Understanding the Influence of Nanocarrier-Mediated Brain Delivery on Therapeutic Performance Through Pharmacokinetic-Pharmacodynamic Modeling

This study aimed at evaluating how encapsulation in a regular nanocarrier (NC) (providing extended circulation time) or in a brain-targeting NC (providing prolonged circulation time and increased brain uptake) may influence the therapeutic index compared with the unformulated drug and to explore the key parameters affecting therapeutic performance using a model-based approach. Pharmacokinetic (PK) models were built with chosen PK parameters. For a scenario where central effect depends on area under the unbound brain concentration curve and peripheral toxicity relates to peak unbound plasma concentration, dose-effect and drug-side effect curves were constructed, and the therapeutic index was evaluated. Regular NC improved the therapeutic index compared with the unformulated drug due to reduced peripheral toxicity, while brain-targeting NC enhanced the therapeutic index by lowering peripheral toxicity and increasing central effect. Decreasing drug release rate or systemic clearance of NC with drug still encapsulated could increase the therapeutic index. Also, a drug with shorter half-life would therapeutically benefit more from a NC encapsulation. This work provides insights into how a NC for brain delivery should be optimized to maximize the therapeutic performance and is helpful to predict if and to what extent a drug with certain PK properties would obtain therapeutic benefit from nanoencapsulation.     

膝痹宁对膝骨关节炎模型大鼠滑膜纤维化的影响

目的观察膝痹宁对膝骨关节炎(KOA)模型大鼠滑膜纤维化的影响。方法大鼠分为空白组、KOA组、膝痹宁组;KOA组、膝痹宁组造模。分别在膝痹宁灌胃治疗的第1、14、28、42、56天测量各组大鼠的膝关节横径;第56天处死大鼠提取滑膜组织,解剖学观察滑膜组织形态;天狼星红染色评估滑膜组织胶原沉积情况;WB和PCR检测纤维化标记物生长转化因子-β(TGF-β)、Ⅰ型胶原α1链(COL1α1)、金属蛋白酶抑制剂1(TIMP1)的蛋白和基因表达。结果膝痹宁用药14天,28天时,膝关节横径变化并不显著,但膝痹宁用药42天,56天时,膝关节横径则较KOA模型明显减小,差异具有统计学意义(P<0.05);用药56天后对大鼠进行膝关节解剖学观察,KOA大鼠滑膜组织较正常大鼠有一定程度的增厚、充血、欠规则;而上述表现在膝痹宁大鼠有所减轻;天狼星红染色显示膝痹宁用药大鼠滑膜组织胶原沉积较少;纤维化标记指标物TGF-β、COL1α1、TIMP1的基因和蛋白表达在膝痹宁组均较KOA组降低,差异具有统计学意义(P<0.05)。结论膝痹宁对能有效减轻KOA滑膜纤维化,以“温经活血”立法的中药复方对组织纤维化具有良性干预效应。     

PI3K抑制剂ZSTK-474对结直肠癌细胞增殖和侵袭的影响

目的:探讨PI3K抑制剂ZSTK-474对结直肠癌细胞增殖和侵袭的影响。方法:采用不同浓度（0、1、2、4、6、8和10 μmol/L）ZSTK-474处理结直肠癌HT-29和HCT-116细胞24 h和48 h，CCK8法检测细胞增殖活性并计算出ZSTK-474在两株结直肠癌细胞中的半数抑制浓度（IC50）。根据IC50的值选用浓度为4 μmol/L的ZSTK-474作用HT-29和HCT-116细胞24 h，同时设置加入等量的0.1%DMSO为对照。采用平板克隆形成实验检测细胞增殖，流式细胞仪检测细胞凋亡，qRT-PCR检测细胞PI3K、Akt的mRNA水平，Western blot 检测细胞PI3K、Akt的蛋白水平。结果:ZSTK-474可明显抑制HT-29和HCT-116细胞的增殖，且呈时间和剂量依赖性。ZSTK-474可抑制HT-29和HCT-116细胞的侵袭能力，但不影响其凋亡。ZSTK-474处理HT-29和HCT-116细胞24 h后，PI3K和Akt的mRNA和蛋白表达水平均显著下降。结论:ZSTK-474能够抑制结直肠癌细胞增殖，并且能抑制其侵袭。     

Clinical characteristics and pregnancy outcomes of infertile patients with endometriosis and endometrial polyps: A retrospective cohort study

ObjectiveThe aim of this study was to discuss the clinical characteristics and the prognosis of surgically diagnosed endometriosis complicated by endometrial polyps and investigate the association between pregnancy outcomes during subsequent pregnancies.Materials and methodsFrom January 2013 to December 2016, 1263 infertile patients were enrolled in the study. We identified 451 patients with endometriosis, and divided them into a polyp group (n = 204) and a non-polyp group (n = 247) based on whether or not they were associated with endometrial polyps. Postoperative clinical pregnant women (n = 82) among the polyp group were then classified into a study group and a control group composed of those undergoing a singleton pregnancy (n = 164) who delivered during the same time period. Clinical statuses and complications during pregnancy and delivery were collected from hospitals and by telephone interviews and surveys through the mail.ResultsThe prevalence rate of endometriosis infertile group was obviously higher than the non-endometriosis infertile group ([45.23%; 204/451] versus [17.12%; 139/812]). Women suffering from stage 1 to 4 endometriosis had a 42.44% (73/172), 40.69% (59/145), 55.89% (38/68) and 51.52% (34/66) occurrence rate of endometrial polyps, respectively. The frequency of endometrial polyps for stage 3 and 4 patients was obviously higher than that of stage 1 and 2 patients ([53.73%; 72/134] versus [41.64%; 132/317]). Moreover, the occurrence rate of deep infiltrating endometriosis (DIE) was 57.81% (37/64), which was obviously higher than that of ovarian endometriosis (42.42%; 98/231) and peritoneal endometriosis (44.23%; 69/156). Of the 204 women diagnosed with posterior endometrial polyps, 89 became pregnant, 7 pregnancies ended in a spontaneous abortion, and 82 successfully delivered a baby. The clinical pregnancy rate of patients in stages 1 and 2 was wholly higher than that of patients in stages 3 and 4 ([48.70%; 56/115] versus [37.71%; 26/82]). The postsurgical pregnancy status of patients suffering from peritoneal endometriosis was slightly better than those with ovarian or DIE, but differences were not statistically significant (P = 0.626). We also found that the pregnancy rate was statistically elevated in patients whose EFI scores range from 7 to 10. When compared to the control group, women with endometriosis and endometrial polyps had a higher risk of their pregnancy being complicated by placenta previa (13.41%) and cesarean delivery (59.76%).ConclusionPatients with endometriosis have a higher frequency of endometrial polyps. We found that a combined hysteroscopy and laparoscopy surgical procedure is an effective way to increase pregnancy rates. Different endometriosis stages and types in patients were associated with clinical pregnancy and spontaneous abortion rates. Women affected by both endometriosis and endometrial polyps have an independently elevated risk of placenta previa and cesarean delivery during pregnancy.     

Adverse childhood experiences,inflammation, and depressive symptoms in later life: a prospective cohort study

BackgroundExposure to adverse childhood experiences (ACEs) has been associated with both inflammation and depression. However, little research has examined the potential mediational role of inflammation in the link between ACEs and depression using longitudinal data. Therefore, we investigated the direct and indirect effects of ACEs on inflammation, depression, and their change trajectories over time.MethodsWe used data from the English Longitudinal Study of Ageing. Four ACE categories were assessed retrospectively at wave 3 (2006–07): abuse (physical or sexual abuse or physical assault), family dysfunction (parent arguments, parent mental illness or substance abuse, or parent separation or divorce), poor parent–child bonding (maternal or paternal), and loss of an attachment figure (separation from mother for >6 months, parent death, foster care or adoption, or institutionalisation). A cumulative ACE score was calculated representing the total number of ACEs experienced by the participants. Concentration of C-reactive protein (CRP), an inflammatory marker, was measured at waves 2 (2004–05), 4 (2008–09), and 6 (2012–13). Depressive symptoms were ascertained using the 8-item Centre for Epidemiological Studies Depression Scale from waves 6 to 8 (2016–17). The longitudinal direct and indirect effects of ACEs were estimated using parallel process latent growth curve modelling. All analyses were adjusted for relevant confounders. Missing data were estimated using multiple imputation.ResultsAmong the study sample (N=4382; mean age 70 years; 56% female), 24% of participants reported one ACE and 13% had two or three ACEs. The percentage of participants with three or more depressive symptoms was 21% at baseline. Greater cumulative exposure to ACEs was associated with increased CRP concentration (β=0·042, p=0·010) and depressive symptoms (β=0·164, p<0·0001) at baseline and predicted a steeper increase in these outcomes throughout the study (β_CRP=0·074, p=0·011; β_Depression=0·338, p<0·0001). However, indirect effects of ACEs on depression mediated by CRP were not observed, with only weak associations between CRP and depressive symptoms (β_iDepression=0·032, p=0·173; β_sDepression=0·067, p=0·240). Sensitivity analyses using only somatic depressive symptoms as the outcome revealed a positive association between CRP and somatic symptoms at baseline (β_iDepression=0·068, p=0·008), although the indirect effects remained non-significant in this model.InterpretationBiological mechanisms other than inflammation might underlie the relationship between ACEs and depression. Psychosocial interventions to reduce the negative effects of ACEs on children's development could help to reduce the risk of depression and of other medical conditions linked to inflammation.FundingEconomic and Social Research Council–Biotechnology and Biological Sciences Research Council Soc-B Centre for Doctoral Training (ES/P000347/1).     

江苏省儿童专科夜间门诊诊察费定价政策成效分析

2019年5月20日,江苏省医保局推出调整了儿童专科夜间门诊诊察费收费标准举措。文章以江苏省某三甲综合医院为样本,围绕上述政策实施后儿科诊疗工作量、病人满意度、医院收入影响等方面进行了调查,结果表明,上述政策可满足儿科病人就诊差异化需求,合理分流病人,保障急诊优先的诊疗秩序。     

面向医患连接的慢性病诊后服务平台设计与应用

目的:构建面向医患连接的慢性病诊后服务平台,实现院内院外慢性病患者诊疗的无缝连接。方法:针对慢性病患者需长期干预指导的需求,重点解决医患连接、健康宣教、体征监测和个性化指导等难题,设计和实现慢性病诊后服务平台。结果:平台投入实际使用,共服务患者1.5万人次以上而且易使用、易维护。结论:面向医患连接的诊后服务方式,实现了慢性病患者的持续干预指导,促进医患关系和谐,提升了慢病治疗的效果以及患者体验。     

《医用有机化学》课程中进行德育渗透

教学与德育有机融会贯通,是当前教育领域的共识。医学本科生秉承"以德载医"的精神,肩负"治病救人"的重任,因此德育教育在整个医学教学中占有重要的地位。《医用有机化学》教材中含有丰富的德育内容,高校教师传授专业知识的同时,在教学过程中巧妙的穿插辩证唯物主义、爱国主义和社会责任感的思政教育,可以帮助学生们树立正确的世界观和人生观。文章以医用有机化学课程为例,主要从教师的自身道德素养、德育在教学过程中的具体实践和德育实施过程中需要注意的问题三方面进行阐述,充分将新时代新理念融入大纲、教案和课堂中,化"知识"为"智慧",变"文化"为"品格",充分发挥医用有机化学课程的德育功能。