Search

Coronavirus disease 2019 (COVID-19) has spread in more than 100 countries and regions around the world, raising grave global concerns. COVID-19 has a similar pattern of infection, clinical symptoms, and chest imaging findings to influenza pneumonia. In this retrospective study, we analysed clinical and chest CT data of 24 patients with COVID-19 and 79 patients with influenza pneumonia. Univariate analysis demonstrated that the temperature, systolic pressure, cough and sputum production could distinguish COVID-19 from influenza pneumonia. The diagnostic sensitivity and specificity for the clinical features are 0.783 and 0.747, and the AUC value is 0.819. Univariate analysis demonstrates that nine CT features, central–peripheral distribution, superior–inferior distribution, anterior–posterior distribution, patches of GGO, GGO nodule, vascular enlargement in GGO, air bronchogram, bronchiectasis within focus, interlobular septal thickening, could distinguish COVID-19 from influenza pneumonia. The diagnostic sensitivity and specificity for the CT features are 0.750 and 0.962, and the AUC value is 0.927. Finally, a multivariate logistic regression model combined the variables from the clinical variables and CT features models was made. The combined model contained six features: systolic blood pressure, sputum production, vascular enlargement in the GGO, GGO nodule, central–peripheral distribution and bronchiectasis within focus. The diagnostic sensitivity and specificity for the combined features are 0.87 and 0.96, and the AUC value is 0.961. In conclusion, some CT features or clinical variables can differentiate COVID-19 from influenza pneumonia. Moreover, CT features combined with clinical variables had higher diagnostic performance. [ABSTRACT FROM AUTHOR]

Mechanical ventilation (MV) can augment sepsis-induced organ injury. Previous studies indicate that human mesenchymal stem cells (hMSCs) have immune-modulatory effect. We hypothesize that human adipose tissue-derived stromal cells (hADSCs) could attenuate MV and sepsis-induced organ injury. Male C57BL/6 mice were randomized to five groups: Sham group; MV group; cecal ligation and puncture (CLP) group; CLP + MV group; and CLP + MV + hADSC group. Anesthetized mice were subjected to cecal ligation and puncture surgery. The mice then received mechanical ventilation (12 ml/kg), with or without the intervention of hADSCs. The survival rate, organ injury of the liver and kidney, total protein and cells in bronchoalveolar lavage fluid (BALF), and histological changes of the lung and liver were examined. The level of IL-6 in BALF was measured by ELISA. Real-time quantitative PCR was used to analyze mRNA of IL-6 and tumor necrosis factor-α (TNF-α). hADSC treatment increased survival rate of septic mice with MV. hADSCs attenuated dysfunction of the liver and kidney and decreased lung inflammation and tissue injury of the liver and lung. IL-6 level in BALF and TNF-α and IL-6 mRNA expression in the tissue of the lung, liver, and kidney were significantly reduced by hADSC treatment. MV with conventional tidal volume aggravates CLP-induced multiple organ injuries. hADSCs inhibited the compound injuries possibly through modulation of immune responses. [ABSTRACT FROM AUTHOR]

Background: Mechanical ventilation (MV) is a clinically important measure for respiratory support in critically ill patients. Although moderate tidal volume MV does not cause lung injury, it can further exacerbate lung injury in pathological state such as sepsis. This pathological process is known as the 'two-hit' theory, whereby an initial lung injury (e.g., infection, trauma, or sepsis) triggers an inflammatory response that activates immune cells, presenting the lung tissue in a fragile state and rendering it more susceptible to subsequent injury. The second hit occurs when mechanical ventilation is applied to lung tissue in a fragile state, and it is noteworthy that this mechanical ventilation is harmless to healthy lung tissue, further aggravating pre-existing lung injury through unknown mechanisms. This interaction between initial injury and subsequent mechanical ventilation develops a malignant cycle significantly exacerbating lung injury and severely hampering patient prognosis. The two-hit theory is critical to understanding the complicated mechanisms of ventilator-associated lung injury and facilitates the subsequent development of targeted therapeutic strategies., Methods and Results: CLP mice model was used to mimic clinical sepsis patients. After 12 hours the mice were mechanical ventilated for 2-6 hours. MV by itself didn't lead to HMGB1 release, but significantly strengthened HMGB1 in plasma and cytoplasm of lung tissue in septic mice. Plasma and lung tissue activation of cytokines and chemokines, MAPK signaling pathway, neutrophil recruitment, and ALI were progressively decreased in LysM HMGB1-/- (Hmgb1 deletion in myeloid cells) and iHMGB1-/- mice (inducible HMGB1-/- mouse strain where the Hmgb1 gene was globally deleted after tamoxifen treatment). Compared with C57BL/6 mice, although EC-HMGB1-/- (Hmgb1 deletion in endothelial cells) mice didn't have lower levels of inflammation, neutrophil recruitment and lung injury were reduced. Compared with LysM HMGB1-/- mice, EC-HMGB1-/- mice had higher levels of inflammation but significantly lower neutrophil recruitment and lung injury. Overall, iHMGB1-/- mice had the lowest levels of all the above indicators. The level of inflammation, neutrophil recruitment and the degree of lung injury were decreased in RAGE-/- mice, and even the above indices were further decreased in TLR4/RAGE-/- mice. Levels of inflammation and neutrophil recruitment were decreased in Caspase-11-/- and Caspase-1/11-/- mice, but no statistical difference between these two gene knockout mice., Conclusions: These data show for the first time that the Caspase-1/Caspase-11-HMGB1-TLR4/RAGE signaling pathway plays a key role in mice model of sepsis induced lung injury exacerbated by MV. Different species of HMGB1 knockout mice have different lung protective mechanisms in the 'two hits' model, and location is the key to function. Specifically, LysM HMGB1-/- mice due to the deletion of HMGB1 in myeloid cells resulted in a pulmonary protective mechanism that was associated with a downregulation of the inflammatory response. EC HMGB1-/- mice are deficient in HMGB1 owing to endothelial cells, resulting in a distinct pulmonary protective mechanism independent of the inflammatory response and more relevant to the improvement of alveolar-capillary permeability. iHMGB1-/- mice, which are systemically HMGB1-deficient, share both of these lung-protective mechanisms., (Copyright © 2024 by the Shock Society.)

After spinal cord injury (SCI), successive systemic administration of microtubule-stabilizing agents has been shown to promote axon regeneration. However, this approach is limited by poor drug bioavailability, especially given the rapid restoration of the blood-spinal cord barrier. There is a pressing need for long-acting formulations of microtubule-stabilizing agents in treating SCI. Here, we conjugated the antioxidant idebenone with microtubule-stabilizing paclitaxel to create a heterodimeric paclitaxel-idebenone prodrug via an acid-activatable, self-immolative ketal linker and then fabricated it into chondroitin sulfate proteoglycan-binding nanomedicine, enabling drug retention within the spinal cord for at least 2 weeks and notable enhancement in hindlimb motor function and axon regeneration after a single intraspinal administration. Additional investigations uncovered that idebenone can suppress the activation of microglia and neuronal ferroptosis, thereby amplifying the therapeutic effect of paclitaxel. This prodrug-based nanomedicine simultaneously accomplishes neuroprotection and axon regeneration, offering a promising therapeutic strategy for SCI.

Abrus mollis (MJGC) has been used as a substitute herb for Abrus cantoniensis (JGC) in China. However, an in-depth comparison on their key metabolites and the mechanism of anti-inflammation between these two is not available. In this report, high pressure liquid chromatography equipped with mass spectrometry was applied to capture their flavonoid profiles; transcriptomics was adopted to analyze their anti-inflammatory mechanisms. The results showed that the main flavonoids in MJGC were vicenin-2, schaftoside and isoschaftoside, while those in JGC were vicenin-1 isomer and schaftoside isomer. The anti-inflammatory activity of JGC was slightly stronger than that of MJGC. The number of differential expression genes regulated by JGC was significantly higher than MJGC. JGC regulated 151 (42 up and 109 down) of inflammation related genes, while MJGC regulated 58 (8 up and 50 down) of inflammation related genes. The results of this study provided scientific evidence and guidance for the substitution of MJGC and JGC., (© 2023 Wiley-VHCA AG, Zurich, Switzerland.)

The incidence of vaginal infection caused by Candida species has considerably increased over the past two decades. Candida albicans is the main cause of vulvovaginal candidiasis (VVC); however, non-albicans Candida (NAC) species, such as Candida glabrata and Candida tropicalis, are now frequently identified in VVC patients. Although the vaginal microbiome (VMB) was well studied in Candida albicans-associated VVC patients, the fungal influence on bacterial communities of NAC species-associated VVC and potential microbial interplay contributing to VVC pathology remain elusive. We characterized VMB via Candida albicans and NAC species-associated VVC patients, as Candida albicans (CA, n = 16), Candida glabrata (CG, n = 16), Candida tropicalis (CT, n = 4), and recruiting healthy (CON, n = 20) women as references of dysbiosis and eubiosis. The bacterial diversity of the vagina in the CG group significantly declined. Further, all VVC patients have a higher abundance of Lactobacillus iners, especially for the CG group. Meanwhile, the predicted functions in all VVC are toned which may be associated with a disruption in the bacterial network. In conclusion, according to the taxonomic analysis, we found that the vaginal microbiome in C. glabrata-associated VVC women is different from that of other Candida species-associated VVC women, implying a different pathogenesis., Competing Interests: Declaration of competing interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023. Published by Elsevier Ltd.)

The aim of the study was to analyze population-based prostate cancer (PCa) screening and the incidence of PCa among males ≥50 years of age residing in the Luqiao district of Taizhou, China. From October to December 2020, male residents ≥50 years of age were screened for serum total prostate-specific antigen (total-PSA). If t-PSA re-test levels persisted above 4 μg/L, subjects underwent further noninvasive examinations, including digital rectal examination or multiparameter magnetic resonance imaging (mpMRI) of the prostate. Subjects underwent prostate biopsy of pathological tissue based on t-PSA and mpMRI results. A total of 3524 (49.1%) residents participated in this PCa screening study. In total, 285 (8.1%) subjects exhibited t-PSA levels ≥4.0 μg/L and 112 (3.2%) underwent noninvasive examinations. Forty-two (1.2%) residents underwent prostate biopsy, of which 16 (0.45%) were diagnosed with PCa. Of those diagnosed with PCa, three (19%) had localized PCa (cT1-cT2N0M0), six (37%) had locally advanced PCa (cT3a- cT4N0-1M0), and seven (44%) had advanced metastatic PCa (M1). Unfortunately, 3477 (48.5%) residents did not participate in the study, mainly due to lack of awareness of PCa based on feedback from local health centers. Age and t-PSA were used as primary screening indicators and, when further combined with mpMRI and prostate biopsy, confirmed the diagnosis of PCa among participating residents. Although this was a relatively economical and convenient screening method, education and knowledge should be further enhanced to increase the participation rate in PCa screening programs.

Intramuscularly injectable long-acting prodrug-based microcrystals (MCs) are of particular interest for chronic disease management. Nevertheless, current prevalently used linkers degraded by enzymes have the potential drawback of substantial differences in enzyme levels between individuals. Here, we reported the synthesis of a stearyl-modified paliperidone prodrug (SKP) with an acid-sensitive ketal linker for developing long-acting MC antipsychotics. SKP-MCs of three different sizes were prepared and systematically examined. We found that paliperidone exposure in SKP-MC-treated rats was prolonged compared with that in rats treated with the commercial antipsychotic Invega Sustenna and that the drug release rate decreased with increasing MC size. In inflammation-inhibition-model rats, paliperidone release from the SKP-MCs was considerably decreased, indicating that the immune-mediated foreign-body response after intramuscular administration boosted paliperidone release. Our findings will provide valuable insights into in vivo drug release from prodrug-based MC formulations. The ketal-linked prodrug strategy might be a new solution for developing long-acting prodrug formulations of hydroxyl-group-bearing drugs.

Purpose: This meta-analysis aimed to assess the efficacy and safety of once-weekly semaglutide among adults with overweight or obesity., Methods: We searched multiple electronic databases for randomized controlled trials that compared once-weekly semaglutide versus placebo in adults with overweight or obesity. The primary outcomes were the percentage change and absolute change in body weight. Secondary outcomes included achievement of categorical weight loss targets (at least 5, 10, 15, or 20%), cardiometabolic risk profiles, and health-related quality of life., Results: This meta-analysis included a total of four trials with 3447 patients. Once-weekly semaglutide was superior to placebo in terms of the percentage change and absolute change in body weight. Compared with placebo, once-weekly semaglutide also led to significant increases in the proportions of achievement of categorical weight reduction targets. Moreover, once-weekly semaglutide induced superior reductions in waist circumference and body-mass index compared with placebo. Furthermore, the effect on improving other cardiometabolic risk factors and health-related quality of life was more pronounced for once-weekly semaglutide relative to placebo., Conclusion: Among adults with overweight or obesity, once-weekly semaglutide could result in clinically meaningful weight loss, which was a promising therapy for treating overweight or obesity., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Accumulating evidence shows that RAGE has an important function in the pathogenesis of sepsis. However, the mechanisms by which RAGE transduces signals to downstream kinase cascades during septic shock are not clear. Here, we identify SLP76 as a binding partner for the cytosolic tail of RAGE both in vitro and in vivo and demonstrate that SLP76 binds RAGE through its sterile α motif (SAM) to mediate downstream signaling. Genetic deficiency of RAGE or SLP76 reduces AGE-induced phosphorylation of p38 MAPK, ERK1/2 and IKKα/β, as well as cytokine release. Delivery of the SAM domain into macrophages via the TAT cell-penetrating peptide blocks proinflammatory cytokine production. Furthermore, administration of TAT-SAM attenuates inflammatory cytokine release and tissue damage in mice subjected to cecal ligation and puncture (CLP) and protects these mice from the lethality of sepsis. These findings reveal an important function for SLP76 in RAGE-mediated pro-inflammatory signaling and shed light on the development of SLP76-targeted therapeutics for sepsis.

Imbalance of macrophage polarization plays an indispensable role in acute lung injury (ALI), which is considered as a promising target. Matrix metalloproteinase-9 (MMP-9) is expressed in the macrophage, and has a pivotal role in secreting inflammatory cytokines. We reported that saquinavir (SQV), a first-generation human immunodeficiency virus-protease inhibitor, restricted exaggerated inflammatory response. However, whether MMP-9 could regulate macrophage polarization and inhibit by SQV is still unknown. We focused on the important role of macrophage polarization in CLP (cecal ligation puncture)-mediated ALI and determined the ability of SQV to maintain M2 over M1 phenotype partially through the inhibition of MMP-9. We also performed a limited clinical study to determine if MMP-9 is a biomarker of sepsis. Lipopolysaccharide (LPS) increased MMP-9 expression and recombinant MMP-9 (rMMP-9) exacerbated LPS-mediated M1 switching. Small interfering RNA to MMP-9 inhibited LPS-mediated M1 phenotype and SQV inhibition of this switching was reversed with rMMP-9, suggesting an important role for MMP-9 in mediating LPS-induced M1 phenotype. MMP-9 messenger RNA levels in peripheral blood mononuclear cells of these 14 patients correlated with their clinical assessment. There was a significant dose-dependent decrease in mortality and ALI after CLP with SQV. SQV significantly inhibited LPS-mediated M1 phenotype and increased M2 phenotype in cultured RAW 264.7 and primary murine bone marrow-derived macrophages as well as lung macrophages from CLP-treated mice. This study supports an important role for MMP-9 in macrophage phenotypic switching and suggests that SQV-mediated inhibition of MMP-9 may be involved in suppressing ALI during systemic sepsis.

Introduction: A novel coronavirus, tentatively designated as 2019 Novel Coronavirus (2019-nCoV), now called severe acute respiratory syndrome coronavirus 2, emerged in Wuhan, China, at the end of 2019 and which continues to expand. On February 11, 2020, the World Health Organization (WHO) named the disease coronavirus disease 2019 (COVID-19). On February 28, WHO increased our assessment of the risk of spread and the risk of impact of COVID-19 to very high at a global level. The COVID-19 poses significant threats to international health.Computed tomography (CT) has been an important imaging modality in assisting in the diagnosis and management of patients withCOVID-19. Some retrospective imaging studies have reported chest CT findings of COVID-19 in the past 2 months, suggesting that several CT findings may be characteristic. To our knowledge, there has been no prospective multicentre imaging study of COVID-19 to date.We proposed a hypothesis: There are some specific CT features on Chest CT of COVID-19 patients. And the mechanism of these CT features is explicable based on pathological findings., Objective: To investigate the specific CT features of COVID-19 and the formation mechanism of these CT features., Method: This study is a prospective multicenter observational study. We will recruit 100 patients with COVID-19 at 55 hospitals. All patients undergo chest CT examination with the same scan protocol. The distribution and morphology of lesions on chest CT, clinical data will be recorded. A number of patients will be pathologically examined after permission is granted. The data of these three aspects will be analyzed synthetically., Discussion: This study will help us to identify the chest CT features of COVID-19 and its mechanism., Ethics and Dissemination: This retrospective study was approved by the Biomedical Research Ethics Committee of West China Hospital of Sichuan University (No. 2020-140). Written informed consent will be obtained from all study participants prior to enrollment in the study. To protect privacy of participants, all private information were kept anonymous. The results will be published in a peer-reviewed journal and will be disseminated electronically and in print regardless of results.

Mechanical ventilation (MV) is frequently employed to manage respiratory failure in sepsis patients and is required for the surgical management of intra-abdominal sepsis. The impact of MV varies dramatically depending on tidal volume, with even moderate tidal volume (MTV) ventilation leading to ventilator-induced lung injury, whereas low tidal volume (LTV) ventilation protects against sepsis-induced acute respiratory distress syndrome. Interleukin (IL)-33 is known to contribute to lung injury in sepsis and its release can be induced by mechanical stress. To determine the relationship between the IL-33-suppression of tumorigenicity 2 (ST2) pathway and patterns of lung injury associated with MV in sepsis, mice were subjected to cecal ligation and puncture (CLP) followed 6 h later by either MTV (10 mL/kg) or LTV (6 mL/kg) ventilation for 4 h. MTV and LTV ventilation alone for 4 h had no impact on lung injury. MTV markedly exacerbated lung injury and inflammation, while LTV significantly suppressed these parameters in septic mice. Lung and plasma levels of IL-33 ST2 were significantly elevated by CLP alone at 10 h. MTV caused further and significant increases in IL-33 and sST2 levels, while LTV significantly suppressed levels induced by CLP. Deletion of IL-33 or ST2 prevented the increase in lung injury and inflammation induced by MTV in septic mice, while administration of recombinant IL-33 in the airway reversed the protection seen with LTV. Taken together, these findings implicate the IL-33-ST2 pathway in the pro-inflammatory changes induced by the mechanical ventilation that leads to lung injury in the setting of intra-abdominal sepsis in a tidal volume-dependent manner.

To identify and quantify the content of nucleoside compounds in the New Zealand native edible mushroom Hericium sp., a high-performance liquid chromatography coupled with a triple quadrupole detector mass method was developed and validated. Four nucleoside substitutes, namely cytidine, uridine, adenosine, and guanosine, were identified. Optimization was conducted to study the effect of extraction method type, solvent pH, and extraction time. The optimal conditions were obtained using ultrasonic treatment in water at pH 3.8 for 30 min. For chromatographic separation, a C 18 column was applied using 0.1% formic acid (pH 3.4) as the mobile phase with detection at 260 nm. The total concentration of the four nucleoside compounds was high, at 10.7 mg/g dry weight, indicating a potential benefit for human health. The excellent validation results based on selectivity, linearity, precision, accuracy and robustness revealed the reliability of the newly developed analytical method, which could be applied routinely in research laboratories., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Hepatic ischemia-reperfusion injury (IRI) is a common pathological phenomenon, which causes hepatic injury as well as remote organ injuries such as the lung. Several mediators, such as oxidative stress, Ca 2+ overload and neutrophil infiltration, have been implied in the pathogenesis of liver and remote organ injuries following reperfusion. WNT1 inducible signaling pathway protein 1 (WISP1) is an extracellular matrix protein that has been associated with the onset of several malignant diseases. Previous work in our group has demonstrated WISP1 is upregulated and contributes to proinflammatory cascades in hepatic IRI. However, the role of WISP1 in the pathogenesis of lung injury after hepatic IRI still remains unknown., Methods: Male C57BL/6 mice were used to examine the expression and role of WISP1 in the pathogenesis of lung injuries after hepatic IRI and explore its potential mechanisms in mediating lung injuries., Results: We found WISP1 was upregulated in lung tissues following hepatic IRI. Treatment with anti-WISP1 antibody ameliorated lung injuries with alteration of cytokine profiles. Administration with rWISP1 aggravated lung injuries following hepatic IRI through excessive production of proinflammatory cytokines and inhibition of anti-inflammatory cytokines., Conclusions: In this study, we concluded that WISP1 contributed to lung injuries following hepatic IRI through TLR4 pathway.