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.     

Lysophosphatidylcholine‐induced cytotoxicity and protection by heparin in mouse brain bEND.3 endothelial cells

A pathological feature in atherosclerosis is the dysfunction and death of vascular endothelial cells (EC). Oxidized low‐density lipoprotein (LDL), known to accumulate in the atherosclerotic arterial walls, impairs endothelium‐dependent relaxation and causes EC apoptosis. A major bioactive ingredient of the oxidized LDL is lysophosphatidylcholine (LPC), which at higher concentrations causes apoptosis and necrosis in various EC. There is hitherto no report on LPC‐induced cytotoxicity in brain EC. In this work, we found that LPC caused cytosolic Ca²⁺ overload, mitochondrial membrane potential decrease, p38 activation, caspase 3 activation and eventually apoptotic death in mouse cerebral bEND.3 EC. In contrast to reported reactive oxygen species (ROS) generation by LPC in other EC, LPC did not trigger ROS formation in bEND.3 cells. Pharmacological inhibition of p38 alleviated LPC‐inflicted cell death. We examined whether heparin could be cytoprotective: although it could not suppress LPC‐triggered Ca²⁺ signal, p38 activation and mitochondrial membrane potential drop, it did suppress LPC‐induced caspase 3 activation and alleviate LPC‐inflicted cytotoxicity. Our data suggest LPC apoptotic death mechanisms in bEND.3 might involve mitochondrial membrane potential decrease and p38 activation. Heparin is protective against LPC cytotoxicity and might intervene steps between mitochondrial membrane potential drop/p38 activation and caspase 3 activation.     

Prostaglandin signaling suppresses beneficial microglial function in Alzheimer’s disease models

Microglia, the innate immune cells of the CNS, perform critical inflammatory and noninflammatory functions that maintain normal neural function. For example, microglia clear misfolded proteins, elaborate trophic factors, and regulate and terminate toxic inflammation. In Alzheimer’s disease (AD), however, beneficial microglial functions become impaired, accelerating synaptic and neuronal loss. Better understanding of the molecular mechanisms that contribute to microglial dysfunction is an important objective for identifying potential strategies to delay progression to AD. The inflammatory cyclooxygenase/prostaglandin E2 (COX/PGE₂) pathway has been implicated in preclinical AD development, both in human epidemiology studies and in transgenic rodent models of AD. Here, we evaluated murine models that recapitulate microglial responses to Aβ peptides and determined that microglia-specific deletion of the gene encoding the PGE₂ receptor EP2 restores microglial chemotaxis and Aβ clearance, suppresses toxic inflammation, increases cytoprotective insulin-like growth factor 1 (IGF1) signaling, and prevents synaptic injury and memory deficits. Our findings indicate that EP2 signaling suppresses beneficial microglia functions that falter during AD development and suggest that inhibition of the COX/PGE₂/EP2 immune pathway has potential as a strategy to restore healthy microglial function and prevent progression to AD.     

Unexpected Return for Follow-up During the First Year of Multidisciplinary Care May Be Predictive of Rapid Deterioration of Renal Function

Multidisciplinary predialysis education and team care (MDC) may slow the decline in renal function in patients with chronic kidney disease (CKD). However, associations between unexpected return during MDC and progression of renal dysfunction have not been characterized in patients with CKD. Our study aimed to determine the association between exacerbation of renal dysfunction and the frequency of unexpected return during follow-up.A total of 437 patients with CKD receiving multidisciplinary care between January 2009 and June 2013 at the Shin-Kong Wu Ho-Su Memorial Hospital were included in this retrospective observational cohort study, and multiple imputations were performed for missing data. The predictor was the frequency of unexpected return for follow-up during the first year after entering MDC. Main outcome was monthly declines in estimated glomerular filtration rates (eGFR). Moreover, the demographic data, comorbidities, history of medication, and routine laboratory data for patients with CKD were collected.Among all patients, 59.7% were male, the mean age at initiation of MDC was 69.4 ± 13.2 years, and the duration of follow-up was 21.4 ± 3.3 months. The subjects were divided into 2 groups according to frequencies of follow-up (≤4 and > 4 visits) during the 1st year of MDC. The patients with CKD were regularly followed up every 3 months as a part of MDC in our hospital, and patients who returned for more than 4 follow-up visits were included in the unexpected return group. In crude regression analyses, unexpected return was significantly associated with higher monthly declines of eGFR (β = 0.092, 95% confidence interval, 0.014–0.170). This association remained after adjustments for multiple variables, and subgroup analyses of unexpected return showed that male gender, older age, CKD stage 1 to 3, hypertension, history of coronary artery disease, and use of renin–angiotensin system blockade were significantly associated with declines in renal function.In conclusion, unexpected return for follow-up during the 1st year of MDC was significantly associated with the deterioration of renal function.     

采用泌尿道前列腺切除器经肛门内镜切除直肠肿瘤：131例患者应用的经验

目的：直肠腺瘤和其他疑似为良性的病变应用经肛门内镜切除术并未普及。该项研究旨在评估经肛门内镜切除术的效能和安全性。方法：回顾性研究分析在1993-2004年之间3所斯德哥尔摩医院中经肛门内镜切除术的患，内容包括患自身及病变特性、并发症、随访时间和复发率。结果：180例中共131例行经肛门内镜切除术。160例经组织学诊断为腺瘤，12例为癌瘤，其余8例分别为增生、纤维化或正常黏膜。直肠腺瘤患中，77例仅行单次经肛门内镜切除术，16例因巨大腺瘤而多次行该手术，27例因复发而需另行经肛门内镜切除术或其他手术。中位复发时间为7个月，但未出现直肠癌。16例手术患出现并发症。2例患必须行Hartman手术，1例因肠穿孔，另1例因出血。手术期间无死亡。未复发的中位随访期为32个月（极差0—67）。[编按]