Effects of tamoxifen on normal breast tissue histological composition: Results from a randomised six-arm placebo-controlled trial in healthy women

Tamoxifen prevents recurrence of breast cancer and is suggested for preventive risk-reducing therapy. Tamoxifen reduces mammographic density, a proxy for therapy response, but little is known about its effects in remodelling normal breast tissue. Our study, a substudy within the double-blinded dose-determination trial KARISMA, investigated tamoxifen-specific changes in breast tissue composition and histological markers in healthy women. We included 83 healthy women randomised to 6 months daily intake of 20, 10, 5, 2.5, 1 mg of tamoxifen or placebo. The groups were combined to “no dose” (0-1 mg), “low-dose” (2.5-5 mg) or “high-dose” (10-20 mg) of tamoxifen. Ultrasound-guided biopsies were collected before and after tamoxifen exposure. In each biopsy, epithelial, stromal and adipose tissues was quantified, and expression of epithelial and stromal Ki67, oestrogen receptor (ER) and progesterone receptor (PR) analysed. Mammographic density using STRATUS was measured at baseline and end-of-tamoxifen-exposure. We found that different doses of tamoxifen reduced mammographic density and glandular-epithelial area in premenopausal women and associated with reduced epithelium and increased adipose tissue. High-dose tamoxifen also decreased epithelial ER and PR expressions in premenopausal women. Premenopausal women with the greatest reduction in proliferation also had the greatest epithelial reduction. In postmenopausal women, high-dose tamoxifen decreased the epithelial area with no measurable density decrease. Tamoxifen at both low and high doses influences breast tissue composition and expression of histological markers in the normal breast. Our findings connect epithelial proliferation with tissue remodelling in premenopausal women and provide novel insights to understanding biological mechanisms of primary prevention with tamoxifen.     

RWMAs in critically ill patients with non-obstructed coronary arteries

Introduction

Left ventricular (LV) dysfunction is estimated to occur in 10%–25% of the general intensive care unit (ICU) population and is frequently seen as regional wall motion abnormalities (RWMAs). Although RWMA is mostly attributed to myocardial ischemia or infarction, some studies have suggested that nonischemic RWMA might also be prevalent. We sought to establish that RWMA can be seen in critically ill patients with normal coronary arteries and to explore reasons for RWMA in this population.

Methods

In this retrospective study, data from the hospital angiography register and the ICU register were collated between 2012 and 2019. Patients were identified who underwent angiography in conjunction with their ICU stay and had RWMA on echocardiography. Patients were divided into either those with non-obstructed or those with obstructed coronary arteries. Cardiac magnetic resonance imaging (cMRI) examinations were reviewed if they had been performed on patients with non-obstructed coronaries.

Results

We identified 53 patients with RWMA and non-obstructed coronary arteries and 204 patients with RWMA and obstructed coronary arteries. Patients with non-obstructed coronary arteries were more often female, younger, and had fewer cardiovascular risk factors. They less commonly had ST elevation, but more frequently had T-wave inversion or serious arrhythmias. Troponin levels were higher in patients with obstructed coronary arteries, but NT-proBNP was similar between the groups. There were no differences in risk-adjusted 90-day mortality between patients with non-obstructed versus obstructed coronary arteries (OR 1.21, [95% CI 0.56–2.64], p = .628). In those with non-obstructed coronary arteries, follow-up echocardiography was available for 38 patients, of whom 30 showed normalization of cardiac function. Of the 14 patients with non-obstructed coronary arteries on whom cMRI was performed, 7 had a tentative diagnosis of Takotsubo syndrome or myocardial stunning; 4 had a myocardial infarction (preexisting in 3 cases); 1 patient had acute myocarditis; 1 patient had post-myocarditis; and 1 patient was diagnosed with dilated cardiomyopathy.

Conclusion

RWMA can be seen to occur in critically ill patients in the absence of coronary artery obstruction. Several conditions can cause regional hypokinesia, and cMRI is useful to evaluate the underlying etiology.     

Correction: Thrombotic and bleeding events,mortality, and anticoagulant use among 546,656 hospitalized patients with COVID‑19 in the United States: a retrospective cohort study

Journal of Thrombosis and Thrombolysis -     

基于网络药理学和分子对接技术探讨黄芪干预腹膜纤维化的机制

目的 运用网络药理学方法及分子对接技术探讨黄芪干预腹膜纤维化的可能机制。方法 利用中药系统药理学数据库及分析平台(TCMSP)检索黄芪的主要化学成分及靶点,并补充文献报道相关药理作用的成分作为潜在活性成分。以"peritoneal fibrosis"为关键词分别在OMIM、Genecards获取目前已知的与腹膜纤维化相关的疾病靶点,后取两者的交集靶点;对交集基因通过STRING数据库与Cytoscape 3.7.2软件构建"药物-成分-靶点-疾病"网络及蛋白互作(PPI)网络并筛选核心网络。基于R软件使用Bioconductor生物信息软件对核心靶点进行GO及KEGG富集分析,最终采用AutoDock软件将主要有效成分与核心靶点进行分子对接,得出其结合能力。结果 筛选出20个黄芪活性成分及文献报道有相关药理作用4个, 457药物作用靶点,与674个腹膜纤维化病靶点取交集,得到86个共同靶点。GO功能富集分析提示黄芪拮抗腹膜纤维化主要参与了蛋白激酶B信号转导的调节、细胞对化学的应激反应、炎症反应的调节等通路; KEGG通路富集分析主要涉及调控肿瘤、磷脂酰肌醇-3-羟激酶-蛋白激酶B(PI3K-Akt)、晚期糖基化终末产物/晚期糖基化终末产物受体(AGE-RAGE)、人类巨细胞病毒感染、HIF-1信号通路等;分子对接结果显示关键靶点与活性成分具有较好的结合能力。结论 黄芪治疗腹膜纤维化的分子机制,可能与抑制炎症及氧化应激反应、调节多种信号通路等相关。     

Measuring Psychological Inflexibility of Suicidal Thoughts: The Acceptance and Action Questionnaire for Suicidal Ideation (AAQ-SI)

Cognitive Therapy and Research - Despite interest in psychological inflexibility as a marker of suicide risk, no measure of psychological inflexibility specific to SI exists. The present study...     

艾司氯胺酮复合麻醉在小儿瘢痕非插管全身麻醉患者超脉冲点阵二氧化碳激光治疗术中的应用及效果观察

目的探讨艾司氯胺酮+七氟烷+小儿布洛芬肛栓在小儿烧伤后增生性瘢痕非插管全身麻醉患者超脉冲二氧化碳点阵激光(UFCL)治疗术中的应用及效果观察。 方法选取2020年1月至2021年4月就诊于空军军医大学第一附属医院烧伤与皮肤外科门诊89例烧伤后增生性瘢痕患儿纳入本随机对照临床试验。将患儿采用随机数字表法分为氯胺酮+丙泊酚组[共42例，其中男22例，女20例，平均年龄为(44.33±14.87)个月]和复合麻醉镇痛组(艾司氯胺酮+七氟烷+小儿布洛芬肛栓)[共47例，男24例，女23例，平均年龄(44.47±14.65)个月]；在麻醉前和术中监测患儿血流动力学指标以及警觉/镇静(OAA/S)量表评分；在麻醉清醒时(T0)、麻醉清醒后1 h(T1)、麻醉清醒后2 h(T2)应用儿童疼痛行为量表(FLACC)对患儿疼痛程度进行评估；分别于术前和术后6个月应用温哥华瘢痕量表(VSS)对瘢痕进行评分。对数据行独立样本t检验和χ²检验。 结果(1)麻醉前氯胺酮+丙泊酚组血流动力学及OAA/S量表评分[平均动脉压(63.71±3.40)mmHg、心率(107.21±9.45)次/min、呼吸(25.29±2.34)次/min、血氧饱和度(99.00±0.80)%、OAA/S量表评分(4.64±0.49)分]与复合麻醉镇痛组[平均动脉压(63.87±3.57)mmHg、心率(109.34±12.21)次/min、呼吸(26.473.53)次/min、血氧饱和度(98.77±0.91)%、OAA/S量表评分(4.57±0.50)分]比较差异均无统计学意义(t＝-0.213、0.490、-1.840、1.280、0.204，P>0.05)；麻醉后手术中氯胺酮+丙泊酚组[平均动脉压(56.29±2.43)mmHg、心率(94.48±7.01)次/min、呼吸(21.07±3.03)次/min、血氧饱和度(96.12±1.64)%、OAA/S量表评分(2.07±0.71)分]与复合麻醉镇痛组[平均动脉压(62.87±3.56)mmHg、心率(108.791±1.93)次/min、呼吸(26.52±3.48)次/min、血氧饱和度(99.23±0.67)%、OAA/S量表评分(1.45±0.50)分]比较差异有统计学意义(t＝-10.068、-6.794、-7.824、-11.960、4.820，P<0.05)。(2)氯胺酮+丙泊酚组患儿麻醉清醒时[T0：(4.40±1.17)分]麻醉清醒后1 h[T1：(2.05±0.88)分]、麻醉清醒后2 h[T2：(0.43±0.63)分]FLACC评分比复合麻醉镇痛组[(1.32±0.96)、(0.43±0.62)、(0.13±0.34)分]评分高，说明患儿疼痛度高，且数据比较差异均有统计学意义(t＝10.139、13.669、2.794，P<0.05)。(3)术前及术后6个月瘢痕评分：氯胺酮+丙泊酚组[(9.33±1.60)、(4.48±1.11)分]与复合麻醉镇痛组[(8.43±2.04)、(4.26±1.04)分]相比差异均无统计学意义(t＝2.320、0.940, P>0.05)。 结论复合麻醉镇痛措施在小儿烧伤后增生性瘢痕非插管全身麻醉患者(UFCL)治疗术中应用效果较好，可使患儿术中血流动力学平稳，术中镇静良好，术后疼痛度较低，对于激光治疗效果无影响。