The effects of breast cancer therapy on estrogen receptor signaling throughout the body

Upon activation by estrogen, the Estrogen Receptor binds the chromatin and influences gene transcription. This ultimately leads to cell proliferation. About 75% of breast cancer patients express this hormonal receptor. These patients are often treated with tamoxifen, which competitively inhibits the proliferative effects of estrogen in breast cancer cells. While tamoxifen inhibits the tumor growth of breast cancer, its effects in other Estrogen Receptor-positive tissues vary, as reviewed in chapter 1. Its most adverse side-effect is that it increases the risk for endometrial cancer. Chapters 2 and 3 describe the effects of tamoxifen on the DNA binding sites of the Estrogen Receptor in tamoxifen-associated endometrial cancer, and the similarities of these binding sites with those found in breast cancer. Unfortunately, there are Estrogen Receptor-positive breast cancer patients who do not respond to hormonal treatment. Chapter 4 reveals a key-role for activating transcription factor 2 on tamoxifen’s inhibitory response on cell proliferation. Chapter 5 discusses components of the Estrogen Receptor pathway and highlights their potential as biomarkers in hormonal response therapy. Finally, chapter 6 provides new questions invoked by this thesis, and discusses the importance of unraveling the Estrogen Receptor pathway in multiple tissues in order to develop tailor-made treatments.  Pink Ribbon; KWF Dutch Cancer Society, the Netherlands; Organisation of Scientific Research (NWO), Top Institute Pharma, A Sister's HopeLUMC / Geneeskund

Effects of supervised exercise training on lower-limb cutaneous microvascular reactivity in adults with venous ulcers

Purpose: To investigate the effects of a 12-week supervised exercise programme on lower-limb cutaneous microvascular reactivity in adults with venous leg ulceration. Methods: Thirty-eight adults with unilateral venous ulceration who were being treated with lower-limb compression therapy (58% male; mean age 65 years; median ulcer size 5 cm2) were randomly allocated to exercise or control groups. Exercise participants (n=18) were invited to attend thrice weekly sessions of lower-limb aerobic and resistance exercise for 12 weeks. Cutaneous microvascular reactivity was assessed in the gaiter region of ulcerated and non-ulcerated legs at baseline and 3 months using laser Doppler fluxmetry coupled with iontophoresis of acetylcholine (ACh) and sodium nitroprusside (SNP). Cutaneous vascular conductance (CVC) was calculated as laser Doppler flux (AU)/mean arterial pressure (mmHg). Results: Thirty-seven participants completed follow-up assessments. Median class attendance was 36 (range 2 to 36). Analyses of covariance revealed greater peak CVC responses to ACh in the exercise group at 3 months in both the ulcerated (adjusted difference = 0.944 AU/mmHg; 95% CI 0.504 to 1.384) and non-ulcerated (adjusted difference = 0.596 AU/mmHg; 95% CI 0.028 to 1.164) legs. Peak CVC responses to SNP were also greater in the exercise group at 3 months in the ulcerated leg (adjusted difference = 0.882 AU/mmHg; 95% CI 0.274 to 1.491), but not the non-ulcerated leg (adjusted difference = 0.392 AU/mmHg; 95% CI -0.377 to 1.161). Conclusion: Supervised exercise training improves lower-limb cutaneous microvascular reactivity in adults with venous leg ulceration. Keywords Randomized controlled trial; Exercise; Ulceration; Vascular function; Laser Doppler fluxmetry; Iontophoresi

Challenges with coverage with evidence development schemes for medical devices: A systematic review

Objectives: Coverage with evidence development (CED) schemes are particularly relevant for medical devices (MDs), since clinical evidence is often limited at the time of launch and their long-term (cost-) effectiveness heavily depends on how they are adopted into routine clinical practice. The objective of this study was to identify and describe the challenges that payers and manufacturers might face when assessing the desirability of, choosing the research design for, implementing, and evaluating CED schemes for MDs. Methods: A systematic literature review was performed on six databases following PRISMA guidelines. Two independent reviewers assessed the eligibility of studies based on predefined criteria and extracted data from the included articles by using a pre-defined extraction template. The data were synthesised in a narrative review. Results: The systematic search yielded 4293 articles of which 27 were eligible for inclusion. We identified 20 challenges that are associated with CED schemes for MDs. Five of these challenges relate directly to the characteristics of MDs, and hence are specific to MDs. These challenges concern deciding on whether a CED scheme is required, understanding the relevant uncertainties and risks, identifying meaningful outcomes, defining an adequate duration for a scheme, and market entry of new technologies. Conclusions: Payers and manufacturers of MDs have to address the identified challenges to improve a CED scheme's chance of success. This can be further improved by public sharing of information about the outcome of applied schemes and way in which stakeholders have addressed the challenges they faced when applying a CED scheme

Increasing vegetable intakes: rationale and systematic review of published interventions

Purpose While the health benefits of a high fruit and vegetable consumption are well known and considerable work has attempted to improve intakes, increasing evidence also recognises a distinction between fruit and vegetables, both in their impacts on health and in consumption patterns. Increasing work suggests health benefits from a high consumption specifically of vegetables, yet intakes remain low, and barriers to increasing intakes are prevalent making intervention difficult. A systematic review was undertaken to identify from the published literature all studies reporting an intervention to increase intakes of vegetables as a distinct food group. Methods Databases—PubMed, PsychInfo and Medline—were searched over all years of records until April 2015 using pre-specified terms. Results Our searches identified 77 studies, detailing 140 interventions, of which 133 (81 %) interventions were conducted in children. Interventions aimed to use or change hedonic factors, such as taste, liking and familiarity (n = 72), use or change environmental factors (n = 39), use or change cognitive factors (n = 19), or a combination of strategies (n = 10). Increased vegetable acceptance, selection and/or consumption were reported to some degree in 116 (83 %) interventions, but the majority of effects seem small and inconsistent. Conclusions Greater percent success is currently found from environmental, educational and multi-component interventions, but publication bias is likely, and long-term effects and cost-effectiveness are rarely considered. A focus on long-term benefits and sustained behaviour change is required. Certain population groups are also noticeably absent from the current list of tried interventions

Ergocalciferol and Microcirculatory Function in Chronic Kidney Disease and Concomitant Vitamin D Deficiency: An Exploratory, Double Blind, Randomised Controlled Trial

Vitamin D deficiency and endothelial dysfunction are non-traditional risk factors for cardiovascular events in chronic kidney disease. Previous studies in chronic kidney disease have failed to demonstrate a beneficial effect of vitamin D on arterial stiffness, left ventricular mass and inflammation but none have assessed the effect of vitamin D on microcirculatory endothelial function.We conducted a randomised controlled trial of 38 patients with non diabetic chronic kidney disease stage 3-4 and concomitant vitamin D deficiency (<16 ng/dl) who received oral ergocalciferol (50,000 IU weekly for one month followed by 50,000 IU monthly) or placebo over 6 months. The primary outcome was change in microcirculatory function measured by laser Doppler flowmetry after iontophoresis of acetylcholine. Secondary endpoints were tissue advanced glycation end products, sublingual functional capillary density and flow index as well as macrovascular parameters. Parallel in vitro experiments were conducted to determine the effect of ergocalciferol on cultured human endothelial cells.Twenty patients received ergocalciferol and 18 patients received placebo. After 6 months, there was a significant improvement in the ergocalciferol group in both endothelium dependent microcirculatory vasodilatation after iontophoresis of acetylcholine (p = 0.03) and a reduction in tissue advanced glycation end products (p = 0.03). There were no changes in sublingual microcirculatory parameters. Pulse pressure (p = 0.01) but not aortic pulse wave velocity was reduced. There were no significant changes in bone mineral parameters, blood pressure or left ventricular mass index suggesting that ergocalciferol improved endothelial function independently of these parameters. In parallel experiments, expression of endothelial nitric oxide synthase and activity were increased in human endothelial cells in a dose dependent manner.Ergocalciferol improved microcirculatory endothelial function in patients with chronic kidney disease and concomitant vitamin D deficiency. This process may be mediated through enhanced expression and activity of endothelial nitric oxide synthase.Clinical trials.gov NCT00882401

Ethnic differences in stillbirth and early neonatal mortality in The Netherlands

Background: Ethnic disparities in perinatal mortality are well known. This study aimed to explore the contribution of demographic, socioeconomic, health behavioural and pre-existent medical risk factors among different ethnic groups on fetal and early neonatal mortality. Methods: We assessed perinatal mortality from 24.0 weeks' gestation onwards in 554 234 singleton pregnancies of nulliparous women in the linked Netherlands Perinatal Registry over the period 2000–2006. Logistic regression modelling was used. Results: Considerable ethnic differences in perinatal mortality exist especially in fetal mortality. Maternal age, socioeconomic status and pre-existent diseases could not explain these ethnic differences. Late booking visit could explain some differences. Compared with the Dutch, African women had an increased fetal mortality risk of OR 1.7 (95% CI 1.4 to 2.1); South Asian women, 1.8 (1.4 to 2.3); other non-Western women, 1.3 (1.1 to 1.6) and Turkish/Moroccan women, 1.3 (1.1 to 1.4). The risk on early neonatal mortality was only increased in other non-Western women, OR 1.3 (1.0 to 1.8). Ethnic differences were even present in the women without risk factors including preterm births. Mortality risk for East Asian and other Western women was lower or comparable with the Dutch. Conclusion: Important ethnic differences in fetal mortality exist, especially among women of African and South Asian origin. Ethnic minorities should be more acquainted with the significance of early start of prenatal care. Tailored prenatal care for women with African and South Asian origin seems necessary. More research on underlying cause of deaths is needed by ethnic group.A C J Ravelli, M Tromp, M Eskes, J C Droog, J A M van der Post, K J Jager, B W Mol, J B Reitsm

Presentation and validation of the Abbreviated Self Completion Teen-Addiction Severity Index (ASC T-ASI): A preference-based measure for use in health-economic evaluations

Economic evaluations of new youth mental health interventions require preference-based outcome measures that capture the broad benefits these interventions can have for adolescents. The Abbreviated Self Completion Teen-Addiction Severity Index (ASC T-ASI) was developed to meet the need for such a broader measure. It assesses self reported problems in seven important domains of adolescents’ lives, including school performance and family relationships, an

Detecting Summary-worthy Sentences: the Effect of Discourse Features

We examine the benefit of a variety of discourse and semantic features for the identification of summary-worthy content in narrative stories. Using logistic regression models, we find that the most informative features are those that relate to the narrative structure of a text. We show that automatic methods for feature extraction perform significantly worse than full manual annotation, but that with optimization, a fully automatic approach can outperform a variety of existing extractive approaches to summarization