醋柳愈酯的体内代谢及药代动力

本文用薄层扫描定量法研究了醋柳愈酯在大鼠体内的代射,并测定代谢物水杨酸(SLA)的血药浓度,所得药一时数据依一定程序进行曲线拟合,计算药代动力学参数。并直接观察在大鼠体内的组织分布和在尿、粪、胆汁中的排泄。以肌肉、肺最高,脾、血浆次之,肾、睾丸、心、肝、脑、脂肪均有分布。小部分SLA径肾排泄,粪及胆汁排出量极低。     

阿司匹林或华法林治疗对非瓣膜病持续性心房颤动患者凝血-纤溶指标影响及安全性

目的探讨阿司匹林(150 mg/d)、调整剂量华法林[国际标准化比值(INR) 1.5～2.5]治疗对中老年非瓣膜病持续性心房颤动(Af)患者凝血-纤溶功能的作用.方法106例非瓣膜病持续性Af患者随机给予阿司匹林(150mg/d)或调整剂量华法林治疗1年.于治疗前、治疗后6个月和12个月,采用免疫比浊法测定D-二聚体(D-Dimer)水平,采用酶联免疫吸附双抗体夹心法(ELISA法)测定组织型纤溶酶原激活物(t-PA)和纤溶酶原激活剂抑制物(PAI-1)水平,进行前后比较分析.对可能影响D-Dimer、t-PA和PAI-1变化的因素,包括年龄、性别、体质指数、血小板数、肌酐、尿酸、血糖、TC、TG、凝血-纤溶指标治疗前水平和抗凝药物等因素进行Pearson相关分析和多元线性回归分析.随访中观察有无血栓栓塞和出血并发症发生.结果①阿司匹林(150 mg/d)治疗12个月后PAI-1水平显著降低,与治疗前比较,差异有统计学意义[(77.92±12.99) ∶(84.86±18.97)μg/L],P＜0.05),但对D-Dimer、t-PA无影响.华法林治疗6个月、12个月后D-Dimer均显著降低[分别为(0.10±0.08)、(0.11±0.08)mg/L]与治疗前[( 0.17±0.09)mg/L]比较,均P＜0.05;治疗12个月后 PAI-1水平较治疗前亦显著降低[( 77.13±18.53)∶(87.58±19.94 )μg/L,P＜0.05],但对t-PA无影响.②Pearson相关分析发现,治疗前后D-Dimer、t-PA和PAI-1的变化幅度均与其各自治疗前水平呈正相关,D-Dimer的变化幅度还与体质指数呈正相关,PAI-1的变化幅度还与TG呈正相关.多元线性回归分析也发现,治疗前D-Dimer、t-PA和PAI-1的水平是影响药物治疗后各指标变化幅度的主要因素.③随访期间无血栓栓塞和严重出血并发症发生.结论阿司匹林(150 mg/d)或调整剂量华法林均能不同程度地改善非瓣膜病Af患者的高凝低纤溶状态,治疗是安全的.     

Vaccine effectiveness estimates from an early-season influenza A(H3N2) epidemic,including unique genetic diversity with reassortment,Canada, 2022/23

The Canadian Sentinel Practitioner Surveillance Network estimated vaccine effectiveness (VE) during the unusually early 2022/23 influenza A(H3N2) epidemic. Like vaccine, circulating viruses were clade 3C.2a1b.2a.2, but with genetic diversity affecting haemagglutinin positions 135 and 156, and reassortment such that H156 viruses acquired neuraminidase from clade 3C.2a1b.1a. Vaccine provided substantial protection with A(H3N2) VE of 54% (95% CI: 38 to 66) overall. VE was similar against H156 and vaccine-like S156 viruses, but with potential variation based on diversity at position 135.     

Ultrastructural analysis of different skeletal cell types in mucopolysaccharidosis dogs at the onset of postnatal growth

The mucopolysaccharidoses (MPS) are a family of lysosomal storage disorders characterized by deficient activity of enzymes that degrade glycosaminoglycans (GAGs). Abnormal development of the vertebrae and long bones is a hallmark of skeletal disease in several MPS subtypes; however, the underlying cellular mechanisms remain poorly understood. The objective of this study was to conduct an ultrastructural examination of how lysosomal storage differentially affects major skeletal cell types in MPS I and VII using naturally occurring canine disease models. We showed that both bone and cartilage cells from MPS I and VII dog vertebrae exhibit significantly elevated storage from early in postnatal life, with storage generally greater in MPS VII than MPS I. Storage was most striking for vertebral osteocytes, occupying more than forty percent of cell area. Secondary to storage, dilation of the rough endoplasmic reticulum (ER), a marker of ER stress, was observed most markedly in MPS I epiphyseal chondrocytes. Significantly elevated immunostaining of light chain 3B (LC3B) in MPS VII epiphyseal chondrocytes suggested impaired autophagy, while significantly elevated apoptotic cell death in both MPS I and VII chondrocytes was also evident. The results of this study provide insights into how lysosomal storage differentially effects major skeletal cell types in MPS I and VII, and suggests a potential relationship between storage, ER stress, autophagy, and cell death in the pathogenesis of MPS skeletal defects.     

Single-cell atlas of the immune microenvironment reveals macrophage reprogramming and the potential dual macrophage-targeted strategy in multiple myeloma

The tumour microenvironment (TME) plays a critical role in disease progression in multiple myeloma (MM). This study aimed to present an atlas of MM-TME in disease progression and explore TME-directed therapeutic strategies. We performed single-cell RNA sequencing (scRNAseq) in samples from different disease stages. We validated the findings by bulk RNAseq, flow cytometry (FCM) and in vitro and in vivo functional experiments. We delineated a compromised TME during disease progression, characterized by enrichment of exhausted NK cells and CD8⁺ T cells and reprogramming of macrophages (MPs). The reprogrammed tumour-associated MPs (TAMs) displayed a mixed phenotype showing both M1 and M2 features, with two TAM clusters exclusively present in the MM stage showing higher M2 scores. We validated the mixed M1/M2 phenotype in TAMs in a clinical cohort and verified phagocytic dysfunction in reprogrammed TAMs. Cellular interaction analysis identified two enriched ligand–receptor pairs between MPs and malignant plasma cells (PCs), including the SIRPA-CD47 pathway suppressing phagocytosis and the CD74–MIF (macrophage inhibitory factor) reshaping the phenotype of MPs. The expression of CD47 and MIF correlated with disease progression and adverse outcomes. We designed a dual-MP-targeted strategy by combining an anti-CD47 antibody and MIF inhibitor to activate phagocytosis and repolarize MP to a functional phenotype and proved its potent antitumour effect in vitro and in vivo. We drafted alterations in MM-TME during disease progression and unravelled TAM's reprogramming. The dual MP-targeted approach blocking both CD47 and MIF showed potent antitumour effects.     

新型冠状病毒感染疾病（COVID-19）病机恶变规律探讨及中医防治思路＊

新型冠状病毒感染疾病（corona virus disease 2019，COVID-19）已成为全球流行性疾病，中医药在防治中发挥了重要的作用，因此分析本病病机演变和恶变的发展规律，对于指导其及早干预和防止向重症进展具有重要意义。本文基于中医药理论，分析和明确了COVID-19属于寒疫和湿疫夹杂的混合疫，为外寒湿引动内湿伏邪所致；系统分析了中医病机演变的动态规律和病机恶变的驱动因素，提出了病机由传变-剧变-恶变-极变-转归动态发展规律，提出以寒湿疫疠直中三阴的六经辨证结合三焦辨证为主要辨证论治的思路，并归纳了中医辨证施药的思路和治疗禁忌，指出“截断病势”和“防止脏寒”疗法在治疗和预后中的关键地位。