Plasminogen Degradation by Neutrophil Elastase in Pleural Infection, Not High Plasminogen Activator Inhibitor 1, Is the Cause of Intrapleural Lytic Failure.

BACKGROUND: Complex pleural space infections often require treatment with multiple doses of intrapleural tissue plasminogen activator (tPA) and deoxyribonuclease, with treatment failure frequently necessitating surgery. Pleural infections are rich in neutrophils, and neutrophil elastase degrades plasminogen, the target substrate of tPA, that is required to generate fibrinolysis. We hypothesized that pleural fluid from patients with pleural space infection would show high elastase activity, evidence of inflammatory plasminogen degradation, and low fibrinolytic potential in response to tPA that could be rescued with plasminogen supplementation. RESEARCH QUESTION: Does neutrophil elastase degradation of plasminogen contribute to intrapleural fibrinolytic failure? STUDY DESIGN AND METHODS: We obtained infected pleural fluid and circulating plasma from hospitalized adults (n = 10) with institutional review board approval from a randomized trial evaluating intrapleural fibrinolytics vs surgery for initial management of pleural space infection. Samples were collected before the intervention and on days 1, 2, and 3 after the intervention. Activity assays, enzyme-linked immunosorbent assays, and Western blot analysis were performed, and turbidimetric measurements of fibrinolysis were obtained from pleural fluid with and without exogenous plasminogen supplementation. Results are reported as median (interquartile range) or number (percentage) as appropriate, with an α value of 0.05. RESULTS: Pleural fluid elastase activity was more than fourfold higher (P = .02) and plasminogen antigen levels were more than threefold lower (P = .04) than their corresponding plasma values. Pleural fluid Western blot analysis demonstrated abundant plasminogen degradation fragments consistent with elastase degradation patterns. We found that plasminogen activator inhibitor 1 (PAI-1), the native tPA inhibitor, showed high antigen levels before the intervention, but the overwhelming majority of this PAI-1 (82%) was not active (P = .003), and all PAI-1 activity was lost by day 2 after the intervention in patients receiving intrapleural tPA and deoxyribonuclease. Finally, using turbidity clot lysis assays, we found that the pleural fluid of 9 of 10 patients was unable to generate a significant fibrinolytic response when challenged with tPA and that plasminogen supplementation rescued fibrinolysis in all patients. INTERPRETATION: Inflammatory plasminogen deficiency, not high PAI-1 activity, is a significant contributor to intrapleural fibrinolytic failure. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT03583931; URL: www. CLINICALTRIALS: gov.

Effectiveness of acupuncture in the governor vessel and Yangming meridian for the treatment of acute ischemic stroke: A systematic review and network meta-analysis.

BACKGROUND: Acupuncture of the governor vessel and Yangming meridian are widely used in the treatment of acute ischemic stroke (AIS). However, the optimal meridian for acupuncture in the treatment of AIS remains uncertain. PURPOSE: This network meta-analysis study aimed to compare the clinical effectiveness of acupuncture at governor vessel and Yangming meridian in the treatment of AIS. METHODS: All relevant studies published in CNKI, WANFANG, VIP, Sinomed, Cochrane Library, Web of Science, Pub Med, and Embase before January 13, 2024 were systematically retrieved. The two researchers independently screened the studies and extracted the data. Cochrane ROB tool was used to evaluate the quality of the studies, and Stata 14.0 software was used to conduct a network meta-analysis of neurological deficit score, activities of daily living (ADL), clinical effective rate and Fugl-meyer motor function evaluation (FMA). RESULTS: A total of 401 studies were obtained, and 17 studies met the inclusion criteria. The surface under the cumulative ranking curve (SUCRA) values of the four outcome indexes were all ranked by "Governor vessel acupuncture + Conventional neurology treatment(GVAc+CT) > Yangming meridian acupuncture + Conventional neurology treatment(YMAc+CT) > Conventional neurology treatment (CT)". Compared to YMAc+CT and CT, GVAc+CT had the best effect in reducing the degree of neurological deficit score (SMD = -0.72, 95%CI = [-1.22,-0.21] and SMD = -1.07,95%CI = [-1.45,-0.69], respectively) and promoting the recovery of ADL((SMD = 0.59,95%CI = [0.31,0.88] and SMD = 0.96,95%CI = [0.70,1.21], respectively). Compared to CT, GVAc+CT also had a better clinical effective rate in the treatment of AIS (RR = 1.14,95%CI = [1.04,1.25]). CONCLUSIONS: Governor vessel acupuncture combined with conventional neurology treatment has the best effect in reducing the degree of neurological deficit score and promoting the recovery of ADL in AIS patientscompared to YMAc+CT and CT. Governor Vessel acupuncture is the most preferable acupoint scheme for clinical acupuncture treatment of AIS.

Efficacy of ferulic acid in the treatment of acute ischemic stroke injury in rats: a systematic review and meta-analysis.

Background: Intravenous thrombolysis is commonly used in the treatment of acute ischemic stroke damage. The existing thrombolytic drugs still suffer significant shortcomings, including a limited fibrin specificity and bleeding complications. Ferulic acid can directly bind the key thrombus enzymes and target to blood clots, suggesting its thrombolytic potency that may be beneficial with thrombolytic potency for the treatment of acute ischemic stroke damage. Objective: The purpose of this systematic review and meta-analysis was to evaluate the efficacy of ferulic acid in the treatment of acute ischemic stroke injury in rats and its potential mechanism of action. Materials and methods: We conducted a literature search in six databases, including CNKI, up to July 2023. Results: Sixteen trials were included in the meta-analysis, which demonstrated that ferulic acid significantly reduced infarct size, neurological deficit score, apoptosis index, cleaved caspase-3, and cytochrome C levels (all p < 0.05). In addition, ferulic acid significantly increased the levels of phosphorylated Akt, mitochondrial Bcl-xL/Bax, phosphorylated astrocyte PEA15, hippocampal calcium binding protein, and mitochondrial Bcl-2/Bax ratio (all p < 0.05). Conclusion: This study demonstrates that ferulic acid protects against acute ischemic stroke injury in rats by inhibiting ischemia-induced excitotoxicity, inflammatory response, and apoptosis.

Bifunctional alginate/chitosan stabilized perfluorohexane nanodroplets as smart vehicles for ultrasound and pH responsive delivery of anticancer agents.

The combination of ultrasound and chemotherapy has been proposed as a promising strategy to achieve a better anticancer therapeutic efficacy. Here we present a facile strategy to construct novel bifunctional nanodroplets as smart vehicles for ultrasound and pH responsive delivery of anticancer agents. PFH is used as core and chitosan/alginate complexes are used as the stable shells of the nanodroplets. The effects of alginate/chitosan ratio, and the amount of surfactant as well as PFH on the size, size distribution, and encapsulation efficiency of nanodroplets are systematically investigated with the optimized formulation identified. The release of the encapsulated doxorubicin hydrochloride can be triggered by changing the pH value of the surrounding environment and the exposure to ultrasound. The nanodroplets also show strong ultrasound contrast via droplet-to-bubble transition as demonstrated by B-mode ultrasound imaging. The hemolytic activity and cytotoxicity are further studied, revealing the biocompatibility of the nanodroplets. The in vivo antitumor results demonstrate that the prepared droplets show excellent antitumor therapeutic efficacy and outstanding tumor-targeting ability. The proposed alginate/chitosan stabilized PFH nanodroplets represent an important advance in fabricating multifunctional therapeutic materials with great promises in the applications of combined antitumor therapies.

Could CT abdomen and PET/CT be helpful in early diagnosis of Whipple's disease? A case report.

Whipple's disease is a rare disease, which can be fatal if not treated. It is often diagnosed at a late stage because of the varied disease presentation and its rare incidence. Classic Whipple's disease presents with arthralgia, abdominal pain, diarrhea and weight loss. CT abdomen may show mesenteric lymphadenopathy with hypodense centers. These CT findings along with clinical presentation should prompt early diagnosis of Whipple's disease. We present a case of classic Whipple's disease with interesting CT abdomen and PET scan findings.

Cell sheet integrity and nanomechanical breakdown during programmed cell death.

Apoptosis is a critical physiological pathway required for the normal functioning, homeostasis, and development of many organisms. This process is highly regulated at the biochemical level and has been intensively studied. Recent evidence has demonstrated that apoptosis is also a controlled nanomechanical process which relies on feedback between biochemical signaling and the nanomechanical properties of the microenvironment. Deregulation of the nanomechanical breakdown of apoptotic cells results in the poorly timed release of cells and cell debris that leads to the pathogenesis of several inflammatory diseases. In this study, we investigate the nanomechanical consequences of early apoptosis in human fibroblasts grown as single cells and as cell monolayers. These fibroblasts are found within the body and are involved in many processes including wound healing and repair in which apoptosis plays a major role. We find that although the cells undergo massive morphological remodeling and nanomechanical breakdown, the extra-cellular matrix (ECM) acts to maintain monolayer integrity. Via strong interactions between fibronectin and F-actin (fibronexus junctions), the ECM maintains and reinforces cell monolayers during breakdown. This study sheds new insights on our understanding of apoptosis and how biological systems utilize multiple inter- and intra-cytoarchitectures to regulate nanomechanical breakdown.