重症监护病房长期机械通气患者撤机困难的原因及死亡影响因素分析

目的:探讨重症监护病房(ICU)长期机械通气患者撤机困难的原因及撤机死亡的影响因素。方法:对2015年6月至2018年10月我院收治的80例长期机械通气患者的临床资料进行回顾性分析,按照患者撤机结果分为撤机成功组52例和撤机困难组28例,根据患者存活情况分为存活组59例和死亡组21例。比较各组临床资料,分析撤机困难的原因及撤机死亡的影响因素。结果:撤机困难组年龄、心功能不全比例、多器官功能障碍(MODS)比例、呼吸机相关肺炎(VAP)比例、肝功能不全比例、肾功能不全比例、血尿素氮显著高于撤机成功组,机械通气时间、气管切开时间显著长于撤机成功组,血清白蛋白显著低于撤机成功组(P0.05)。死亡组年龄、合并糖尿病比例、心功能不全比例、MODS比例、VAP比例、肝功能不全比例、肾功能不全比例、血尿素氮显著高于存活组,机械通气时间、气管切开时间显著长于存活组,血清白蛋白显著低于存活组(P0.05)。多因素Logistic回归分析显示:年龄、合并糖尿病、MODS、VAP、机械通气时间、气管切开时间、血清白蛋白是ICU长期机械通气患者撤机死亡的影响因素(P0.05)。结论:患者治疗期间发生脏器功能不全或器官功能衰竭、机械通气时间较长、气管切开时间较长、营养状态较差是长期机械通气患者撤机困难的主要原因,年龄、合并糖尿病、MODS、VAP、机械通气时间、气管切开时间、血清白蛋白是ICU长期机械通气患者撤机死亡的影响因素。     

Targeting TRAIL

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), also known as Apo2L, has been investigated in the past decade for its promising anticancer activity due to its ability to selectively induce apoptosis in tumoral cells by binding to TRAIL receptors (TRAIL-R). Macromolecules such as agonistic monoclonal antibodies and recombinant TRAIL have not proven efficacious in clinical studies, therefore several small molecules acting as TRAIL-R agonists are emerging in the scientific literature. In this work we focus on systemizing these drug molecules described in the past years, in order to better understand and predict the requirements for a novel anti-tumoral therapy based on the TRAIL-R-induced apoptotic mechanism.     

Immune checkpoint blockade and its combination therapy with small-molecule inhibitors for cancer treatment

Initially understood for its physiological maintenance of self-tolerance, the immune checkpoint molecule has recently been recognized as a promising anti-cancer target. There has been considerable interest in the biology and the action mechanism of the immune checkpoint therapy, and their incorporation with other therapeutic regimens. Recently the small-molecule inhibitor (SMI) has been identified as an attractive combination partner for immune checkpoint inhibitors (ICIs) and is becoming a novel direction for the field of combination drug design. In this review, we provide a systematic discussion of the biology and function of major immune checkpoint molecules, and their interactions with corresponding targeting agents. With both preclinical studies and clinical trials, we especially highlight the ICI + SMI combination, with its recent advances as well as its application challenges.     

Characteristics of the killing mechanism of human natural killer cells against hepatocellular carcinoma cell lines HepG2 and Hep3B

Purpose Unlike normal hepatocytes, most hepatocellular carcinomas (HCCs) are quite resistant to death receptor-mediated apoptosis when the cell surface death receptor is cross linked with either agonistic antibodies or soluble death ligand proteins in vitro. The resistance might play an essential role in the escape from the host immune surveillance; however, it has not been directly demonstrated that HCCs are actually resistant to natural killer (NK) cell-mediated death. Therefore, this study investigated the molecular mechanism of NK cell-mediated cytotoxicity against the HCCs, HepG2, and Hep3B, using two distinct cytotoxic assays: a 4-h ⁵¹Cr-release assay and a 2-h [³H] thymidine release assay which selectively measures the extent of necrotic and apoptotic target cell death, respectively.Methods Most of the target cells exhibited marked morphologic changes when they were co-incubated with the NK cells, and the NK cytotoxicity against these HCCs was comparable to that against K562, a NK-sensitive leukemia cell line, when the cytotoxicity was assessed by a 4-h ⁵¹Cr release assay.Results The NK cells also induced significant apoptotic cell death in the Hep3B targets, but not in the HepG2 targets, when the cytotoxicity was assessed by a 2-h [³H]-thymidine release assay. In agreement with these results, procaspase-3 was activated in the Hep3B targets, but not in the HepG2 targets. Interestingly, mildly fixed NK cells had no detectable activity in the 4-h ⁵¹Cr release assay against both HepG2 and Hep3B targets, while they were similarly effective as the untreated NK cells in the 2-h [³H]-thymidine release assay, suggesting that the level of apoptotic cell death of the Hep3B targets is granule independent and might be primarily mediated by the death ligands of the NK cells.Conclusion This study found that a tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)/TRAIL receptor interaction is involved in the NK cell-mediated apoptotic death of the Hep3B targets, but a Fas/Fas ligand (FasL) interaction is not.     

Characterization of chicken TNFR superfamily decoy receptors,DcR3 and osteoprotegerin

Tumor necrosis factor (TNF) family ligands bind to death domain-containing TNF receptors (death receptors), which can subsequently activate intracellular signaling pathways to initiate caspase activity and apoptotic cell death. Decoy receptors, without intracellular death domains, have been reported to prevent cytotoxic effects by binding to and sequestering such ligands, or by interfering with death receptor trimerization. The chicken death receptors, Fas, TNFR1, DR6, and TVB, are constitutively expressed in a relatively wide variety of hen tissues. In this study, two chicken receptors with sequence homology to the mammalian decoys, DcR3 and osteoprotegerin, were identified and their pattern of expression was characterized. Unlike the previously identified chicken death receptors, the newly characterized decoy receptors show comparatively limited expression among tissues, suggesting a tissue-specific function. Finally, characterization of these chicken receptors further contributes to understanding the evolutionary divergence of TNFR superfamily members among vertebrate species.     

Role of astrocytes in trimethyltin neurotoxicity

Although the neurotoxicity of trimethyltin (TMT) is well known, mechanisms are still not clear. Glia have been proposed to mediate the toxic action of TMT on nerve cells. Accordingly, the effects of TMT were tested in primary neuronal cultures from rat cerebellum and compared to effects in astrocytes and mixed cultures. Neuronal damage observed following TMT exposure was less in the presence of astrocytes and astrocytes alone were resistant to TMT. Thus, astrocytes have a protective effect against TMT-induced neurotoxicity. TMT caused an oxidative stress in granule cell cultures involving a variety of oxidative species (O2)*-, H2O2, NO), but astrocytes were less sensitive to TMT-induced oxidative species generation. Antioxidants, glutathione and 7-nitroindazole attenuated neuronal cell death induced by TMT. It appears that oxidative stress mediates a large part of the destructive action of TMT in neuronal cultures. The presence of astrocytes appears to modulate TMT-induced oxidative stress so that TMT causes only a small increase in lipid peroxidation in mouse brain after systemic administration. Thus, TMT induces a pronounced oxidative stress in cultured neurons, but when astrocytes are present, oxidative species play a lesser role in the neurotoxic action of TMT.     

Relation between the outer cover of the egg case of Argiope aurantia (Araneae: Araneidae) and the emergence of its spiderlings

To emerge from the egg case, Argiope aurantia spiderlings must penetrate a tightly woven outer cover composed primarily of large-diameter cylindrical gland fibers and small-diameter fibers, likely of aciniform gland origin. They accomplish this using enzymatic digestion and mastication to form a communal hole in the outer cover. The involvement of proteolytic enzymes in this process was demonstrated by zymography of spiderling homogenates and washes made from the edges of holes. The specific source(s) of the proteases is unknown, but histological examination of spiderling sections indicates that the digestive tract, venom glands, and gnathocoxal glands are all functioning at the time of emergence from the egg case. Observations on edges of holes indicate that spiderlings are able to solubilize the small-diameter fibers completely, but cylindrical gland fibers only partially. In the outer cover, cylindrical fibers are composed of numerous fibrils embedded within a matrix. Spiderlings appear to be unable to solubilize the fibrils, but digestion of the matrix allows the spiderlings to push the fibrils aside to create the opening.     

Paleodemographic comparison of a catastrophic and an attritional death assemblage

The aim of this contribution is to examine the effect of an indiscriminate epidemic on a population to assess whether or not a catastrophic event can be identified from examination of paleodemographic data. Using paleodemographic techniques, the death assemblage from the Royal Mint site, London, a Black Death cemetery dated 1349 AD, is compared with that from St. Helen-on-the-Walls, York, which dates from the twelfth to the sixteenth centuries AD. The Royal Mint site represents a catastrophic cemetery, while that of St. Helen-on-the-Walls is of an attritional type. Certain features of the paleodemographic profile of the plague victims suggest that the population had been affected by factors other than natural wastage. Three factors are proposed which may define an indiscriminate catastrophic event in preindustrial populations.