the transport of water/glycerol, was highly expressed in the epidermis and CD4+ T cells of both rosacea patients and experimental mice. Specifically, AQP3 deletion blocked the development of rosacea-like skin inflammation in model mice with LL37-induced rosacea-like disease. We also present mechanistic evidence showing that AQP3 was essential to the activation of NF-κB signaling and subsequent production of disease-characteristic chemokines in keratinocytes. Moreover, we show that AQP3 was upregulated during T cell differentiation and promotes helper T (Th) 17 differentiation possibly via the activation of STAT3 signaling. Our findings reveal that AQP3-mediated activation of NF-κB in keratinocytes and activation of STAT3 in CD4+ T cells acted synergistically and contributed to the inflammation in rosacea.
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Acuaporina 3 , Rosácea , Humanos , Animales , Ratones , Acuaporina 3/genética , FN-kappa B/metabolismo , Queratinocitos/metabolismo , Piel/metabolismo , Rosácea/metabolismo , Inflamación/metabolismoRESUMEN
Hydrogels' exceptional mechanical strength and skin-adhesion characteristics offer significant advantages for various applications, particularly in the fields of tissue adhesion and wearable sensors. Herein, we incorporated a combination of metal-coordination and hydrogen-bonding forces in the design of stretchable and adhesive hydrogels. We synthesized four hydrogels, namely PAID-0, PAID-1, PAID-2, and PAID-3, consisting of acrylamide (AAM), N,N'-methylene-bis-acrylamide (MBA), and methacrylic-modified dopamine (DA). The impact of different ratios of iron (III) ions to DA on each hydrogel's performance was investigated. Our results demonstrate that the incorporation of iron-dopamine complexes significantly enhances the mechanical strength of the hydrogel. Interestingly, as the DA content increased, we observed a continuous and substantial improvement in both the stretchability and skin adhesiveness of the hydrogel. Among the hydrogels tested, PAID-3, which exhibited optimal mechanical properties, was selected for adhesion testing on various materials. Impressively, PAID-3 demonstrated excellent adhesion to diverse materials and, combined with the low cytotoxicity of PAID hydrogel, holds great promise as an innovative option for biomedical engineering applications.
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The mechanism of electroacupuncture (EA) pretreatment-induced neuroprotection remains unclear. In this study, we found that neuronal Triggering receptor expressed on myeloid cells 2 (TREM2) expression was increased and peaked at 48 h and 72 h after ischemia/reperfusion. After specific knockdown of TREM2 in excitatory neurons, neurological function was damaged, and the infarct volume was enlarged. Furthermore, the expression of LC3II/LC3I and Beclin1 was decreased, while the expression of p62 was increased. EA pretreatment enhanced TREM2, LC3II/LC3I and Beclin1 expression while reducing p62 in the ischemic penumbra area. The EA-induced neuroprotective effects and improvements in autophagic flux were abolished by specific knockdown of TREM2 in excitatory neurons. Taken together, our findings provide novel mechanistic insight into EA-induced ischemic tolerance and suggest a promising therapeutic strategy of targeting neuronal TREM2 to treat brain ischemia.
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Isquemia Encefálica , Electroacupuntura , Glicoproteínas de Membrana , Receptores Inmunológicos , Daño por Reperfusión , Beclina-1/metabolismo , Isquemia Encefálica/metabolismo , Isquemia/metabolismo , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Neuronas/metabolismo , Receptores Inmunológicos/metabolismo , Daño por Reperfusión/metabolismo , AnimalesRESUMEN
BACKGROUND: This study aimed to identify preoperative and postoperative risk factors of venous thromboembolism (VTE) after gastrectomy in gastric cancer (GC) patients. METHODS: 757 GC patients underwent gastrectomy at our institution and 246 patients with elevated postoperative D-dimer levels who received Doppler ultrasonography of lower/upper extremity veins were enrolled. Clinicopathological factors data were collected, and the differences in clinicopathological factors between postoperative VTE (+) and VTE (-) groups were analyzed. Univariate and multivariate logistic regression analyses were performed to identify independent risk factors of postgastrectomy VTE. RESULTS: Of 246 patients with elevated postgastrectomy D-dimer concentrations, 74 patients showed thrombosis in lower/upper extremity veins. Among preoperative factors, age, WBC level, D-dimer concentration, and blood glucose level were significantly higher in the postoperative VTE (+) group. Among the postoperative factors, hemoglobin level was significantly lower in the postoperative VTE (+) group. Among the pathological factors, tumor stage, depth of invasion and TNM classification indicated higher malignancy in the postoperative VTE (+) group. Univariate logistic regression analysis indicated age, preoperative blood glucose level, postoperative hemoglobin level, tumor stage, depth of invasion, and TNM classification as the independent risk factors for postgastrectomy VTE, whereas multivariate logistic regression analysis revealed age and tumor stage as independent risk factors for postgastrectomy VTE. CONCLUSION: Our study revealed that age, preoperative blood glucose level, postoperative anemia, and tumor malignancy were independent risk factors for GC patients exhibiting postgastrectomy VTE. Therefore, the perioperative monitoring, assessment and management of risk factors are important in achieving better outcomes after gastrectomy.