Thursday, July 31, 2014
Paulsen G, Cumming KT, Hamarsland H, Borsheim E, Berntsen S, Raastad T. Can supplementation with vitamin C and E alter physiological adaptations to strength training? BMC Sports Sci Med Rehabil 2014;6:28. http://www.biomedcentral.com/2052-1847/6/28
BACKGROUND: Antioxidant supplementation has recently been demonstrated to be a double-edged sword, because small to moderate doses of exogenous antioxidants are essential or beneficial, while high doses may have adverse effects. The adverse effects can be manifested in attenuated effects of exercise and training, as the antioxidants may shut down some redox-sensitive signaling in the exercised muscle fibers. However, conditions such as age may potentially modulate the need for antioxidant intake. Therefore, this paper describes experiments for testing the hypothesis that high dosages of vitamin C (1000 mg/day) and E (235 mg/day) have negative effects on adaptation to resistance exercise and training in young volunteers, but positive effects in older men.
METHODS/DESIGN: We recruited a total of 73 volunteers. The participants were randomly assigned to receiving either vitamin C and E supplementation or a placebo. The study design was double-blinded, and the participants followed an intensive training program for 10-12 weeks. Tests and measurements aimed at assessing changes in physical performance (maximal strength) and physiological characteristics (muscle mass), as well as biochemical and cellular systems and structures (e.g., cell signaling and morphology).
DISCUSSION: Dietary supplements, such as vitamin C and E, are used by many people, especially athletes. The users often believe that high dosages of supplements improve health (resistance to illness and disease) and physical performance. These assumptions are, however, generally not supported in the scientific literature. On the contrary, some studies have indicated that high dosages of antioxidant supplements have negative effects on exercise-induced adaptation processes. Since this issue concerns many people and few randomized controlled trials have been conducted in humans, further studies are highly warranted.
Testosterone alters Iron metabolism and Stimulates Red Cell Production Independently of Dihydrotestosterone
Beggs LA, et al. Testosterone alters Iron metabolism and Stimulates Red Cell Production Independently of Dihydrotestosterone. American Journal of Physiology - Endocrinology and Metabolism. http://ajpendo.physiology.org/content/early/2014/07/24/ajpendo.00184.2014.abstract
Testosterone (T) stimulates erythropoiesis and regulates iron homeostasis. However, it remains unknown whether the (type II) 5α-reduction of T to dihydrotestosterone (DHT) mediates these androgenic effects, as it does in some other tissues.
Our purpose was to determine whether inhibition of type II 5α-reductase (via finasteride) alters red blood cell (RBC) production and serum markers of iron homeostasis subsequent to testosterone-enanthate (TE) administration in older hypogonadal men.
Sixty men aged ≥60 years with serum T <300ng/dL or bioavailable T <70ng/dL received treatment with TE (125mg/week) vs. vehicle, paired with finasteride (5mg/day) vs. placebo using a 2x2 factorial design.
Over the course of 12 months, TE increased RBC count 9%, hematocrit 4%, and hemoglobin 8%, while suppressing serum hepcidin 57% (p<0.001 for all measures). Most of the aforementioned changes occurred in the first 3 months of treatment and finasteride co-administration did not significantly alter any of these effects.
TE also reduced serum ferritin 32% (p=0.002) within 3 months of treatment initiation, without altering iron, transferrin or transferrin saturation.
We conclude that TE stimulates erythropoiesis and alters iron homeostasis independently of the type II 5α-reductase enzyme. These results demonstrate that elevated DHT is not required for androgen-mediated erythropoiesis or for alterations in iron homeostasis that would appear to support iron incorporation into RBCs.
Wednesday, July 30, 2014
Low Free Testosterone Levels Predict Disease Reclassification in Men with Prostate Cancer Undergoing Active Surveillance
San Francisco IF, Rojas PA, DeWolf WC, Morgentaler A. Low free testosterone levels predict disease reclassification in men with prostate cancer undergoing active surveillance. BJU International 2014;114(2):229-35. http://onlinelibrary.wiley.com/doi/10.1111/bju.12682/full
Objective To determine whether total testosterone and free testosterone levels predict disease reclassification in a cohort of men with prostate cancer (PCa) on active surveillance (AS).
Patients and Methods Total testosterone and free testosterone concentrations were determined at the time the men began the AS protocol. Statistical analysis was performed using Student's t-test and a chi-squared test to compare groups. Odds ratios (ORs) with 95% confidence intervals (CIs) were obtained using univariate logistic regression. Receiver–operator characteristic curves were generated to determine the investigated testosterone thresholds. Kaplan–Meier curves were used to estimate time to disease reclassification. A Cox proportional hazard regression model was used for multivariate analysis.
Results A total of 154 men were included in the AS cohort, of whom 54 (35%) progressed to active treatment. Men who had disease reclassification had significantly lower free testosterone levels than those who were not reclassified (0.75 vs 1.02 ng/dL, P = 0.03). Men with free testosterone levels <0.45 ng/dL had a higher rate of disease reclassification than patients with free testosterone levels ≥0.45 (P = 0.032). Free testosterone levels <0.45 ng/dL were associated with a several-fold increase in the risk of disease reclassification (OR 4.3, 95% CI 1.25–14.73). Multivariate analysis showed that free testosterone and family history of PCa were independent predictors of disease reclassification.
Conclusions Free testosterone levels were lower in men with PCa who had reclassification during AS. Men with moderately severe reductions in free testosterone level are at increased risk of disease reclassification.
Narayanan R, Ahn S, Cheney MD, et al. Selective Androgen Receptor Modulators (SARMs) Negatively Regulate Triple-Negative Breast Cancer Growth and Epithelial:Mesenchymal Stem Cell Signaling. PLoS One 2014;9(7):e103202. http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0103202
INTRODUCTION: The androgen receptor (AR) is the most highly expressed steroid receptor in breast cancer with 75-95% of estrogen receptor (ER)-positive and 40-70% of ER-negative breast cancers expressing AR. Though historically breast cancers were treated with steroidal androgens, their use fell from favor because of their virilizing side effects and the emergence of tamoxifen. Nonsteroidal, tissue selective androgen receptor modulators (SARMs) may provide a novel targeted approach to exploit the therapeutic benefits of androgen therapy in breast cancer.
MATERIALS AND METHODS: Since MDA-MB-453 triple-negative breast cancer cells express mutated AR, PTEN, and p53, MDA-MB-231 triple-negative breast cancer cells stably expressing wildtype AR (MDA-MB-231-AR) were used to evaluate the in vitro and in vivo anti-proliferative effects of SARMs. Microarray analysis and epithelial:mesenchymal stem cell (MSC) co-culture signaling studies were performed to understand the mechanisms of action.
RESULTS: Dihydrotestosterone and SARMs, but not bicalutamide, inhibited the proliferation of MDA-MB-231-AR. The SARMs reduced the MDA-MB-231-AR tumor growth and tumor weight by greater than 90%, compared to vehicle-treated tumors. SARM treatment inhibited the intratumoral expression of genes and pathways that promote breast cancer development through its actions on the AR. SARM treatment also inhibited the metastasis-promoting paracrine factors, IL6 and MMP13, and subsequent migration and invasion of epithelial:MSC co-cultures.
CONCLUSION: 1. AR stimulation inhibits paracrine factors that are important for MSC interactions and breast cancer invasion and metastasis. 2. SARMs may provide promise as novel targeted therapies to treat AR-positive triple-negative breast cancer.
Krasowski MD, Drees D, Morris CS, Maakestad J, Blau JL, Ekins S. Cross-reactivity of steroid hormone immunoassays: clinical significance and two-dimensional molecular similarity prediction. BMC Clin Pathol 2014;14:33. http://www.biomedcentral.com/1472-6890/14/33
BACKGROUND: Immunoassays are widely used in clinical laboratories for measurement of plasma/serum concentrations of steroid hormones such as cortisol and testosterone. Immunoassays can be performed on a variety of standard clinical chemistry analyzers, thus allowing even small clinical laboratories to do analysis on-site. One limitation of steroid hormone immunoassays is interference caused by compounds with structural similarity to the target steroid of the assay. Interfering molecules include structurally related endogenous compounds and their metabolites as well as drugs such as anabolic steroids and synthetic glucocorticoids.
METHODS: Cross-reactivity of a structurally diverse set of compounds were determined for the Roche Diagnostics Elecsys assays for cortisol, dehydroepiandrosterone (DHEA) sulfate, estradiol, progesterone, and testosterone. These data were compared and contrasted to package insert data and published cross-reactivity studies for other marketed steroid hormone immunoassays. Cross-reactivity was computationally predicted using the technique of two-dimensional molecular similarity.
RESULTS: The Roche Elecsys Cortisol and Testosterone II assays showed a wider range of cross-reactivity than the DHEA sulfate, Estradiol II, and Progesterone II assays. 6-Methylprednisolone and prednisolone showed high cross-reactivity for the cortisol assay, with high likelihood of clinically significant effect for patients administered these drugs. In addition, 21-deoxycortisol likely produces clinically relevant cross-reactivity for cortisol in patients with 21-hydroxylase deficiency, while 11-deoxycortisol may produce clinically relevant cross-reactivity in 11beta-hydroxylase deficiency or following metyrapone challenge. Several anabolic steroids may produce clinically significant false positives on the testosterone assay, although interpretation is limited by sparse pharmacokinetic data for some of these drugs. Norethindrone therapy may impact immunoassay measurement of testosterone in women. Using two-dimensional similarity calculations, all compounds with high cross-reactivity also showed a high degree of similarity to the target molecule of the immunoassay.
CONCLUSIONS: Compounds producing cross-reactivity in steroid hormone immunoassays generally have a high degree of structural similarity to the target hormone. Clinically significant interactions can occur with structurally similar drugs (e.g., prednisolone and cortisol immunoassays; methyltestosterone and testosterone immunoassays) or with endogenous compounds such as 21-deoxycortisol that can accumulate to very high concentrations in certain disease conditions. Simple similarity calculations can help triage compounds for future testing of assay cross-reactivity.
Dupree JM, Langille GM, Khera M, Lipshultz LI. The safety of testosterone supplementation therapy in prostate cancer. Nat Rev Urol;advance online publication. http://www.nature.com/nrurol/journal/vaop/ncurrent/full/nrurol.2014.163.html
Patients with prostate cancer can present with hypogonadism and experience health and quality-of-life declines related to low testosterone levels.
Despite generations of urological dogma suggesting that testosterone supplementation therapy (TST) for hypogonadism causes prostate-cancer progression, a review of the contemporary literature provides evidence to the contrary.
The prostate saturation model suggests that the androgen receptor (AR) is saturated at serum testosterone levels of 150-200 ng/dl, and that additional serum testosterone above this level has limited, if any, effects within the prostate.
Indeed, studies in the modern era of PSA assessments indicate that TST does not affect prostate size, intraprostatic testosterone levels, or prostate-cancer progression, provided the baseline serum testosterone level is greater than this AR saturation point.
However, the body of data on this subject comes from a small number of cases, and TST should only be administered to patients with prostate cancer after thorough discussions of the risks and benefits, with subsequent careful monitoring.
Tuesday, July 29, 2014
An Abrupt Climate Change Scenario and Its Implications for United States National Security
Imagining the Unthinkable
The purpose of this report is to imagine the unthinkable – to push the boundaries of current research on climate change so we may better understand the potential implications on United States national security.
We have interviewed leading climate change scientists, conducted additional research, and reviewed several iterations of the scenario with these experts. The scientists support this project, but caution that the scenario depicted is extreme in two fundamental ways. First, they suggest the occurrences we outline would most likely happen in a few regions, rather than on globally. Second, they say the magnitude of the event may be considerably smaller.
We have created a climate change scenario that although not the most likely, is plausible, and would challenge United States national security in ways that should be considered immediately.
There is substantial evidence to indicate that significant global warming will occur during the 21st century. Because changes have been gradual so far, and are projected to be similarly gradual in the future, the effects of global warming have the potential to be manageable for most nations. Recent research, however, suggests that there is a possibility that this gradual global warming could lead to a relatively abrupt slowing of the ocean’s thermohaline conveyor, which could lead to harsher winter weather conditions, sharply reduced soil moisture, and more intense winds in certain regions that currently provide a significant fraction of the world’s food production. With inadequate preparation, the result could be a significant drop in the human carrying capacity of the Earth’s environment.
The research suggests that once temperature rises above some threshold, adverse weather conditions could develop relatively abruptly, with persistent changes in the atmospheric circulation causing drops in some regions of 5-10 degrees Fahrenheit in a single decade. Paleoclimatic evidence suggests that altered climatic patterns could last for as much as a century, as they did when the ocean conveyor collapsed 8,200 years ago, or, at the extreme, could last as long as 1,000 years as they did during the Younger Dryas, which began about 12,700 years ago.
In this report, as an alternative to the scenarios of gradual climatic warming that are so common, we outline an abrupt climate change scenario patterned after the 100- year event that occurred about 8,200 years ago. This abrupt change scenario is characterized by the following conditions:
• Annual average temperatures drop by up to 5 degrees Fahrenheit over Asia and North America and 6 degrees Fahrenheit in northern Europe
• Annual average temperatures increase by up to 4 degrees Fahrenheit in key areas throughout Australia, South America, and southern Africa.
• Drought persists for most of the decade in critical agricultural regions and in the water resource regions for major population centers in Europe and eastern North America.
• Winter storms and winds intensify, amplifying the impacts of the changes. Western Europe and the North Pacific experience enhanced winds.
The report explores how such an abrupt climate change scenario could potentially de-stabilize the geo-political environment, leading to skirmishes, battles, and even war due to resource constraints such as:
1) Food shortages due to decreases in net global agricultural production
2) Decreased availability and quality of fresh water in key regions due to shifted precipitation patters, causing more frequent floods and droughts
3) Disrupted access to energy supplies due to extensive sea ice and storminess
As global and local carrying capacities are reduced, tensions could mount around the world, leading to two fundamental strategies: defensive and offensive. Nations with the resources to do so may build virtual fortresses around their countries, preserving resources for themselves. Less fortunate nations especially those with ancient enmities with their neighbors, may initiate in struggles for access to food, clean water, or energy. Unlikely alliances could be formed as defense priorities shift and the goal is resources for survival rather than religion, ideology, or national honor.
This scenario poses new challenges for the United States, and suggests several steps to be taken:
• Improve predictive climate models to allow investigation of a wider range of scenarios and to anticipate how and where changes could occur
• Assemble comprehensive predictive models of the potential impacts of abrupt climate change to improve projections of how climate could influence food, water, and energy
• Create vulnerability metrics to anticipate which countries are most vulnerable to climate change and therefore, could contribute materially to an increasingly disorderly and potentially violent world.
• Identify no-regrets strategies such as enhancing capabilities for water management
• Rehearse adaptive responses
• Explore local implications
• Explore geo-engineering options that control the climate.
There are some indications today that global warming has reached the threshold where the thermohaline circulation could start to be significantly impacted. These indications include observations documenting that the North Atlantic is increasingly being freshened by melting glaciers, increased precipitation, and fresh water runoff making it substantially less salty over the past 40 years.
This report suggests that, because of the potentially dire consequences, the risk of abrupt climate change, although uncertain and quite possibly small, should be elevated beyond a scientific debate to a U.S. national security concern.