- 作者列表："Becattini C","Agnelli G
:All patients with venous thromboembolism (VTE) should receive anticoagulant treatment in the absence of absolute contraindications. Initial anticoagulant treatment is crucial for reducing mortality, preventing early recurrences, and improving long-term outcome. Treatment and patient disposition should be tailored to the severity of clinical presentation, to comorbidities, and to the potential to receive appropriate care in the outpatient setting. Direct oral anticoagulants (DOACs) used in fixed doses without laboratory monitoring are the agents of choice for the treatment of acute VTE in the majority of patients. In comparison with conventional anticoagulation (parenteral anticoagulants followed by vitamin K antagonists), these agents showed improved safety (relative risk [RR] of major bleeding, 0.61; 95% confidence interval [CI], 0.45-0.83) with a similar risk of recurrence (RR, 0.90; 95% CI, 0.77-1.06). Vitamin K antagonists or low molecular weight heparins are still alternatives to DOACs for the treatment of VTE in specific patient categories such as those with severe renal failure or antiphospholipid syndrome, or cancer, respectively. In addition to therapeutic anticoagulation, probably less than 10% of patients require reperfusion by thrombolysis or interventional treatments; those patients are hemodynamically unstable with acute pulmonary embolism, and a minority of them have proximal limb-threatening deep vein thrombosis (DVT). The choice of treatment should be driven by the combination of evidence from clinical trials and by local expertise. The majority of patients with acute DVT and a proportion of selected hemodynamically stable patients with acute pulmonary embolism can be safely managed as outpatients.
: 所有静脉血栓栓塞 (VTE) 患者应在没有绝对禁忌症的情况下接受抗凝治疗。初始抗凝治疗对于降低死亡率、预防早期复发和改善长期预后至关重要。治疗和患者处置应根据临床表现的严重程度、合并症以及在门诊接受适当护理的可能性进行调整。在没有实验室监测的情况下以固定剂量使用的直接口服抗凝剂 (DOACs) 是大多数患者治疗急性 VTE 的首选药物。与常规抗凝 (胃肠外抗凝药，然后是维生素k 拮抗剂) 相比，这些药物显示安全性提高 (大出血的相对风险 [RR]，0.61; 95% 置信区间 [CI], 0.45-0.83)，复发风险相似 (RR，0.90; 95% CI，0.77-1.06)。维生素 K 拮抗剂或低分子量肝素仍然是 DOACs 的替代药物，分别用于治疗特定患者类别的 VTE，如严重肾衰竭或抗磷脂综合征或癌症。除了治疗性抗凝之外，可能不到 10% 的患者需要溶栓或介入治疗的再灌注; 这些患者血流动力学不稳定，伴有急性肺栓塞, 其中少数患者有近端肢体威胁的深静脉血栓形成 (DVT)。治疗的选择应该由来自临床试验的证据和当地专业知识的结合来驱动。大多数急性 DVT 患者和部分选定的血流动力学稳定的急性肺栓塞患者可以作为门诊患者安全管理。
METHODS:BACKGROUND AND PURPOSE:A critical role for sphingosine kinase/sphingosine-1-phosphate (S1P) pathway in the control of airway function has been demonstrated in respiratory diseases. Here, we address S1P contribution in a mouse model of mild chronic obstructive pulmonary disease (COPD). EXPERIMENTAL APPROACH:C57BL/6J mice have been exposed to room air or cigarette smoke up to 11 months and killed at different time points. Functional and molecular studies have been performed. KEY RESULTS:Cigarette smoke caused emphysematous changes throughout the lung parenchyma coupled to a progressive collagen deposition in both peribronchiolar and peribronchial areas. The high and low airways showed an increased reactivity to cholinergic stimulation and α-smooth muscle actin overexpression. Similarly, an increase in airway reactivity and lung resistances following S1P challenge occurred in smoking mice. A high expression of S1P, Sph-K2 , and S1P receptors (S1P2 and S1P3 ) has been detected in the lung of smoking mice. Sphingosine kinases inhibition reversed the increased cholinergic response in airways of smoking mice. CONCLUSIONS AND IMPLICATIONS:S1P signalling up-regulation follows the disease progression in smoking mice and is involved in the development of airway hyperresponsiveness. Our study defines a therapeutic potential for S1P inhibitors in management of airways hyperresponsiveness associated to emphysema in smokers with both asthma and COPD.
METHODS::The interim results from this 90-day multi-dose, inhalation toxicology study with life-time post-exposure observation has shown an important fundamental difference in persistence and pathological response in the lung between brake dust derived from brake-pads manufactured with chrysotile, TiO2 or chrysotile alone in comparison to the amphiboles, crocidolite and amosite asbestos. In the brake dust exposure groups no significant pathological response was observed at any time. Slight macrophage accumulation of particles was noted. Wagner-scores, were from 1 to 2 (1 = air-control group) and were similar to the TiO2 group. Chrysotile being biodegradable, shows a weakening of its matrix and breaking into short fibers & particles that can be cleared by alveolar macrophages and continued dissolution. In the chrysotile exposure groups, particle laden macrophage accumulation was noted leading to a slight interstitial inflammatory response (Wagner-score 1-3). There was no peribronchiolar inflammation and occasional very slight interstitial fibrosis. The histopathology and the confocal analyses clearly differentiate the pathological response from amphibole asbestos, crocidolite and amosite, compared to that from the brake dust and chrysotile. Both crocidolite and amosite induced persistent inflammation, microgranulomas, and fibrosis (Wagner-scores 4), which persisted through the post exposure period. The confocal microscopy of the lung and snap-frozen chestwalls quantified the extensive inflammatory response and collagen development in the lung and on the visceral and parietal surfaces. The interim results reported here, provide a clear basis for differentiating the effects from brake dust exposure from those following amphibole asbestos exposure. The subsequent results through life-time post-exposure will follow.
METHODS::The respiratory tract is lined by a pseudo-stratified epithelium from the nose to terminal bronchioles. This first line of defense of the lung against external stress includes five main cell types: basal, suprabasal, club, goblet and multiciliated cells, as well as rare cells such as ionocytes, neuroendocrine and tuft/brush cells. At homeostasis, this epithelium self-renews at low rate but is able of fast regeneration upon damage. Airway epithelial cell lineages during regeneration have been investigated in the mouse by genetic labeling, mainly after injuring the epithelium with noxious agents. From these approaches, basal cells have been identified as progenitors of club, goblet and multiciliated cells, but also of ionocytes and neuroendocrine cells. Single-cell RNA sequencing, coupled to lineage inference algorithms, has independently allowed the establishment of comprehensive pictures of cell lineage relationships in both mouse and human. In line with genetic tracing experiments in mouse trachea, studies using single-cell RNA sequencing (RNAseq) have shown that basal cells first differentiate into club cells, which in turn mature into goblet cells or differentiate into multiciliated cells. In the human airway epithelium, single-cell RNAseq has identified novel intermediate populations such as deuterosomal cells, 'hybrid' mucous-multiciliated cells and progenitors of rare cells. Novel differentiation dynamics, such as a transition from goblet to multiciliated cells have also been discovered. The future of cell lineage relationships in the respiratory tract now resides in the combination of genetic labeling approaches with single-cell RNAseq to establish, in a definitive manner, the hallmarks of cellular lineages in normal and pathological situations.