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OBJECTIVE: This study investigated the predictive value of albumin-related inflammatory markers for short-term outcomes in in-hospital cardiac arrest (IHCA) patients. METHODS: A linear mixed model investigated the dynamic changes of markers within 72 hours after return of spontaneous circulation (ROSC). Time-Dependent COX regression explored the predictive value. Mediation analysis quantified the association of markers with organ dysfunctions and adverse outcomes. RESULTS: Prognostic Nutritional Index (PNI) and RDW-Albumin Ratio (RAR) slightly changed (p > 0.05). Procalcitonin-Albumin Ratio (PAR1) initially increased and then slowly decreased. Neutrophil-Albumin Ratio (NAR) and Platelet-Albumin Ratio (PAR2) decreased slightly during 24-48 hours (all p<0.05). PNI (HR = 1.646, 95%CI (1.033,2.623)), PAR1 (HR = 1.69, 95%CI (1.057,2.701)), RAR (HR = 1.752,95%CI (1.103,2.783)) and NAR (HR = 1.724,95%CI (1.078,2.759)) were independently associated with in-hospital mortality. PNI (PM = 45.64%, 95%CI (17.05%,87.02%)), RAR (PM = 45.07%,95%CI (14.59%,93.70%)) and NAR (PM = 46.23%,95%CI (14.59%,93.70%)) indirectly influenced in-hospital mortality by increasing SOFA (central) scores. PNI (PM = 21.75%, 95%CI(0.67%,67.75%)) may also indirectly influenced outcome by increasing SOFA (renal) scores (all p < 0.05). CONCLUSIONS: Within 72 hours after ROSC, albumin-related inflammatory markers (PNI, PAR1, RAR, and NAR) were identified as potential predictors of short-term prognosis in IHCA patients. They may mediate the adverse outcomes of patients by causing damages to the central nervous system and renal function.
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Autophagy in alveolar macrophages (AMs) is an important mechanism for maintaining immune homeostasis and normal lung tissue function, and insufficient autophagy in AMs may mediate the development of sepsis-induced acute lung injury (SALI). Insufficient autophagy in AMs and the activation of the NLRP3 inflammasome were observed in a mouse model with SALI induced by cecal ligation and puncture (CLP), resulting in the release of a substantial quantity of proinflammatory factors and the formation of SALI. However, after andrographolide (AG) intervention, autophagy in AMs was significantly promoted, the activation of the NLRP3 inflammasome was inhibited, the release of proinflammatory factors and pyroptosis were suppressed, and SALI was then ameliorated. In the MH-S cell model stimulated with LPS, insufficient autophagy was discovered to promote the overactivation of the NLRP3 inflammasome. AG was found to significantly promote autophagy, inhibit the activation of the NLRP3 inflammasome, and attenuate the release of proinflammatory factors. The primary mechanism of AG promoting autophagy was to inhibit the activation of the PI3K/AKT/mTOR pathway by binding RAGE to the membrane. In addition, it inhibited the activation of the NLRP3 inflammasome to ameliorate SALI. Our findings suggest that AG promotes autophagy in AMs through the RAGE/PI3K/AKT/mTOR pathway to inhibit the activation of the NLRP3 inflammasome, remodel the functional homeostasis of AMs in SALI, and exert anti-inflammatory and lung-protective effects. It has also been the first to suggest that RAGE is likely a direct target through which AG regulates autophagy, providing theoretical support for a novel therapeutic strategy in sepsis.
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Lesión Pulmonar Aguda , Autofagia , Diterpenos , Macrófagos Alveolares , Ratones Endogámicos C57BL , Proteína con Dominio Pirina 3 de la Familia NLR , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Receptor para Productos Finales de Glicación Avanzada , Sepsis , Transducción de Señal , Serina-Treonina Quinasas TOR , Animales , Lesión Pulmonar Aguda/tratamiento farmacológico , Lesión Pulmonar Aguda/metabolismo , Lesión Pulmonar Aguda/patología , Serina-Treonina Quinasas TOR/metabolismo , Autofagia/efectos de los fármacos , Sepsis/tratamiento farmacológico , Sepsis/complicaciones , Sepsis/metabolismo , Sepsis/inmunología , Macrófagos Alveolares/efectos de los fármacos , Macrófagos Alveolares/inmunología , Macrófagos Alveolares/metabolismo , Diterpenos/farmacología , Diterpenos/uso terapéutico , Ratones , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal/efectos de los fármacos , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Masculino , Receptor para Productos Finales de Glicación Avanzada/metabolismo , Inflamasomas/metabolismo , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Modelos Animales de EnfermedadRESUMEN
Identification of cues originating from skeletal muscle that govern bone formation is essential for understanding the crosstalk between muscle and bone and for developing therapies for degenerative bone diseases. Here, we identified that skeletal muscle secreted multiple extracellular vesicles (Mu-EVs). These Mu-EVs traveled through the bloodstream to reach bone, where they were phagocytized by bone marrow mesenchymal stem/stromal cells (BMSCs). Mu-EVs promoted osteogenic differentiation of BMSCs and protected against disuse osteoporosis in mice. The quantity and bioactivity of Mu-EVs were tightly correlated with the function of skeletal muscle. Proteomic analysis revealed numerous proteins in Mu-EVs, some potentially regulating bone metabolism, especially glycolysis. Subsequent investigations indicated that Mu-EVs promoted the glycolysis of BMSCs by delivering lactate dehydrogenase A into these cells. In summary, these findings reveal that Mu-EVs play a vital role in BMSC metabolism regulation and bone formation stimulation, offering a promising approach for treating disuse osteoporosis.
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Vesículas Extracelulares , MicroARNs , Osteoporosis , Ratones , Animales , Osteogénesis , Proteómica , Vesículas Extracelulares/metabolismo , Músculo Esquelético/metabolismo , Diferenciación Celular , Osteoporosis/metabolismo , MicroARNs/metabolismoRESUMEN
Chromofungin (CHR) is a biologically active peptide derived from chromogranin A that exhibits anti-inflammatory effects. However, it remains unclear whether and how CHR protects against sepsis-induced acute lung injury (ALI). A murine model of sepsis-induced ALI was established through cecal ligation and puncture, with intraperitoneal injection of CHR. Lung inflammation and macrophage polarization were examined by measuring the levels of cytokines and markers of M1 (CD86, inducible nitric oxide synthase [iNOS]) or M2 macrophages (arginase-1 [Arg1], resistin-like molecule α1 [Fizz1] and CD206). In vitro, mouse MH-S cells pretreated with CHR was employed to explore the interplay between the lipopolysaccharide-binding protein (LBP)/toll-like receptor 4 (TLR4) signaling pathway and M1/M2 polarity. The results revealed CHR's ability to enhance the 7-day survival rate and protect lung pathological injury in sepsis-induced ALI. CHR increased the expression of interleukin-4 and interleukin-10 but decreased the expression of tumour necrosis factor-α and interleukin-1ß. In addition, CHR notably facilitated M2 macrophage polarization, while significantly suppressingM1 polarization of alveolar macrophages. Mechanistic investigations delineated CHR's role in macrophage polarization by downregulating nuclear factor-κB expression through modulation of the LBP/TLR4 signaling pathway. Therefore, CHR may represent a novel strategy for the prevention of sepsis-induced ALI.
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Purpose: To investigate the synergistic effect of bovine cateslytin-loaded nanoparticles (bCAT-NPs) combined with ultrasound against Candida albicans biofilm and uncover the underlying mechanism. Methods: bCAT-NPs were prepared by the double emulsion method, and toxicity was observed by the hemolysis ratio. The metabolic activity and viable cell biomass, morphology and membrane permeability of C. albicans biofilm were observed. The expression of ALS3 mRNA, the content of reactive oxygen species, was detected. Finally, bCAT structure was analyzed. Results & conclusion: The hemolysis ratio of the bCAT-NPs group was significantly lower than that of the bCAT group. bCAT-NPs combined with ultrasound significantly reduced biofilm metabolic activity, inhibited the formation of hyphae, decreased the expression of ALS3 mRNA and increased the intracellular reactive oxygen species content. In the in vivo experiments, the colony-forming units/ml in the ultrasound+bCAT-NPs group decreased, and a few planktonic fungal cells were observed.
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Candida albicans , Nanopartículas , Animales , Bovinos , Especies Reactivas de Oxígeno , Hemólisis , Biopelículas , Nanopartículas/química , ARN Mensajero , Antifúngicos/farmacologíaRESUMEN
CGA47-66 (Chromofungin, CHR), is a peptide derived from the N-terminus of chromogranin A (CgA), has been proven to inhibit the lipopolysaccharide (LPS)-induced brain injury. However, the underlying mechanism is still unknown. We found that CGA47-66 exerted a protective effect on cognitive impairment by inhibiting the destruction of the blood-brain barrier (BBB) in the LPS-induced sepsis mice model. In addition, the hCMEC/D3 cell line was used to establish an in vitro BBB model. Under LPS stimulation, CGA47-66 could significantly alleviate the hyperpermeability of the BBB, the destruction of tight junction proteins, and the rearrangement of F-actin. To investigate the underlying mechanism, we used LY294002, a PI3K inhibitor, which partially reduced the protective effect of CGA47-66 on the integrity of BBB. Indicating that the PI3K/AKT pathway plays a vital role in the brain-protective function of CGA47-66, which might be a potential therapeutic target for septic brain injury.
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Barrera Hematoencefálica , Lesiones Encefálicas , Animales , Barrera Hematoencefálica/metabolismo , Encéfalo/metabolismo , Lesiones Encefálicas/tratamiento farmacológico , Lesiones Encefálicas/metabolismo , Lesiones Encefálicas/prevención & control , Cromogranina A/metabolismo , Cromogranina A/farmacología , Lipopolisacáridos/farmacología , Ratones , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismoRESUMEN
A system consisting of a plano-convex mirror and reflecting surfaces of Vertical Cavity Surface-Emitting Laser (VCSEL) Strip Array of Diode Lasers has been calculated and proved to have a self-reproducing ray sink in it. The initial positions and slopes of two representative groups of light rays are set, and the position and slope of each light ray at each Distributed Bragg Reflector (DBR) of Diode lasers are obtained by computation. The system is a folded resonator, every VCSEL is connected by the axis of the resonator, and this axis is formed by linking the correspondent reflective points on the inner spherical surface of the mirror and the reflective points on the Bragg mirrors. One approach could be to fabricate the array directly on a plane of a GaAs (or Si) plano-convex mirror. The resonator can contain many VCSELs, and therefore can afford a high quality laser beam and high-power output.
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OBJECTIVE: To investigate the risk factors, predilection sites in pulmonary embolism (PE) patients caused by deep venous thrombosis (DVT) and explore the value of scoring systems in assessing the risk of PE in DVT patients. METHODS: A total of 692 DVT patients were enrolled, and divided into no pulmonary embolism (NPE, 226, 32.66%), silent pulmonary embolism (SPE, 330, 47.67%) and featuring pulmonary embolism (FPE, 136, 19.65%) groups. For each group, the differences of clinical data and PE locations were compared, and the risk factors of PE secondary to DVT were analyzed. The predictive value of the scoring system for the diagnosis of PE and FPE was evaluated. RESULTS: PE presented more in the bilateral pulmonary arteries (PAs) (249, 53.43%) and has no significant difference in PESI scores in different locations. Gender, DVT locations, and previous surgery were the independent risk factors of PE. DVT locations, previous history of COPD, and previous surgical interventions were the independent risk factors of FPE. The results for areas under the ROC curves were: AUC(Wells) = 0.675, AUC (Revised Geneva) = 0.601, AUC(D-dimer) = 0.595 in the PE group; AUC(Wells) = 0.722, AUC (Revised Geneva) = 0.643, AUC(D-dimer) = 0.557 in the FPE group. CONCLUSIONS: PE secondary to DVT mostly occurs in the bilateral PAs. Male gender, DVT locations, and previous surgery increased the risk of PE. The Wells scoring system was more advantageous for evaluating the diagnosis of PE in patients with DVT.
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Embolia Pulmonar , Trombosis de la Vena , Humanos , Masculino , Embolia Pulmonar/epidemiología , Embolia Pulmonar/etiología , Estudios Retrospectivos , Medición de Riesgo , Factores de Riesgo , Trombosis de la Vena/diagnóstico por imagen , Trombosis de la Vena/epidemiología , Trombosis de la Vena/etiologíaRESUMEN
Background The use of adrenaline in out-of-hospital cardiac arrest (OHCA) patients is still controversial. This study aimed to determine the effects of early pre-hospital adrenaline administration in OHCA patients. Methods and Results PubMed, EMBASE, Google Scholar, and the Cochrane Library database were searched from study inception to February 2019 to identify studies that reported OHCA patients who received adrenaline. The primary outcome was survival to discharge, and the secondary outcomes were return of spontaneous circulation, favorable neurological outcome, and survival to hospital admission. A total of 574 392 patients were included from 24 studies. The use of early pre-hospital adrenaline administration in OHCA patients was associated with a significant increase in survival to discharge (risk ratio [RR], 1.62; 95% CI, 1.45-1.83; P<0.001) and return of spontaneous circulation (RR, 1.50; 95% CI, 1.36-1.67; P<0.001), as well as a favorable neurological outcome (RR, 2.09; 95% CI, 1.73-2.52; P<0.001). Patients with shockable rhythm cardiac arrest had a significantly higher rate of survival to discharge (RR, 5.86; 95% CI, 4.25-8.07; P<0.001) and more favorable neurological outcomes (RR, 5.10; 95% CI, 2.90-8.97; P<0.001) than non-shockable rhythm cardiac arrest patients. Conclusions Early pre-hospital administration of adrenaline to OHCA patients might increase the survival to discharge, return of spontaneous circulation, and favorable neurological outcomes. Registration URL: https://www.crd.york.ac.uk/PROSPERO; Unique identifier: CRD42019130542.
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Agonistas Adrenérgicos/administración & dosificación , Servicios Médicos de Urgencia , Epinefrina/administración & dosificación , Paro Cardíaco Extrahospitalario/tratamiento farmacológico , Agonistas Adrenérgicos/efectos adversos , Adulto , Anciano , Anciano de 80 o más Años , Esquema de Medicación , Epinefrina/efectos adversos , Femenino , Mortalidad Hospitalaria , Humanos , Masculino , Persona de Mediana Edad , Paro Cardíaco Extrahospitalario/diagnóstico , Paro Cardíaco Extrahospitalario/mortalidad , Paro Cardíaco Extrahospitalario/fisiopatología , Alta del Paciente , Retorno de la Circulación Espontánea/efectos de los fármacos , Factores de Tiempo , Resultado del TratamientoRESUMEN
OBJECTIVE: The objective was to investigate the correlation between single nucleotide polymorphism (SNP) of chromogranin A (CHGA) and prognosis of critically ill patients. METHODS: We screened 357 critically ill patients consecutively admitted to our intensive care unit. The -89/-415/-462 SNP locus in the promoter region and the +9559/+9578/+9590/+9611 SNP locus in exon 7 coding of CHGA were genotyped by polymerase chain reaction and DNA sequencing technology. Subsequently, the correlation between genotype and prognosis of patients was analyzed. RESULTS: (1) Three hundred critically ill Chinese Han patients were enrolled in the study. CHGA-415/-462/+9559/+9611 SNPs were polymorphically distributed. Phenotypes of the 4 SNPs were shown not to be in linkage disequilibrium, and there were no significant differences in the minor allele frequencies (MAFs) of the 4 SNPs between participants of this study and healthy people in Asia. (2) The CHGA-415 T/C MAF of the nonsurvival group was significantly higher than that of the survival group (MAF 0.3813 and 0.2864, respectively; P=.026). Survival analysis showed that there were significant differences between the CHGA-415 T/C mutation group (including TC and CC genotypes) and the wild-type group (TT genotype) (log rank=8.887, P=.003). The mortality in the mutant group was significantly higher than that in the wild-type group (0.3333 and 0.1852, respectively; P=.004). (3) Binary logistic analysis showed that CHGA-415 T/C polymorphism was an independent risk factor for the mortality of critically ill patients (odds ratio, 2.286; 95% confidence interval, 1.165-4.484; P=.016). CONCLUSIONS: Critically ill patients with CHGA-415 T/C mutant genotype display higher 30-day mortality than those with the wild-type group. CHGA-415 T/C polymorphism is an independent risk factor of poor prognosis in critically ill Chinese Han patients.
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Cromogranina A/genética , Enfermedad Crítica , Polimorfismo de Nucleótido Simple/genética , Adulto , Anciano , China/etnología , Femenino , Frecuencia de los Genes/genética , Genotipo , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Reacción en Cadena de la Polimerasa , Pronóstico , Factores de RiesgoRESUMEN
BACKGROUND: Weaning-induced pulmonary oedema (WiPO) is a well-recognised cause of failure of weaning from mechanical ventilation, but its incidence and risk factors have not been reliably described. We wanted to determine the incidence and risk factors in a population of critically ill patients. In addition, we wanted to describe the effects of diuretics when they are administered in this context. METHODS: We monitored 283 consecutive spontaneous breathing trials (SBT; T-piece trial) performed in 81 patients. In cases with cardiac output monitoring (n = 85, 29 patients), a passive leg raising (PLR) test was performed before SBT. Three experts established the diagnosis of WiPO based on various patient characteristics. RESULTS: SBT failed in 128 cases (45 % of all SBT). WiPO occurred in 59 % of these failing cases. Compared to patients without WiPO (n = 52), patients with at least one WiPO (n = 29) had a higher prevalence of chronic obstructive pulmonary disease (COPD) (38 % vs. 12 %, respectively; p < 0.01), previous "structural" cardiopathy (dilated and/or hypertrophic and/or hypokinetic cardiopathy and/or significant valvular disease, 9 % vs. 25 %, respectively; p < 0.01), obesity (45 % vs. 17 %, respectively; p < 0.01), and low left ventricular ejection fraction (55 % vs. 21 %, respectively; p = 0.01). At logistic regression, COPD (odds ratio (OR) 8.7, 95 % confidence interval (CI) 2.0-37.3), previous structural cardiopathy (OR 4.5, 95 % CI 1.4-14.1), and obesity (OR 3.6, 95 % CI 1.2-12.6) were independent risk factors for experiencing at least one episode of WiPO. In 16 cases with WiPO and a negative PLR at baseline, treatment including diuretics was started. In 9 of these cases, the PLR remained negative before the following SBT. A new episode of WiPO occurred in 7 of these instances, while the two other were extubated. In 7 other cases, the PLR became positive before the following SBT. WiPO did not occur anymore in 6 of these 7 patients who were extubated, while the remaining one was not. CONCLUSIONS: In our population of critically ill patients, WiPO was responsible for 59 % of weaning failures. COPD, previous "structural" cardiopathy, and, to a lesser extent, obesity were the main risk factors. When a treatment including fluid removal had changed preload-independence to preload-dependence, the following SBT was very likely to succeed.
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Cardiopatías/epidemiología , Edema Pulmonar/epidemiología , Respiración Artificial/efectos adversos , Desconexión del Ventilador/efectos adversos , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Cardiopatías/diagnóstico , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Enfermedad Pulmonar Obstructiva Crónica/diagnóstico , Enfermedad Pulmonar Obstructiva Crónica/epidemiología , Enfermedad Pulmonar Obstructiva Crónica/terapia , Edema Pulmonar/diagnóstico , Edema Pulmonar/terapia , Respiración Artificial/métodos , Factores de Riesgo , Termodilución/métodos , Resultado del Tratamiento , Desconexión del Ventilador/métodosRESUMEN
OBJECTIVE: To explore the role of chromogranin A ( CGA) derived peptide CGA47~ ( Chromfungin, CHR) on septic serum induced high permeability of vascular endothelial cells. METHODS: Human umbilical venous endothelial cell line (EA.hy926 cells) was exposed to CHR, serum of septic shock patient, and tumor necrosis factor-a (TNF-a) respectively. Methyl thiazolyl tetrazolium (MTT) method, Transwell assay and immunofluorescence were performed to determine cell viability (absorbance (A) value J, permeability of monolayer endothelial cells (A value) , and the morphological characteristic and distribution ofF -actin respectively. RESULTS: Compared with the blank control group, when EA.hy926 were exposed to CHR with 1, 10, 100 nmol/L the cell activity was not significantly affected (A value: 1.219 ± 0.253, 1.179 ± 0.065, 1.179 ± 0.062 vs. 1.306 ± 0.162, all P>0.05), while when the cells was exposed to CHR in 1 000 nmol/L the cell activity was significantly inhibited (A value: 1.049 ± 0.256 vs. 1.306 ± 0.162, t=-2.390, P=0.031 ). Compared with blank control group, when the cells were exposed to CHR of 1, 10, 100 nmol/L a significant decrease in permeability in EA.hy926 cells was observed (A value: 1.619 ± 0.324, 1.496 ± 0.356, 1.132 ± 0.280 vs. 2.315 ± 0.440, P<0.05 or P<0.01 ). Treatment of septic shock patient's serum or TNF-a to EA. hy926 produced an obvious increase in its permeability (septic serum group A value: 1.204 ± 0.248 vs. 0.277 ± 0.017, P<0.01; TNF-a group A value: 2.485 ± 0.113 vs. 1.602 ± 0.679, P<0.05). High-permeability induced by TNF-a or septic shock patient's serum was alleviated hy CHR in the concentration of 1, 10, 100 nmol/L in a dose-dependent manner (septic serum + CHR group A value: 0.299 ± 0.065, 0.224 ± 0.028, 0.131 ± 0.015 vs. 1.204 ± 0.248; TNF -a + CHR group A value: 1.995 ± 0.394, 1.920 ± 0.096, 1.744 ± 0.475 vs. 2.485 ± 0.113, P<0.05 or P<0.01 ). Under a laser scanning confocal microscope, it was found that the F-actin cytoskeleton of EA.hy926 cells was redistributed, and more stress fibers were found in the septic shock patient's serum group and TNF-α group, while CHR obviously alleviated the above effects induced by septic shock patient's serum or TNF-α. CONCLUSION: In a dose-dependent manner, CHR may inhibit increased permeability of vascular endothelial cells induced by septic shock patient's serum, its underlying mechanism may be related to inhibition of the effect of TNF-α.
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Permeabilidad de la Membrana Celular/efectos de los fármacos , Cromogranina A/farmacología , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/metabolismo , Fragmentos de Péptidos/farmacología , Suero , Células Cultivadas , Células Endoteliales de la Vena Umbilical Humana/citología , Humanos , Sepsis/sangre , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
A He-Ne laser with an annular gain zone is studied theoretically. It is demonstrated that the He-Ne medium in the annular discharge zone possesses enough gain to maintain laser oscillation. A multipass ring resonator, which is composed of two annular spherical mirrors, is described, and it is shown that the resonator is suitable for extracting optical energy from the He-Ne medium in the annular gain zone. Considering the availability of population inversion in the traveling-wave cavity and the influence of the crossover of the folded light beam in the resonator on the output power, a calculation formula for the output power of the laser with the multipass ring resonator is given. Calculating results prove that a 1 W output of the He-Ne laser can be obtained by a 1 m length annular discharge zone.