Clinical significance of thrombocytopenia in patients with septic shock: An observational retrospective study

PurposeWhether thrombocytopenia in critically ill patients accounts for a bystander of severity or drives specific complications is unclear. We addressed the effect of thrombocytopenia on septic shock, with emphasis on intensive care unit (ICU)-acquired bleeding, infections and thrombotic complications.Materials and methodsA retrospective (2008–2019) single-center study of patients with septic shock. Thrombocytopenia was assessed over the first seven days and was defined as severe (nadir <50 G/L), mild (nadir 50–150 G/L) and relative (30% decrease with nadir >150 G/L). Outcomes were ICU mortality and ICU-acquired complications defined by severe bleeding, infections and thrombotic events during the ICU stay.ResultsThe study comprised 1024 patients. Severe, mild and relative thrombocytopenia occurred in 33%, 40% and 9% of patients. The in-ICU mortality rate was 27%, independently associated with severe thrombocytopenia. ICU-acquired infections, hemorrhagic and thrombotic complications occurred in 27.5%, 13.3% and 11.6% of patients, respectively. Patients with severe, mild or relative thrombocytopenia exhibited higher incidences of bleeding events (20.3%, 15.3% and 14.4% vs. 3.6% in non-thrombocytopenic, p < 0.001), infections (35.2%, 21.9% and 33.3% vs. 23.1% in non-thrombocytopenic, p < 0.001) and thrombotic events (14.6%, 10.8% and 17.8% vs. 7.8% in non-thrombocytopenic, p = 0.03). Only severe thrombocytopenia remained independently associated with increased risk of bleeding.ConclusionsSevere thrombocytopenia was independently associated with ICU mortality and increased risk of bleeding, but not with infectious and thrombotic events.     

淫羊藿总黄酮对干眼症雄兔泪腺中Bax和Bcl-2表达的作用研究

目的　观察淫羊藿总黄酮对干眼症雄兔泪腺中Bax和Bcl-2表达的作用。方法　随机将80只雄性健康新西兰大耳白兔分为A组（空白组）、B组（手术组）、C组（淫羊藿总黄酮组）、D组（雄激素组）,每组20只。A组以生理盐水进行灌胃,B、C、D三组建立干眼症模型后分别以生理盐水灌胃、淫羊藿总黄酮灌胃、丙酸睾酮肌肉注射进行干预。每组根据喂养时间不同又分为A1~D1组（喂养1个月）和A2~D2组（喂养2个月）,每组10只。A1~D1组于造模前及造模后2周、4周时,A2~D2组于造模后6周及末次最后一次用药后对雄兔进行泪液分泌实验（Schirmer Ⅰ test,SIT）和泪膜破裂时间（BUT）检查;A1~D1组和A2~D2组分别在饲养1个月及2个月时处死雄兔,即刻摘取泪腺,应用Western blot检测凋亡相关因子Bax和Bcl-2的蛋白表达。结果　SIT、BUT检查结果显示,B、C、D三组雄兔均在造模1个月后形成干眼症。C1组、C2组及D1组、D2组雄兔泪腺组织中的Bax相对含量均较B1组、B2组低,差异均有统计学意义(均为P<0.01);C2组Bax相对含量低于C1组,差异有统计学意义 (P<0.05),而C2组与D2组Bax相对含量差异无统计学意义(P＞0.05);C1、C2组及D1组、D2组雄兔泪腺组织中Bcl-2相对含量均较B1组、B2组高,差异均有统计学意义(均为P<0.01);C2组Bcl-2表达高于C1组,差异有统计学意义 (P<0.05),而C2组与D2组Bcl-2表达差异无统计学意义(P＞0.05)。结论　淫羊藿总黄酮可提高干眼症雄兔泪腺中Bcl-2 的表达,减少Bax的表达,且随用药时间增长其效果逐渐与雄激素相当。淫羊藿总黄酮很可能是通过促进凋亡相关基因Bcl-2、调低Bax的表达达到抑制细胞凋亡的作用。     

Mechanical and hypoxia stress can cause chondrocytes apoptosis through over-activation of endoplasmic reticulum stress

ObjectiveTo examine the role of mechanical force and hypoxia on chondrocytes apoptosis and osteoarthritis (OA)-liked pathological change on mandibular cartilage through over-activation of endoplasmic reticulum stress (ERS).MethodsWe used two in vitro models to examine the effect of mechanical force and hypoxia on chondrocytes apoptosis separately. The mandibular condylar chondrocytes were obtained from three-week-old male Sprague–Dawley rats. Flexcell 5000T apparatus was used to produce mechanical forces (12%, 0.5 Hz, 24 h vs 20%, 0.5 Hz, 24 h) on chondrocytes. For hypoxia experiment, the concentration of O₂ was down regulated to 5% or 1%. Cell apoptosis rates were quantified by annexin V and propidium iodide (PI) double staining and FACS analysis. Quantitative real-time PCR and western blot were performed to evaluate the activation of ERS and cellular hypoxia. Then we used a mechanical stress loading rat model to verify the involvement of ERS in OA-liked mandibular cartilage pathological change. Histological changes in mandibular condylar cartilage were assessed via hematoxylin & eosin (HE) staining. Immunohistochemistry of GRP78, GRP94, HIF-1α, and HIF-2α were performed to evaluate activation of the ERS and existence of hypoxia. Apoptotic cells were detected by the TUNEL method.ResultsTunicamycin, 20% mechanical forces and hypoxia (1% O₂) all significantly increased chondrocytes apoptosis rates and expression of ERS markers (GRP78, GRP94 and Caspase 12). However, 12% mechanical forces can only increase the apoptotic sensitivity of chondrocytes. Mechanical stress resulted in OA-liked pathological change on rat mandibular condylar cartilage which included thinning cartilage and bone erosion. The number of apoptotic cells increased. ERS and hypoxia markers expressions were also enhanced. Salubrinal, an ERS inhibitor, can reverse these effects in vitro and in vivo through the down-regulation of ERS markers and hypoxia markers.ConclusionWe confirmed that mechanical stress and local hypoxia both contributed to the chondrocytes apoptosis. Mechanical stress can cause OA-like pathological change in rat mandibular condylar cartilage via ERS activation and hypoxia existed in the meantime. Both mechanical forces and hypoxia can induce ERS and cause chondrocytes apoptosis only if the stimulate was in higher level. Salubrinal can protect chondrocytes from apoptosis, and relieve OA-liked pathological change on mandibular condylar cartilage under mechanical stress stimulation.     

Optimality,cost minimization and the design of arterial networks

The arterial circulation acts as a network to deliver nutrients and oxygen to cells. The design of the cardiovascular system is subject to a variety of constraints and costs. It has been postulated that the design of the arterial network might be understood in terms of the need to minimize competing ‘costs’ within the context of physical or material limits to the system. These designs can also be envisaged as being subservient to space filling or fractal considerations. The signalling mechanisms underlying these designs remain to be fully characterized although shear stress, wall tensile stress and metabolic stimuli are likely candidates. I will also review evidence that deviations from a minimal cost condition or optimal design may provide both a measure of disease severity and insights into the underlying disease mechanism.     

Blood-based immune-endocrine biomarkers of treatment response in depression

Antidepressant treatment for major depressive disorder remains suboptimal with response rates of just over 50%. Although treatment guidelines, algorithms and clinical keys are available to assist the clinician, the process of finding an effective pharmacotherapy to maximise benefit for the individual patient is largely by “trial and error” and remains challenging. This highlights a clear need to identify biomarkers of treatment response to help guide personalised treatment strategies. We have carried out the largest multiplex immunoassay based longitudinal study to date, examining up to 258 serum markers involved in immune, endocrine and metabolic processes as potential biomarkers associated with treatment response in 332 depression patients recruited from four independent clinical centres. We demonstrated for the first time that circulating Apolipoprotein A-IV, Endoglin, Intercellular Adhesion Molecule 1, Tissue Inhibitor of Metalloproteinases 1, Plasminogen Activator Inhibitor 1, Thrombopoietin, Complement C3, Hepatocyte Growth Factor and Insulin-like Growth Factor-Binding Protein 2 were associated with response to different antidepressants. In addition, we showed that specific sets of immune-endocrine proteins were associated with response to Venlafaxine (serotonin–norepinephrine reuptake inhibitor), Imipramine (tricyclic antidepressant) and other antidepressant drugs. However, we were not able to reproduce the literature findings on BDNF and TNF-α, two of the most commonly reported candidate treatment response markers. Despite the need for extensive validation studies, our preliminary findings suggest that a pre-treatment immune-endocrine profile may help to determine a patient's likelihood to respond to specific antidepressant and/or alternative treatments such as anti-inflammatory drugs, providing hope for future personalised treatment approaches.