Hepatic venous gas secondary to pulmonary barotrauma: rat model study.

Intrahepatic gas (IHG) is commonly observed during early postmortem examinations of humans with upper or lower airway obstructions. We conducted a study to test the hypothesis that intrapulmonary gas could retrogradely spread to the hepatic vein following pulmonary barotrauma (PB). To establish a rat model of pulmonary barotrauma, we utilized a controllable pressure-vacuum pump to apply airway pressure (40, 60, or 80 mmHg). The rats were dissected directly at the end of the experiment, and histological analysis was performed through microscopic examination of the rats. Additionally, the rats were ventilated with meglumine diatrizoate under pressures of 160 and 250 mmHg to observe the signal dynamic diffusion using X-ray fluoroscopy examination. Rats exhibited classical changes associated with PB, such as alveolar rupture, pulmonary interstitial emphysema, and hemorrhage, as well as IHG characterized by the presence of gas in the hepatic vein and hepatic sinusoids. Air emboli were not observed in the liver in any of the 40 mmHg groups. However, they were observed in the liver in the 60 and 80 mmHg groups, the amount and size of air emboli in the 80 mmHg group were greater than those in the 60 mmHg group (p < 0.05). The 80 mmHg group presented radial grape-like bubbles in the centrilobular portion of the liver accompanied by congestion in the peripheral region of the hepatic lobule. X-ray fluoroscopy examination revealed a gradual enhancement of dynamic contrast medium signals from the lung to the inferior vena cava and then to the liver. Our findings indicate that pulmonary barotrauma can lead to the retrograde spread of intrapulmonary gas to the hepatic vein. When it is clear that no decomposition of the body has occurred, the presence of IHG serves as a novel indicator for the diagnosis of obstructive pulmonary disease or obstruction in the upper or lower airway.

Nickel-Doped Graphite and Fusible Alloy Bilayer Back Electrode for Vacuum-Free Perovskite Solar Cells.

With the rapid development of perovskite solar cells (PSCs), lowering fabrication costs for PSCs has become a prominent challenge for commercialization. At present, gold is commonly used as the back metal electrode in state-of-the-art n-i-p structured PSCs due to its compatible work function, chemical inertness, and high conductivity. However, the high cost of gold and the expensive and time-consuming vacuum-based thin-film coating facilities may impede large-scale industrialization of PSCs. Here, we report a bilayer back electrode configuration consisting of an Ni-doped natural graphite layer with a fusible Bi-In alloy. This back electrode can be deposited in a vacuum-free approach and enables PSCs with a power conversion efficiency of 21.0%. These inexpensive materials and facile ambient fabrication techniques provide an appealing disruptive solution to low-cost PSC industrialization.

Association of Attenuated Niacin Response With Inflammatory Imbalance and Prediction of Conversion to Psychosis From Clinical High-risk Stage.

Objective: Attenuated niacin responses and changes in cytokine levels have been reported in schizophrenia. However, prior studies have typically focused on schizophrenia, and little is known about the association between niacin response and inflammatory imbalance in clinically high-risk psychosis (CHR). This study aimed to assess the niacin response to inflammatory imbalance for association with conversion to psychosis within 2 years.Methods: A prospective case-control study was performed to assess the niacin response and interleukin (IL)-1ß, IL-2, IL-6, IL-8, IL-10, and tumor necrosis factor-α levels in 60 CHR individuals and 60 age- and sex-matched healthy controls (HC) from May 2019 to December 2021. Participants with CHR were identified using the Structured Interview for Prodromal Syndromes. The niacin-induced responses were measured using laser Doppler flowmetry. From the dose-response curves, the log-transferred concentration of methylnicotinate required to elicit a half-maximal blood flow response (LogEC50) and maximal minus minimal blood flow response (Span) values were calculated for each subject. Serum cytokine levels were measured using enzyme-linked immunosorbent assay. Individuals with CHR were then divided into converters (CHR-C, n = 15) and non-converters (CHR-NC, n = 45) to psychosis based on their 2-year follow-up clinical status.Results: The CHR group exhibited significantly higher LogEC50 (t = 3.650, P < .001) and Span (t = 2.657, P = .009) values than the HC group. The CHR-C group exhibited a significantly shorter Span (t = 4.027, P < .001) than the CHR-NC group. The LogEC50 showed a trend toward significance (t = 1.875, P = .066). None of the cytokine levels were significant. The conversion outcome can therefore be predicted by applying LogEC50 (P = .049) and Span (P < .001). The regression model with variables of LogEC50, Span, family history, and scores of positive symptoms showed good discrimination of subsequent conversion to psychosis and achieved a classification accuracy of 91.7%. The decreased LogEC50 in the CHR-C group was significantly correlated with the increased IL-1ß/IL-10 ratio (Spearman ρ = -0.600, P = .018), but this correlation was nonsignificant in the CHR-NC group.Conclusions: Our findings indicate a significant association between niacin response and psychosis conversion outcomes in individuals with CHR. Compared with peripheral inflammatory cytokines, the niacin response can better predict conversion, although there may be an intersection between the two in biological mechanisms.

Intraoperative Hypotension and Related Risk Factors for Postoperative Mortality After Noncardiac Surgery in Elderly Patients: A Retrospective Analysis Report.

BACKGROUND: Blood pressure fluctuation is very common during non-cardiac surgery in elderly. This retrospective study was to analyse whether intraoperative hypotension in elderly and other risk factors relate to the postoperative mortality. METHODS: A total of 118 cases (Observational group), who underwent noncardiac surgery in three medical centers between September 2014 and March 2017, and died in the hospital after the noncardiac surgery. With 1:2 ratio of propensity matching, 236 survival cases (Control group) were selected for comparison analyses with the death cases. Intraoperative blood pressure and perioperative parameters from both groups were collected from electronic anaesthesia charts. Data were analysed with univariate logistic regression analysis where variables with p values less than 0.05 were analysed with multivariate logistic regression analysis. The receiver operating characteristic (ROC) curve was constructed. RESULTS: There are five risk factors related to postoperative death in elderly patients: ASA grade, COPD, emergency surgery, general anesthesia, 60 < MAP ≤ 65mmHg (OR > 1), and one factor may reduce the risk of postoperative mortality, which is PACU therapy (OR < 1). Compared with the Control group, the Observational group had a higher proportion of cerebral hernia, kidney injury and trauma (p < 0.001). The intraoperative blood transfusion volume and intraoperative blood loss volume were higher in the Observational group than the Control group (p < 0.001). The proportion of using vasoactive drugs was higher in the Observational group (p < 0.001), and there was more urine output during the operation in the Observational group (p = 0.005). CONCLUSION: The intraoperative MAP of geriatric patients lower than 65mmHg is highly related to the postoperative mortality. Elderly patients with emergency surgery, high ASA grade and a history of COPD have an increased risk of postoperative mortality. General anesthesia is a risk factor for postoperative death in elderly patients, and the PACU therapy is a protective factor to avoid postoperative death. TRIAL REGISTRATION: This study has been retrospectively registered in the Chinese Clinical Trials Registry (ChiCTR2000038912, 10/10/2020).

Axitinib overcomes multiple imatinib resistant cKIT mutations including the gatekeeper mutation T670I in gastrointestinal stromal tumors.

BACKGROUND: cKIT kinase overexpression and gain-of-function mutations are the critical pathogenesis of gastrointestinal stromal tumors (GISTs). Although the multiple kinase inhibitors such as imatinib, sunitinib, and regorafenib have been approved for GISTs, the acquisition of polyclonal secondary resistance mutations in KIT is still a limitation for GIST treatment. Here we explored the KIT inhibitory activity of axitinib in preclinical models and describe initial characterization of its activity in GIST patient-derived primary cells. METHODS: The activities of axitinib against mutant KIT were evaluated using protein-based assay and a panel of engineered and GIST-derived cell lines. The binding modes of axitinib-KIT/KIT mutants were analyzed. Four primary cells derived from GIST patients were also used to assess the drug response of axitinib. RESULTS: Axitinib exhibited potent activities against a variety of cKIT associated primary and secondary mutations. It displayed better activity against cKIT wild-type, cKIT V559D/A/G, and L576P primary gain-of-function mutations than imatinib, sunitinib, and regorafenib. In addition, it could inhibit imatinib resistant cKIT T670I and V654A mutants in vitro and in vivo GIST preclinical models. CONCLUSION: Our results provide the basis for extending the application of axitinib to GISTs patients who are unresponsive or intolerant to the current therapies.

Beneficial effects of platelet-derived growth factor on hemorrhagic shock in rats and the underlying mechanisms.

Studies have shown that local application of platelet-derived growth factor (PDGF) can be used for the treatment of acute and chronic wounds. We investigated if systemic application of PDGF has a protective effect on acute hemorrhagic shock in rats in the present study. Using hemorrhagic shock rats and isolated superior mesenteric arteries, the effects of PDGF-BB on hemodynamics, animal survival, and vascular reactivity as well as the roles of the gap junction proteins connexin (Cx)40 and Cx43, PKC, and Rho kinase were observed. PDGF-BB (1­15 µg/kg iv) significantly improved the hemodynamics and blood perfusion to vital organs (liver and kidney) as well as vascular reactivity and improved the animal survival in hemorrhagic shock rats. PDGF recovering shock-induced vascular hyporeactivity depended on the integrity of the endothelium and myoendothelial gap junction. Cx43 antisense oligodeoxynucleotide abolished these improving effects of PDGF, whereas Cx40 oligodeoxynucleotide did not. Further study indicated that PDGF increased the activity of Rho kinase and PKC as well as vascular Ca2+ sensitivity, whereas it did not interfere with the intracellular Ca2+ concentration in hypoxia-treated vascular smooth muscle cells. In conclusion, systemic application of PDGF-BB may exert beneficial effects on hemorrhagic shock, which are closely related to the improvement of vascular reactivity and hemodynamics. The improvement of PDGF-BB in vascular reactivity is vascular endothelium and myoendothelial gap junction dependent. Cx43, Rho kinase, and PKC play very important role in this process. These findings suggest that PDGF may be a potential measure to treat acute clinical critical diseases such as severe trauma, shock, and sepsis.

Age and sex differences in vascular responsiveness in healthy and trauma patients: contribution of estrogen receptor-mediated Rho kinase and PKC pathways.

Several medical conditions exhibit age- and sex-based differences. Whether or not traumatic shock exhibits such differences with regard to vascular responsiveness is not clear. In a cohort of 177 healthy subjects and 842 trauma patients (21-82 years) as well as different ages (4, 8, 10, 14, 18, and 24 wk; 1 and 1.5 years) and sexes of Sprague-Dawley normal and traumatic shock rats, the age- and sex-based differences of vascular responsiveness and the underlying mechanisms were investigated. Middle-aged and young women as well as female rats of reproductive age had higher vascular responsiveness in the normal condition and a lower decrease in vascular responsiveness after traumatic shock than older men and male rats of identical age. Exogenous supplementation of 17ß-estrdiol increased vascular reactivity in both male and femal rats of 8-24 wk and preserved vascular responsiveness in rats following traumatic shock. No effect was observed in rats 1 to 1.5 years. These protective effects of estrogen were closely related to G protein-coupled receptor (GPR)30, estrogen receptor-mediated Rho kinase, and PKC pathway activation. Vascular responsiveness exhibits age- and sex-based differences in healthy subjects and trauma patients. Estrogen and its receptor (GPR30) mediated activation of Rho kinase and PKC using genomic and nongenomic mechanisms to elicit protective effects in vascular responsiveness. This finding is important for the personalized treatment for several age- and sex-related diseases involving estrogen.

Bkca opener, NS1619 pretreatment protects against shock-induced vascular hyporeactivity through PDZ-Rho GEF-RhoA-Rho kinase pathway in rats.

BACKGROUND: Our previous study showed that the ischemic preconditioning and pretreatment of adenosine triphosphate-sensitive potassium channel (KATP) opener, pinacidil, may induce a good protective effect on shock-induced vascular hyporeactivity. Whether the pretreatment of opener/activator of the large-conductance calcium-activated potassium channel (Bkca), NS1619, can also induce a protective effect on vascular reactivity and play a beneficial effect on subsequent hemorrhagic shock is not clear. METHODS: With Sprague-Dawley rats subjected to hemorrhagic shock and their isolated superior mesenteric artery, the protective effect of NS1619 (0.5, 1, 2, and 4 mg/kg) pretreatment (30 minutes before hemorrhage shock) on vascular reactivity and the underlying mechanisms were observed. RESULTS: NS1619 pretreatment significantly improved the 72-hour survival of hemorrhagic shock rats, alleviated shock-induced decrease of vascular reactivity and calcium sensitivity, and increased the cardiac output and oxygen delivery. NS1619 2 mg/kg had the best effect. These protective effects of NS1619 pretreatment on vascular reactivity and calcium sensitivity were antagonized by RhoA inhibitor, C3 transferase, and Rho kinase antagonist, Y-27632. NS1619 pretreatment up-regulated the activities of RhoA, Rho-kinase, and PDZ-Rho GEF (guanine nucleotide exchange factor). These effects of NS1619 pretreatment were eliminated by RhoA inhibitor, C3 transferase. CONCLUSION: Bkca opener, NS1619 pretreatment has good protective effect on vascular reactivity and calcium sensitivity, which plays a good beneficial effect on hemorrhagic shock. The mechanism may be mainly through PDZ-Rho GEF-RhoA-Rho kinase pathway. Bkca channel may be a potential target for the treatment of shock-induced vascular hyporeactivity.

Cell assay using a two-photon-excited europium chelate.

We report application of two-photon excitation of europium chelates to immunolabeling of epidermal growth factor receptor (EGFR) cell surface proteins on A431 cancer cells. The europium chelates are excited with two photons of infrared light and emit in the visible. Europium chelates are conjugated to antibodies for EGFR. A431 (human epidermoid carcinoma) cells are labeled with this conjugate and imaged using a multiphoton microscope. To minimize signal loss due to the relatively long-lived Eu(3+) emission, the multiphoton microscope is used with scanning laser two-photon excitation and non-scanning detection with a CCD. The chelate labels show very little photobleaching (less than 1% during continuous illumination in the microscope for 20 minutes) and low levels of autofluorescence (less than 1% of the signal from labeled cells). The detection limit of the europium label in the cell assay is better than 100 zeptomoles.

High-speed multispectral fluorescence lifetime imaging implementation for in vivo applications.

Fluorescence lifetime imaging microscopy (FLIM) offers a noninvasive approach for characterizing the biochemical composition of biological tissue. In recent years, there has been an increasing interest in the application of multispectral FLIM for medical diagnosis. Central to the clinical translation of FLIM technology is the development of robust, fast, and cost-effective FLIM instrumentation suitable for in vivo tissue imaging. Unfortunately, the predominant multispectral FLIM approaches suffer from limitations that impede the development of high-speed instruments for in vivo applications. We present a cost-effective scanning multispectral FLIM implementation capable of achieving pixel rates on the order of tens of kilohertz, which will facilitate the evaluation of FLIM for in vivo applications.