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Nice Guys Finish Last

Showing a happy face is considered essential to any friendly social interaction, including those involving sexual attraction. Yet few studies have examined whether a happy expression is, in fact, attractive. Are women interested in men who smile, or do they prefer men who appear confident? Do men seek happy women, or are they more drawn to those who are demure, averting their gaze and showing shame? Given that most social interactions entail the spontaneous display of emotion expressions, and are, to some extent, guided by judgments of attractiveness, it is likely that emotion expressions have some impact on attractiveness. Furthermore, although emotion expressions tend to be fleeting, they are often perceived as indicators of the expresser’s dispositional qualities, and some have argued that they evolved in part to serve this broader communicative function. Yet, previous research has not systematically addressed the question of how distinct emotion expressions influence sexual attractiveness.

The present research examined whether three emotion expressions known to be cross culturally recognized and to communicate information relevant to an individual’s mate value (i.e., information that should influence attractiveness) have reliable effects on the perceived sexual attractiveness of targets showing them. Specifically, we compared attractiveness judgments made for individuals displaying expressions of happiness, pride, and shame, as well as a neutral control. All three of these expressions show evidence of cross-cultural universality, suggesting evolutionary origins, and convey important social information relevant to mating and romantic relationships.

Pride signals the expresser’s high status; studies have shown that individuals displaying pride are automatically perceived as higher status than individuals showing a range of other emotions (including shame, happiness, and neutral), and this signaling function generalizes across cultures.

Shame, an appeasement display, signals both the expresser’s low status and his/her awareness that he/she has violated a social norm; the adaptive benefit of this message may lie in its communication of the expresser’s regret and implied submission to social norms.

Happiness communicates the expresser’s friendliness and approachability; happy displays tend to elicit trust and approach-oriented behaviors in onlookers.

All of these messages may influence attractiveness, but, given evidence for gender-specific mating strategies, they may do so in different ways for male and female expressers.


Tracy JL, Beall A. Nice guys finish last: The impact of emotion expressions on sexual attraction. Emotion (in press). http://ubc-emotionlab.ca/wp-content/uploads/2006/10/Happy-Guys...in-pres-Emotion.pdf

This research examined the relative sexual attractiveness of individuals showing emotion expressions of happiness, pride, and shame, compared with a neutral control. Across two studies using different images and samples ranging broadly in age (total N = 1041), a large gender difference emerged in the sexual attractiveness of happy displays: happiness was the most attractive female emotion expression, and one of the least attractive in males. In contrast, pride showed the reverse pattern; it was the most attractive male expression, and one of the least attractive in women. Shame displays were relatively attractive in both genders, and, among younger adults, male shame was more attractive than male happiness, and not substantially less than male pride. Effects were largely consistent with evolutionary and socio-cultural-norm accounts. Overall, this research provides the first evidence that distinct emotion expressions have divergent effects on sexual attractiveness, which vary by gender but largely hold across age.
 
This review examines androgen endocrine physiology (i.e. testosterone and the androgen receptor [AR]) and its relationship to resistance exercise and training. Knowledge of the general testosterone physiology is important because it is the foundation for understanding the physiological implications of changes in testosterone and AR concentrations. The first section provides an overview of testosterone production and the signals for testosterone production and release. The next section examines the biological effects of testosterone including transport, signaling, and physiological functions with special attention given to the importance of testosterone for normal muscle development and maintenance. Finally, the acute and chronic testosterone and AR responses to resistance exercise and training is discussed with the focus on upper regulatory elements: acute exercise programme variable domains, sex, and age.


Vingren JL, Kraemer WJ, Ratamess NA, Anderson JM, Volek JS, Maresh CM. Testosterone physiology in resistance exercise and training: the up-stream regulatory elements. Sports Med 2010;40(12):1037-53. Testosterone physiology in resistance exercise and... [Sports Med. 2010] - PubMed result

Testosterone is one of the most potent naturally secreted androgenic-anabolic hormones, and its biological effects include promotion of muscle growth. In muscle, testosterone stimulates protein synthesis (anabolic effect) and inhibits protein degradation (anti-catabolic effect); combined, these effects account for the promotion of muscle hypertrophy by testosterone. These physiological signals from testosterone are modulated through the interaction of testosterone with the intracellular androgen receptor (AR). Testosterone is important for the desired adaptations to resistance exercise and training; in fact, testosterone is considered the major promoter of muscle growth and subsequent increase in muscle strength in response to resistance training in men. The acute endocrine response to a bout of heavy resistance exercise generally includes increased secretion of various catabolic (breakdown-related) and anabolic (growth-related) hormones including testosterone. The response of testosterone and AR to resistance exercise is largely determined by upper regulatory elements including the acute exercise programme variable domains, sex and age. In general, testosterone concentration is elevated directly following heavy resistance exercise in men. Findings on the testosterone response in women are equivocal with both increases and no changes observed in response to a bout of heavy resistance exercise. Age also significantly affects circulating testosterone concentrations. Until puberty, children do not experience an acute increase in testosterone from a bout of resistance exercise; after puberty some acute increases in testosterone from resistance exercise can be found in boys but not in girls. Aging beyond 35-40 years is associated with a 1-3% decline per year in circulating testosterone concentration in men; this decline eventually results in the condition known as andropause. Similarly, aging results in a reduced acute testosterone response to resistance exercise in men. In women, circulating testosterone concentration also gradually declines until menopause, after which a drastic reduction is found. In summary, testosterone is an important modulator of muscle mass in both men and women and acute increases in testosterone can be induced by resistance exercise. In general, the variables within the acute programme variable domains must be selected such that the resistance exercise session contains high volume and metabolic demand in order to induce an acute testosterone response.
 
In both men and women, the majority of circulating testosterone is bound to proteins. In healthy adult men, about 98% of circulating testosterone is bound to serum proteins, primarily sex hormone-binding globulin (SHBG) and albumin, whereas only 1-2% of serum testosterone is free of bound protein. Albumin-bound testosterone and free testosterone are referred to as bioavailable testosterone. A significant correlation between salivary and serum free testosterone has been demonstrated in healthy subjects, indicating that salivary testosterone can be a good index of serum free testosterone. Due to these reasons, salivary testosterone has recently attracted attention for use in the evaluation of physiological and pathological conditions based on steroid assays.

Among the steroid assays, immunoassay-based methods for salivary testosterone evaluation are known to be unsatisfactory due to cross-reactivity between a variety of endogenous materials, and the measured values often overestimate the true concentrations, especially at the low levels of testosterone typically found in women, children, men with androgen deficiencies, and patients undergoing anti-androgenic therapies. To circumvent these problems, LC MS/MS assay has been used as a highly specific and sensitive tool for evaluating salivary testosterone in healthy adults in Japan or USA, using protocols specified by the Federal Drug Administration (FDA).

The aims of the present study were to validate the LC ESI MS/MS method for measuring testosterone concentrations in saliva samples from both sexes and to quantify the salivary testosterone levels in Korean adults.


Lee S, Kwon S, Shin HJ, et al. Quantitative measurement of salivary testosterone in Korean adults by stable isotope-dilution liquid chromatography electrospray-tandem mass spectrometry. BMB Rep 2010;43(11):761-5. http://www.bmbreports.org/fulltext/bmbreports/view.php?vol=43&page=761

Salivary testosterone levels in Korean adults were quantitatively measured for the first time by liquid chromatography-electrospray-tandem mass spectrometry (LC ESI MS/MS). Salivary testosterone was separated on a multiple reaction monitoring (MRM) chromatogram within 7 min. The LC ESI MS/MS assay was validated over the linearity range of 0.01-2.00 ng/ml (r=0.99987) using testosterone-d(3) as an internal standard. The lower limit of quantification (LOQ) was 0.01 ng/ml. The intra- and inter-assay precisions were 1.54% to 4.09% and 0.96% to 4.29%, respectively. The mean recovery was 93.32% (range 88.43-98.05%). The validated assay was then applied to measure the salivary testosterone levels of Korean adults. In men, the salivary testosterone level collected between 9:00-11:00 am was approximately 2.8 times higher than that in women (P < 0.0001). Salivary testosterone levels in both sexes negatively correlated with age. The present assay would also be useful in measuring salivary testosterone levels in clinical laboratories.
 
Paton CD, Lowe T, Irvine A. Caffeinated chewing gum increases repeated sprint performance and augments increases in testosterone in competitive cyclists. Eur J Appl Physiol 2010;110(6):1243-50. Caffeinated chewing gum increases repeated sprint ... [Eur J Appl Physiol. 2010] - PubMed result

This investigation reports the effects of caffeinated chewing gum on fatigue and hormone response during repeated sprint performance with competitive cyclists. Nine male cyclists (mean +/- SD, age 24 +/- 7 years, VO(2max) 62.5 +/- 5.4 mL kg(-1) min(-1)) completed four high-intensity experimental sessions, consisting of four sets of 30 s sprints (5 sprints each set). Caffeine (240 mg) or placebo was administered via chewing gum following the second set of each experimental session. Testosterone and cortisol concentrations were assayed in saliva samples collected at rest and after each set of sprints. Mean power output in the first 10 sprints relative to the last 10 sprints declined by 5.8 +/- 4.0% in the placebo and 0.4 +/- 7.7% in the caffeine trials, respectively. The reduced fatigue in the caffeine trials equated to a 5.4% (90% confidence limit +/-3.6%, effect size 0.25; +/-0.16) performance enhancement in favour of caffeine. Salivary testosterone increased rapidly from rest (~53%) and prior to treatments in all trials. Following caffeine treatment, testosterone increased by a further 12 +/- 14% (ES 0.50; +/- 0.56) relative to the placebo condition. In contrast, cortisol concentrations were not elevated until after the third exercise set; following the caffeine treatment cortisol was reduced by 21 +/- 31% (ES -0.30; +/- 0.34) relative to placebo. The acute ingestion of caffeine via chewing gum attenuated fatigue during repeated, high-intensity sprint exercise in competitive cyclists. Furthermore, the delayed fatigue was associated with substantially elevated testosterone concentrations and decreased cortisol in the caffeine trials.
 
Occasional Physical, Sexual Activity Associated With Short-Term Increased Risk of Heart Attack
Occasional physical, sexual activity associated with short-term increased risk of heart attack

ScienceDaily (Mar. 22, 2011) — An analysis of previous studies that examined whether episodic physical activity and sexual activity can act as a trigger for cardiac events found an association between these activities and a short-term increased risk of heart attack and sudden cardiac death, although the absolute risk was small and lessened among persons with high levels of regular physical activity, according to an article in the March 23/30 issue of JAMA.

Acute cardiac events are a major cause of illness and death, with as many as a million acute myocardial infarctions (MIs; heart attacks) and 300,000 cardiac arrests occurring in the United States each year. "Regular physical activity has been identified as strongly associated with a decreased risk of cardiovascular disease and related mortality. Despite the well-established benefits of regular physical activity, anecdotal evidence has suggested that physical activity, as well as other acute exposures, such as sexual activity and psychological stress, can act as triggers of acute cardiac events," the authors write.

Issa J. Dahabreh, M.D., of Tufts Medical Center, Boston, and Jessica K. Paulus, Sc.D., of Tufts University, Medford, Mass., and the Harvard School of Public Health, Boston, conducted a systematic review and meta-analysis to examine the association between episodic physical activity and sexual activity and acute cardiac events and also the interaction of regular physical activity levels with the triggering effect of these exposures. The researchers identified 14 studies that met criteria for inclusion in the analysis.

The researchers found that overall, the studies suggested an association (3.5 times increased risk) between episodic physical activity and heart attack. Also, there was evidence of an increase in the risk of sudden cardiac death (SCD) triggered by episodic physical exertion. Overall, episodic sexual activity was associated with a 2.7 times increased risk of heart attack. The authors also found that because these exposures of episodic physical exertion and sexual activity are infrequent, the absolute risk of these activities triggering an event is small.

Subgroups of patients with higher habitual activity levels tended to be less susceptible to the triggering effect of episodic physical activity. Analysis indicated that the relative risk of heart attack triggered by episodic physical activity was decreased by approximately 45 percent, and SCD 30 percent, for each additional time per week a person was habitually exposed to physical activity.

"Habitual activity levels significantly affected the association of episodic physical activity and MI, episodic physical activity and SCD, and sexual activity and MI; in all cases, individuals with lower habitual activity levels had an increased relative risk for the triggering effect," the authors write.

"In conclusion, based on our review of 14 case-crossover studies of acute cardiac events, we found a significant association between episodic physical and sexual activity and MI and suggestive evidence of an association between episodic physical activity and SCD. Most importantly, these associations appear to be strongly modified by habitual physical activity, with individuals with higher habitual activity levels experiencing much smaller increases in risk compared with individuals with low activity levels. In view of this, as well as the small absolute magnitude of the risk associated with acute exposure to episodic physical or sexual activity, our findings should not be misinterpreted as indicating a net harm of physical or sexual activity; instead they demonstrate that these exposures are associated with a temporary short-term increase in the risk of acute cardiac events.”


Dahabreh IJ, Paulus JK. Association of Episodic Physical and Sexual Activity With Triggering of Acute Cardiac Events. JAMA: The Journal of the American Medical Association 2011;305(12):1225-33. Association of Episodic Physical and Sexual Activity With Triggering of Acute Cardiac Events, March 23/30, 2011, Dahabreh and Paulus 305 (12): 1225 — JAMA

Context - Evidence has suggested that physical and sexual activity might be triggers of acute cardiac events.

Objective - To assess the effect of episodic physical and sexual activity on acute cardiac events using data from case-crossover studies.

Data Sources - MEDLINE and EMBASE (through February 2, 2011) and Web of Science (through October 6, 2010).

Study Selection - Case-crossover studies investigating the association between episodic physical or sexual activity and myocardial infarction (MI) or sudden cardiac death (SCD).

Data Extraction - Two reviewers extracted descriptive and quantitative information from each study. We calculated summary relative risks (RRs) using random-effects meta-analysis and absolute event rates based on US data for the incidence of MI and SCD. We used the Fisher P value synthesis method to test whether habitual physical activity levels modify the triggering effect and meta-regression to quantify the interaction between habitual levels of physical activity and the triggering effect.

Results - We identified 10 studies investigating episodic physical activity, 3 studies investigating sexual activity, and 1 study investigating both exposures. The outcomes of interest were MI (10 studies), acute coronary syndrome (1 study), and SCD (3 studies). Episodic physical and sexual activity were associated with an increase in the risk of MI (RR = 3.45; 95% confidence interval [CI], 2.33-5.13, and RR = 2.70; 95% CI, 1.48-4.91, respectively). Episodic physical activity was associated with SCD (RR = 4.98; 95% CI, 1.47-16.91). The effect of triggers on the absolute rate of events was limited because exposure to physical and sexual activity is infrequent and their effect is transient; the absolute risk increase associated with 1 hour of additional physical or sexual activity per week was estimated as 2 to 3 per 10 000 person-years for MI and 1 per 10 000 person-years for SCD. Habitual activity levels significantly affected the association of episodic physical activity and MI (P < .001), episodic physical activity and SCD (P < .001), and sexual activity and MI (P = .04); in all cases, individuals with lower habitual activity levels had an increased RR for the triggering effect. For every additional time per week an individual was habitually exposed to physical activity, the RR for MI decreased by approximately 45%, and the RR for SCD decreased by 30%.

Conclusion - Acute cardiac events were significantly associated with episodic physical and sexual activity; this association was attenuated among persons with high levels of habitual physical activity.
 
Thats right in there with the guy whos only exercise is shoveling out his driveway once a year after the big snowstorm and keels over.
 
Metabolic diseases are often present for years before becoming clinically apparent. For instance, by the time relative insulin deficiency manifests as hyperglycemia and a diagnosis of type 2 diabetes is made, considerable pancreatic beta cell insufficiency has already occurred. Current clinical and laboratory predictors such as body mass index or fasting glucose can be helpful in gauging diabetes risk, but they often reflect extant disease, are most useful when assayed in temporal proximity to the development of overt diabetes and may provide little additional insight regarding pathophysiologic mechanisms. Given the availability of effective interventions for delaying or preventing the onset of type 2 diabetes and the increasing burden of the condition worldwide, earlier identification of individuals at risk is particularly crucial.

Emerging technologies have made it more feasible to acquire high-throughput profiles of a whole organism’s metabolic status (metabolite profiling, or metabolomics). These techniques, which allow assessment of large numbers of metabolites that are substrates and products in metabolic pathways, are particularly relevant for studying metabolic diseases such as diabetes. Furthermore, in addition to serving as potential biomarkers of disease, metabolites may have unanticipated roles as regulatory signals with hormone-like functions or effectors of the disease process itself.

Recent cross-sectional studies have documented differences in blood metabolite profiles before and after glucose loading and in obese compared with lean individuals. These studies have noted differences in the abundance of C3 and C5 acylcarnitines, glutamine and glutamate, additional amino acids and other small molecules. These observations raise the possibility that alterations in plasma metabolite concentrations could presage the onset of overt diabetes and therefore aid in the identification of at-risk individuals by adding information over standard clinical markers. Researchers performed metabolite profiling in participants from two large, longitudinal studies, with the goal of identifying early pathophysiological changes that might also serve as new predictors of future diabetes.


Wang TJ, Larson MG, Vasan RS, et al. Metabolite profiles and the risk of developing diabetes. Nat Med. Metabolite profiles and the risk of developing diabetes : Nature Medicine : Nature Publishing Group

Emerging technologies allow the high-throughput profiling of metabolic status from a blood specimen (metabolomics). We investigated whether metabolite profiles could predict the development of diabetes. Among 2,422 normoglycemic individuals followed for 12 years, 201 developed diabetes. Amino acids, amines and other polar metabolites were profiled in baseline specimens by liquid chromatography–tandem mass spectrometry (LC-MS). Cases and controls were matched for age, body mass index and fasting glucose. Five branched-chain and aromatic amino acids had highly significant associations with future diabetes: isoleucine, leucine, valine, tyrosine and phenylalanine. A combination of three amino acids predicted future diabetes (with a more than fivefold higher risk for individuals in top quartile). The results were replicated in an independent, prospective cohort. These findings underscore the potential key role of amino acid metabolism early in the pathogenesis of diabetes and suggest that amino acid profiles could aid in diabetes risk assessment.
 
Because the prevalence of primary hypothyroidism is high among the general population, levothyroxine sodium is one of the most prescribed medications. Absorption of levothyroxine is approximately 70% to 80% and occurs in the small bowel. There is consensus that levothyroxine should be taken before breakfast to prevent interference of its intestinal uptake by food or other medications. In our clinics, we observed several patients whose thyroid hormone levels improved markedly after changing the scheduled intake of levothyroxine to bedtime. A pilot study confirmed this observation among 11 patients. The mean (SD) plasma thyrotropin level significantly decreased from 5.1 (0.9) to 1.2 (0.3) mIU/L (to convert thyrotropin level to micrograms per liter, multiply by 1.0), and free thyroxine (FT4) and triiodothyronine (T3) levels increased when levothyroxine was taken at bedtime. The circadian pattern of thyrotropin rhythm remained intact, which was important regarding the time of blood sampling for thyrotropin levels to monitor levothyroxine therapy.

Accordingly, researchers conducted a randomized double-blind crossover trial to confirm whether levothyroxine taken at bedtime leads to lower thyrotropin and higher FT4 and T3 levels. Hypothyroidism can have major effects on health and quality of life (QOL), as it is associated with fatigue, weight gain, cold intolerance, depression, neuromuscular symptoms, diastolic dysfunction, and impairment of renal function. It is also associated with risk factors for cardiovascular disease, such as hyperlipidemia, hyperhomocystinemia, and arterial hypertension, notably in the case of insufficient thyroid hormone supplementation.

The primary objective of this study was to determine whether a change occurred in thyrotropin and thyroid hormone levels when levothyroxine was taken at bedtime vs in the morning. Researchers further investigated whether a bedtime regimen would affect creatinine and lipid levels, body mass index, heart rate, and QOL.


Bolk N, Visser TJ, Nijman J, Jongste RNIJ, Tijssen JGP, Berghout A. Effects of Evening vs Morning Levothyroxine Intake: A Randomized Double-blind Crossover Trial. Arch Intern Med 2010;170(22):1996-2003. Arch Intern Med -- Abstract: Effects of Evening vs Morning Levothyroxine Intake: A Randomized Double-blind Crossover Trial, Dec 13/27, 2010, Bolk et al. 170 (22): 1996

Background - Levothyroxine sodium is widely prescribed to treat primary hypothyroidism. There is consensus that levothyroxine should be taken in the morning on an empty stomach. A pilot study showed that levothyroxine intake at bedtime significantly decreased thyrotropin levels and increased free thyroxine and total triiodothyronine levels. To date, no large randomized trial investigating the best time of levothyroxine intake, including quality-of-life evaluation, has been performed.

Methods - To ascertain if levothyroxine intake at bedtime instead of in the morning improves thyroid hormone levels, a randomized double-blind crossover trial was performed between April 1, 2007, and November 30, 2008, among 105 consecutive patients with primary hypothyroidism at Maasstad Hospital Rotterdam in the Netherlands. Patients were instructed during 6 months to take 1 capsule in the morning and 1 capsule at bedtime (one containing levothyroxine and the other a placebo), with a switch after 3 months. Primary outcome measures were thyroid hormone levels; secondary outcome measures were creatinine and lipid levels, body mass index, heart rate, and quality of life.

Results - Ninety patients completed the trial and were available for analysis. Compared with morning intake, direct treatment effects when levothyroxine was taken at bedtime were a decrease in thyrotropin level of 1.25 mIU/L (95% confidence interval [CI], 0.60-1.89 mIU/L; P < .001), an increase in free thyroxine level of 0.07 ng/dL (0.02-0.13 ng/dL; P = .01), and an increase in total triiodothyronine level of 6.5 ng/dL (0.9-12.1 ng/dL; P = .02) (to convert thyrotropin level to micrograms per liter, multiply by 1.0; free thyroxine level to picomoles per liter, multiply by 12.871; and total triiodothyronine level to nanomoles per liter, multiply by 0.0154). Secondary outcomes, including quality-of-life questionnaires (36-Item Short Form Health Survey, Hospital Anxiety and Depression Scale, 20-Item Multidimensional Fatigue Inventory, and a symptoms questionnaire), showed no significant changes between morning vs bedtime intake of levothyroxine.

Conclusions - Levothyroxine taken at bedtime significantly improved thyroid hormone levels. Quality-of-life variables and plasma lipid levels showed no significant changes with bedtime vs morning intake. Clinicians should consider prescribing levothyroxine intake at bedtime.
 
Sperm grown in a test tube
Immature mouse testicles yield fully developed sperm in culture.
Sperm grown in a test tube : Nature News

Researchers in Japan have made fertile mammalian sperm in a culture dish, a feat long thought to be impossible. The technique, reported today in Nature, could help to reveal the molecular steps involved in sperm formation and might even lead to treatments for male infertility.

Biologists have been trying to make sperm outside the body for almost a century. Failure has often struck at the stage of meiosis, a type of cell division during which paired chromosomes swap DNA and the number of chromosomes per cell is halved. The result of this process is sperm cells ready to fuse with an egg.

Takehiko Ogawa and colleagues at Yokohama City University discovered that the key to getting sperm through meiosis lay in a simple change to standard culture conditions.

"The report is quite exciting because it represents the fulfilment of a goal held by many reproductive biologists over many years," says Mary Ann Handel, an expert in reproductive genetics at the Jackson Laboratory in Bar Harbor, Maine.

Culture shock

By trial and error, Ogawa's team worked out which culture methods allowed sperm in tissue fragments from neonatal mouse testes to mature. To track sperm development, they used a fluorescent protein that marked cells undergoing — or that had undergone — meiosis.

Initially, the researchers placed the fragments on a gel and soaked them in fetal bovine serum, a typical ingredient of cell cultures. But nothing they added to this mix worked, not even factors known to stimulate sperm maturation.

The authors' success came when they replaced the fetal bovine serum with a serum-free medium, KnockOut Serum Replacement, which is often used to grow embryonic stem cells.

After several weeks of bathing in this mixture, almost all tissue samples contained some cells with the same number of chromosomes found in sperm. Nearly half of the samples contained cells with flagella, tail-like projections that sperm use to swim. Sperm formation peaked after about a month, although it lasted for more than two months.

The researchers injected the sperm into egg cells. A few weeks later, surrogates delivered a dozen live, fertile offspring. The team also grew sperm from neonatal testis tissue that had been frozen for days or weeks.

Matter of time

Ali Honaramooz, a reproductive biologist at the University of Saskatchewan in Saskatoon, Canada, says that the technique could aid prepubescent boys about to undergo cancer therapies that destroy fertility. It could also protect the reproductive potential of endangered animals that might die before reaching sexual maturity, he adds.

The procedure will also be useful for studying the molecular events that underlie sperm production, says Martin Dym, a cell biologist at Georgetown University in Washington DC. But before the technique can be used in treatments for male infertility, researchers will have to generate millions of sperm cells and translate the work to humans, Dym adds.

Honaramooz says that is just a matter of time. "If the same methodology can be applied, with many minor changes, to other species, that's great," He says. "If not, then it would take almost the same amount of work, but at least now you know that eventually it's going to work."


Gohbara A, Katagiri K, Sato T, et al. In Vitro Murine Spermatogenesis in an Organ Culture System. Biology of Reproduction 2010;83(2):261-7. http://www.biolreprod.org/content/83/2/261.full

Achieving mammalian spermatogenesis in vitro has a long history of research but remains elusive. The organ culture method has advantages over the cell culture method, because germ cells are in situ albeit the tissue as a whole is in vitro. The method was used in the 1960s and 1970s but encountered difficulties in inducing complete meiosis, i.e., in getting meiosis to proceed beyond the pachytene stage. In the present study, we reevaluated the organ culture method using two lines of transgenic mice, Acr-GFP and Gsg2 (haspin)-GFP mice, whose germ cells express green fluorescent protein (GFP) at the mid and end stages of meiosis onward, respectively. Immature testicular tissues from these mice, ranging from 4.5 to 14.5 days postpartum, were cultured on the surface of the medium, providing a liquid-gas interface. Culturing testicular tissues of all ages tested resulted in the expression of both Acr- and Gsg2-GFP. Round spermatids were identified by a combination of Gsg2-GFP expression, cell size, and the presence of a single nucleus with a dot stained by Hoechst. In addition, the chromosome number of one of such presumptive spermatids was found to be 20 by the premature chromosome condensation method. As our semiquantitative assay system using GFP expression grading was useful for monitoring the effects of different environmental factors, including temperature, oxygen concentration, and antiretinoic molecules, further improvement of the culture conditions should be possible in the future.
 
Estrogens in the Etiology of Human Cancer

Organic chemistry is divided into three major classes of compounds: aliphatic, aromatic, and heteroaromatic. Aliphatic and heteroaromatic molecules are widely represented in the human body, whereas aromatic molecules are rarely present. Heteroaromatic chemicals contain in their aromatic rings one or more heteroatoms, such as nitrogen.

Aromatic chemistry is the chemistry of benzene and polycyclic aromatic hydrocarbons. The few aromatic biomolecules have only one benzene ring, and include the estrogen hormones. Conversion of testosterone to estradiol (E2) and androstenedione to estrone (E1) constitutes the biosynthesis of estrogens, catalyzed by the enzyme aromatase, cytochrome P450 (CYP)19.

The parent compound of aromatic chemistry is benzene, and it was found to induce leukemia a long time ago. The recognition that benzene is a human leukemogen required evaluation of large populations exposed to the chemical. These data were obtained from Italian and Turkish workers in the shoemaking and printing industries, who had high incidences of acute myeloid leukemia. More recently, the induction of non-Hodgkin lymphoma by benzene has been demonstrated.

Many polycyclic aromatic hydrocarbons (PAH) are carcinogenic, with potencies ranging from weak to very strong. Metabolic activation of benzene and PAH to ultimate carcinogenic forms follows the principles of chemical carcinogenesis pioneered by James and Elizabeth Miller in the early 1960s, i.e., most chemical carcinogens (95%) are metabolically activated to electrophilic species that bind covalently to nucleophilic sites in DNA, forming predominantly DNA adducts of Ade[nine] and Gua[nine]. The other 5% are carcinogens that directly react with DNA without metabolic activation.

Most of the adducts of PAH are the depurinating adducts, which detach from DNA, leaving behind apurinic sites. The apurinic sites can be erroneously repaired to give rise to mutations that can initiate the cancer process. The sites of the depurinating adducts correlate with the sites of mutations in the Harvey (H)-ras oncogene. The stable adducts, which remain in DNA unless removed by repair, are formed to a much smaller extent.

PAH have two major mechanisms of metabolic activation to form ultimate carcinogens: one is formation of radical cations, and the other is formation of bay-region diol-epoxides. A third mechanism of metabolic activation, which produces extremely weak ultimate carcinogens, generally involves compounds containing one or two benzene rings. In these compounds, activation occurs through formation of electrophilic catechol quinones, which react with DNA by Michael addition to form adducts. This mechanism of activation occurs with benzene, naphthalene, E1(E2), diethylstilbestrol (DES), hexestrol, and dopamine. In this mechanism, the benzene ring is enzymatically oxidized to form a phenol. A second hydroxylation leads to formation of a catechol, followed by a third oxidation to form the ultimate carcinogenic metabolite, an ortho-quinone. The electrophilic ortho-quinone reacts with the purine bases of DNA to form N3Ade and N7Gua adducts.

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Cavalieri EL, Rogan EG. Unbalanced Metabolism of Endogenous Estrogens in the Etiology and Prevention of Human Cancer. J Steroid Biochem Mol Biol. Unbalanced metabolism of endogenous estrogens in t... [J Steroid Biochem Mol Biol. 2011] - PubMed result

Among the numerous small molecules in the body, the very few aromatic ones include the estrogens and dopamine. In relation to cancer initiation, the estrogens should be considered as chemicals, not as hormones. Metabolism of estrogens is characterized by two major pathways. One is hydroxylation to form the 2- and 4- catechol estrogens, and the second is hydroxylation at the 16alpha position. In the catechol pathway, the metabolism involves further oxidation to semiquinones and quinones, including formation of the catechol estrogen-3,4-quinones, the major carcinogenic metabolites of estrogens. These electrophilic compounds react with DNA to form the depurinating adducts 4-OHE(1)(E(2))-1-N3Ade and 4-OHE(1)(E(2))-1-N7Gua. The apurinic sites obtained by this reaction generate the mutations that may lead to the initiation of cancer. Oxidation of catechol estrogens to their quinones is normally in homeostasis, which minimizes formation of the quinones and their reaction with DNA. When the homeostasis is disrupted, excessive amounts of catechol estrogen quinones are formed and the resulting increase in depurinating DNA adducts can lead to initiation of cancer. Substantial evidence demonstrates the mutagenicity of the estrogen metabolites and their ability to induce transformation of mouse and human breast epithelial cells, and tumors in laboratory animals. Furthermore, women at high risk for breast cancer or diagnosed with the disease, men with prostate cancer, and men with non-Hodgkin lymphoma all have relatively high levels of estrogen-DNA adducts, compared to matched control subjects. Specific antioxidants, such as N-acetylcysteine and resveratrol, can block the oxidation of catechol estrogens to their quinones and their reaction with DNA. As a result, the initiation of cancer can be prevented.
 

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Shah PK. Atherosclerosis: Targeting endogenous apo A-I: a new approach for raising HDL. Nat Rev Cardiol 2011;8(4):187-8. Atherosclerosis: Targeting endogenous apo A-I[mdash]a new approach for raising HDL : Article : Nature Reviews Cardiology

New therapeutic strategies are needed for patients with atherosclerosis. Despite failing to reach its primary end point, a multicenter, phase II, randomized, placebo-controlled trial of RVX-208—an oral, synthetic quinazoline molecule that stimulates expression of endogenous apolipoprotein A-I—has provided somewhat encouraging results. Nevertheless, detailed investigations are still needed if we are ever to realize the full atheroprotective potential of novel HDL-targeted therapies.


Atherosclerotic cardiovascular disease continues to be a major cause of morbidity and mortality, despite substantial progress in the field over the past several decades. Researchers, therefore, are actively searching for new therapeutic strategies for patients with atherosclerosis. One promising approach is to stimulate increased synthesis of endogenous apolipoprotein A-I (apo A-I), the major structural protein component of HDL particles. The results of a multicenter, phase II, randomized, placebo-controlled safety and efficacy trial using the oral quinazoline molecule RVX-208 have now been reported.1Although failing to reach its prespecified primary end point, the highest dose of RVX-208 (150 mg twice daily) provided some encouraging results for investigators interested in pursuing this strategy.

Preventive interventions—including adoption of a healthy lifestyle and control of modifiable risk factors, for example via use of LDL-cholesterol-lowering drugs (such as statins) and antithrombotic agents—have contributed to a substantial decline in atherothrombotic cardiovascular events; however, a substantial residual risk persists. In the past 10 years, improved understanding of the biological actions of HDL, and epidemiological data, experimental studies, and small-scale clinical trials involving infusion of HDL or wild-type or Milano-mutant apo A-I have highlighted the potential atheroprotective effects of HDL.2, 3, 4 HDL-based interventions have, therefore, become a focus of attention. However, over the past decade, the composition and functional properties of HDL particles, rather than simply the level of circulating HDL-cholesterol levels, have emerged as potential determinants of whether HDL particles are atheroprotective or not.4, 5 Indeed, the cholesterol ester transfer protein inhibitor torcetrapib failed to reduce cardiovascular events, despite being associated with large increases in HDL cholesterol and decreases in LDL cholesterol;4, 6, 7 this finding demonstrated that simply raising HDL-cholesterol levels does not predict clinical benefit, regardless of whether the torcetrapib failure resulted from off-target adverse effects or creation of dysfunctional HDL.

Apo A-I has several biological actions that might contribute to its atheroprotective effects (Figure 1).4 Therefore, a method to stimulate increased synthesis of endogenous apo A-I, normally synthesized in the liver and intestines, could potentially be a valuable new weapon against atherosclerosis. In 2010, a novel, orally bioavailable small synthetic quinazoline molecule, RVX-208, developed by Nathan Wong and colleagues at Resverlogix, was shown to transcriptionally stimulate apo A-I synthesis in HepG2 cells.8This agent, when administered to African green monkeys, increased levels of circulating apo A-I by 60% and HDL-cholesterol by 97%, with enhanced cholesterol efflux promoting capacity of serum.8

The results of a multicenter, phase II, randomized, placebo-controlled safety and efficacy trial using oral RVX-208 were reported by Stephen Nicholls and colleagues in early 2011.1 A total of 299 patients with chronic stable coronary artery disease, who were taking stable doses of statins, were randomly assigned to one of three doses of RVX-208 (50 mg, 100 mg, or 150 mg twice daily) or a matching placebo for 12 weeks. The primary end point was the change in circulating apo A-I levels at each dose of RVX-208, compared with placebo. Unfortunately, the study failed to reach its prespecified primary end point. Nevertheless, the highest dose of RVX-208 provided some encouraging results. Although increases in levels of apo A-I and HDL cholesterol were 5.6% and 8.3%, respectively, which is considerably smaller than the increases noted in monkeys8 and those observed with niacin in humans,1 the investigators reported a more-robust 21% increase in large HDL particles, with an increase in lipid-rich HDL particles with alpha 1 mobility on two-dimensional gel electrophoresis. Nicholls et al. appropriately acknowledged that the aforementioned changes were rather modest; however, it should be noted that the short duration of the study might have precluded a full assessment of any additional time-dependent changes in lipoprotein profile.

Unfortunately, the authors did not provide any data on the functionality of the RVX-208-generated HDL particles, such as their capacity to promote cholesterol efflux and their antioxidant and anti-inflammatory activities. Additional data on functionality would have been valuable, especially since it remains far from certain as to whether changes in HDL-particle size alone can provide confident estimates of the functionality and atheroprotective effects of the HDL.9, 10

In terms of safety, RVX-208 was generally well tolerated; however, in 10% of patients, hepatic transaminase levels were at least three times higher than normal levels.1Although the increased levels tended to reverse shortly after cessation of therapy, potential for hepatic toxicity with long-term RVX-208 therapy certainly remains an issue of concern. Furthermore, 4% of the patients in the groups administered the two highest doses of RVX-208 experienced a greater than 1.5-fold increase in serum creatinine concentration,8 raising yet another red flag with regard to the potential for renal toxicity.

Since no information regarding the precise cellular target of RVX-208 action has been provided by the investigators, whether off-target adverse effects could pose problems for further clinical development of RVX-208 remains uncertain. Additional studies of RVX-208, involving further assessment of safety, HDL functionality, and effect on arterial structure and function, are needed before more-definitive morbidity and mortality trials are undertaken. The thorough investigation of developed apo A-I-based therapies, such as RVX-208, and the search for novel apo A-I-targeted treatments must continue if we are ever to realize the full atheroprotective potential of HDL for clinical benefit.

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References

1. Nicholls, S. J. et al. Efficacy and safety of a novel oral inducer of apolipoprotein A-I synthesis in statin-treated patients with stable coronary artery disease: a randomized controlled trial. J. Am. Coll. Cardiol. doi: 10.1016/j.jacc.2010.11.015.

2. Shah, P. K., Kaul, S., Nilsson, J. & Cercek, B. Exploiting the vascular protective effects of high-density lipoprotein and its apolipoproteins: an idea whose time for testing is coming, part I. Circulation 104, 2376–2383 (2001).

3. Shah, P. K., Kaul, S., Nilsson, J. & Cercek, B. Exploiting the vascular protective effects of high-density lipoprotein and its apolipoproteins: an idea whose time for testing is coming, part II. Circulation 104, 2498–2502 (2001).

4. Shah, P. K. Evolving concepts on benefits and risks associated with therapeutic strategies to raise HDL. Curr. Opin. Cardiol. 25, 603–608 (2010).

5. Heinecke, J. W. The protein cargo of HDL: implications for vascular wall biology and therapeutics. J. Clin. Lipidol. 4, 371–375 (2010).

6. Barter, P. J. et al. Effects of torcetrapib in patients at high risk for coronary events.N. Engl. J. Med. 357, 2109–2122 (2007).

7. Shah, P. K. The yin and yang of cholesteryl ester transfer protein in cardiovascular disease. Circulation 120, 2408–2410 (2009).

8. Bailey, D. et al. RVX-208: a small molecule that increases apolipoprotein A-I and high-density lipoprotein cholesterol in vitro and in vivo. J. Am. Coll. Cardiol. 55, 2580–2589 (2010).

9. van der Steeg, W. A. et al. High-density lipoprotein cholesterol, high-density lipoprotein particle size, and apolipoprotein A-I: significance for cardiovascular risk: the IDEAL and EPIC-Norfolk studies. J. Am. Coll. Cardiol. 51, 634–642 (2008).

10. Khera, A. V. et al. Cholesterol efflux capacity, high-density lipoprotein function, and atherosclerosis. N. Engl. J. Med. 364, 127–135 (2011).



Nicholls SJ, Gordon A, Johansson J, et al. Efficacy and Safety of a Novel Oral Inducer of Apolipoprotein A-I Synthesis in Statin-Treated Patients With Stable Coronary Artery Disease: A Randomized Controlled Trial. Journal of the American College of Cardiology 2011;57(9):1111-9. http://content.onlinejacc.org/cgi/reprint/57/9/1111.pdf

Objectives The purpose of this study was to investigate the safety, tolerability, and efficacy of RVX-208, the first oral agent designed to enhance apolipoprotein (apo) A-I synthesis.

Background No agent that selectively induces synthesis of apoA-I has reached an advanced stage of clinical development.

Methods A total of 299 statin-treated patients with coronary artery disease were treated with placebo or with RVX-208 at a dose of 50, 100, or 150 mg twice daily for 12 weeks. Changes in lipid-related biomarkers, in addition to safety and tolerability, of RVX-208 were investigated.

Results For each dose of RVX-208, individual pairwise comparisons of apoA-I changes with placebo, the primary end point, did not achieve statistical significance. However, treatment with RVX-208 was associated with a dose-dependent increase in apoA-I levels by up to 5.6% (p = 0.035 for trend). Administration of RVX-208 resulted in significant increases in levels of high-density lipoprotein cholesterol (HDL-C) ranging from 3.2% to 8.3% (p = 0.02), and large HDL particles increased by 11.1% to 21.1% (p = 0.003). ApoA-I levels increased rapidly from 8 to 12 weeks, suggesting that peak pharmacological effect has not been achieved by the end of the 12-week study. Transient and reversible elevations in liver transaminases >3 times the upper limit of normal were observed in 18 patients treated with RVX-208, with no associated increase in bilirubin levels.

Conclusions Administration of RVX-208 for 12 weeks was associated with increases in apoA-I, HDL-C, and concentration of large HDL particles, consistent with facilitation of cholesterol mobilization. Maximal increases in apoA-I may require longer exposure. An increase in liver enzymes was observed with active treatment.
 

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Salzburg Global S. Salzburg statement on shared decision making. BMJ 2011;342. http://www.bmj.com/content/342/bmj.d1745.full.pdf

In December 2010, 58 people from 18 countries attended a Salzburg Global Seminar to consider the role patients can and should play in healthcare decisions.1Those listed below have agreed a statement that calls on patients and clinicians to work together to be coproducers of health.

Salzburg statement on shared decision making

We call on clinicians to:

• Recognise that they have an ethical imperative to share important decisions with patients

• Stimulate a two way flow of information and encourage patients to ask questions, explain their circumstances, and express their personal preferences

• Provide accurate information about options and the uncertainties, benefits, and harms of treatment in line with best practice for risk communication

• Tailor information to individual patient needs and allow them sufficient time to consider their options

• Acknowledge that most decisions do not have to be taken immediately, and give patients and their families the resources and help to reach decisions

We call on clinicians, researchers, editors, journalists, and others to:

• Ensure that the information they provide is clear, evidence based, and up to date and that conflicts of interest are declared

We call on patients to:

• Speak up about their concerns, questions, and what’s important to them

• Recognise that they have a right to be equal participants in their care

• Seek and use high quality health information

We call on policy makers to:

• Adopt policies that encourage shared decision making, including its measurement, as a stimulus for improvement

• Amend informed consent laws to support the development of skills and tools for shared decision making

Why

Much of the care patients receive is based on the ability and readiness of individual clinicians to provide it, rather than on widely agreed standards of best practice or patients’ preferences for treatment.

Clinicians are often slow to recognise the extent to which patients wish to be involved in understanding their health problems, in knowing the options available to them, and in making decisions that take account of their personal preferences.

Many patients and their families find it difficult to take an active part in healthcare decisions. Some lack the confidence to question health professionals. Many have only a limited understanding about health and its determinants and do not know where to find information that is clear, trustworthy, and easy to understand.
 
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Human Chorionic Gonadotropin in Intractable Pain

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AAPM: Hormone Tx May Relieve Intractable Pain
Medical News: AAPM: Hormone Tx May Relieve Intractable Pain - in Meeting Coverage, AAPM from MedPage Today

WASHINGTON -- Human chorionic gonadotropin (hCG), a drug frequently used in fertility therapy, relieved intractable pain for most patients in a small pilot study, researchers said here.

After a year of hCG therapy, seven out of eight patients were able to reduce opiate use by 30% to 50%, Forest Tennant, MD, DrPH, of the Veract Intractable Pain Clinic in West Covina, Calif., reported at the American Academy of Pain Medicine meeting.

"Our pilot study was developed out of total serendipity," Tennant told MedPage Today, who said no side effects were observed. Originally 12 patients were included in the study. After a challenge with the drug, eight opted for long-term treatment.

HCG is commonly used for in vitro fertilization procedures and is also used in some weight loss programs. Because it's also used in conjunction with anabolic steroids, use of hCG is barred by some professional sports associations including Major League Baseball.

"We got involved with hCG when colleagues at a weight loss clinic told us that obese fibromyalgia patients treated with hCG were experiencing great pain relief," Tennant explained.

He said he was skeptical until he investigated the pharmacodynamics of the hormone and determined that it might have actions that are similar to steroids. "It is unclear whether hCG acts as a hormonal stimulant and/or an anabolic, connective tissue agent," Tennant said.

What was apparent, however, was that most of the patients diagnosed with intractable pain appeared to benefit from the therapy.

"Open label studies such as this one are problematic in that they are biased, nonrandom and have small numbers," Tennant admitted. However, he said "the improvement in these patients, has been impressive. In my experience severe intractable pain patients with presumed abnormal neuroplasticity and who are maintained on opioids seldom report improvement in any nonopioid clinical trials."

He said all the patients in the continuation study reported increased energy and mental concentration, less depression, and fewer pain flares. Five of the patients reported pain-free hours.

"I was very interested in this study," said Erik Shaw, DO, senior pain specialist at Shepherd Pain Institute in Atlanta. "This kind of response seen in the patients is unexpected. We do not have a lot of options for patients with intractable pain," he told MedPage Today when asked to comment on the study.

Shaw said he agrees with Tennant that further studies using hCG in tractable pain are warranted.

The 12 patients in the study were ambulatory adults who had been experiencing intractable pain for at least five years. All had presumed central abnormal neuroplasticity based on several criteria: consistent pain, peripheral pain sites that failed to respond to therapy; severe insomnia; severe hyperactivity evidenced by two or more conditions such as hypertension, tachycardia, tremor, hyperactive reflexes, mydriasis, diaphoresis or cold hands or feet.

Seven of the patients had spine conditions and the others had fibromyalgia, neuropathy, arthropathy or headache. They were all given a challenge dose of 500 to 1,000 units of hCG to determine a potentially effective dosage.

For the eight patients in whom positive results were seen within in week, doctors administered weekly doses of 1,000 to 3,000 units for more than 52 weeks.

"Because we have seen responses, we have begun extending the treatment to other patients," Tennant said. "We have treated 30 to 40 people with intractable pain with hCG."

Shaw suggested clinical trials of hCG could give doctors a better handle on the extent of improvement seen with the therapy and also determine if some populations fare better than others.


Human Chorionic Gonadotropin in Intractable Pain
http://www.painmed.org/library/posters/poster-164/
http://www.painmed.org/files/poster164.pdf

Introduction/Statement of Problem: Human Chorionic Gonadotropin (HCG) is comprised of two amino acid sub-units which provide a theoretical basis for use in pain treatment.1-3 One unit contains follicle stimulating hormone (FSH), luteinizing hormone (LH), and thyroid stimulating hormone (TSH). The other unit is an androgenic compound that increases cyclic adenosine monophosphate (cAMP) and nitric oxide (NO).

Methods and Material: Initially HCG was given in challenge dosages of 500 to 1,000 units to 12 intractable pain patients to determine possible side-effects and a potentially effective dosage regimen. Patients described their pain as severe and constant and it interfered with sleep and eating patterns. All patients required a long-acting opioid for pain suppression and a short-acting opioid for breakthrough pain. All patients gave informed consent via in a protocol approved by an institutional review board. Eight (8) patients who felt positive effects from their challenge dosage within one week continued HCG for over one year in a dosage or 1,000 to 3,000 units a week.

Results: No side-effects have been observed. All patients report the following positive effects: increased energy, improved mental concentration and memory, less depression, and fewer pain flares. Seven of the 8 (87.5%) reduced their opioid use by 30 to 50%.

Conclusions: The symptom improvement observed here calls for advanced clinical trials and suggests that HCG may correct some of the adverse neuroplasticity associated with severe intractable pain.

References:
1) Matura S, Okashi M, Chen HC, et al. Physiochemical and Immunological Characterization of an HCG-Like Substance from Human Pituitary Glands. Nature 1980; 286: 740-741.
2) Odell WD, Griffin J. Pulsatile secretion of Human Chorionic Gonadotropin in Normal Adults. N Engl J Med 1987; 317: 1688-1692.
3) Braunstein GD. Human Chorionic Gonadotopin in William's Textbook of Endocrinology. 10th Ed. Saunders, Philadelphia. 2003; pp800-803.
 

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Impact of Coronary Artery Calcium Scanning

Calcium Screening Prompts Patients to Take Action
Medical News: Calcium Screening Prompts Patients to Take Action - in Cardiovascular, Prevention from MedPage Today

Patients who get their coronary calcium scores take steps to reduce their heart disease risk factors more often than those who don't get the scan, researchers say.

Scanned patients had significantly better improvements in several risk factors, including systolic blood pressure, LDL cholesterol, and waist circumference, Daniel Berman, MD, of Cedars-Sinai Medical Center in Los Angeles, and colleagues reported in the Journal of the American College of Cardiology.

"Patients who knew their coronary calcium scores improved their coronary heart disease risk compared with those with no scan, and those with high calcium scores were motivated to take even more aggressive steps to reduce their risk," Berman said in a statement.

In addition, these patients had no increased medical procedure costs during four years of follow-up compared with those who weren't scanned, although their drug costs did tend to be higher, the researchers said.

It's well-established that calcium screening predicts cardiac events, but its impact on subsequent medical management and coronary artery disease risk is not known.

So researchers at Cedars-Sinai conducted the Early Identification of Subclinical Atherosclerosis by Noninvasive Imaging Research (EISNER) trial in 2,137 patients with coronary artery disease risk factors but no history of heart disease. Of those, 1,424 had a coronary artery calcium scan, while the remaining 713 didn't get the scan.

All participants were followed for four years, and the primary endpoint was change in coronary artery disease risk factors and Framingham Risk Score at that time.

The researchers found that those who were scanned had significantly better improvements in systolic blood pressure (P=0.02), LDL cholesterol (P=0.04), and waist circumference among those with increased abdominal girth (P=0.01).

There was also a trend toward weight loss in overweight patients, although it wasn't significant.

There were no differences between the groups with respect to HDL cholesterol, triglycerides, glucose levels, smoking cessation, and new exercise activity.

In terms of Framingham Risk Score, there was a mean rise among those who didn't get scanned, but risk score remained static among those who were scanned, the researchers said.

They also found, in the scanned group, an inverse relationship between increasing baseline coronary calcium scores and systolic and diastolic blood pressure (P<0.001), total cholesterol (P<0.001), LDL cholesterol (P<0.001), triglycerides (P<0.001), weight (P<0.001), and Framingham Risk Score (P=0.003).

Subsequent medical testing and costs were comparable between groups.

There were no differences in four-year utilization of stress tests, carotid ultrasound studies, noninvasive and invasive coronary angiogram studies, and revascularization procedures, the researchers said, and overall medical procedure costs were comparable.

Yet drug costs tended to be higher in the scan group, likely due to the fact that more scan subjects were started on antihypertensives and lipid-lowering medications.

Though there were no differences in rates of myocardial infarction or fatal events, the researchers said overall rates were low and thus the study was underpowered statistically to adequately address this question.

They noted that the study was limited in generalizability because patients were highly educated, fairly affluent, and were all motivated to volunteer for the study.

Still, they said that the results "are consistent with the hypothesis that coronary artery calcium scanning can improve cardiac management without incurring significant increase in downstream medical costs."

They called for further study of calcium scanning, including prespecified treatment recommendations, to assess its impact on cardiovascular outcomes.


Rozanski A, Gransar H, Shaw LJ, et al. Impact of Coronary Artery Calcium Scanning on Coronary Risk Factors and Downstream Testing: The EISNER (Early Identification of Subclinical Atherosclerosis by Noninvasive Imaging Research) Prospective Randomized Trial. J Am Coll Cardiol:j.jacc.2011.01.019. http://content.onlinejacc.org/cgi/reprint/j.jacc.2011.01.019v1.pdf

Objectives: We conducted a prospective randomized trial to compare the clinical impact of conventional risk factor modification to that associated with the addition of coronary artery calcium (CAC) scanning.

Background: Although CAC scanning predicts cardiac events, its impact on subsequent medical management and coronary artery disease risk is not known.

Methods: We assigned 2,137 volunteers to groups that either did undergo CAC scanning or did not undergo CAC scanning before risk factor counseling. The primary end point was 4-year change in coronary artery disease risk factors and Framingham Risk Score. We also compared the groups for differences in downstream medical resource utilization.

Results: Compared with the no-scan group, the scan group showed a net favorable change in systolic blood pressure (p = 0.02), low-density lipoprotein cholesterol (p = 0.04), and waist circumference for those with increased abdominal girth (p = 0.01), and tendency to weight loss among overweight subjects (p = 0.07). While there was a mean rise in Framingham Risk Score (FRS) in the no-scan group, FRS remained static in the scan group (0.7 ± 5.1 vs. 0.002 ± 4.9, p = 0.003). Within the scan group, increasing baseline CAC score was associated with a dose-response improvement in systolic and diastolic blood pressure (p < 0.001), total cholesterol (p < 0.001), low-density lipoprotein cholesterol (p < 0.001), triglycerides (p < 0.001), weight (p < 0.001), and Framingham Risk Score (p = 0.003). Downstream medical testing and costs in the scan group were comparable to those of the no-scan group, balanced by lower and higher resource utilization for subjects with normal CAC scans and CAC scores 400, respectively.

Conclusions: Compared with no scanning, randomization to CAC scanning was associated with superior coronary artery disease risk factor control without increasing downstream medical testing. Further study of CAC scanning, including pre-specified treatment recommendations, to assess its impact of cardiovascular outcomes is warranted.
 
Is there a physiological explanation for being fat and dumb???

The present study examined the association between body mass index (BMI) and white matter (WM) integrity, as well as potential interaction effects with age, in the corpus callosum and fornix of otherwise medically and psychiatrically healthy individuals across the adult life span. Researchers used a diffusion tensor imaging (DTI) index of tract coherence-fractional anisotropy (FA) to examine the structure of the corpus callosum and fornix. These areas of dense WM bundles, were chosen for their connectivity to brain regions important to cognition (i.e., interhemispheric and hippocampal connections), as well as previous work linking them to conditions associated with obesity in adulthood, including mild cognitive impairment and Alzheimer’s disease. Based on previous cognitive findings, researchers expected to find an association between reduced WM integrity and elevated BMI and to find greater reductions in WM integrity in obese, compared to normal weight, persons when examined across weight groups.


Stanek KM, Grieve SM, Brickman AM, et al. Obesity Is Associated With Reduced White Matter Integrity in Otherwise Healthy Adults. Obesity 2011;19(3):500-4. http://www.nature.com/oby/journal/v19/n3/pdf/oby2010312a.pdf

Existing work demonstrates that obesity is independently associated with cognitive dysfunction and macrostructural brain changes; however, little is known about the association between obesity and white matter (WM) integrity. We explore this relationship in a large cohort of otherwise healthy subjects. The present study classified 103 adult participants from the Brain Resource International Database between 21 and 86 years of age without history of neurological, medical, or psychiatric illness according to BMI (normal weight, overweight, obese) and subjected them to diffusion tensor imaging (DTI). Resulting fractional anisotropy (FA) indexes for the corpus callosum and fornix were examined in relation to BMI and age in a multiple regression framework. Results indicated that increasing BMI was independently associated with lower FA in the genu, splenium, and fornix, and a BMI × age interaction emerged for FA in the splenium and body of the corpus callosum.

When categorized, obese persons demonstrated lower FA than normal and overweight persons for all WM indexes, but no FA differences emerged between overweight and normal persons. Results indicate both a direct association between obesity and reduced WM tract integrity and an interaction between obesity and aging processes on certain WM tracts in otherwise healthy adults. While such findings suggest a possible role for adiposity in WM dysfunction and associated cognitive deficits, prospective studies are needed to clarify the nature of these relationships and elucidate underlying mechanisms.


Obesity messes with the brain
Memory and concentration diminish as organ's wiring sustains damage
http://www.sciencenews.org/view/generic/id/71742/title/Obesity_messes_with_the_brain

Obesity subtly diminishes memory and other features of thinking and reasoning even among seemingly healthy people, an international team of scientists reports. At least some of these impairments appear reversible through weight loss. Researchers also report one likely mechanism for those cognitive deficits: damage to the wiring that links the brain’s information-processing regions.

A number of studies in recent years have shown that individuals with diseases linked to obesity, including cardiovascular disease, hypertension and type 2 diabetes, don’t score as well on cognitive tests as less hefty individuals do. To test whether weight alone — and not disease — might be partially responsible, John Gunstad of Kent State University in Ohio and his colleagues recruited 150 obese individuals for a series of cognitive tests. These people weighed on average just under 300 pounds, although some were substantially heavier. Two-thirds would shortly undergo weight-loss surgery.

Scores on the tests were assessed against those of people in the Brain Resource International Database, a large multicenter project with data on very healthy people. Obese individuals in the new study initially performed on the low end of the normal range for healthy individuals from the database on average, Gunstad says, although nearly one-quarter of the obese participants’ scores on memory and learning actually fell within what researchers consider the impaired range.

Tested again 12 weeks after bariatric surgery — when most had shed some 50 pounds — the lighter but still heavy patients scored substantially better. Most now performed “within the average or greater-than-average range for all cognitive tests,” the researchers report online in Surgery for Obesity and Related Diseases.

Study participants who didn’t have surgery — or lose weight — performed worse on the second test. “That was a bit surprising,” Gunstad says.

Neurologist Stefan Knecht of the University of Münster in Germany, who is not involved in the new research, says he is not surprised that the untreated participants experienced rapid, continuing drops in cognitive performance. Among the morbidly obese, he says, “You can actually watch them getting worse from one three-month period to the next if you have sufficiently sensitive measures, which [Gunstad’s group] did.”

The second new study by Gunstad’s group used a form of magnetic resonance imaging, or MRI, to probe the wiring that connects nerve cells to move information throughout the brain. The bundled fibers are sheathed in a protective layer of white insulation, giving rise to the tissue’s name: white matter.

In obese individuals — but not normal-weight or overweight people — this sheathing shows signs of damage. “It’s not as though a cable has been cut,” Gunstad says. “It’s just that its integrity is diminished,” jeopardizing the strength or clarity of signals that must traverse these cognitive highways. His group’s findings appear in the March 2011 Obesity.

This white matter study “is interesting, and the methodology looks sensible,” says brain-imaging expert Mark Bastin of the University of Edinburgh Western General Hospital, who is also studying white matter integrity. But he argues it must be viewed as preliminary owing to “the very small numbers of subjects” — just 17 obese individuals among the 103 people studied.

Using the same MRI technique last year, Knecht’s team linked C-reactive protein — a blood marker of systemic inflammation — with white matter integrity in a group of 447 older adults. Both type 2 diabetes and obesity can chronically elevate CRP levels in the blood.

As CRP levels in blood increased, Knecht and his colleagues found, so did the likelihood that white matter’s insulation would be impaired. This suggests “that low-grade inflammation, which is strongly correlated with obesity, could be an important mediator,” Knecht says.

In that study, the researchers reported in the March 30, 2010 Neurology, higher levels of CRP also correlated with “with worse performance in executive function, including tests of psychomotor speed and attention.”
 
Analysis Of The Efficacy, Safety, And Regulatory Status Of Novel Forms Of Creatine
[full-text available at link below]


Creatine (N-(aminoiminomethyl)-N-methyl glycine) is an ingredient commonly found in food, mainly in fish and meat, and is sold as a dietary supplement in markets around the world. Its use as an ergogenic aid and possible treatment for certain neuromuscular disorders is well documented in scientific literature. In recent years, the popularity of creatine has risen dramatically, especially among athletes. In the USA alone, creatine-containing dietary supplements make up a large portion of the estimated $2.7 billion in annual sales of sports nutrition supplements.

Accompanying this explosive growth in sales has been the introduction of different forms of creatine. Creatine monohydrate (CM), first marketed in the early 1990s, is the form most commonly found in dietary supplement/food products and most frequently cited in scientific literature. The introduction into the marketplace of alternate forms of creatine, beginning in the late 1990s, was presumably an attempt to differentiate the multitude of creatine-containing products available to consumers and improve certain attributes such as solubility and efficacy. However, the legal and regulatory status of these various forms of creatine in the USA and other markets around the world is at best uncertain. To date, with the exception of Japan, CM is the only form of creatine to be officially approved or accepted in key markets such as the USA, European Union (EU), Canada and South Korea. The continued presence of other forms of creatine in the marketplace, especially in the US, may be due to a multitude of factors. These include, but may not be limited to, a lack of awareness or understanding on the part of marketers of applicable laws and regulations, intentional noncompliance with the law, and/or inadequate enforcement of the law. The public health implications of widespread distribution and use of these unauthorized forms of creatine is unknown and warrants careful monitoring.

New forms of creatine are marketed with claims of improved physical, chemical, and physiological properties in comparison to CM. Claims include improved stability when combined with other ingredients or in liquids, improved solubility in water, improved bioavailability, and even an increase in performance. This review will evaluate the available literature on new forms of creatine and compare them to available data on CM in terms of efficacy and safety. In addition, the current international regulatory status of the various forms of creatine that are commercially available will be examined.

cm-forms-gif.9077



Jager R, Purpura M, Shao A, Inoue T, Kreider RB. Analysis of the efficacy, safety, and regulatory status of novel forms of creatine. Amino Acids. Analysis of the efficacy, safety, and regulatory status of novel forms of creatine - Springer

Creatine has become one of the most popular dietary supplements in the sports nutrition market. The form of creatine that has been most extensively studied and commonly used in dietary supplements is creatine monohydrate (CM). Studies have consistently indicated that CM supplementation increases muscle creatine and phosphocreatine concentrations by approximately 15-40%, enhances anaerobic exercise capacity, and increases training volume leading to greater gains in strength, power, and muscle mass. A number of potential therapeutic benefits have also been suggested in various clinical populations. Studies have indicated that CM is not degraded during normal digestion and that nearly 99% of orally ingested CM is either taken up by muscle or excreted in urine. Further, no medically significant side effects have been reported in literature.

Nevertheless, supplement manufacturers have continually introduced newer forms of creatine into the marketplace. These newer forms have been purported to have better physical and chemical properties, bioavailability, efficacy, and/or safety profiles than CM. However, there is little to no evidence that any of the newer forms of creatine are more effective and/or safer than CM whether ingested alone and/or in combination with other nutrients. In addition, whereas the safety, efficacy, and regulatory status of CM is clearly defined in almost all global markets; the safety, efficacy, and regulatory status of other forms of creatine present in today's marketplace as a dietary or food supplement is less clear.
 

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To increase choice and satisfy patient needs, several pen devices for administering recombinant growth hormone have been developed. In this review, developments in the administration of growth hormone treatment for children and adults are discussed, with a particular focus on the most recently available pen device developed by Novo Nordisk A/S (Bagsvaerd, Denmark), Flexpro®, that delivers Norditropin®, and its place in the context of other growth hormone delivery devices, sustained-release growth hormone formulations in development, and future prospects.


Yuen KC, Amin R. Developments in administration of growth hormone treatment: focus on Norditropin Flexpro. Patient Prefer Adherence 2011;5:117-24. Developments in administration of growth hormone t... [Patient Prefer Adherence. 2011] - PubMed result

Recombinant human growth hormone is used for the treatment of growth failure in children and metabolic dysfunction in adults with growth hormone deficiency. However, conventional growth hormone therapy requires daily subcutaneous injections that may affect treatment adherence, and subsequently efficacy outcomes. To enhance potential treatment adherence, improved ease of use of growth hormone delivery devices and long-acting growth hormone formulations are now being developed. Flexpro((R)), approved by the US Food and Drug Administration in March 2010, is the most recent pen device developed by Novo Nordisk A/S to deliver Norditropin((R)). It is a multidose, premixed, preloaded, disposable pen device that requires relatively less force to inject and does not require refrigeration after initial use. Dose adjustments can be optimized by small dose increments of the pen delivery device at 0.025 mg, 0.05 mg and 0.1 mg. In addition, for patients with needle anxiety, NovoFine((R)) needles, some of the shortest and thinnest available, and Autocover((R)), which hides the needle during injections, can be used with the Flexpro pen device. This article reviews the Norditropin Flexpro pen device in the context of other growth hormone delivery devices, sustained-release growth hormone formulations in development, and future prospects.
 

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Branched-Chain Amino Acids (Leucine, Isoleucine, Valine) Supplementation & Amyotrophic Lateral Sclerosis (ALS)

Previous published epidemiological studies have reported an increased occurrence of Amyotrophic Lateral Sclerosis (ALS) among Italian soccer players, although the question is still debated. ALS is one of the most common adult-onset neurodegenerative diseases, characterized by progressive and selective degeneration of the upper and lower motor neurons in the motor cortex, brainstem and spinal cord. The cause of this cell-specific loss is still unknown. Although sport participation has been hypothesized as a risk factor for ALS, and previous studies have indicated that one or more factors related to professional football in Italy could have a role in determining an increased risk of ALS, the eventual relationship between ALS and Italian soccer players is still to be elucidated.

One of the hypotheses regarding the ALS risk is the use of toxic substances and/or of therapeutic drugs employed in excessive doses. In particular, branched-chain amino acids (BCAAs, leucine, isoleucine, valine) supplementation is frequently used by athletes to stimulate muscular protein synthesis, to improve mental and physical performance and to accelerate the body's recovery after particularly intense and prolonged sport activities.

BCAAs are easily taken up by the brain. They cross the blood–brain barrier via L-system transporters and are taken up by neurons and glia by several transporter systems. BCAAs activate glutamate dehydrogenase (GDH), which has been reported to be defective in ALS. For this reason, three clinical trials were undertaken to test efficacy and safety of BCAAs in ALS patients. All trials failed to show any therapeutic advantage when BCAAs were administered to ALS patients and one of these was stopped in 1991 because of the excessive mortality rate among the patients treated with BCAAs. It is known that nutrients, especially BCAAs, modulate the activity of many proteins involved in the control of mRNA translation. Several of them are controlled by phosphorylation through signaling events involving the mammalian target of rapamycin (mTOR). mTOR is a serine/threonine kinase that controls protein synthesis related to cell growth and proliferation and in the brain it may also regulate neuronal development and synaptic plasticity. Recently, altered mTOR signaling was observed in many cortical malformations, neurodegenerative diseases and epileptogenesis, strongly indicating a role in neurological pathologies.

The aim of the present study was to investigate a possible role of BCAAs and their pathway in the electrophysiological properties of cortical neurons and also to compare BCAA-treated neurons with those obtained from the G93A transgenic mouse model of ALS.


Carunchio I, Curcio L, Pieri M, et al. Increased levels of p70S6 phosphorylation in the G93A mouse model of Amyotrophic Lateral Sclerosis and in valine-exposed cortical neurons in culture. Exp Neurol 2011;226(1):218-30. Increased levels of p70S6 phosphorylation in the G... [Exp Neurol. 2010] - PubMed result

The higher risk factor for Amyotrophic Lateral Sclerosis (ALS) among Italian soccer players is a question that is still debated. One of the hypotheses that have been formulated to explain a possible link between ALS and soccer players is related to the abuse of dietary supplements and drugs for enhancing sporting performance. In particular, it has been reported that branched-chain amino acids (BCAAs) are widely used among athletes as nutritional supplements. To observe the possible effect of BCAAs on neuronal electrical properties, we performed electrophysiological experiments on Control cultured cortical neurons and on neurons after BCAA treatment. BCAA-treated neurons showed hyperexcitability and rapamycin was able to suppress it and significantly reduce the level of mTOR, Akt and p70S6 phosphorylation. Interestingly, the hyperexcitability previously reported in cortical neurons from a genetic mouse model of ALS (G93A) was also reversed by rapamycin treatment. Moreover, both G93A and valine-treated neurons presented significantly higher levels of Pp70S6 when compared to control neurons, strongly indicating the involvement of this substrate in ALS pathology. Finally, we performed electrophysiological experiments on motor cortex slices from Control and G93A mice and those fed with a BCAA-enriched diet. We observed that neuron excitability was comparable between G93A and BCAA-enriched diet mice, but was significantly higher than in Control mice. These findings, besides strongly indicating that BCAAs specifically induce hyperexcitability, seem to suggest the involvement of p70S6 substrate in ALS pathology.

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Manuel M, Heckman CJ. Stronger is not always better: could a bodybuilding dietary supplement lead to ALS? Exp Neurol 2011;228(1):5-8. Stronger is not always better: could a bodybuildin... [Exp Neurol. 2011] - PubMed result

In the November 2010 issue of Experimental Neurology, Carunchio et al. explore the possible role in ALS of another type of amino acid, the branched-chain amino acids (BCAAs), which are amino acids with an aliphatic side chain, and are commonly used as dietary supplements by athletes to stimulate muscle growth and recovery after intense exercise. BCAAs have been suggested to be the cause of a high incidence of ALS among professional American football players and Italian soccer players. Carunchio et al. compared the effect of a diet enriched in BCAAs on mouse cortical motoneurons (the population of cortical neurons that command the spinal motoneurons, and which are specifically affected along with spinal motoneurons, in ALS) to the effect of a genetic mutation causing ALS (the substitution of a glycine for an alanine in position 93 of the human SOD1 gene, a.k.a. “G93A”) in mice. In the present work, Carunchio et al. show that a diet enriched in BCAAs also induced a hyperexcitability of the cortical motoneurons. This effect was dose dependent and specific to BCAAs, as diet enriched with non-branched-chained amino acids such as alanine or phenylalanine did not alter the excitability of the cells.

The impact of environmental factors on ALS needs to be carefully studied. The work by Carunchio et al. in the November 2010 issue of Experimental Neurology provides a significant breakthrough for the potential role of such a toxin (BCAAs in this case) in sporadic ALS, as well as a promising new therapeutic target, the mTOR pathway. Yet the link between BCAAs and ALS remains to be fully established. The present work shows that BCAAs can induce a hyperexcitability similar to the one observed in G93A mice, but they did not show if a BCAA-enriched diet, given to mice over a prolonged period, induces ALS-like symptoms. More experiments are needed to establish if the hyperexcitability of upper and lower motoneurons is a direct consequence of the disease, or a compensatory mechanism of the CNS.
 
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Accuracy Of Calculated Free Testosterone

Measurement of serum testosterone concentrations is a central component of the assessment of androgen status. Increased concentrations can be seen in women with congenital adrenal hyperplasia or polycystic ovarian syndrome (PCOS), and in both genders due to exogenous testosterone administration, adrenal- , testicular-, or ovarian tumors, and in children with precocious puberty. Conversely, decreased serum testosterone concentrations are the hallmark of both primary and secondary hypogonadism in men, and, to a lesser degree, women, regardless of the underlying etiology. Androgen deficiency in males is believed to be a particular common problem, affecting an estimated to 4.7 million men between the ages of 30 and 79 in the United States in 2000, and predicted to rise to 6.5 million by 2025.Most of these cases represent mild to moderate deficiency, often referred to as “andropause” or “late-onset hypogonadism”, a state that is blamed for anergia, sexual dysfunction, declining mental ability, diminished muscle strength and reduced bone density.

Measurement of total testosterone, often combined with gonadotropin measurements, is generally sufficient to diagnose significant androgen excess or deficiency. However, for suspected mild to moderate deficiency, measurement of the free, bioactive, fraction of testosterone (fT) is believed to be of superior diagnostic value, especially under circumstances of altered sex hormone binding globulin (SHBG) serum concentrations or binding affinity, as may be found in hyper- or hypothyroidism, liver cirrhosis, obesity, or exogenous sex hormone use, especially estrogen treatments. Serum concentrations of SHBG also increase with age, often affecting fT levels disproportionately to total testosterone concentrations.

Because the majority of testosterone is bound to SHBG or albumin, fT accounts for only 1–4% of the total testosterone levels. Furthermore, the protein-bound distribution of testosterone is gender dependent because of differences in sex steroid distribution, with 44% of testosterone bound to SHBG in men and 66% bound to SHBG in women. These factors conspire to make measurements of fT challenging. The gold standard method of measurement is isotope dilution equilibrium dialysis.While this method is considered the most accurate, its technical and laborious nature can result in high assay variability. Analog immunoassays that detect fT have been proposed as an alternative. However, they have been widely criticized for their lack of accuracy and variability of results with fluctuating SHBG concentrations, suggesting that they do not truly measure fT.

Another alternative is to calculate fT using equations based on the law of mass action. These equations typically incorporate the results of serum measurements of total testosterone, albumin, and SHBG. The equation originally described by Sodergard et al. and derived by Vermeulen et al. also includes the testosterone association constants for albumin and SHBG. However, calculated results for fT have often been found to vary significantly from isotope dilution equilibrium dialysis. Potential sources for this variation include biological factors such inter-individual variability in the concentrations of competing hormones and binding proteins and in the affinity of testosterone for SHBG or albumin, and laboratory factors including different SHBG and testosterone methodologies, equations, and association constants used. Several different constants have been published and some studies have used empirically derived constants and equations to provide the best fit for their individual combinations of patient population, and total testosterone-, SHBG- and albumin assays. Overall, there appears to be little consensus on the best method for calculating fT, likely because of the wide variability of performance of these equations between studies, patient groups, and laboratories and a lack of understanding of how these factors impact calculated fT measurements.

The purpose of this study was to improve the understanding of how these parameters affect calculated fT results, and to determine whether satisfactory agreement with isotope dilution equilibrium dialysis can be achieved. To this end, researchers assessed the performance of three established equations and two new equations, generated using two different patient groups. These equations differed only in their testosterone association constants for SHBG and albumin. Results calculated with each of these five equations in these two patient groups were compared with those obtained by isotope dilution equilibrium dialysis performed on the same specimens. Demographic characteristics of the two patient populations and equation variables including albumin, SHBG, and choice of association constants were examined to determine how they affected the correlation with isotope dilution equilibrium dialysis results. Samples with poor correlation between calculated and measured fT results were examined further to find common characteristics that could explain the deviations.


Hackbarth JS, Hoyne JB, Grebe SK, Singh RJ. Accuracy of calculated free testosterone differs between equations and depends on gender and SHBG concentration. Steroids 2011;76(1-2):48-55. Accuracy of calculated free testosterone differs b... [Steroids. 2011] - PubMed result

Serum free testosterone (fT) concentrations are often calculated, however different equations often yield discrepant results. This study explores the sources of this variability. We compared three established and two new equations that differed only by their testosterone association constants with isotope dilution equilibrium dialysis in two patient groups with different gender distributions. Equation components were examined to determine how they impacted correlation with isotope dilution equilibrium dialysis. Association constants derived for each patient group correlated best with isotope dilution equilibrium dialysis for that group and not the other set. Samples with the poorest correlation between isotope dilution equilibrium dialysis and calculated fT results had significantly higher SHBG concentrations. Regardless of equation, >/= 25% of samples showed unacceptable deviation from isotope dilution equilibrium dialysis. Association constants and gender makeup and SHBG concentration of the patient groups used to establish an equation all significantly impact correlation with isotope dilution equilibrium dialysis. Application of many fT equations to wider populations will therefore frequently yield results that differ substantially from isotope dilution equilibrium dialysis.
 
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