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[Michael Scally MD]

Finasteride induced depression

In addition to catalyzing the reduction in testosterone, 5-alpha-reductase is also involved as a rate-limiting enzyme in the metabolism of other steroid hormones. A recent study in humans has shown that even the treatment with a daily dose of 5 mg finasteride is sufficient to significantly decrease the concentrations of serum levels of 5-alpha-reduced steroids. Several of these 5-alpha-reduced steroids are considered as neuroactive steroids, owing to their potent neuromodulatory effects. Neuroactive steroids are also considered as candidate modulators in the pathophysiology and therapy of psychiatric disorders, in particular affective and anxiety disorders. Furthermore, they possess neuroprotective and neurotrophic effects. Neuroactive steroids rapidly alter neuronal excitability by acting at inhibitory GABAA and ? or excitatory NMDA receptors. Well studied in this context are the 5a-reduced steroids allopregnanolone and tetrahydrodeoxycorticosterone that have anxiolytic, analgesic, and sedative effects by modulating GABAA receptors.

Both 5-alpha-reductase activity and 5-alpha-reduced steroid concentrations are reduced in depressed patients and can both be increased by antidepressant (fluoxetine) and atypical antipsychotic (olanzapine) drug treatment. Interestingly, coadministration of finasteride inhibits antidepressant and anxiolytic effects of these drugs, suggesting that collateral effects on neuroactive steroid metabolism are part of their therapeutic efficacy.

In animal studies, inhibition of 5-alpha-reductase leads to behavioral changes with increase in depressive and anxious behaviors. Several reports and one preliminary clinical study suggest that finasteride treatment might induce depressive symptoms in humans. A recent animal study focussed on the effects of finasteride on neuronal plasticity, a process thought to play a major role in the pathogenesis of and recovery from affective disorders. In this study, finasteride treatment decreased adult neurogenesis in the murine hippocampus. Adult hippocampal neurogenesis, i.e., the lifelong proliferation of neural precursor cells and their maturation to granule cells which integrate into and modify preexisting neuronal networks, is regarded as a crucial adaptive mechanisms to environmental stimuli. Adult neurogenesis has been shown to play a role in several hippocampus-dependent memory processes, including emotion-associated memories. Thus, the inhibition of hippocampal neurogenesis by finasteride could be an important contributor to changes in central nervous function and emotional behavior. In any case, finasteride has been proven to cause structural changes in a crucial area of the central nervous system, i.e., the limbic system coding for emotional behavior. Further controlled clinical trials are needed to investigate depressogenic effects of finasteride treatment in humans. However, patients using finasteride should be informed about the potential neuropsychiatric side effects, in particular if taking this drug for cosmetic reasons.

Romer B, Gass P. Finasteride-induced depression: new insights into possible pathomechanisms. J Cosmet Dermatol 2010;9(4):331-2. Finasteride-induced depression: new insights into ... [J Cosmet Dermatol. 2010] - PubMed result

5-alpha-reductase is involved as a rate-imitating enzyme in the metabolism of steroids. Several 5-alpha-reduced steroids such as dihydrotestosterone, allopregnanolone or tetrahydrocorticosterone have neurotrophic, neuroprotective, and anxiolytic properties. Reduced 5-alpha-reductase activity has been observed during depressive illness in humans. Finasteride inhibits 5-alpha-reductase and can robustly induce anxious and depressive behaviors in rodents. In humans finasteride treatment has been linked to an increase of depressive symptoms. A recent study reported that finasteride treatment inhibits hippocampal neurogenesis in mice. As hippocampal neurogenesis has been linked to emotional behavior, this could be of possible relevance for the pathophysiology of affective disorders. Further studies are needed to evaluate potential neuropsychiatric side effects of finasteride treatment in humans.

 

[Michael Scally MD]

YK11 Is a Partial Agonist of the Androgen Receptor

The androgen receptor (AR) is a member of the nuclear receptor (NR) superfamily of ligand-dependent transactivation factors. AR is structurally characterized by an amino-terminal trans-activation domain [NTD/activation function 1 (AF1)], a DNA binding domain (DBD), and a ligand binding domain (LBD) including a carboxy-terminal transactivation domain [activation function 2 (AF2)].

In the absence of a ligand, AR is localized in the cytoplasm, where it forms complexes with chaperones. Upon ligand binding, AR translocates into the nucleus. Following nuclear translocation, AR binds to androgen responsive elements (ARE) in the promoter regions of its target genes as a homodimer. Generally, the transcriptional activity of nuclear receptors is modulated by their interaction with cofactors such as coactivators and corepressors. The type of ligand that binds to the receptor determines which type of cofactor is chosen. In the case of agonists, AR interacts with coactivators dominantly over corepressors, and vice versa in the case of antagonists.

Unlike other nuclear receptors, AR AF2 demonstrates weak transcriptional activity. However, ligand-dependent interaction between NTD and LBD/AF2 (which is termed as the N/C interaction) endows AR with synergistic transactivation potential. Thus, the N/C interaction is important for the ligand-dependent transactivation potential of AR.

In a preliminary screening for novel AR ligands, a steroid compound, (17a ,20E)-17,20-[(1-methoxyethylidene) bis(oxy)]-3-oxo-19-norpregna-4,20-diene-21-carboxylic acid methyl ester (YK11), behaved apparently as a partial agonist of AR in an ARE-luciferase reporter assay (unpublished data). In this report, they show that YK11 blocks the N/C-interaction required for the full-agonistic function of wild-type AR, inducing selective AR-target genes owing to the constitutive transactivation potential of AF-1 subdomain in endogenous AR-expressing MDA-MB 453 cells.

Kanno Y, Hikosaka R, Zhang SY, et al. (17alpha,20E)-17,20-[(1-Methoxyethylidene)bis(oxy)]-3-oxo-19-norpregna-4,20-diene -21-carboxylic Acid Methyl Ester (YK11) Is a Partial Agonist of the Androgen Receptor. Biol Pharm Bull 2011;34(3):318-23. http://www.jstage.jst.go.jp/article/bpb/34/3/318/_pdf

A novel steroid compound, (17alpha,20E)-17,20-[(1-methoxyethylidene)bis(oxy)]-3-oxo-19-norpregna-4,20-diene -21-carboxylic acid methyl ester (YK11), was found to be a partial agonist of the androgen receptor (AR) in an androgen responsive element (ARE)-luciferase reporter assay. YK11 accelerates nuclear translocation of AR. Furthermore, YK11 does not induce amino/carboxyl-terminal (N/C) interaction and prevents 5-alpha-dihydrotestosterone (DHT)-mediated N/C interaction. Thus, YK11 activates AR without causing N/C interaction, which may in turn be responsible for the partially agonistic nature of YK11 observed in the ARE-luciferase reporter system. YK11 acts as a gene-selective agonist of AR in MDA-MB 453 cells. The effect of YK11 on gene expression relative to that of androgen agonist varies depending on the gene context. YK11 activated the reporter gene by inducing the translocation of the AR into the nuclear compartment, where its amino-terminal domain (NTD) functions as a constitutive activator of AR target genes. Our results suggest that YK11 might act as selective androgen receptor modulator (SARM).

 

[Michael Scally MD]

Diabetes Belt [And More] Identified In Southern United States
Diabetes belt identified in southern United States

THE TITLE MIGHT BE MORE LIKELY "FAT, DUMB, & LAZY BELT."

In the 1960s, a group of U.S. states with high age-adjusted stroke mortality defined a "stroke belt." Until recently, geographic patterns of diabetes had not been specifically characterized in the same manner. In an article published in the April 2011 issue of the American Journal of Preventive Medicine, researchers were able to identify clustered high prevalence areas, or a "diabetes belt" of 644 counties in 15 mostly southeastern states using data compiled for the first time of estimates of the prevalence of diagnosed diabetes for every U.S. county.

"Identifying a diabetes belt by counties allows community leaders to identify regions most in need of efforts to prevent type 2 diabetes and to manage existing cases of the disease," commented lead investigator Lawrence E. Barker, PhD, Division of Diabetes Translation, National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention (CDC), Atlanta, GA. "Although many risk factors for type 2 diabetes can't be changed, others can. Community design that promotes physical activity, along with improved access to healthy food, can encourage the healthy lifestyle changes that reduce the risk of developing type 2 diabetes."

Nearly one third of the difference in diabetes prevalence between the diabetes belt and the rest of the U.S. is associated with sedentary lifestyle and obesity. Thirty percent of the excess risk was associated with modif?able risk factors, and 37% with nonmodif?able factors, such as age and race/ethnicity.

Data from the diabetes belt showed prevalence rates greater than 11.0% or higher. By comparing demographics and risk factors such as gender, age, education, sedentary lifestyle, obesity, and race/ethnicity, they found four factors that distinguished the diabetes belt from the rest of the country.

Population of the diabetes belt counties contained substantially more non-Hispanic African Americans compared to the rest of the country (23.8% for the diabetes belt, 8.6% for the rest of the country).

Prevalence of obesity (32.9% vs. 26.1%) was greater in the diabetes belt than in the rest of the U.S.

Sedentary lifestyle (30.6% vs. 24.8%) was greater in the diabetes belt than in the rest of the U.S.

Proportion of people with a college degree was smaller (24.1% vs. 34.3%).

644 counties make up the diabetes belt. This belt includes portions of the states of Alabama, Arkansas, Florida, Georgia, Kentucky, Louisiana, North Carolina, Ohio, Pennsylvania, South Carolina, Tennessee, Texas, Virginia, and West Virginia, as well as the entire state of Mississippi.

According to Dr. Barker, "People who live in the diabetes belt will reduce their chance of developing type 2 diabetes if they are more active physically and, for those who are overweight or obese, if they lose weight. Taking these steps will eventually lower the prevalence of diabetes within the diabetes belt."


Barker LE, Kirtland KA, Gregg EW, Geiss LS, Thompson TJ. Geographic Distribution of Diagnosed Diabetes in the U.S.: A Diabetes Belt. American Journal of Preventive Medicine, Volume 40(4) (April 2011).

Dark red portions of this county-by-county map show that high rates of diabetes are common in the South and in Appalachia.

 

[zkt]

See!, those Walmart Houston girls are skinny as compared to Ky. :drooling:

 

[zkt]

I`ll bet my bottom dollar there is a correlation btwn T2D and HFCS drinks sales in that map.

 

[Michael Scally MD]

It is virtually impossible to have Vitamin D Toxicity. It is much better to have these levels in an optimal range.

Garland CF, French CB, Baggerly LL, Heaney RP. Vitamin d supplement doses and serum 25-hydroxyvitamin d in the range associated with cancer prevention. Anticancer Res 2011;31(2):607-11. Vitamin d supplement doses and serum 25-hydroxyvit... [Anticancer Res. 2011] - PubMed result

BACKGROUND: Studies indicate that intake of vitamin D in the range from 1,100 to 4,000 IU/d and a serum 25-hydroxyvitamin D concentration [25(OH)D] from 60-80 ng/ml may be needed to reduce cancer risk. Few community-based studies allow estimation of the dose-response relationship between oral intake of vitamin D and corresponding serum 25(OH)D in the range above 1,000 IU/d.

MATERIALS AND METHODS: A descriptive study of serum 25(OH)D concentration and self-reported vitamin D intake in a community-based cohort (n=3,667, mean age 51.3+/-13.4 y).

RESULTS: Serum 25(OH)D rose as a function of self-reported vitamin D supplement ingestion in a curvilinear fashion, with no intakes of 10,000 IU/d or lower producing 25(OH)D values above the lower-bound of the zone of potential toxicity (200 ng/ml). Unsupplemented all-source input was estimated at 3,300 IU/d. The supplemental dose ensuring that 97.5% of this population achieved a serum 25(OH)D of at least 40 ng/ml was 9,600 IU/d.

CONCLUSION: Universal intake of up to 40,000 IU vitamin D per day is unlikely to result in vitamin D toxicity.

 

[Michael Scally MD]

Social groups are often organized into status hierarchies. Higher status within a hierarchy comes with important benefits, including increased access to resources and greater influence over subordinates. It is not surprising, then, that low ranking individuals are often motivated to rise in the hierarchy whereas high-ranking individuals are often motivated to maintain their status. One behavioral strategy that can be adopted to gain or maintain high status is to display dominance: a behavioral style that is assertive and self-assured. Indeed, dominance behavior is associated with higher status across animal and human groups. Given the importance of dominance in hierarchical interactions, a large body of research has been devoted to understanding the biological factors that influence dominance behavior. In the current research, they examine neuroendocrine influences on dominance in humans. They test the hypothesis that two hormones – testosterone and cortisol – jointly regulate dominance.

This study provides compelling support for the claim that TESTOSTERONE (T) and CORTISOL (C) jointly regulate dominance. In individuals with low C, higher T was related to increased dominance. But in individuals with high C, the relation between T and dominance was either blocked or reversed. The findings generalized across different status-relevant domains (competition and leadership), across multiple measures of dominance, and across men and women. These results point to a new direction for research on the neuroendocrinology of dominance. Traditional theories posit that T and C should influence behavior independent of each other, but research to date has failed to provide consistent support for these theories. Consistent with some previous null findings, T and C alone were unrelated to dominance in our studies. The T/C ratio was not a significant predictor of dominance either. Only when the interaction between T and C was taken into account was there strong evidence for neuroendocrine regulation of behavior. In future studies, they suggest that researchers consider using a dual-hormone approach instead of traditional single-hormone approaches when investigating the neuroendocrinology of dominance and other status-seeking behaviors.


Mehta PH, Josephs RA. Testosterone and cortisol jointly regulate dominance: evidence for a dual-hormone hypothesis. Horm Behav 2010;58(5):898-906. Testosterone and cortisol jointly regulate dominan... [Horm Behav. 2010] - PubMed result

Traditional theories propose that testosterone should increase dominance and other status-seeking behaviors, but empirical support has been inconsistent. The present research tested the hypothesis that testosterone's effect on dominance depends on cortisol, a glucocorticoid hormone implicated in psychological stress and social avoidance. In the domains of leadership (Study 1, mixed-sex sample) and competition (Study 2, male-only sample), testosterone was positively related to dominance, but only in individuals with low cortisol. In individuals with high cortisol, the relation between testosterone and dominance was blocked (Study 1) or reversed (Study 2). Study 2 further showed that these hormonal effects on dominance were especially likely to occur after social threat (social defeat). The present studies provide the first empirical support for the claim that the neuroendocrine reproductive (HPG) and stress (HPA) axes interact to regulate dominance. Because dominance is related to gaining and maintaining high status positions in social hierarchies, the findings suggest that only when cortisol is low should higher testosterone encourage higher status. When cortisol is high, higher testosterone may actually decrease dominance and in turn motivate lower status.

 

[Michael Scally MD]

Human growth hormone receptor expression in obesity

Adipose tissue is a major target of growth hormone (GH) action. This is clear from studies of GH-deficient individuals and patients with defective GH receptors (GHR), all of whom display increased adiposity, and of those suffering from GH excess (acromegaly), who have reduced fat. GHRs are abundantly expressed in human adipocytes where GH has an important role in regulating proliferation and differentiation as well as inducing lipolysis. Clinical and experimental investigations have shown that GH administration leads to the reduction in fat mass in GH-deficient individuals as well as individuals suffering from certain genetic forms of obesity, such as Prader–Willi syndrome, and in obese animal models, such as ob/ob mice, which display diminished GH secretion. However, despite these positive effects of GH on adipose reduction, GH treatments of individuals with idiopathic obesity (not associated with an endocrinopathy or syndrome) have had little success, even though their GH levels are generally reduced. These observations suggest that idiopathic obesity may be associated with GH resistance at the level of the adipocyte because of altered GHR expression.

The adipose tissue is one of the major targets of growth hormone (GH) action: GH receptors (GHRs) are abundantly expressed and GH has profound effects on adipogenesis, lipogenesis and lipolysis. Despite positive effects of GH treatments on the reduction of fat mass in individuals with endocrinopathy-related obesity, GH treatments in individuals with idiopathic obesity are generally ineffective. In their first analysis, they found, for the first time, significantly lower GHR mRNA levels in the omental and subcutaneous fat depots of obese compared to lean individuals. These data suggest that GH insensitivity in obesity may result from decreased GHR availability and that this phenomenon is an important component of obesity-related adiposopathy.


Erman A, Veilleux A, Tchernof A, Goodyer CG. Human growth hormone receptor (GHR) expression in obesity: I. GHR mRNA expression in omental and subcutaneous adipose tissues of obese women. Int J Obes (Lond). Human growth hormone receptor (GHR) expression in ... [Int J Obes (Lond). 2011] - PubMed result

Objectives: Growth hormone (GH)-deficient individuals display increased adiposity that can be effectively reduced by GH therapy because of GH's lipolytic effects. However, similar GH treatments of individuals with idiopathic obesity (not associated with an endocrinopathy/syndrome) have had little success. We hypothesized that this form of obesity may be associated with GH resistance at the level of the adipocyte because of reduced GH receptor (GHR) expression.Subjects and methods:We studied GHR expression in omental and subcutaneous fat tissues from a cohort of 55 women ranging from lean to obese by various adiposity parameters. mRNA levels of total GHR and the dominant-negative truncated GHR(1-279) (trGHR) form were assayed by quantitative reverse transcriptase-PCR. Associations between adiposity measures and GHR levels as well as trGHR/GHR ratios were analyzed.

Results: Total GHR mRNA expression was 2-3-fold lower in omental as well as subcutaneous adipose tissues of obese compared with lean women (P</=0.05-0.001). Lean individuals expressed higher GHR mRNA levels in omental fat compared with subcutaneous (P</=0.01); in obese women, this depot-specific difference was lost. Omental and subcutaneous adipose GHR mRNA levels displayed significant negative correlations with a spectrum of indicators of obesity while, in subcutaneous fat, there was a significantly higher trGHR/GHR ratio with increasing adiposity (P</=0.05).

Conclusion: These results support our hypothesis that, with obesity, there is lower GHR expression in the adipocyte, and suggest one possible explanation why GH supplementation is not an effective treatment for individuals with idiopathic obesity.


Erman A, Wabitsch M, Goodyer CG. Human growth hormone receptor (GHR) expression in obesity: II. Regulation of the human GHR gene by obesity-related factors. Int J Obes (Lond). Human growth hormone receptor (GHR) expression in ... [Int J Obes (Lond). 2011] - PubMed result

Background and methods: In our previous analyses, we found significantly lower levels of growth hormone receptor (GHR) mRNA in adipose tissues of obese than in those of lean individuals, suggesting that idiopathic obesity involves GH resistance due to decreased GHR availability. To understand the mechanism(s) behind this downregulation, we performed an in silicoanalysis of the three most relevant GHR gene promoters, which revealed putative response elements (REs) for a number of obesity adipose-associated factors, including tumor necrosis factor-alpha (TNF?), hypoxia-inducible factor-1-alpha (HIF-1?) and glucocorticoids. We then characterized the dose-dependent effects of these factors on GHRexpression in HEK293 cells and in mature human SGBS (Simpson–Golabi–Behmel syndrome) adipocytes using quantitative reverse transcriptase-PCR and assessed the function of their putative REs by luciferase-reporter assays, site-directed mutagenesis and chromatin immunoprecipitation (ChIP) assays.

Results: TNF? treatments significantly reduced GHR mRNA levels and GHRpromoter activities at doses 10?ng?ml?1 in both cell lines. Transient overexpression of HIF-1? or exposure to the hypoxia mimetic CoCl2significantly increased GHR mRNA levels and promoter activities. Dexamethasone had biphasic effects: there was a significant increase in GHR mRNA levels at 10?10?m and in promoter activities at 10?10 and 10?8?m, whereas a significant decrease in both mRNA levels and promoter activities occurred at 10?6?m. Site-directed mutagenesis of the putative nuclear factor-?B, HIF-1? and glucocorticoid REs resulted in the loss of these effects, whereas ChIP analysis confirmed specific transcription factor–promoter interactions.

Conclusions: Our results suggest that the increased activity of TNF?, HIF-1? and glucocorticoids in obese adipose tissues could alter GHR gene transcription through specific REs and that TNF? may be involved in the development of GH resistance.

 

[Michael Scally MD]

The Evolving Role of HDL in the Treatment of High-Risk Patients with Cardiovascular Disease

Brewer HB, Jr. The Evolving Role of HDL in the Treatment of High-Risk Patients with Cardiovascular Disease. J Clin Endocrinol Metab:jc.2010-0163. http://jcem.endojournals.org/cgi/content/abstract/jc.2010-0163v1 (The Evolving Role of HDL in the Treatment of High-Risk Patients with Cardiovascular Disease -- Brewer, 10.1210/jc.2010-0163 -- Journal of Clinical Endocrinology &amp; Metabolism)

Context - Statin treatment of cardiovascular patients reduces clinical events by 25 to 45%. High-density lipoprotein (HDL) has been proposed as a therapeutic target to further reduce this residual cardiovascular risk.

Evidence Acquisition - PubMed from 1940 to the present was searched for all relevant citations related to the structure, function, and role of HDL in atherosclerosis.

Evidence Synthesis - Epidemiological data, animal models with increased plasma HDL levels, as well as initial clinical and cardiovascular imaging trials suggest that increasing HDL in clinical patients will decrease the risk of cardiovascular disease. Proposed mechanisms by which HDL may reduce atherosclerosis include facilitating cholesterol efflux from cholesterol-loaded foam cells, role as an antiinflammatory lipoprotein, decreasing atherogenic oxidized low-density lipoprotein, increasing nitric oxide synthesis, serving as a plasma transport lipoprotein for biologically important proteins, and as an antithrombotic agent. The identification of the major receptors, enzymes, cellular transporters, and plasma lipid transfer proteins has provided major new insights into the pathways for HDL metabolism and cholesterol transport as well as targets for future drug development to increase HDL.

Conclusions - Clinical trials with new HDL-raising drugs are currently under way to provide definitive evidence that increasing HDL will reduce cardiovascular events. The marked increase in our knowledge of the roles of HDL in cholesterol transport and the development of atherosclerosis now provides the framework for a more effective assessment of the plasma level and the function of HDL in an individual patient, as well as the lipoprotein profile after new drugs that increase HDL.

 

[Michael Scally MD]

Fat Alone, Not Where It Sits, May Be Key to Heart Problems
http://consumer.healthday.com/Article.asp?AID=650751

Study upends long-held belief that apple-shaped people face highest risk

In a finding that contradicts earlier research, an international study suggests that being obese boosts the likelihood of a heart attack or stroke regardless of where the excess fat is stored in the body.

That challenges the widely adopted notion that not all obesity is alike, with so-called apple-shaped people, who carry fat mainly in their midsections, facing a bigger risk for heart problems than those whose excess fat is carried on the hips or elsewhere.

Not so, say the researchers behind the new study. When it comes to obesity and heart disease, no excess fat is good fat, regardless of where it ends up, their analysis has found.

"Society has accepted the idea that if you carry more weight around the middle, your risk of heart disease is higher," said Dr. Emanuele Di Angelantonio, the study's co-author and a lecturer in medical screening at the University of Cambridge in England. "But actually this study shows that it doesn't matter where your fat is located. If you're overweight you're at risk, full stop."

Complicating matters, however, is the study's additional finding that the standard diagnostic measurements of fat -- such as body mass index (BMI), waist circumference and waist-to-hip ratio -- are not the most reliable tools for assessing heart disease risk.

Better indicators, it says, are blood cholesterol measurements and blood pressure readings.

"While excess fat level does remain a very important risk factor, for [doctors] who really want to predict cardiovascular risk in patients, it is enough to look at cholesterol, blood pressure, diabetes and smoking background, regardless of the patient's obesity status," Di Angelantonio said.

The study's findings, developed by a global team of 200 scientists from 17 countries and based at the University of Cambridge in the United Kingdom, are reported online March 11 in The Lancet.

To explore the predictive power of various heart disease risk factors, the researchers examined data from 58 studies that included more than 222,000 men and women from 17 countries.

None of the study participants had a history of heart disease. Data for most people included BMI readings, waist circumference measurements, waist-to-hip ratios, age, gender, smoking history, blood pressure readings, diabetes history and cholesterol measurements. For nearly 64,000 people, fat deposit assessments were conducted periodically for a number of years.

Over about a decade, more than 14,000 participants had a heart attack or a stroke.

The study concluded that being obese certainly raises the overall risk for heart disease, but that those who carry much of their excess fat in the stomach region do not appear to face a particularly higher risk, compared with those whose fat deposits are distributed differently.

They also found that tracking a person's blood pressure and cholesterol levels, as well as monitoring their history of diabetes, appeared to be best way to assess heart disease risk. When such indicators were readily available, they noted, adding in BMI and waist measurement information did not improve risk diagnosis.

The team was quick to emphasize, however, that being obese should not be deemed any less of a problem when it comes to heart disease. Excess weight, they said, remains a key culprit in the onset of medical conditions that boost the risk for cardiovascular illness.

Because of that, they suggested, calculations of weight, waist circumference and BMI might continue to be of value because the patient portrait they create can help health-care providers promote better diets and lifestyle choices that ultimately reduce risk. An editorial accompanying the study in The Lancet agreed, noting that BMI measurements can still serve as an early warning signal, especially in teens, young adults and middle-aged people without many other obvious signs of heart disease risks.

Dr. Walter Willett, a nutrition professor at Harvard Medical School and chairman of the nutrition department at the Harvard School of Public Health, indicated that the study conclusions make sense.

"It was not surprising that measures of fat distribution, such as waist circumference, did not do substantially better" in predicting heart disease, he noted.

But he said that obesity as a whole remains a key consideration, given that the factors that proved most useful in assessing heart risks -- such as high blood pressure and cholesterol -- are themselves the product of the "adverse effects of overweight."

Lona Sandon, a registered dietician and assistant professor of clinical nutrition at the University of Texas Southwestern, agreed that the findings "are reasonable in the grand scheme of things." But she, too, stressed that the findings should not be interpreted as permission to pack on the pounds.

"First of all, certainly people who are obese, no matter where the obesity is occurring on the body, should not dismiss their risk for heart disease," she said. "Carrying around excess weight puts you at a higher risk for heart disease than someone of normal weight, period."

"So while I'm not necessarily surprised that metabolic testing to measure your cholesterol levels, for example, is a better indicator of risk than, say, BMI, people should still be concerned about what's going on around their waistline," Sandon said. "In the end, people should think of that extra weight as a risk factor that leads to more risk factors, which lead to heart disease."


Separate and combined associations of body-mass index and abdominal adiposity with cardiovascular disease: collaborative analysis of 58 prospective studies. The Lancet. Separate and combined associations of body-mass index and abdominal adiposity with cardiovascular disease: collaborative analysis of 58 prospective studies : The Lancet

Background - Guidelines differ about the value of assessment of adiposity measures for cardiovascular disease risk prediction when information is available for other risk factors. We studied the separate and combined associations of body-mass index (BMI), waist circumference, and waist-to-hip ratio with risk of first-onset cardiovascular disease.

Methods - We used individual records from 58 cohorts to calculate hazard ratios (HRs) per 1 SD higher baseline values (4•56 kg/m2 higher BMI, 12•6 cm higher waist circumference, and 0•083 higher waist-to-hip ratio) and measures of risk discrimination and reclassification. Serial adiposity assessments were used to calculate regression dilution ratios.

Results - Individual records were available for 221 934 people in 17 countries (14 297 incident cardiovascular disease outcomes; 1•87 million person-years at risk). Serial adiposity assessments were made in up to 63 821 people (mean interval 5•7 years [SD 3•9]). In people with BMI of 20 kg/m2 or higher, HRs for cardiovascular disease were 1•23 (95% CI 1•17—1•29) with BMI, 1•27 (1•20—1•33) with waist circumference, and 1•25 (1•19—1•31) with waist-to-hip ratio, after adjustment for age, sex, and smoking status. After further adjustment for baseline systolic blood pressure, history of diabetes, and total and HDL cholesterol, corresponding HRs were 1•07 (1•03—1•11) with BMI, 1•10 (1•05—1•14) with waist circumference, and 1•12 (1•08—1•15) with waist-to-hip ratio. Addition of information on BMI, waist circumference, or waist-to-hip ratio to a cardiovascular disease risk prediction model containing conventional risk factors did not importantly improve risk discrimination (C-index changes of ?0•0001, ?0•0001, and 0•0008, respectively), nor classification of participants to categories of predicted 10-year risk (net reclassification improvement ?0•19%, ?0•05%, and ?0•05%, respectively). Findings were similar when adiposity measures were considered in combination. Reproducibility was greater for BMI (regression dilution ratio 0•95, 95% CI 0•93—0•97) than for waist circumference (0•86, 0•83—0•89) or waist-to-hip ratio (0•63, 0•57—0•70).

Interpretation - BMI, waist circumference, and waist-to-hip ratio, whether assessed singly or in combination, do not importantly improve cardiovascular disease risk prediction in people in developed countries when additional information is available for systolic blood pressure, history of diabetes, and lipids.

 

[Michael Scally MD]

This study reports the findings of a 2008 survey of the use of dietary supplements by cardiologists, orthopedists, and dermatologists, and the extent to which they recommend dietary supplements to their patients.


Dickinson A, Shao A, Boyon N, Franco J. Use of dietary supplements by cardiologists, dermatologists and orthopedists: report of a survey. Nutrition Journal 2011. http://www.nutritionj.com/content/pdf/1475-2891-10-20.pdf

Background - Dietary supplements are regularly used by a majority of the American population, and usage by health professionals is also common. There is considerable interest in usage patterns within the population and in the reasons for using dietary supplements. The "Life...supplemented" Healthcare Professionals 2008 Impact Study (HCP Impact Study) surveyed usage of dietary supplements by physicians in three specialties: cardiology, dermatology, and orthopedics.

Methods - The HCP Impact Study was conducted online by Ipsos Public Affairs for the Council for Responsible Nutrition (CRN), a trade association of the dietary supplement industry. Respondents were 900 physicians, including 300 each from three specialties - cardiology, dermatology, and orthopedics.

Results - Fifty-seven percent of cardiologists said they use dietary supplements at least occasionally, as did 75% of dermatologists and 73% of orthopedists. The product most commonly reported to be used was a multivitamin, but over 25% in each specialty said they used omega-3 fatty acids and over 20% said they used some botanical supplements. Regular dietary supplement use was reported by 37% of cardiologists, 59% of dermatologists, and 50% of orthopedists. Seventy-two percent of cardiologists, 66% of dermatologists, and 91% of orthopedists reported recommending dietary supplements to their patients. The primary reason given for recommending dietary supplements to patients was for heart health or lowering cholesterol for the cardiologists; benefits for skin, hair and nails for the dermatologists; and bone and joint health for the orthopedists.

Conclusions - Reported dietary supplement use was relatively common in this sample of physicians, and when they recommended dietary supplements to patients, they tended to do so for reasons related to their specialty.

 

[Michael Scally MD]

Mucosal damage by radiation in the small intestine may occur after a radiation accident or after pelvic irradiation during cancer therapy, and this causes severe pathological alterations. Although whether the primary damage occurs in epithelial cells of the mucosal membrane or endothelial cells of the capillary vessel remains controversial, damage to mucosa in the intestine appears within a few days after irradiation. The small intestine is more sensitive than the rectum or colon, and damage is observed after 6 Gy irradiation. Although the damaged mucosa can regenerate after low doses of radiation, high-dose exposure leads to lethal bacterial infection via disturbance of barrier function in experimental animals and lethal loss of body fluids in the intestine. Although post irradiation treatment against radiation damage in intestine may be valuable for accidental irradiation, the pharmacological therapy has not been established. Researchers focused on the regeneration process of mucosa in the small intestine after irradiation and compared the effects of sex steroids on regeneration.

Androgen, gestagen and estrogen are used clinically to treat postmenopausal symptoms, and their safety is well established. After these steroids bind to their own receptors, transcriptional activation and subsequent proliferation of cells occur mainly in genital organs. Androgen receptor and estrogen receptor are expressed in the intestine, and these steroids are involved in the functions of the non-genital organs. In studies of radioprotectors, prophylactic administration of 5-androstenediol showed life-saving effects against a lethal dose of radiation in experimental animals via action on hematopoietic cells. Here they compared the effects of steroid hormones on proliferation of mucosa and found that an anabolic steroid ameliorated lethal intestinal damage by radiation.


Ishihara H, Tanaka I, Yakumaru H, et al. Acceleration of regeneration of mucosa in small intestine damaged by ionizing radiation using anabolic steroids. Radiat Res 2011;175(3):367-74. Acceleration of regeneration of mucosa in small in... [Radiat Res. 2011] - PubMed result

Damage to intestine is a serious problem after accidental radiation exposure. To examine substances to ameliorate damage by postirradiation administration, we focused on the regeneration process after irradiation of the intestine. Using experimental systems, the effects of clinically used sex hormones on regeneration were compared. An anabolic steroid, nandrolone (19-nortestosterone), stimulated proliferation in IEC-6 epithelial cells. A single injection of 19-nortestosterone ester with prolonged action into mice 24 h after abdominal irradiation at a lethal dose of 15.7 Gy showed significant life-saving effects. Regeneration indicators such as microcolonies of BrdU-incorporated cells at day 5 and c-myb mRNA expression levels at day 4 were enhanced by 19-nortestosterone administration. In contrast, high concentrations of estradiol inhibited growth of IEC-6 cells. Treatment of abdominally irradiated mice with estradiol ester decreased levels of regeneration indicators and survival. These results suggest the effectiveness of the anabolic steroid as well as the importance of manipulation of steroid receptors in the recovery of mucosa damaged by radiation.

 

[Michael Scally MD]

NAFLD is a spectrum of disease that ranges from steatosis to steatohepatitis (nonalcoholic steatohepatitis or NASH: inflammation around the fat) to fibrosis/cirrhosis. Hepatic steatosis can be measured non-invasively using computed tomography (CT) whereas NASH/fibrosis is assessed histologically. The genetic underpinnings of NAFLD remain to be determined. Here we estimate that 26%–27% of the variation in CT measured hepatic steatosis is heritable or genetic. We identify three variants near PNPLAL3, NCAN, and PPP1R3B that associate with CT hepatic steatosis and show that variants in or near NCAN, GCKR, LYPLAL1, and PNPLA3, but not PPP1R3B, associate with histologic lobular inflammation/fibrosis. Variants in or near NCAN, GCKR, and PPP1R3B associate with altered serum lipid levels, whereas those in or near LYPLAL1 and PNPLA3 do not. Variants near GCKR and PPP1R3B also affect glycemic traits. Thus, researchers show that NAFLD is genetically influenced and expand the number of common genetic variants that associate with this trait. The findings suggest that development of hepatic steatosis, NASH/fibrosis, or abnormalities in metabolic traits are probably influenced by different metabolic pathways that may represent distinct therapeutic targets.


Speliotes EK, Yerges-Armstrong LM, Wu J, et al. Genome-Wide Association Analysis Identifies Variants Associated with Nonalcoholic Fatty Liver Disease That Have Distinct Effects on Metabolic Traits. PLoS Genet 2011;7(3):e1001324. PLoS Genetics: Genome-Wide Association Analysis Identifies Variants Associated with Nonalcoholic Fatty Liver Disease That Have Distinct Effects on Metabolic Traits

Nonalcoholic fatty liver disease (NAFLD) clusters in families, but the only known common genetic variants influencing risk are near PNPLA3. We sought to identify additional genetic variants influencing NAFLD using genome-wide association (GWA) analysis of computed tomography (CT) measured hepatic steatosis, a non-invasive measure of NAFLD, in large population based samples. Using variance components methods, we show that CT hepatic steatosis is heritable (~26%–27%) in family-based Amish, Family Heart, and Framingham Heart Studies (n = 880 to 3,070). By carrying out a fixed-effects meta-analysis of genome-wide association (GWA) results between CT hepatic steatosis and ~2.4 million imputed or genotyped SNPs in 7,176 individuals from the Old Order Amish, Age, Gene/Environment Susceptibility-Reykjavik study (AGES), Family Heart, and Framingham Heart Studies, we identify variants associated at genome-wide significant levels (p<5×10?8) in or near PNPLA3, NCAN, and PPP1R3B. We genotype these and 42 other top CT hepatic steatosis-associated SNPs in 592 subjects with biopsy-proven NAFLD from the NASH Clinical Research Network (NASH CRN). In comparisons with 1,405 healthy controls from the Myocardial Genetics Consortium (MIGen), we observe significant associations with histologic NAFLD at variants in or near NCAN, GCKR, LYPLAL1, and PNPLA3, but not PPP1R3B. Variants at these five loci exhibit distinct patterns of association with serum lipids, as well as glycemic and anthropometric traits. We identify common genetic variants influencing CT–assessed steatosis and risk of NAFLD. Hepatic steatosis associated variants are not uniformly associated with NASH/fibrosis or result in abnormalities in serum lipids or glycemic and anthropometric traits, suggesting genetic heterogeneity in the pathways influencing these traits.

 

[Michael Scally MD]

This review provides an update on the importance of Vitamin D in athletes and provides tips for assessing and treating vitamin D deficiency and insufficiency. It is my opinion, they are using levels too low, preferably >/= 50 ng/ml.


Larson-Meyer DE, Willis KS. Vitamin D and athletes. Curr Sports Med Rep 2010;9(4):220-6. Vitamin D and athletes. [Curr Sports Med Rep. 2010 Jul-Aug] - PubMed result

While it is well recognized that vitamin D is necessary for optimal bone health, emerging evidence is finding that adequate vitamin D intake reduces risk for conditions such as stress fracture, total body inflammation, infectious illness, and impaired muscle function. Studies in athletes have found that vitamin D status is variable and is dependent on outdoor training time (during peak sunlight), skin color, and geographic location. Although research has found that athletes generally do not meet the U.S. dietary reference intake for vitamin D, inadequate endogenous synthesis is the most probable reason for insufficient/deficient status. Given the recent findings, it is imperative that sports dietitians and physicians routinely assess vitamin D status and make recommendations to help athletes achieve a serum 25(OH)D concentration of >or=32 and preferably >or=40 ng.mL(-1). Further research is needed to determine the effect of vitamin D status on injury, training, and performance in athletes.

 

[Michael Scally MD]

Apparently, these investigators are NOT the least concerned for the adverse effects of FINASTERIDE. Also, there is the issue of E2.

Current testosterone therapies approved for use in the United States include intramuscular injections, transdermal patches and gels, subdermal pellets, buccal tablets, and oral alkylated testosterone derivatives (eg, methyltestosterone and oxandrolone). Each of these formulations has drawbacks. Injections must be given intramuscularly every 1 to 3 weeks and can be painful. Patches cause skin reactions in more than one-half of patients using them. Testosterone gels are safe and effective but are expensive and must be applied to a fairly large area of skin. In addition, gels have a risk of inadvertently exposing women and children to testosterone, which has recently resulted in a “black box” warning regarding their use from the U.S. Food and Drug Administration.

Oral administration of testosterone might be preferable to currently available options. Unfortunately, the currently available oral testosterone formulations, all of which are alkylated at the 17-carbon position, are associated with an unacceptably high rate of liver toxicity, including cholestatic jaundice, peliosis hepatis, and even liver tumors in one-third to one-half of long-term users. As a result, these oral androgens are not considered safe for the long-term treatment of male hypogonadism.

Oral administration of nonalkylated testosterone was previously thought to be ineffective because of rapid hepatic metabolism. Nevertheless, researchers recently reported that when nonalkylated testosterone was administered at a sufficient dose, serum testosterone levels within the normal range were achieved without adverse effects on liver function. In addition, they demonstrated that when oral testosterone was combined with a 5?-reductase inhibitor, which inhibits the conversion of testosterone to dihydrotestosterone (DHT), the resulting serum testosterone concentrations were roughly doubled and serum concentrations of DHT were reduced. Combining 5?-reductase inhibition with testosterone therapy is potentially attractive because DHT concentrations are elevated above the normal range after administration of oral testosterone formulations such as oral testosterone undecanoate, and DHT has been implicated in the pathophysiology of androgenic alopecia, acne, benign prostatic hyperplasia, and possibly prostate cancer. Therefore, because current “immediate-release” formulations of oral testosterone exhibit suboptimal pharmacokinetics, with supraphysiologic peaks of testosterone and DHT immediately after dosing, researchers developed 2 novel modified-release formulations of oral testosterone designed to slow absorption from the gut and improve hormone delivery. In this study, they sought to determine the pharmacokinetics of these novel formulations of oral testosterone alone and in combination with the 5?-reductase inhibitor finasteride in normal men with experimentally induced hypogonadism.

Serum estradiol levels after dosing with 300 mg of the immediate-release, modified fast-release, and modified slow-release formulations of oral testosterone in normal men rendered experimentally hypogonadal with acyline in the testosterone-only (A) and testosterone plus finasteride (B) groups (n = 8/group). The dotted lines represent the upper and lower limits of the normal range. All values are means ± SEM.


Snyder CN, Clark RV, Caricofe RB, et al. Pharmacokinetics of 2 novel formulations of modified-release oral testosterone alone and with finasteride in normal men with experimental hypogonadism. J Androl 2010;31(6):527-35. Pharmacokinetics of 2 Novel Formulations of Modified-Release Oral Testosterone Alone and With Finasteride in Normal Men With Experimental Hypogonadism

Oral administration of testosterone might be useful for the treatment of testosterone deficiency. However, current "immediate-release" formulations of oral testosterone exhibit suboptimal pharmacokinetics, with supraphysiologic peaks of testosterone and its metabolite, dihydrotestosterone (DHT), immediately after dosing. To dampen these peaks, we have developed 2 novel modified-release formulations of oral testosterone designed to slow absorption from the gut and improve hormone delivery. We studied these testosterone formulations in 16 normal young men enrolled in a 2-arm, open-label clinical trial. Three hundred-mg and 600-mg doses of immediate-release and modified fast-release or slow-release formulations were administered sequentially to 8 normal men rendered hypogonadal by the administration of the gonadotropin-releasing hormone antagonist acyline. Blood for measurement of serum testosterone, DHT, and estradiol was obtained before and 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 hours after each dose. A second group of 8 men was studied with the coadministration of 1 mg of the 5alpha-reductase inhibitor finasteride daily throughout the treatment period. Serum testosterone was increased with all formulations of oral testosterone. The modified slow-release formulation significantly delayed the postdose peaks of serum testosterone and reduced peak concentrations of serum DHT compared with the immediate-release formulation. The addition of finasteride further increased serum testosterone and decreased serum DHT. We conclude that the oral modified slow-release testosterone formulation exhibits superior pharmacokinetics compared with immediate-release oral testosterone both alone and in combination with finasteride. This formulation might have efficacy for the treatment of testosterone deficiency. [Note: They FAIL to include the E2 results!]

 

[Michael Scally MD]

Attention deficit hyperactivity disorder (ADHD) is a neuropsychological disorder, marked by inattentiveness, impulsivity, and hyperactivity, beginning in childhood and persisting into adulthood. ADHD may contribute to functional impairment in academic, vocational, and social situations. On the flip side, one benefit of ADHD may be exceptional creativity. Indeed, empirical studies suggest that individuals with ADHD have relatively high divergent thinking ability and may be less influenced by contextual constraints during creative activities. Collectively, these findings suggest that individuals with ADHD may excel at tasks or in situations that require divergent, unconstrained thinking. However, it is not clear whether or not the advantage observed on laboratory measures extends to creative achievement in real life. Thus, the present study measured creative achievement in ADHD and non-ADHD adults in several different domains, using the Creativity Achievement Questionnaire. To further characterize real-world creativity, researchers measured creative problem solving style preference using the FourSight Thinking Profile. Together, these two measures allow them to go beyond previous studies that have focused on short, laboratory-based measures. Their second objective was to replicate previous findings using a standardized measure of divergent thinking, the Abbreviated Torrance Test of Creativity for Adults. In the sections that follow, they first review previous research in this area, and then discuss the rationale for the present study.


White HA, Shah P. Creative style and achievement in adults with attention-deficit/hyperactivity disorder. Personality and Individual Differences 2011;50(5):673-7.

Previous research has suggested that adults with ADHD perform better on some measures of creativity than non-ADHD adults (White & Shah, 2006). The present study replicated previous findings using a standardized measure of creativity (the Abbreviated Torrance Test for Adults, Goff & Torrance, 2002) and extended previous research by investigating real-world creative achievement among adults with ADHD. Results indicated that adults with ADHD showed higher levels of original creative thinking on the verbal task of the ATTA and higher levels of real-world creative achievement, compared to adults without ADHD. In addition, comparison of creative styles using the FourSight Thinking Profile (Puccio, 2002) found that preference for idea generation was higher among ADHD participants, whereas preference for problem clarification and idea development was greater among non-ADHD participants. These findings have implications for real-world application of the creative styles of adults with and without ADHD.

 

[Michael Scally MD]

How the penis lost its spikes
Humans ditched DNA to evolve smooth penises and bigger brains.
How the penis lost its spikes : Nature News

Zoë Corbyn

Sex would be a very different proposition for humans if — like some animals including chimpanzees, macaques and mice — men had penises studded with small, hard spines.

Now researchers at Stanford University in California have found a molecular mechanism for how the human penis could have evolved to be so distinctly spine-free. They have pinpointed it as the loss of a particular chunk of non-coding DNA that influences the expression of the androgen receptor gene involved in hormone signalling.

"It is a small but fascinating part of a bigger picture about the evolution of human-specific traits," said Gill Bejerano, a developmental biologist at Stanford who led the work along with colleague David Kingsley. "We add a molecular perspective to a discussion that has been going on for several decades at least."

Published in Nature today 1, the research also suggests a molecular mechanism for how we evolved bigger brains than chimpanzees and lost the small sensory whiskers that the apes — who are amongst our closest relatives and with whom it has been estimated we share 96% of our DNA — have on their face.

Monogamous strategy

It has long been believed that humans evolved smooth penises as a result of adopting a more monogamous reproductive strategy than their early human ancestors. Those ancestors may have used penile spines to remove the sperm of competitors when they mated with females. However, exactly how this change came about is not known.

The researchers did not set out to study penile spines. Rather, they were looking for chunks of DNA that had been lost from the human genome but not the chimp genome, so they could then try to pinpoint what those chunks did.

The approach differs from that in most studies, explain Bejerano and Kingsley, in looking at what has been deleted from the human genome rather than what is present. "In the case of our study, had you started from the human genome, there would be nothing there to see," says Bejerano.

They first systematically identified 510 DNA sequences missing in humans and present in chimps, finding that those sequences were almost exclusively from the non-coding regions of the genome, between genes. They then homed in on two sequences whose absence in humans they thought might be interesting — one from near the androgen receptor (AR) gene and one from near a gene involved in tumour suppression (GADD45G).

Inserting the chimpanzee sequences into mouse embryos revealed that the former sequence produced both the hard penile spines and sensory whiskers present in some animals. The latter sequence acted as a kind of brake on the growth of specific brain regions — with the removal of its function appearing to have paved the way for the evolution of the larger human brain.

"The goal of the project was to find molecular lesions [losses] that underlie human evolutionary traits, with the examples illustrating different aspects of the principle," says Kingsley.

"Until we looked at where the DNA was expressed, we had no idea which switch — if any — it would actually control," adds Bejerano.

Other molecular biologists praised the work for its clever approach and said it would open up new avenues of inquiry, particularly for those working on the evolution of the human brain.

"It is detective work and a great reminder that, in the course of evolution, information is both gained and lost," said Sean Carroll, an expert in animal genetics and evolution at the University of Wisconsin, Madison.

"As so often with very good ideas, it seems almost obvious in hindsight," said Svante Pääbo, who directs the genetics department of the Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany, and was part of the team that recently sequenced the Neanderthal genome. "Since two of the almost 500 deleted sequences they identified turn out to be interesting, I am sure that several other ones on their list will turn out to be interesting too," he added. The researchers are continuing to analyse the remaining 508 DNA sequences.

David Haussler, who studies the molecular evolution of the human genome at the University of California, Santa Cruz, added that our ancestors' loss of penile spines is our gain today. "Couples everywhere can be thankful that this particular piece of DNA was ditched," he says.

References

1. McLean, C. Y. et al. Nature 471, 216-219 (2011).


McLean CY, Reno PL, Pollen AA, et al. Human-specific loss of regulatory DNA and the evolution of human-specific traits. Nature 2011;471(7337):216-9. Human-specific loss of regulatory DNA and the evol... [Nature. 2011] - PubMed result

Humans differ from other animals in many aspects of anatomy, physiology, and behaviour; however, the genotypic basis of most human-specific traits remains unknown. Recent whole-genome comparisons have made it possible to identify genes with elevated rates of amino acid change or divergent expression in humans, and non-coding sequences with accelerated base pair changes. Regulatory alterations may be particularly likely to produce phenotypic effects while preserving viability, and are known to underlie interesting evolutionary differences in other species. Here we identify molecular events particularly likely to produce significant regulatory changes in humans: complete deletion of sequences otherwise highly conserved between chimpanzees and other mammals. We confirm 510 such deletions in humans, which fall almost exclusively in non-coding regions and are enriched near genes involved in steroid hormone signalling and neural function. One deletion removes a sensory vibrissae and penile spine enhancer from the human androgen receptor (AR) gene, a molecular change correlated with anatomical loss of androgen-dependent sensory vibrissae and penile spines in the human lineage. Another deletion removes a forebrain subventricular zone enhancer near the tumour suppressor gene growth arrest and DNA-damage-inducible, gamma (GADD45G), a loss correlated with expansion of specific brain regions in humans. Deletions of tissue-specific enhancers may thus accompany both loss and gain traits in the human lineage, and provide specific examples of the kinds of regulatory alterations and inactivation events long proposed to have an important role in human evolutionary divergence.

 

[Michael Scally MD]

Testosterone Linked to Men's Ability to 'Woo' Potential Mates
Testosterone linked to men's ability to 'woo' potential mates

ScienceDaily (Mar. 13, 2011) — Theories have long proposed that testosterone influences competition among males trying to attract females. Findings from a recent study at Wayne State University give a clearer understanding of the links between testosterone and human mating behavior, and how testosterone is associated with dominance and competitive success when men battle for the attention of an attractive woman.

The study engaged pairs of men in a seven-minute videotaped competition for the attention of an attractive female undergraduate. Pre-competition testosterone levels were positively associated with men's dominance behaviors in the mate competition-including how assertive they were and how much they "took control" of the conversation-and with how much the woman indicated that she "clicked" with each of the men.

According to Richard Slatcher, Ph.D., assistant professor of psychology in WSU's College of Liberal Arts and Sciences and a resident of Birmingham, Mich., the effects of testosterone on dominance behaviors were especially pronounced among men who reported having a high need for social dominance. In his study, "Testosterone and Self-Reported Dominance Interact to Influence Human Mating Behavior," published online Feb. 28 in the journal, Social Psychological and Personality Science, these men showed a strong positive association between their own testosterone and their own dominance behaviors and, most surprisingly, a strong negative association between their own testosterone and their opponents' dominance behaviors. In other words, men both high in testosterone and who reported a high need for social dominance appeared to be able somehow suppress their competitors' ability to attract potential mates. However, when men reported low need for dominance, there was no association between testosterone and dominance behaviors-either their own or their competitors'.

"We found that testosterone levels influenced men's dominance behaviors during the competitions, how much they derogated (or 'bashed') their competitors afterward, and how much the woman said she 'clicked' with them," said Slatcher. "Books, film and television often portray men who are bold and self-assured with women as being high in testosterone. Our results suggest that there is a kernel of truth to this stereotype, that naturally circulating testosterone indeed is associated with men's behaviors when they try to woo women."

Although many animal studies have shown that testosterone is associated with dominance when males compete for mates, none-until now-have demonstrated this association in humans.

"These findings highlight an important difference between humans and animals," said Slatcher. "In humans-unlike animals-explicit, conscious motives can affect how a hormone such as testosterone shapes behavior. Our findings indicate that testosterone is associated with dominance behaviors and success when men compete for the attention of an attractive woman, particularly when men also have a strong conscious desire for social dominance."


Slatcher RB, Mehta PH, Josephs RA. Testosterone and Self-Reported Dominance Interact to Influence Human Mating Behavior. Social Psychological and Personality Science. Testosterone and Self-Reported Dominance Interact to Influence Human Mating Behavior

In this study, 76 men came into the lab in pairs and engaged in a 7-minute videotaped mate competition for the attention of an attractive female confederate. Pre-competition testosterone (T) levels were positively associated with men’s dominance behaviors and with how much the confederate indicated that she “clicked” with each participant. Dyadic analyses showed that self-reported dominance moderated the effects of T on one’s own dominance behaviors and on opponents' dominance behaviors. Specifically, among men high in self-reported dominance, there was a strong positive association between T and their own dominance behaviors and a strong negative association between T and opponents' dominance behaviors. However, among men low in self-reported dominance, there was no association between T and dominance behaviors. These findings provide novel evidence linking T with evolutionarily adaptive behaviors in humans and suggest that T interacts with people’s explicit dominance motives to regulate behaviors that enhance mating success.

 

[Michael Scally MD]

Judging Couples’ Chemistry Influenced by Serotonin
Judging couples’ chemistry influenced by serotonin

ScienceDaily (Mar. 13, 2011) — The judgments we make about the intimacy of other couples' relationships are influenced by the brain chemical serotonin, an Oxford University study has found.

Healthy adult volunteers, whose levels of serotonin activity had been lowered, rated couples in photos as being less 'intimate' and less 'romantic' than those with normal serotonin activity.

The results raise the possibility that lower serotonin activity in people with depression and other psychiatric conditions could contribute to changes in the way they perceive personal relationships.

The Medical Research Council-funded study is published in the journal Biological Psychiatry.

'Serotonin is important in social behavior, and also plays a significant role in psychological disorders such as depression', explains Professor Robert Rogers of the Department of Psychiatry at Oxford University, who led the research. 'We wanted to see whether serotonin activity influences the judgments we make about peoples' close personal relationships.'

Problems with social relationships, and a feeling of social isolation, are a feature of depression in some people. It is possible that alterations in brain systems -- such as serotonin -- contribute to these difficulties by changing the way people think about relationships with partners.

Such understanding is important as supportive close relationships are known to protect against the development of mental illnesses and to promote recovery in those affected by psychiatric conditions. The opposite is also true: dysfunctional relationships can be triggers for those at risk of these conditions.

The team from Oxford University, along with colleagues from the University of Liverpool and King's College London, manipulated the serotonin activity in healthy adult volunteers, and then asked them to make judgments about sets of photographs of couples.

The approach involved giving amino acid drinks to two groups of volunteers. One group received drinks that contained tryptophan, the amino acid from which serotonin is made in the brain. The other group received drinks that did not contain tryptophan. Differences in the judgments made by the two groups reflected changes in serotonin activity.

The 22 volunteers who received the drink without tryptophan consistently rated the couples in the photos as being less 'intimate' and 'romantic' than the 19 participants who received the control drink.

'Although this is only a small study, the same patterns may well extend to the way we perceive our own relationships,' says Professor Rogers. 'Serotonin activity may affect people's ability in depression to maintain positive or intimate personal relationships.’


Bilderbeck AC, McCabe C, Wakeley J, et al. Serotonergic Activity Influences the Cognitive Appraisal of Close Intimate Relationships in Healthy Adults. Biological Psychiatry. http://biologicalpsychiatryjournal.com/content/1000942abs

Background: Close supportive relationships protect against psychological disorders and also facilitate recovery. However, little is known about the neurochemical mechanisms that mediate these effects. Variation in serotonin function influences affiliative behavior in humans and nonhuman primates. Here, we used tryptophan depletion in healthy adults to investigate the role of serotonin in the cognitive appraisal of close personal relationships.

Methods: Twenty-two healthy adults drank an amino acid drink without tryptophan, and 19 healthy adults drank an amino acid drink containing tryptophan. Participants were presented with color photographs of heterosexual "couples" standing apart or making affiliative touch gestures and rated the couples for descriptors that capture qualities of close personal relationships. Trait attachment style and state affect of participants were also measured.

Results: Tryptophan depletion reduced the judged intimacy and romance of photographed couples. Tryptophan-depleted women rated men as more dominant in relationships and touching couples as more able to resolve their conflicts, when compared with nondepleted women. These effects were not due to changes in mood and remained statistically reliable when the marked impact of attachment style upon relationship judgments was statistically controlled.

Conclusions: Our results suggest that central serotonin activity influences the appraisal of close intimate partnerships, raising the possibility that serotonergic dysfunction contributes to altered cognitions about relationships in psychiatric illnesses.

 

[Michael Scally MD]

First-in-human clinical trials represent a critical juncture in the translation of laboratory discoveries. However, because they involve the greatest degree of uncertainty at any point in the drug development process, their initiation is beset by a series of nettlesome ethical questions: has clinical promise been sufficiently demonstrated in animals? Should trial access be restricted to patients with refractory disease? Should trials be viewed as therapeutic? Have researchers adequately minimized risks?

The resolution of such ethical questions inevitably turns on claims about future events like harms, therapeutic response, and clinical translation. Recurrent failures in clinical translation, like Eli Lilly's Alzheimer candidate semagacestat, highlight the severe limitations of current methods of prediction. In this case, patients in the active arm of the placebo-controlled trial had earlier onset of dementia and elevated rates of skin cancer.

Various authoritative accounts of human research ethics state that decision-making about risk and benefit should be careful, systematic, and non-arbitrary. Yet, these sources provide little guidance about what kinds of evidence stakeholders should use to ensure their estimates of such events ground responsible ethical decisions. In this article, we suggest that investigators, oversight bodies, and sponsors often base their predictions on a flawed and inappropriately narrow preclinical evidence base.


Summary Points

Ethical judgments about risk, benefit, and patient eligibility in clinical trials hinge on predictions about harm, therapeutic response, and clinical promise.

Predictions for novel interventions in preclinical stages of development suffer from two problems: insufficient attention to threats to validity in preclinical research and a reliance on an overly narrow base of evidence that includes only animal and clinical studies of the intervention in question (“evidential conservatism”).

To improve ethical and scientific decision-making in early phase studies, decision-makers should explicitly attend to reporting quality and methodological features in preclinical experiments that address threats to internal, construct, and external validity.

Decision-makers should also use evidence that sheds light on the reliability of causal claims embedded within a proposed trial. This evidence can be gathered from outcomes of previous trials involving agents targeting related biological pathways (“reference classes”).


Kimmelman J, London AJ. Predicting Harms and Benefits in Translational Trials: Ethics, Evidence, and Uncertainty. PLoS Med 2011;8(3):e1001010. PLoS Medicine: Predicting Harms and Benefits in Translational Trials: Ethics, Evidence, and Uncertainty