Tamoxifen metabolism predicts drug concentrations and outcome in premenopausal patients with early breast cancer

Tamoxifen is the standard-of-care treatment for estrogen receptor-positive premenopausal breast cancer. We examined tamoxifen metabolism via blood metabolite concentrations and germline variations of CYP3A5, CYP2C9, CYP2C19 and CYP2D6 in 587 premenopausal patients (Asians, Middle Eastern Arabs, Caucasian-UK; median age 39 years) and clinical outcome in 306 patients. N-desmethyltamoxifen (DM-Tam)/(Z)-endoxifen and CYP2D6 phenotype significantly correlated across ethnicities (R2: 53%, P<10?77). CYP2C19 and CYP2C9 correlated with norendoxifen and (Z)-4-hydroxytamoxifen concentrations, respectively (P<0.001). DM-Tam was influenced by body mass index (P<0.001). Improved distant relapse-free survival (DRFS) was associated with decreasing DM-Tam/(Z)-endoxifen (P=0.036) and increasing CYP2D6 activity score (hazard ratio (HR)=0.62; 95% confidence interval (CI), 0.43–0.91; P=0.013). Low (<14?nM) compared with high (>35?nM) endoxifen concentrations were associated with shorter DRFS (univariate P=0.03; multivariate HR=1.94; 95% CI, 1.04–4.14; P=0.064). Our data indicate that endoxifen formation in premenopausal women depends on CYP2D6 irrespective of ethnicity. Low endoxifen concentration/formation and decreased CYP2D6 activity predict shorter DRFS

Happiness through leisure

Happiness is important to individuals. If one were to make a judgment based on the vast amount of self-help books available in any bookstore, the conclusion would have to be that happiness is a very important aspect of people’s lives. Whether such books actually provide any solutions to increase happiness is doubtful (Bergsma, 2008). Nevertheless, many are clearly interested in happiness

Happiness Through Vacationing: Just a Temporary Boost or Long-Term Benefits?

Does vacationing add to our happiness in the long run? This question was addressed in a study of 3,650 Dutch citizens who reported their leisure travel every 3 months during 2 years and rated their happiness at the end of each year. Participants who had been on vacation appeared to be marginally happier, in terms of hedonic level of affect, than those who had not. This difference in Affect balance between vacationers and non-vacationers is probably due to a very minor causal effect of vacationing on hedonic level of affect. Possibly, vacationing is positively reminisced and these memories allow for the prevalence of more positive affect in people's lives. Happiness did not predict vacationing. The effect of holiday trips on vacationers' happiness is mostly short-lived; among vacationers, happiness was unrelated to the number of trips and days spent on vacation. A separate analysis of vacationers, who value vacationing most, yielded the same results. Implications for future research are discussed

The importance of the cellular stress response in the pathogenesis and treatment of type 2 diabetes

Organisms have evolved to survive rigorous environments and are not prepared to thrive in a world of caloric excess and sedentary behavior. A realization that physical exercise (or lack of it) plays a pivotal role in both the pathogenesis and therapy of type 2 diabetes mellitus (t2DM) has led to the provocative concept of therapeutic exercise mimetics. A decade ago, we attempted to simulate the beneficial effects of exercise by treating t2DM patients with 3 weeks of daily hyperthermia, induced by hot tub immersion. The short-term intervention had remarkable success, with a 1 % drop in HbA1, a trend toward weight loss, and improvement in diabetic neuropathic symptoms. An explanation for the beneficial effects of exercise and hyperthermia centers upon their ability to induce the cellular stress response (the heat shock response) and restore cellular homeostasis. Impaired stress response precedes major metabolic defects associated with t2DM and may be a near seminal event in the pathogenesis of the disease, tipping the balance from health into disease. Heat shock protein inducers share metabolic pathways associated with exercise with activation of AMPK, PGC1-a, and sirtuins. Diabetic therapies that induce the stress response, whether via heat, bioactive compounds, or genetic manipulation, improve or prevent all of the morbidities and comorbidities associated with the disease. The agents reduce insulin resistance, inflammatory cytokines, visceral adiposity, and body weight while increasing mitochondrial activity, normalizing membrane structure and lipid composition, and preserving organ function. Therapies restoring the stress response can re-tip the balance from disease into health and address the multifaceted defects associated with the disease

Cytokines as mediators of chemotherapy-associated cognitive changes: Current evidence, limitations and directions for future research

10.1371/journal.pone.0081234PLoS ONE812-POLN

Early chronic kidney disease: diagnosis, management and models of care

Chronic kidney disease (CKD) is prevalent in many countries, and the costs associated with the care of patients with end-stage renal disease (ESRD) are estimated to exceed US$1 trillion globally. The clinical and economic rationale for the design of timely and appropriate health system responses to limit the progression of CKD to ESRD is clear. Clinical care might improve if early-stage CKD with risk of progression to ESRD is differentiated from early-stage CKD that is unlikely to advance. The diagnostic tests that are currently used for CKD exhibit key limitations; therefore, additional research is required to increase awareness of the risk factors for CKD progression. Systems modelling can be used to evaluate the impact of different care models on CKD outcomes and costs. The US Indian Health Service has demonstrated that an integrated, system-wide approach can produce notable benefits on cardiovascular and renal health outcomes. Economic and clinical improvements might, therefore, be possible if CKD is reconceptualized as a part of primary care. This Review discusses which early CKD interventions are appropriate, the optimum time to provide clinical care, and the most suitable model of care to adopt

Ecological approaches in veterinary epidemiology: mapping the risk of bat-borne rabies using vegetation indices and night-time light satellite imagery

Rabies remains a disease of significant public health concern. In the Americas, bats are an important source of rabies for pets, livestock, and humans. For effective rabies control and prevention, identifying potential areas for disease occurrence is critical to guide future research, inform public health policies, and design interventions. To anticipate zoonotic infectious diseases distribution at coarse scale, veterinary epidemiology needs to advance via exploring current geographic ecology tools and data using a biological approach. We analyzed bat-borne rabies reports in Chile from 2002 to 2012 to establish associations between rabies occurrence and environmental factors to generate an ecological niche model (ENM). The main rabies reservoir in Chile is the bat species Tadarida brasiliensis; we mapped 726 occurrences of rabies virus variant AgV4 in this bat species and integrated them with contemporary Normalized Difference Vegetation Index (NDVI) data from the Moderate Resolution Imaging Spectroradiometer (MODIS). The correct prediction of areas with rabies in bats and the reliable anticipation of human rabies in our study illustrate the usefulness of ENM for mapping rabies and other zoonotic pathogens. Additionally, we highlight critical issues with selection of environmental variables, methods for model validation, and consideration of sampling bias. Indeed, models with weak or incorrect validation approaches should be interpreted with caution. In conclusion, ecological niche modeling applications for mapping disease risk at coarse geographic scales have a promising future, especially with refinement and enrichment of models with additional information, such as night-time light data, which increased substantially the model’s ability to anticipate human rabies

Body image disturbance and surgical decision making in egyptian post menopausal breast cancer patients

<p>Abstract</p> <p>Background</p> <p>In most developing countries, as in Egypt; postmenopausal breast cancer cases are offered a radical form of surgery relying on their unawareness of the subsequent body image disturbance. This study aimed at evaluating the effect of breast cancer surgical choice; Breast Conservative Therapy (BCT) versus Modified Radical Mastectomy (MRM); on body image perception among Egyptian postmenopausal cases.</p> <p>Methods</p> <p>One hundred postmenopausal women with breast cancer were divided into 2 groups, one group underwent BCT and the other underwent MRM. Pre- and post-operative assessments of body image distress were done using four scales; Breast Impact of Treatment Scale (BITS), Impact of Event Scale (IES), Situational Discomfort Scale (SDS), and Body Satisfaction Scale (BSS).</p> <p>Results</p> <p>Preoperative assessment showed no statistical significant difference regarding cognitive, affective, behavioral and evaluative components of body image between both studied groups. While in postoperative assessment, women in MRM group showed higher levels of body image distress among cognitive, affective and behavioral aspects.</p> <p>Conclusion</p> <p>Body image is an important factor for postmenopausal women with breast cancer in developing countries where that concept is widely ignored. We should not deprive those cases from their right of less mutilating option of treatment as BCT.</p