Evodiamine-inspired dual inhibitors of histone deacetylase 1 (HDAC1) and topoisomerase 2 (TOP2) with potent antitumor activity

A great challenge in multi-targeting drug discovery is to identify drug-like lead compounds with therapeutic advantages over single target inhibitors and drug combinations. Inspired by our previous efforts in designing antitumor evodiamine derivatives, herein selective histone deacetylase 1 (HDAC1) and topoisomerase 2 (TOP2) dual inhibitors were successfully identified, which showed potent in vitro and in vivo antitumor potency. Particularly, compound 30a was orally active and possessed excellent in vivo antitumor activity in the HCT116 xenograft model (TGI = 75.2%, 150 mg/kg, p.o.) without significant toxicity, which was more potent than HDAC inhibitor vorinostat, TOP inhibitor evodiamine and their combination. Taken together, this study highlights the therapeutic advantages of evodiamine-based HDAC1/TOP2 dual inhibitors and provides valuable leads for the development of novel multi-targeting antitumor agents.     

逐瘀止血汤加减治疗慢性子宫内膜炎气虚血瘀证的疗效观察

目的 评价逐瘀止血汤加减对慢性子宫内膜炎（CE）气虚血瘀证患者妊娠结局的影响及对免疫炎症因子的调节作用。方法 将144例患者随机按数字表法分为观察组和对照组各72例。观察组脱落、失访4例，剔除2例，完成66例；对照组脱落、失访3例，剔除5例，完成65例。两组均给予抗感染治疗14 d。对照组口服妇科千金片，6片/次，3次/d。观察组内服逐瘀止血汤加减，1剂/d。两组疗程均为3个月，并随访6个月。记录治疗前后月经经量、经期和周期变化情况；进行治疗前后宫腔镜和阴道彩色多普勒超声检查，评价子宫内膜形态、子宫内膜容受性（CP）［子宫内膜厚度、阻力指数（RI），搏动指数（PI）和血流指数（FI）］等，并进行子宫内膜病理检查；进行治疗前后气虚血瘀证评分；检测治疗前后月经血白细胞介素-1β（IL-1β），IL-6和肿瘤坏死因子-α（TNF-α）水平和外周血测T淋巴亚群（CD3⁺，CD4⁺，CD8⁺）水平；随访记录妊娠情况和流产情况。进行安全性评价。结果 治疗后观察组经量、经期、周期和月经完全正常率均高于对照组（P<0.05）；观察组子宫内膜厚度和FI均高于对照组（P<0.01），RI和PI均低于对照组（P<0.01）；观察组月经血IL-1β，IL-6和TNF-α水平均低于对照组（P<0.01）；观察组CD3⁺，CD4⁺水平和CD4⁺/ CD8⁺均高于对照组（P<0.01），CD8⁺水平低于对照组（P<0.01）；在6个月随访期间，观察组妊娠率46.97%（31/66），高于对照组的27.69%（18/65）（χ²=5.197，P<0.05）；观察组子宫内膜形态疗效总有效率为96.97%（64/66），高于对照组的86.15%（56/65）（χ²=4.981，P<0.05）；观察组子宫内膜病理组织疗效总有效率为95.45%（63/66），高于对照组的84.62%（55/65）（χ²=4.304，P<0.05）；观察组综合临床疗效总有效率为93.94%（62/66），高于对照组的81.54%（55/65）（χ²=4.696，P<0.05）；两组治疗期间均未发现与中药相关不良反应。结论 逐瘀止血汤加减治疗CE气虚血瘀证患者，可调经月经、减轻临床症状，改善宫腔镜下内膜形态，调节全身和局部的免疫炎症反应，提高了CP，从而改善了妊娠结局，有着较好的综合疗效，且安全。     

The Importance of Venous Return in Starling‐Like Control of Rotary Ventricular Assist Devices

Rotary ventricular assist devices (VADs) are less sensitive to preload than the healthy heart, resulting in inadequate flow regulation in response to changes in patient cardiac demand. Starling‐like physiological controllers (SLCs) have been developed to automatically regulate VAD flow based on ventricular preload. An SLC consists of a cardiac response curve (CRC) which imposes a nonlinear relationship between VAD flow and ventricular preload, and a venous return line (VRL) which determines the return path of the controller. This study investigates the importance of a physiological VRL in SLC of dual rotary blood pumps for biventricular support. Two experiments were conducted on a physical mock circulation loop (MCL); the first compared an SLC with an angled physiological VRL (SLC‐P) against an SLC with a vertical VRL (SLC‐V). The second experiment quantified the benefit of a dynamic VRL, represented by a series of specific VRLs, which could adapt to different circulatory states including changes in pulmonary (PVR) and systemic (SVR) vascular resistance versus a fixed physiological VRL which was calculated at rest. In both sets of experiments, the transient controller responses were evaluated through reductions in preload caused by the removal of fluid from the MCL. The SLC‐P produced no overshoot or oscillations following step changes in preload, whereas SLC‐V produced 0.4 L/min (12.5%) overshoot for both left and right VADs. Additionally, the SLC‐V had increased settling time and reduced controller stability as evidenced by transient controller oscillations. The transient results comparing the specific and standard VRLs demonstrated that specific VRL rise times were improved by between 1.2 and 4.7 s ( = 3.05 s), while specific VRL settling times were improved by between 2.8 and 16.1 seconds ( = 8.38 s) over the standard VRL. This suggests only a minor improvement in controller response time from a dynamic VRL compared to the fixed VRL. These results indicate that the use of a fixed physiologically representative VRL is adequate over a wide variety of physiological conditions.     

高通量血液透析和低通量血液透析不同模式对老年维持性血液透析患者血压的影响

目的 观察高通量血液透析(HFHD)与低通量血液透析(LFHD)的不同模式运用到老年患者维持性血液透析(MHD)中对其血压的影响。方法 选择2015年2月—2017年10月本院治疗的MHD老年患者74例,先为其施LFHD 3个月,再为其辅以3个月的HFHD,3次/周,4 h/次,对比不同透析模式对患者血压的影响。结果 实施HFHD后患者的平均动脉压(MAP)有所降低,在第3 h与第4 h透析后,血压把控优于LFHD(P<0.05)。结论 对于MHD老年患者来说,实施HFHD是优良的透析方法。     

全国著名骨伤专家梁铁民教授学术思想和正骨经验

总结了全国著名骨伤专家梁铁民教授的学术思想和正骨经验,简述了梁老生平。梁老学术思想表现在突出整体观念,主张辨证施术;注重调理气血,强调药物接续;重视望问切触量法五诊结合等三个方面。对于梁老正骨经验先进行了综合论述,进一步佐证其学术思想;后分别从小儿桡骨头半脱位、颈椎错位、胸腰椎小关节错位、肋骨骨折等梁老研究较深入和比较擅长的几个方面进行了阐述。特别是颈椎错位这种高难度高风险的手法操作,体现出梁老高超的手法技艺。     

Haemodynamic profiles of etomidate vs propofol for induction of anaesthesia: a randomised controlled trial in patients undergoing cardiac surgery

Background

Etomidate is frequently selected over propofol for induction of anaesthesia because of a putatively favourable haemodynamic profile, but data confirming this perception are limited.

In Vitro-In Vivo Extrapolation and Hepatic Clearance-Dependent Underprediction

Accurately predicting the hepatic clearance of compounds using in vitro to in vivo extrapolation (IVIVE) is crucial within the pharmaceutical industry. However, several groups have recently highlighted the serious error in the process. Although empirical or regression-based scaling factors may be used to mitigate the common underprediction, they provide unsatisfying solutions because the reasoning behind the underlying error has yet to be determined. One previously noted trend was intrinsic clearance-dependent underprediction, highlighting the limitations of current in vitro systems. When applying these generated in vitro intrinsic clearance values during drug development and making first-in-human dose predictions for new chemical entities though, hepatic clearance is the parameter that must be estimated using a model of hepatic disposition, such as the well-stirred model. Here, we examine error across hepatic clearance ranges and find a similar hepatic clearance-dependent trend, with high clearance compounds not predicted to be so, demonstrating another gap in the field.     

老年轻度认知障碍患者血清瘦素、甲状腺激素水平与局部脑血流量关系的研究

目的 通过检测老年轻度认知障碍（MCI）患者血清瘦素（LEP）、甲状腺激素水平，分析其与局部脑血流量（rCBF）的关系。方法 选择本院收治的128 例老年MCI 患者，另选健康者128 例作为对照组。检测血清LEP、甲状腺激素、大脑各区域rCBF 水平并分析其相关性。结果 老年MCI 组患者左右侧额叶、右侧颞叶、左侧顶叶、左右侧基底节区域脑血流量[（43.81±8.62）mL/（100 g·min）、（43.24±7.93）mL/（100 g·min）、（45.14±6.98）mL/（100 g·min）、（45.86±6.77）mL/（100 g·min）、（67.95±8.52）mL/（100 g·min）、（68.36±8.34）mL/（100 g·min）]低于对照组[（46.39±8.31）mL/（100 g·min）、（46.52±8.56）mL/（100 g·min）、（47.37±7.04）mL/（100 g·min）、（48.25±6.98）mL/（100 g·min）、（70.34±8.96）mL/（100 g·min）、（70.58±8.57）mL/（100 g·min）]（P＜0.05）。老年MCI 组患者血清LEP、T3、FT3 水平[（4.87±1.56）μg/L、（1.21±0.16）nmol/L、（3.04±0.36）pmol/L]低于对照组[（11.45±3.92）μg/L、（1.68±0.21）nmol/L、（4.82±1.21）pmol/L]（P＜0.05），TSH 水平为（2.78±0.75）IU/mL，高于对照组的（1.13±0.38）IU/mL（P＜0.05）。老年MCI 患者血清LEP 水平与左侧额叶、右侧颞叶、左侧顶叶rCBF 呈正相关（r=0.452、0.537、0.544，P 均＜0.05），T3 水平与左侧额叶、右侧颞叶rCBF 呈正相关（r=0.427、0.521，P 均＜0.05），FT3 水平与右侧颞叶rCBF 呈正相关（r=0.492，P＜0.05），TSH 水平与左侧额叶、右侧颞叶rCBF 呈负相关（r=-0.463、-0.489，P 均＜0.05）。结论 老年MCI 患者血清中LEP、T3、FT3 水平降低，TSH 水平升高，且与不同区域rCBF 有相关性，可通过调控脑血管功能影响rCBF 变化水平。