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.     

Is Involvement a Good Thing? The Undesirable Consequences of Topical and Conversational Involvement in the Context of Alcohol Consumption

Whereas there is evidence that interpersonal communication, or conversation, influences predictors of alcohol consumption, the role of involvement in conversation effects remains unclear. This study explored how three aspects of involvement (topical relevance, or how relevant the topic of alcohol is; conversational relevance, or how relevant a conversation about alcohol is; and conversational effort, or how much effort people put into such a conversation), influence conversation effects. After assessing topical relevance, 46 same-sex dyads were requested to talk about the negative consequences of heavy drinking. Within each dyad, one participant was asked to take on an active talking role and the other participant a passive listening role. Next, conversational relevance, effort, and predictors of heavy drinking were measured. Results showed that participants who drank more alcohol found the topic of heavy drinking more relevant. This topical relevance increased conversational relevance and conversational effort. Conversational effort further increased when a talking role was assigned. Furthermore, participants who put more effort in the conversation and found it more relevant had more positive norms, identified more strongly with alcohol, and had higher intentions to drink. These findings suggest that more involvement in an alcohol-related conversation does not always lead to desirable outcomes.     

Application of the adverse outcome pathway framework to genotoxic modes of action

In May 2017, the Health and Environmental Sciences Institute's Genetic Toxicology Technical Committee hosted a workshop to discuss whether mode of action (MOA) investigation is enhanced through the application of the adverse outcome pathway (AOP) framework. As AOPs are a relatively new approach in genetic toxicology, this report describes how AOPs could be harnessed to advance MOA analysis of genotoxicity pathways using five example case studies. Each of these genetic toxicology AOPs proposed for further development includes the relevant molecular initiating events, key events, and adverse outcomes (AOs), identification and/or further development of the appropriate assays to link an agent to these events, and discussion regarding the biological plausibility of the proposed AOP. A key difference between these proposed genetic toxicology AOPs versus traditional AOPs is that the AO is a genetic toxicology endpoint of potential significance in risk characterization, in contrast to an adverse state of an organism or a population. The first two detailed case studies describe provisional AOPs for aurora kinase inhibition and tubulin binding, leading to the common AO of aneuploidy. The remaining three case studies highlight provisional AOPs that lead to chromosome breakage or mutation via indirect DNA interaction (inhibition of topoisomerase II, production of cellular reactive oxygen species, and inhibition of DNA synthesis). These case studies serve as starting points for genotoxicity AOPs that could ultimately be published and utilized by the broader toxicology community and illustrate the practical considerations and evidence required to formalize such AOPs so that they may be applied to genetic toxicity evaluation schemes. Environ. Mol. Mutagen. 61:114–134, 2020. © 2019 Wiley Periodicals, Inc.     

Communication Between HIV Patients and Their Providers: A Qualitative Preference Match Analysis

Since the introduction of cART (combination antiretroviral therapy), HIV has evolved into a chronic disease such that it requires lifelong medical treatment to which patients must adhere. Communication with health care providers is pivotal in supporting patients to adapt to having HIV and adhering to treatment, in order to maintain health and quality of life. Previous research indicates that communication is optimal when it matches patient preferences for information exchange, relationship establishment, and involvement in treatment decisions. The aim of the present study is to explore HIV patient communication preferences as well as patient experiences with their providers (not) matching their preferences. A second aim is to explore provider beliefs about patient preferences and provider views on optimal communication. Data were collected through interviews with 28 patients and 11 providers from two academic hospitals. Results indicate that patient preferences reflect their cognitive, emotional, and practical needs such that patients look to increase their sense of control over their HIV. Patients aim to further increase their sense of control (by proxy) through their relationship with their providers and through their decisional involvement preferences. Providers are well aware of patient communication preferences but do not explicate underlying control needs. Implications for clinical practice are discussed.     

Multidisciplinary evaluation of rat renal cell carcinoma

The rat renal cell carcinoma system as described by deVere White and Olsson in 1980 is used widely as a model for its human counterpart. The tumor arose spontaneously in a male Wistar Lewis rat and its behaviour has been shown to be stable during multiple passages. We have compared this tumor with the human renal cell carcinoma using a multidisciplinary approach. Light microscopy and electron microscopy showed a great resemblance of this rat tumor to a human renal cell carcinoma of the clear cell type with the ultrastructural presence of desmosomes. With the use of tissue specific antibodies against intermediate filament proteins, it could be shown that their expression is comparable to human renal cell carcinoma, i.e. coexpression of vimentin and different cytokeratins in the tumor cells. The cells could also be shown to contain cytokeratin 18. An aneuploid cell population in the tumor, expressing both vimentin and keratin, could be characterized by DNA flow cytometry in double labeling experiments. Comparison of normal and malignant rat kidney tissue by Northern blot analysis revealed increased levels of vimentin mRNA. In conclusion, this tumor model seems to have several histological and biological properties in common with the human renal tumor.     

Closure of the cribriform fascia: an efficient anatomical barrier against postoperative neovascularisation at the saphenofemoral junction? A prospective study.

BACKGROUND: Neovascularisation at the sapheno-femoral junction (SFJ) ligation site in the groin may occur within one year after great saphenous vein (GSV) surgery. Several anatomical and prosthetic barrier techniques have been proposed to prevent this evolution. OBJECTIVE: A prospective study examined whether closing the cribriform fascia could reduce the incidence of postoperative neovascularisation in the groin. PATIENTS AND METHODS: Patients with primary varicose veins and incompetence at the level of the SFJ were included. After SFJ ligation in 235 limbs of 193 patients an anatomical barrier was constructed by closing the cribriform fascia. Postoperative duplex scanning was performed after 2 and 12 months. Results were compared with historical control groups in which either a silicone patch saphenoplasty or no barrier technique had been performed. RESULTS: After one year, 10 limbs had developed recurrent thigh varicose veins and duplex scan showed neovascularisation at the SFJ ligation site in 15 of 223 re-examined limbs (6.7%). This was comparable to the group of 191 limbs with silicone patch saphenoplasty (5.2%) (P=0.526) and superior to the group of 189 limbs without barrier (14.8%) (P<0.01). CONCLUSION: Interposition of an anatomical barrier by closing the cribriform fascia after SFJ ligation reduced ultrasound detected neovascularisation at the SFJ after one year. In primary varicose vein operations application of an anatomical barrier technique (without prosthetic patch) is an alternative option to prevent postoperative neovascularisation.     

Meningitis due toFusobacterium necrophorum subspeciesnecrophorum. Case report and review of the literature

Summary This paper reports a case of fatal meningitis caused byFusobacterium necrophorum subsp.necrophorum in a previously healthy five-year-old child. The organism was isolated in pure culture from the cerebrospinal fluid and from intracranial pus obtained at autopsy. The role ofF. necrophorum in the development of meningitis is reaffirmed and its isolation and identification are discussed. The clinical presentation of the present case resembles the previously published reports and highlights the poor prognosis in spite of appropriate antibiotic treatment.

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Meningitis durch Fusobacterium necrophorum Subspecies necrophorum. Fallbeschreibung und Literaturübersicht

Zusammenfassung In der vorliegenden Arbeit wird der Fall eines vorher gesunden fünfjährigen Kindes beschrieben, das an einer Meningitis, verursacht durchFusobacterium necrophorum Subspeciesnecrophorum, verstorben ist. Der Keim wurde aus Liquor und autoptisch entnommenem intrakranialem Eiter in Reinkultur isoliert. Die Rolle vonFusobacterium necrophorum als Meningitiserreger und die Techniken zur Isolierung und Identifikation des Keimes werden diskutiert. Der vorgestellte Fall ähnelt früher publizierten Beschreibungen und verdeutlicht die schlechte Prognose der Infektion auch bei adäquater Antibiotika-Therapie.