Background and purpose
High blood pressure (BP) at presentation is associated with poor outcomes in acute ischaemic stroke, but serial BP measurements may better delineate the clinical implications ...of BP. The aim was to investigate the association between various BP parameters and functional outcomes in acute ischaemic stroke patients treated with endovascular thrombectomy (EVT).
Methods
This study reports a retrospective analysis of a prospective registry of a comprehensive stroke centre. Patients treated with EVT due to large vessel occlusion in the anterior circulation were enrolled. BP was measured hourly during the first 24 h after admission. Associations of various BP parameters, including BP variability, with functional outcomes at 3 months, including good outcomes (modified Rankin Scale score of 0–2), were analysed.
Results
Of the 378 enrolled patients (mean age 70 ± 11 years, male 54.2%), 313 (82.8%) achieved successful reperfusion after EVT, and 149 (39.4%) had good outcomes at 3 months. Higher mean systolic BP each 10 mmHg increase, odds ratio 0.82 (0.69–0.97) and higher systolic successive variation (SV) each 10% increase, odds ratio 0.37 (0.18–0.76) were associated with a reduced likelihood of achieving good outcomes. In addition, reperfusion status after EVT moderated the influence of higher systolic SV on good outcomes (Pint = 0.05).
Conclusion
The results showed that a higher mean systolic BP and systolic SV during the first 24 h of EVT reduced the likelihood of good outcomes at 3 months. The effects of these parameters on outcomes are more substantial amongst patients with successful reperfusion after EVT, suggesting that different BP control strategies should be employed according to reperfusion status.
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Abstract Background Programmed death-ligand 1 (PD-L1) expression has been suggested as a potential predictive biomarker of response to anti-PD-1/PD-L1 therapy. In this study, we investigated whether ...the expression of PD-L1 in tumour cells is affected by neoadjuvant concurrent chemoradiotherapy (CCRT) or chemotherapy in oesophageal squamous cell carcinoma. Patients and methods Between 2004 and 2014, we collected the medical records of locally advanced oesophageal cancer patients consecutively diagnosed and treated with neoadjuvant CCRT or chemotherapy, followed by curative resection. PD-L1 expression in acquired tissue specimens was evaluated by immunohistochemistry using the H-score. The changes in PD-L1 expression between paired samples were evaluated and we also analysed PD-L1 expression in surgical tumour specimens to evaluate its prognostic role. Results Twenty-eight paired tumour tissues that were acquired before and after neoadjuvant therapy were available: 19 patients with CCRT and 9 with chemotherapy before complete oesophagectomy. The PD-L1 H-score increased significantly from baseline tumour tissues to surgical tumour tissues after neoadjuvant CCRT ( P = 0.007, median H-score from 28 to 52), whereas it decreased significantly after neoadjuvant chemotherapy ( P = 0.048, median H-score from 53 to 22). In a total of 73 patients, including 45 additional cases for the prognosis analysis, patients with higher PD-L1 H-scores (≥20) had poorer overall survival (median 16.7 versus 32.9 months, P = 0.02) than those with lower H-scores (<20). Conclusions PD-L1 expression in tumour cells increased in oesophageal cancer patients who received neoadjuvant CCRT. Further studies with more cases are necessary to validate these findings.
Objectives: To examine the prevalence of sarcopenia and sarcopenic obesity (SO) as defined by different indices, including appendicular skeletal muscle mass (ASM)/height2, skeletal muscle mass index ...(SMI) and residuals for Korean adults, and to explore the association between SO and metabolic syndrome. Methods: Our study sample included 526 participants (328 women, 198 men) for whom complete data on body composition were collected using available dual X-ray absorptiometry. Modified National Cholesterol Education Program Adult Treatment Panel III criteria were used to identify the individuals with metabolic syndrome. Results: The prevalence of sarcopenia and SO is higher in older adults. Using two s.d. of ASM/height2 below reference values from young, healthy adults as a definition of sarcopenia, the prevalence of sarcopenia and SO was 6.3% and 1.3% in older (60 years) men and 4.1% and 0.8% in older women, respectively. The prevalence of sarcopenia using the residuals method was 15.4% in older men and 22.3% in older women. In addition, using two s.d. of SMI, the prevalence of sarcopenia and SO was 5.1% and 5.1%, respectively, in older men and 14.2% and 12.5%, respectively, in older women. Among women, SO subjects defined by the SMI had three times the risk of metabolic syndrome (odds ratios (OR)=3.24, 95% confidence interval (CI)=1.21-8.66) and non-sarcopenic obese subjects had approximately twice the risk of metabolic syndrome (OR=2.17, 95% CI=1.22-3.88) compared with normal subjects. Similar trends were observed in men. Conclusion: The prevalence and cutoff values of sarcopenia and SO in the Korean population were evaluated using different methods. Among the different indices of sarcopenia and SO, SO only defined using the SMI was associated with the risk of metabolic syndrome. As the Korean population gets older and more obese, the problematics of SO need to be elucidate.
Mitochondria in lung disease Cloonan, Suzanne M; Choi, Augustine M K
The Journal of clinical investigation,
2016-Mar-01, 2016-3-1, 20160301, Letnik:
126, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Mitochondria are a distinguishing feature of eukaryotic cells. Best known for their critical function in energy production via oxidative phosphorylation (OXPHOS), mitochondria are essential for ...nutrient and oxygen sensing and for the regulation of critical cellular processes, including cell death and inflammation. Such diverse functional roles for organelles that were once thought to be simple may be attributed to their distinct heteroplasmic genome, exclusive maternal lineage of inheritance, and ability to generate signals to communicate with other cellular organelles. Mitochondria are now thought of as one of the cell's most sophisticated and dynamic responsive sensing systems. Specific signatures of mitochondrial dysfunction that are associated with disease pathogenesis and/or progression are becoming increasingly important. In particular, the centrality of mitochondria in the pathological processes and clinical phenotypes associated with a range of lung diseases is emerging. Understanding the molecular mechanisms regulating the mitochondrial processes of lung cells will help to better define phenotypes and clinical manifestations associated with respiratory disease and to identify potential diagnostic and therapeutic targets.
Epithelial cell death is a major contributor to fibrogenesis in the lung. In this study, we sought to determine the function of mitochondria and their clearance (mitophagy) in alveolar epithelial ...cell death and fibrosis.
We studied markers of mitochondrial injury and the mitophagy marker, PTEN-induced putative kinase 1 (PINK1), in IPF lung tissues by Western blotting, transmission electron microscopy (TEM), and immunofluorescence. In vitro experiments were carried out in lung epithelial cells stimulated with transforming growth factor-β1 (TGF-β1). Changes in cell function were measured by Western blotting, flow cytometry and immunofluorescence. In vivo experiments were performed using the murine bleomycin model of lung fibrosis.
Evaluation of IPF lung tissue demonstrated increased PINK1 expression by Western blotting and immunofluorescence and increased numbers of damaged mitochondria by TEM. In lung epithelial cells, TGF-β1 induced mitochondrial depolarization, mitochondrial ROS, and PINK1 expression; all were abrogated by mitochondrial ROS scavenging. Finally, Pink1-/- mice were more susceptible than control mice to bleomycin induced lung fibrosis.
TGF-β1 induces lung epithelial cell mitochondrial ROS and depolarization and stabilizes the key mitophagy initiating protein, PINK1. PINK1 ameliorates epithelial cell death and may be necessary to limit fibrogenesis.
Accumulating evidence illustrates a fundamental role for mitochondria in lung alveolar type 2 epithelial cell (AEC2) dysfunction in the pathogenesis of idiopathic pulmonary fibrosis. However, the ...role of mitochondrial fusion in AEC2 function and lung fibrosis development remains unknown. Here we report that the absence of the mitochondrial fusion proteins mitofusin1 (MFN1) and mitofusin2 (MFN2) in murine AEC2 cells leads to morbidity and mortality associated with spontaneous lung fibrosis. We uncover a crucial role for MFN1 and MFN2 in the production of surfactant lipids with MFN1 and MFN2 regulating the synthesis of phospholipids and cholesterol in AEC2 cells. Loss of MFN1, MFN2 or inhibiting lipid synthesis via fatty acid synthase deficiency in AEC2 cells exacerbates bleomycin-induced lung fibrosis. We propose a tenet that mitochondrial fusion and lipid metabolism are tightly linked to regulate AEC2 cell injury and subsequent fibrotic remodeling in the lung.
Increasing evidence has shown that Coronavirus disease 19 (COVID-19) severity is driven by a dysregulated immunologic response. We aimed to assess the differences in inflammatory cytokines in ...COVID-19 patients compared to contemporaneously hospitalized controls and then analyze the relationship between these cytokines and the development of Acute Respiratory Distress Syndrome (ARDS), Acute Kidney Injury (AKI) and mortality. In this cohort study of hospitalized patients, done between March third, 2020 and April first, 2020 at a quaternary referral center in New York City we included adult hospitalized patients with COVID-19 and negative controls. Serum specimens were obtained on the first, second, and third hospital day and cytokines were measured by Luminex. Autopsies of nine cohort patients were examined. We identified 90 COVID-19 patients and 51 controls. Analysis of 48 inflammatory cytokines revealed upregulation of macrophage induced chemokines, T-cell related interleukines and stromal cell producing cytokines in COVID-19 patients compared to the controls. Moreover, distinctive cytokine signatures predicted the development of ARDS, AKI and mortality in COVID-19 patients. Specifically, macrophage-associated cytokines predicted ARDS, T cell immunity related cytokines predicted AKI and mortality was associated with cytokines of activated immune pathways, of which IL-13 was universally correlated with ARDS, AKI and mortality. Histopathological examination of the autopsies showed diffuse alveolar damage with significant mononuclear inflammatory cell infiltration. Additionally, the kidneys demonstrated glomerular sclerosis, tubulointerstitial lymphocyte infiltration and cortical and medullary atrophy. These patterns of cytokine expression offer insight into the pathogenesis of COVID-19 disease, its severity, and subsequent lung and kidney injury suggesting more targeted treatment strategies.
Autophagy is a dynamic process by which cytosolic material, including organelles, proteins, and pathogens, are sequestered into membrane vesicles called autophagosomes, and then delivered to the ...lysosome for degradation. By recycling cellular components, this process provides a mechanism for adaptation to starvation. The regulation of autophagy by nutrient signals involves a complex network of proteins that include mammalian target of rapamycin, the class III phosphatidylinositol-3 kinase/Beclin 1 complex, and two ubiquitin-like conjugation systems. Additionally, autophagy, which can be induced by multiple forms of chemical and physical stress, including endoplasmic reticulum stress, and hypoxia, plays an integral role in the mammalian stress response. Recent studies indicate that, in addition to bulk assimilation of cytosol, autophagy may proceed through selective pathways that target distinct cargoes to autophagosomes. The principle homeostatic functions of autophagy include the selective clearance of aggregated protein to preserve proteostasis, and the selective removal of dysfunctional mitochondria (mitophagy). Additionally, autophagy plays a central role in innate and adaptive immunity, with diverse functions such as regulation of inflammatory responses, antigen presentation, and pathogen clearance. Autophagy can preserve cellular function in a wide variety of tissue injury and disease states, however, maladaptive or pro-pathogenic outcomes have also been described. Among the many diseases where autophagy may play a role include proteopathies which involve aberrant accumulation of proteins (e.g., neurodegenerative disorders), infectious diseases, and metabolic disorders such as diabetes and metabolic syndrome. Targeting the autophagy pathway and its regulatory components may eventually lead to the development of therapeutics.
Department of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine, The University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; and Department of Molecular Genetics, ...Alton Ochsner Medical Foundation, Louisiana State University Medical Center, New Orleans, Louisiana
The heme oxygenases, which consist of constitutive and inducible isozymes (HO-1, HO-2), catalyze the rate-limiting step in the metabolic conversion of heme to the bile pigments (i.e., biliverdin and bilirubin) and thus constitute a major intracellular source of iron and carbon monoxide (CO). In recent years, endogenously produced CO has been shown to possess intriguing signaling properties affecting numerous critical cellular functions including but not limited to inflammation, cellular proliferation, and apoptotic cell death. The era of gaseous molecules in biomedical research and human diseases initiated with the discovery that the endothelial cell-derived relaxing factor was identical to the gaseous molecule nitric oxide (NO). The discovery that endogenously produced gaseous molecules such as NO and now CO can impart potent physiological and biological effector functions truly represented a paradigm shift and unraveled new avenues of intense investigations. This review covers the molecular and biochemical characterization of HOs, with a discussion on the mechanisms of signal transduction and gene regulation that mediate the induction of HO-1 by environmental stress. Furthermore, the current understanding of the functional significance of HO shall be discussed from the perspective of each of the metabolic by-products, with a special emphasis on CO. Finally, this presentation aspires to lay a foundation for potential future clinical applications of these systems.
Chronic obstructive pulmonary disease (COPD) is a progressive lung disease characterized by abnormal cellular responses to cigarette smoke, resulting in tissue destruction and airflow limitation. ...Autophagy is a degradative process involving lysosomal turnover of cellular components, though its role in human diseases remains unclear.
Increased autophagy was observed in lung tissue from COPD patients, as indicated by electron microscopic analysis, as well as by increased activation of autophagic proteins (microtubule-associated protein-1 light chain-3B, LC3B, Atg4, Atg5/12, Atg7). Cigarette smoke extract (CSE) is an established model for studying the effects of cigarette smoke exposure in vitro. In human pulmonary epithelial cells, exposure to CSE or histone deacetylase (HDAC) inhibitor rapidly induced autophagy. CSE decreased HDAC activity, resulting in increased binding of early growth response-1 (Egr-1) and E2F factors to the autophagy gene LC3B promoter, and increased LC3B expression. Knockdown of E2F-4 or Egr-1 inhibited CSE-induced LC3B expression. Knockdown of Egr-1 also inhibited the expression of Atg4B, a critical factor for LC3B conversion. Inhibition of autophagy by LC3B-knockdown protected epithelial cells from CSE-induced apoptosis. Egr-1(-/-) mice, which displayed basal airspace enlargement, resisted cigarette-smoke induced autophagy, apoptosis, and emphysema.
We demonstrate a critical role for Egr-1 in promoting autophagy and apoptosis in response to cigarette smoke exposure in vitro and in vivo. The induction of autophagy at early stages of COPD progression suggests novel therapeutic targets for the treatment of cigarette smoke induced lung injury.
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