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[Michael Scally MD]

Clenbuterol Is Additive To The Hypertrophic Effect Of Myostatin Suppression [Mice]

Loss of muscle mass can adversely affect human health and viability, and molecules involved in the regulation of skeletal muscle growth are valuable targets in developing therapeutic strategies for muscle-wasting conditions. Myostatin (MSTN) and some b-adrenergic agonists, such as clenbuterol (CL), have emerged as powerful regulators of skeletal muscle growth and mass. Both CL administration and MSTN inhibition have individually demonstrated their therapeutic potential for preventing or reversing muscle loss in various conditions that lead to muscle atrophy or wasting.

Although there have been numerous demonstrations of the muscle growth–promoting effect of CL administration or MSTN suppression, the effect of a combination of CL administration and MSTN inhibition on skeletal muscle growth has not been investigated. Therefore, researchers designed an experiment in which CL was fed to wild-type and MSTN suppressed mice to assess the combined effect of CL administration and MSTN suppression on body and muscle growth. At the same time, they examined the phosphorylation of 4E-BP1 and p70S6k, two key downstream effectors of the mTOR pathway, during treatment.


Kim KH, Kim YS, Yang J. The muscle-hypertrophic effect of clenbuterol is additive to the hypertrophic effect of myostatin suppression. Muscle & Nerve 2011;43(5):700-7. http://www.distrofiamuscular.net/clenbuterol.pdf

Introduction: In this study we investigated the combined effect of myostatin (MSTN) suppression and ?-agonist (clenbuterol) administration on muscle hypertrophy and the phosphorylation of muscle 4E-BP1 and p70S6k, two downstream effectors of the Akt/mTOR anabolic pathway.

Methods: Female heterozygous MSTN-prodomain transgenic mice (an MSTN suppression model) and wild-type littermates were given 0 or 20 ppm of clenbuterol (CL) in their drinking water, and muscle samples were collected at 1 and 2 weeks after treatment.

Results: CL increased body and muscle mass in both genotypes. Levels of phosphorylated muscle 4E-BP1 and p70S6k were higher in MSTN-prodomain transgenic mice than in wild-type mice. CL increased the phosphorylation of 4E-BP1 and p70S6k in both genotypes.

Conclusions: The muscle-hypertrophic effect of CL is additive to the effect of MSTN suppression. The combination of MSTN suppression and treatment with ?-agonists may be an effective therapeutic approach to combat muscle-wasting conditions.

 

[Michael Scally MD]

Vitamin D Status, Adiposity, and Lipids in Black American and Caucasian Children

Studies in adults and children have shown a link between obesity and vitamin D status. Serum 25- hydroxyvitamin D [25(OH)D], the recognized biomarker of vitamin D status, is inversely associated with clinical and laboratory measures of adiposity such as body mass index (BMI), waist circumference, and percentage of total body fat in adults and adolescents. Sequestration of vitamin D in body fat stores and its consequent reduced bioavailability offer a plausible explanation for this association. Racial and ethnic differences in the degree of adiposity and distribution of body fat are well recognized. For a given BMI, African-American children have lower levels of adiposity than Caucasian children. Furthermore, distribution of abdominal adipose tissue varies by race—compared with Caucasian children, African-American children have lower visceral adipose tissue (VAT) and higher sc adipose tissue (SAT). Racial differences in abdominal fat topography may explain the racial variations in the metabolic risks of abdominal adiposity, such as higher diabetogenic risk and better lipid profile in African-Americans compared with Caucasians.

Data characterizing the racial differences in the relationship between vitamin D status and adiposity, particularly abdominal adipose tissue distribution, are limited. Because adiposity is a risk factor for hypovitaminosis D and dyslipidemia and abdominal fat topography (distribution of SAT and VAT) influences the metabolic risks of adiposity, researchers examined the racial differences in the relationship between vitamin D status, BMI, total body adiposity, intraabdominal SAT and VAT, and lipid levels in healthy obese and nonobese 8- to 18-yr-old black and white children.


Rajakumar K, de las Heras J, Chen TC, Lee S, Holick MF, Arslanian SA. Vitamin D Status, Adiposity, and Lipids in Black American and Caucasian Children. J Clin Endocrinol Metab:jc.2010-388. http://jcem.endojournals.org/cgi/content/abstract/jc.2010-2388v1 (Vitamin D Status, Adiposity, and Lipids in Black American and Caucasian Children -- Rajakumar et al., 10.1210/jc.2010-2388 -- Journal of Clinical Endocrinology & Metabolism)

Objective: The aim of the study was to examine the relationship between vitamin D status, total and abdominal adiposity, and lipids in black and white children.

Methods: Plasma 25-hydroxyvitamin D [25(OH)D], adiposity [body mass index (BMI), percentage of total body fat, visceral adipose tissue (VAT), sc adipose tissue (SAT)], and fasting lipids were assessed in healthy obese and nonobese 8- to 18-yr-old black and white children.

Results: We studied 237 children (mean ± SD age, 12.7 ± 2.2 yr; 47% black, 47% obese, and 43% male). Mean 25(OH)D concentration for the entire cohort was 19.4 ± 7.4 ng/ml. The majorityof the children were vitamin D deficient [25(OH)D < 20 ng/ml; 73% blacks, 40% whites]. Plasma 25(OH)D was associated inversely with BMI, BMI percentile, percentage of total body fat, VAT, and SAT and positively with HDL cholesterol in the entire cohort. VAT was higher in vitamin D-deficient whites, and SAT was higher in vitamin D-deficient blacks compared with their respective vitamin D-nondeficient counterparts. Race, season, pubertal status, and VAT were independent significant predictors of 25(OH)D status.

Conclusions: In black and white youth examined together, lower levels of 25(OH)D are associated with higher adiposity measures and lower HDL. Furthermore, vitamin D deficiency is associated with higher VAT in whites and greater SAT in blacks. Besides therapeutic interventions to correct the high rates of vitamin D deficiency in youth, benefits of vitamin D optimization on adiposity measures and lipid profile need to be explored.

 

[Michael Scally MD]

[The study, in women, is sure to be disturbing. It is also very very funny! It has long been my opinion that liposuction was and is a procedure for the vain and uninitiated. We treat fat as something that has no discernable physiological role, a nuisance, therefore to be removed, excised, or “liposucked.” And this does not count the well documented and well-described complications. Will these same preliminary results be found in men? Regardless, exercise and diet is much healthier for fat loss. Lest anyone be confused, the image changes are fat, NOT muscle!]

With Liposuction, the Belly Finds What the Thighs Lose
Liposuction Study Finds That Lost Fat Returns - NYTimes.com

April 30, 2011
By GINA KOLATA

THE woman’s hips bulged in unsightly saddlebags. Then she had liposuction and, presto, those saddlebags disappeared.

Photo after photo on plastic surgery Web sites make liposuction look easy, its results transformative. It has become the most popular plastic surgery, with more than 450,000 operations a year, each costing a few thousand dollars.

But does the fat come back? And if it does, where does it show up?

Until now, no one knew for sure. But a new study, led by Drs. Teri L. Hernandez and Robert H. Eckel of the University of Colorado, has answered those questions. And what he found is not good news.

In the study, the researchers randomly assigned nonobese women to have liposuction on their protuberant thighs and lower abdomen or to refrain from having the procedure, serving as controls. As compensation, the women who were control subjects were told that when the study was over, after they learned the results, they could get liposuction if they still wanted it. For them, the price would also be reduced from the going rate.

The result, published in the latest issue of Obesity, was that fat came back after it was suctioned out. It took a year, but it all returned. But it did not reappear in the women’s thighs. Instead, Dr. Eckel said, “it was redistributed upstairs,” mostly in the upper abdomen, but also around the shoulders and triceps of the arms.

Dr. Felmont Eaves III, a plastic surgeon in Charlotte, N.C., and president of the American Society for Aesthetic Plastic Surgery, said the study was “very well done,” and the results were surprising. He said he would mention it to his patients in the context of other information on liposuction.

The finding raises questions about plastic surgery. Liposuction has been around since 1974 and is heavily advertised. Why did it take so long for anyone to do this study?

Maybe it’s because such a study is very difficult, said Dr. Samuel Klein, director of the Center for Human Nutrition at the Washington University School of Medicine. It takes a team of researchers, and money. Fat must be measured precisely, with scans.

And surgery, said Jonathan Moreno, an ethicist at the University of Pennsylvania who has studied the field, is not like other areas of medicine.

“A lot of it has to do with the culture of surgery, which is literally hands-on,” he said. Surgeons, he added, often feel a deep connection to their patients that makes it difficult for them to agree to clinical trials that involve randomizing patients.

Another problem, Dr. Moreno said, is that different surgeons have different skills and different techniques. Surgery is not like taking a drug, where one pill is just like every other.

So instead of doing rigorous studies, surgeons tend to innovate, inventing their own procedures and publishing anecdotes about patients, a practice that can be misleading.

But in this case, the outcome did not depend on the surgeon. It depended on the biology of fat. And obesity researchers say they are not surprised that the women’s fat came back. The body, they say “defends” its fat. If you lose weight, even by dieting, it comes back. And, the study showed, if you suck out the fat with liposuction, even if it’s only a pound, as it was for subjects in the study, it still comes back.

“It’s another chapter in the ‘You can’t fool Mother Nature’ story,’ ” said Dr. Rudolph Leibel, an obesity researcher at Columbia University.

Some researchers have their own anecdotes. Dr. George Bray, a professor of medicine at Louisiana State University, once saw a young woman who was so distraught by her protruding abdomen that she had an operation to slice off some of her abdominal fat.

“Her lower abdomen was considerably thinner,” Dr. Bray said. “But the areas above it picked up the extra fat.”

Then there are the studies with laboratory rodents that had fat surgically removed. The fat always came back. And, like the women in the new study, the rodents got their fat back in places other than the place where it was removed, Dr. Klein reported. They grow new fat cells to replace the ones that were lost.

The same thing happened to the women who had liposuction. It turns out, Dr. Leibel said, that the body controls the number of its fat cells as carefully as it controls the amount of its fat. Fat cells die and new ones are born throughout life. Scientists have found that fat cells live for only about seven years and that every time a fat cell dies, another is formed to take its place.

But why wouldn’t the women grow new fat cells in their thighs? The answer, Dr. Klein said, may be that liposuction violently destroys the fishnet structure under the skin where fat cells live.

Nonetheless, the women in the study who had liposuction were happy, Dr. Eckel said. They had hated their hips and thighs and just wanted that fat gone.

As for the women in the control group, when the study ended and they knew the results, more than half still chose to have liposuction.


Hernandez TL, Kittelson JM, Law CK, et al. Fat Redistribution Following Suction Lipectomy: Defense of Body Fat and Patterns of Restoration. Obesity. Obesity - Abstract of article: Fat Redistribution Following Suction Lipectomy: Defense of Body Fat and Patterns of Restoration

No randomized studies in humans have examined whether fat returns after removal or where it returns. We undertook a prospective, randomized-controlled trial of suction lipectomy in nonobese women to determine if adipose tissue (AT) is defended and if so, the anatomic pattern of redistribution. Healthy women with disproportionate AT depots (lower abdomen, hips, or thighs) were enrolled. Baseline body composition measurements included dual-energy X-ray absorptiometry (DXA) (a priori primary outcome), abdominal/limb circumferences, subcutaneous skinfold thickness, and magnetic resonance imaging (MRI) (torso/thighs). Participants (n = 32; 36 ± 1 year) were randomized to small-volume liposuction (n = 14, mean BMI: 24 ± 2 kg/m2) or control (n=18, mean BMI: 25 ± 2) following baseline. Surgery group participants underwent liposuction within 2–4 weeks. Identical measurements were repeated at 6 weeks, 6 months, and 1 year later. Participants agreed not to make lifestyle changes while enrolled. Between-group differences were adjusted for baseline level of the outcome variable.

After 6 weeks, percent body fat (%BF) by DXA was decreased by 2.1% in the lipectomy group and by 0.28% in the control group (adjusted difference (AD): ?1.82%; 95% confidence interval (CI): ?2.79% to ?0.85%; P = 0.0002). This difference was smaller at 6 months, and by 1 year was no longer significant (0.59% (control) vs. ?0.41% (lipectomy); AD: ?1.00%; CI: ?2.65 to 0.64; P = 0.23). AT reaccumulated differently across various sites. After 1 year the thigh region remained reduced (0.77% (control) vs. ?1.83% (lipectomy); AD: ?2.59%; CI: ?3.91 to ?1.28; P = 0.0001), but AT reaccumulated in the abdominal region (0.64% (control) vs. 0.42% (lipectomy); AD: ?0.22; CI: ?2.35 to 1.91; P = 0.84). Following suction lipectomy, BF was restored and redistributed from the thigh to the abdomen.

 

[Michael Scally MD]

Our Bulging Medicine Cabinets

Shrank WH. Our Bulging Medicine Cabinets - The Other Side of Medication Nonadherence. New England Journal of Medicine 2011;364(17):1591-3.

Last September, the Drug Enforcement Agency, in partnership with local police departments throughout the country, held a “National Prescription Drug Take-Back Day.” More than 4000 police departments participated, and in Orange County, Florida, alone, more than 1.5 tons of prescription medications were returned. The point of the initiative was to permit safe disposal of controlled substances, and Americans took the opportunity to dispose of all types of medications that they had amassed in their medicine cabinets. Another such event is scheduled for April 30, 2011.

 

[Michael Scally MD]

Screening for Future Cardiovascular Disease Using Age Alone

Age Alone May Be All That's Needed to Predict Heart Risk
Medical News: Age Alone May Be All That&apos;s Needed to Predict Heart Risk - in Cardiovascular, Prevention from MedPage Today

That's the conclusion of a statistical model that found age alone was as good a predictor of cardiovascular events as Framingham Risk Score, with the same 86% sensitivity. The study was reported by Nicholas Wald, MD, of the Wolfson Institute of Preventive Medicine in London, and colleagues in PLoS One.

"Age screening loses little in screening performance compared with multiple risk factor measurement methods," they wrote.

Framingham risk scores are the gold standard of risk assessment for cardiovascular disease, but Wald -- who holds patents on a polypill for heart disease prevention -- and his colleagues argue that age is the strongest determinant.

Screening based on age alone and targeting those 55 and up would save money on the battery of tests and office visits used in assessing Framingham risk, they argued, adding that it's also cost-effective since most prevention methods -- i.e., statins -- are inexpensive.

Cardiovascular disease (CVD: coronary death, non-fatal myocardial infarction, and stroke) is the commonest cause of death and a major cause of morbidity worldwide. Preventive treatments should therefore be more widely used, given their efficacy, low cost, and safety.

Guidelines recommend that primary preventive treatment be based on assessment of absolute risk of cardiovascular events using multiple risk factor algorithms such as the Framingham risk equations, which include age, sex, smoking status, diabetic status, serum cholesterol, and blood pressure. Age is by far the strongest determinant of CVD risk in multiple risk factor algorithms. Offering preventive treatment to everyone over a specified age without measuring other risk factors would be a simpler screening strategy than offering preventive treatment to everyone exceeding a specified CVD risk cut-off based on multiple risk factor measurement. It would avoid the multiple risk factor measurement costs. The loss in screening performance may be small enough to warrant consideration of using age alone as the screening method of choice.

To investigate this, researchers compared the efficacy of offering preventive treatment based on age alone (age screening) with Framingham risk estimation (Framingham screening). Using illustrative costs, they also compared the cost effectiveness of these methods.


Wald NJ, Simmonds M, Morris JK. Screening for Future Cardiovascular Disease Using Age Alone Compared with Multiple Risk Factors and Age. PLoS ONE;6(5):e18742. PLoS ONE: Screening for Future Cardiovascular Disease Using Age Alone Compared with Multiple Risk Factors and Age

Background - Risk factors such as blood pressure and serum cholesterol are used, with age, in screening for future cardiovascular disease (CVD) events. The value of using these risk factors with age compared with using age alone is not known. We compared screening for future CVD events using age alone with screening using age and multiple risk factors based on regular Framingham risk assessments.

Methods - Ten-year CVD risk was estimated using Framingham risk equations in a hypothetical sample population of 500,000 people aged 0–89 years. Risk estimates were used to identify individuals who did and did not have a CVD event over a ten-year period. For screening using age alone (age screening) and screening using multiple risk factors and age (Framingham screening) we estimated the (i) detection rate (sensitivity); (ii) false–positive rate; (iii) proportion of CVD-free years of life lost in affected individuals with positive results (person-years detection rate); and (iv) cost per CVD-free life year gained from preventive treatment.

Results - Age screening using a cut-off of 55 years detected 86% of all first CVD events arising in the population every year and 72% of CVD-free years of life lost for a 24% false-positive rate; for five yearly Framingham screening the false-positive rate was 21% for the same 86% detection rate. The estimated cost per CVD-free year of life gained was £2,000 for age screening and £2,200 for Framingham screening if a Framingham screen costs £150 and the annual cost of preventive treatment is £200.

Conclusion - Age screening for future CVD events is simpler than Framingham screening with a similar screening performance and cost-effectiveness. It avoids blood tests and medical examinations. The advantages of age screening in the prevention of heart attack and stroke warrant considering its use in preference to multiple risk factor screening.

 

[Michael Scally MD]

Prevalence and Incidence of Diabetes Mellitus on Growth Hormone Replacement

According to a study published online May 4 in the Journal of Clinical Endocrinology and Metabolism, the "incidence of diabetes in adults taking growth hormone replacement (GHR) is not significantly higher than that of controls." After assessing "incidence of diabetes over 4.1 years in 5,839 patients" and a like number of controls, researchers concluded that the "increased incidence of diabetes mellitus during GHR therapy is associated with the continuing presence of obesity and metabolic syndrome rather than GHR therapy, per se."


Attanasio AF, Jung H, Mo D, et al. Prevalence and Incidence of Diabetes Mellitus in Adult Patients on Growth Hormone Replacement for Growth Hormone Deficiency: a Surveillance Database Analysis. J Clin Endocrinol Metab:jc.2011-0448. http://jcem.endojournals.org/cgi/content/abstract/jc.2011-0448v1 (Prevalence and Incidence of Diabetes Mellitus in Adult Patients on Growth Hormone Replacement for Growth Hormone Deficiency: a Surveillance Database Analysis -- Attanasio et al., 10.1210/jc.2011-0448 -- Journal of Clinical Endocrinology &amp; Metabolism)

Context: GH replacement in adult GH-deficient patients may cause insulin resistance, raising concerns of potential increased risk of developing diabetes mellitus (DM).

Objective: Our objective was to assess DM prevalence and incidence in the international Hypopituitary Control and Complications Study (HypoCCS) surveillance database.

Design and Participants: GH-treated patients enrolled into HypoCCS (2922 U.S. and 3709 European patients) were assessed for DM, defined as recorded on the clinical report form, reported as adverse events, fasting glucose at least 7 mmol/liter recorded at least twice, or insulin treatment reported.

Results: DM prevalence was 8.2% [95% confidence interval (CI) = 7.6–8.9] overall, 11.3% in the United States and 5.7% in Europe. Incidence (n/1000 patient-years) was 9.7 (95% CI = 8.4–10.9) overall, 14.1 (11.5–16.7) in the United States, and 7.0 (5.6–8.3) in Europe. Overall incidence was 2.1 (0.9–3.3) for patients with body mass index (BMI) below 25 kg/m2 increasing to 16.4 (13.7–19.1) for BMI over 30 kg/m2. Obesity (BMI > 30 kg/m2) prevalence was higher in the United States than Europe and higher in U.S. patients than a U.S. reference population. After age, gender, and BMI adjustment, U.S. HypoCCS DM incidence was 10.6 (8.1–13.0), compared with 7.1 (6.0–8.1) in the National Health Interview Survey. In Europe, incidence for French and German patients was comparable to reference populations; for Sweden, the point estimate was higher than the reference population, but 95% CI overlapped. GH dose was not correlated with DM incidence.

Conclusions: The present analysis showed no evidence for increased DM incidence in GH-treated adult hypopituitary patients. However, those more prone to develop DM exhibited a higher than normal prevalence of obesity.

 

[Michael Scally MD]

Screening for Future Cardiovascular Disease Using Age Alone

Age Alone May Be All That's Needed to Predict Heart Risk
Medical News: Age Alone May Be All That&apos;s Needed to Predict Heart Risk - in Cardiovascular, Prevention from MedPage Today

That's the conclusion of a statistical model that found age alone was as good a predictor of cardiovascular events as Framingham Risk Score, with the same 86% sensitivity. The study was reported by Nicholas Wald, MD, of the Wolfson Institute of Preventive Medicine in London, and colleagues in PLoS One.

"Age screening loses little in screening performance compared with multiple risk factor measurement methods," they wrote.

Framingham risk scores are the gold standard of risk assessment for cardiovascular disease, but Wald -- who holds patents on a polypill for heart disease prevention -- and his colleagues argue that age is the strongest determinant.

Screening based on age alone and targeting those 55 and up would save money on the battery of tests and office visits used in assessing Framingham risk, they argued, adding that it's also cost-effective since most prevention methods -- i.e., statins -- are inexpensive.

________________________________________

Cardiovascular disease (CVD: coronary death, non-fatal myocardial infarction, and stroke) is the commonest cause of death and a major cause of morbidity worldwide. Preventive treatments should therefore be more widely used, given their efficacy, low cost, and safety.

Guidelines recommend that primary preventive treatment be based on assessment of absolute risk of cardiovascular events using multiple risk factor algorithms such as the Framingham risk equations, which include age, sex, smoking status, diabetic status, serum cholesterol, and blood pressure. Age is by far the strongest determinant of CVD risk in multiple risk factor algorithms. Offering preventive treatment to everyone over a specified age without measuring other risk factors would be a simpler screening strategy than offering preventive treatment to everyone exceeding a specified CVD risk cut-off based on multiple risk factor measurement. It would avoid the multiple risk factor measurement costs. The loss in screening performance may be small enough to warrant consideration of using age alone as the screening method of choice.

To investigate this, researchers compared the efficacy of offering preventive treatment based on age alone (age screening) with Framingham risk estimation (Framingham screening). Using illustrative costs, they also compared the cost effectiveness of these methods.


Wald NJ, Simmonds M, Morris JK. Screening for Future Cardiovascular Disease Using Age Alone Compared with Multiple Risk Factors and Age. PLoS ONE;6(5):e18742. PLoS ONE: Screening for Future Cardiovascular Disease Using Age Alone Compared with Multiple Risk Factors and Age

Background - Risk factors such as blood pressure and serum cholesterol are used, with age, in screening for future cardiovascular disease (CVD) events. The value of using these risk factors with age compared with using age alone is not known. We compared screening for future CVD events using age alone with screening using age and multiple risk factors based on regular Framingham risk assessments.

Methods - Ten-year CVD risk was estimated using Framingham risk equations in a hypothetical sample population of 500,000 people aged 0–89 years. Risk estimates were used to identify individuals who did and did not have a CVD event over a ten-year period. For screening using age alone (age screening) and screening using multiple risk factors and age (Framingham screening) we estimated the (i) detection rate (sensitivity); (ii) false–positive rate; (iii) proportion of CVD-free years of life lost in affected individuals with positive results (person-years detection rate); and (iv) cost per CVD-free life year gained from preventive treatment.

Results - Age screening using a cut-off of 55 years detected 86% of all first CVD events arising in the population every year and 72% of CVD-free years of life lost for a 24% false-positive rate; for five yearly Framingham screening the false-positive rate was 21% for the same 86% detection rate. The estimated cost per CVD-free year of life gained was £2,000 for age screening and £2,200 for Framingham screening if a Framingham screen costs £150 and the annual cost of preventive treatment is £200.

Conclusion - Age screening for future CVD events is simpler than Framingham screening with a similar screening performance and cost-effectiveness. It avoids blood tests and medical examinations. The advantages of age screening in the prevention of heart attack and stroke warrant considering its use in preference to multiple risk factor screening.

 

[Michael Scally MD]

IGF-1 is positively associated with PrCa. I do not have a clear picture of IGF-1 and PrCa, but it is worrisome enough that I would recommend against hGH therapy, particularly for "anti-aging."

Two recent meta-analyses of circulating insulin-like growth factor (IGF-1) in relation to prostate cancer risk consistently report moderately increased risks of prostate cancer with higher circulating IGF-1 concentrations. Results for IGFBP- 3, its major binding protein, are less consistent, possibly reflecting complexities in the immunoassays regarding whether intact or digested IGFBP-3 is being assessed, each with perhaps quite different effects on IGF physiology and cancer risk.

Whether IGF-1 and IGFBP-3 act differentially on subtypes of prostate cancer as defined by stage and grade has not been studied sufficiently. In this study, researchers extended their previous findings with extended follow-up to 2004 and including 1,331 case–control pairs. They evaluated the hypotheses that plasma IGF-1 is differentially associated with advanced versus organ-confined or high-grade versus low grade prostate cancer. They also provide an updated analysis of the association between plasma IGF-1 and IGFBP-3 concentrations in relation to prostate cancer overall. In addition, they investigated potential effect modifying factors, including age at diagnosis, family history of prostate cancer, and lycopene intake, which has been shown to reduce IGF-1 signaling through increasing membrane associated IGFBP-3 concentrations.


Nimptsch K, Platz EA, Pollak MN, et al. Plasma insulin-like growth factor 1 is positively associated with low-grade prostate cancer in the Health Professionals Follow-up Study 1993-2004. Int J Cancer 2011;128(3):660-7. Plasma insulin-like growth factor 1 is positively ... [Int J Cancer. 2011] - PubMed result

The insulin-like growth factor (IGF) axis plays a role in growth and progression of prostate cancer. High circulating IGF-1 levels have been associated with an increased risk of prostate cancer. Results for IGF binding protein 3 (IGFBP-3) are inconclusive. Some studies have indicated that the positive association with IGF-1 is observed only for low-grade prostate cancer (Gleason sum < 7). We previously reported in the Health Professionals Follow-up Study (HPFS) a direct positive association between ELISA-measured plasma IGF-1 and IGFBP-3 and risk of prostate cancer (462 cases diagnosed after providing a blood specimen (between 1993 and 1995), but before February 1998). With additional follow-up through January 31st 2004, and 1,331 case-control pairs in total, we were now able to investigate low-grade (Gleason sum < 7, n = 635) and high-grade (Gleason sum >/= 7, n = 515) prostate cancer separately.

Matched odds ratios (OR) and 95% confidence intervals (CI) were estimated using conditional logistic regression. ORs of total prostate cancer comparing top to bottom quartiles were 1.41 (95% CI 1.12-1.78, p-trend = 0.001) for IGF-1 and 1.58 (95% CI 1.24-2.01, p-trend = 0.003) for IGFBP-3. IGF-1 was more strongly associated with low-grade (OR = 1.61 top versus bottom quartile, 95% CI 1.16-2.25, p-trend = 0.01), than with high-grade (OR = 1.29, 95% CI 0.89-1.88, p-trend = 0.12) prostate cancer (p-heterogeneity = 0.08). We hypothesize that these findings reflect that high-grade prostate cancers are more autonomous, and, thus, less sensitive to the action of IGF-1 than low-grade cancers.

IGF, Insulin, and Cancer

“We know many interesting effects of insulin, but we have much to learn before the picture is complete,” were the words of Charles Best in the Banting Memorial Lecture of 1945. At the time of its discovery in 1922, insulin was hailed as the “cure” for diabetes. Almost 90 years on, reports that higher endogenous insulin levels and insulin analogs are linked to an increased risk of cancer have once again placed insulin in the spotlight. The recent concern about insulin and cancer stemmed from epidemiological studies reporting that insulin therapy and insulin secretagogues may increase cancer risk.

Before the publication of these articles, epidemiological studies reported that obese individuals and those with type 2 diabetes were at a higher risk of dying from various cancers when compared with those with a normal body mass index and those without diabetes. Insulin resistance in metabolic tissues, such as muscle, liver, and adipose tissue, occurs in obesity and type 2 diabetes. In an attempt to overcome the peripheral insulin resistance, a compensatory hyperinsulinemia develops. Some cancer cells have increased insulin receptor (IR) content, and in the setting of hyperinsulinemia, certain tumors may demonstrate increased activation of IR signaling pathways.

The roles of the closely related IGF-I, IGF-II, and their receptor interactions in cancer have also been extensively studied. Insulin indirectly increases hepatic IGF-I production. In addition, hyperinsulinemia may increase the quantity of bioavailable IGF-I by directly or indirectly decreasing levels of IGF binding protein (IGFBP)-1 and IGFBP-3. Lower levels of these binding proteins result in more unbound IGF-I that is free to interact with the IGF-I receptor (IGF-IR). Additionally, many tumors overexpress IGF-II, which also signals through the IGF-IR and one of the IR isoforms, IR-A. Uncovering the interplay between insulin, IGF-I, IGF-II, IGFBP, the IR, IGF-IR, and their signaling pathways has created a more elaborate illustration of the effects of insulin since the Banting Lecture of 1945. However, even now, much remains to be learned to complete the picture. In this minireview, they will discuss in further detail some of the recent studies and the current understanding of insulin, IGFs, their receptors, and signaling pathways in cancer development.


Gallagher EJ, LeRoith D. Minireview: IGF, Insulin, and Cancer. Endocrinology:en.2011-0231. http://endo.endojournals.org/cgi/content/abstract/en.2011-0231v1 (Minireview: IGF, Insulin, and Cancer -- Gallagher and LeRoith, 10.1210/en.2011-0231 -- Endocrinology)

In recent years, the influence of the IGF system and insulin on cancer growth has been widely studied. Observational human studies have reported increased cancer mortality in those with obesity and type 2 diabetes, which may be attributable to hyperinsulinemia, elevated IGF-I, or potentially both factors. Conversely, those with low insulin, IGF-I and IGF-II levels appear to be relatively protected from cancer development. Initial attention focused on the role of IGF-I in tumor development. The results of these investigations allowed for the development of therapies targeting the IGF-I receptor signaling pathway. However, after in vitro and in vivo studies demonstrating that insulin may also play a significant and independent role in tumorigenesis, insulin is now receiving more attention in this regard. Some studies suggest that targeting insulin receptor signaling may be an important alternative or adjunct to targeting IGF-I receptor signaling. In this minireview, we discuss some of the recent in vitro, animal, and clinical studies that have elaborated our understanding of the influence of IGF and insulin on tumorigenesis. These studies have shed more light on the interaction between insulin and IGF signaling in cancer cells. They have made possible the development of novel targeted therapies and highlighted some of the potential future directions for research and therapeutics.

 

[Michael Scally MD]

The NERI Hypogonadism Screener

Despite the prevalence and clinical importance of the disorder, symptoms of HG may not be recognized by health providers or patients and are frequently attributed to other medical or psychiatric conditions. Few validated screening instruments are available for clinical or research purposes, nor are they widely used in office practice. Moreover, available screeners were not developed according to current guidelines for test construction and validation, and lack adequate measurement properties. A screener should ideally be based on a combination of qualitative and quantitative methods. Responding to the need for a validated and clinically useful screening tool, researchers have developed the New England Research Institutes (NERI) HG Screener. Domains and items for the new questionnaire were developed in part on the basis of a conceptual model and expert review of the literature, in addition to open-ended qualitative interviews with hypogonadal patients and controls. The present report describes the results of a second psychometric validation study, including content validation and item reduction procedures.


Rosen RC, Araujo AB, Connor MK, et al. The NERI Hypogonadism Screener: psychometric validation in male patients and controls. Clinical Endocrinology 2011;74(2):248-56. The NERI Hypogonadism Screener: psychometric validation in male patients and controls - Rosen - 2011 - Clinical Endocrinology - Wiley Online Library

Objective Hypogonadism (HG) is a clinical disorder consisting of reduced testosterone (T) levels and characteristic signs and symptoms of low T. Current instruments used to assess hypogonadal symptoms in men lack adequate measurement properties. To present data on the quantitative validation of a new self-report instrument (HG Screener) developed to identify men with symptoms of HG.

Design This is a psychometric validation study conducted at 16 clinical sites across the Unites States. Subjects completed two visits separated by 2–4 weeks.

Patients One hundred and thirty-one men (82 hypogonadal patients with total T ? 10•4 nmol/l and 49 controls with total T > 10•4 nmol/l) aged 21–75 years were enrolled.

Measurements Self-reported assessments including the HG Screener (at both visits) along with seven validated questionnaires.

Results The results of a factor analysis identified five functional factors or domains. The resulting instrument contains 25 items consisting of 18 functional items in five core domains (sexual function, mood, memory, sleep function and fatigue) and seven physical symptom items. Overall, the new instrument was found to have strong psychometric properties, including acceptable discriminant, construct and content validity, as well as good internal consistency and test–retest reliability.

Conclusions A new screening tool (HG Screener) for identifying men with HG has been developed and validated according to FDA standards. This new instrument possesses acceptable psychometrics and is available for clinical or research use.

 

[Michael Scally MD]

[IMO, the future lies in validated bioactivity assays. As the technology currently stands, assays measure a static number that is supposed to reflect in vivo activity. While this might be accurate for certain testes, it surely is lacking or others.]

IGF-I Bioactivity Better Reflects Growth Hormone Deficiency than Total IGF-I

GHis considered to be the main regulator of circulating IGF-I. Circulating total (extractable) IGF-I is therefore routinely used for diagnosing and monitoring treatment of adult GH deficiency (GHD). Nevertheless, it has been proven that the diagnosis of GH disorders cannot solely rely on determination of total IGF-I. In a substantial fraction of patients diagnosed as GH deficient, total IGF-I levels remain within the normal range, especially in patients above 40 yr of age. However, during GH replacement therapy, the GH dose is titrated against total IGF-I levels and according to consensus guidelines, total IGF-I values should be kept in the age related normal range.

Many of the methods currently used for measurement of circulating total IGF-I are hampered by interferences of IGF-binding proteins (IGFBPs) remaining after extraction. On the other hand, by extracting IGFBPs, the modifying effects of these proteins on IGF-I action are ignored. In 2003 a kinase receptor activation (KIRA) bioassay was developed to measure IGF-I bioactivity at physiological conditions. The principle of this assay is based on quantification of IGF-I receptor (IGF-IR) activation after stimulation with serum in vitro. In this way bioavailable IGF-I is quantified while taking into account the modifying effects of IGFBPs. Moreover, although it has been reported that cross-reactivity for IGF-II in this IGF-IR KIRA assay is only 12%, the contribution of IGF-II in GH-deficient subjects may be relatively more significant, considering the fact that IGF-II production is relatively GH independent.

The aim of this study was to investigate the diagnostic value of IGF-I bioactivity in patients with proven GHD.


Varewijck AJ, Lamberts SWJ, Uitterlinden P, Hofland LJ, Janssen JAMJL. IGF-I Bioactivity Better Reflects Growth Hormone Deficiency than Total IGF-I. J Clin Endocrinol Metab:jc.2011-0051. http://jcem.endojournals.org/cgi/content/abstract/jc.2011-0051v1 (IGF-I Bioactivity Better Reflects Growth Hormone Deficiency than Total IGF-I -- Varewijck et al., 10.1210/jc.2011-0051 -- Journal of Clinical Endocrinology &amp; Metabolism)

Context: GH is considered the main regulator of circulating IGF-I. Total (extractable) IGF-I is therefore routinely used for diagnosis of GH deficiency (GHD) and for monitoring treatment. Methodscurrently used for measurement of circulating total IGF-I may be hampered by interferences of IGF-binding proteins. Recently a kinase receptor activation assay was developed to determine IGF-I bioactivity in human serum. The principle of this assay is based on quantification of IGF-I receptor activation after stimulation with serum in vitro.

Objective: The objective of the study was to investigate the diagnostic potential of IGF-I bioactivity in adults with GHD.

Design: This was a single-center observational study.

Study Participants: Ninety-four GH-untreated patients diagnosed with GHD by GH-provocative tests were included.

Main Outcome Measures: IGF-I bioactivity (determined by the IGF-I kinase receptor activation assay) and total IGF-I (determined by immunoassay) were measured in fasting blood samples.

Results: IGF-I bioactivity was more frequently below the normal range (<–2 SD) in untreated GH-deficient patients than total IGF-I levels (81.9 vs. 61.7%, respectively), especially in patients older than 40 years of age. IGF-I bioactivity decreased with the duration of GHD, whereas total IGF-I did not. With a decreasing number of additional pituitary deficits, total IGF-I levels more frequently remained within the normal range, whereas the percentage below the normal range was high for IGF-I bioactivity, independent of additional deficits.

Conclusion: Determination of IGF-I bioactivity may offer advantages in the evaluation of adult GHD compared with total IGF-I as bioactivity better reflects GHD as defined by GH stimulation tests, especially in subjects older than 40 years of age.

 

[Michael Scally MD]

[There are a WHOLE lot of facts missing from this story.]

New Onset Diabetes Associated With Bovine Growth Hormone And Testosterone Abuse

Geraci MJ, Cole M, Davis P. New onset diabetes associated with bovine growth hormone and testosterone abuse in a young body builder. Hum Exp Toxicol. New onset diabetes associated with bovine growth h... [Hum Exp Toxicol. 2011] - PubMed result

Case: A 33-year-old male presented to the emergency department with complaints of polydipsia, polyuria, nausea, headaches, blurry vision and malaise. Lab work revealed a serum glucose level of 1166 mg/dl (64.8 mmol/L). The patient admitted to completing a cycle of androgenic anabolic steroids (AASs) for bodybuilding. His regimen consisted of supraphysiologic intramuscular injections of a bovine growth hormone, trenbolone acetate and testosterone. The patient received intravenous fluids and insulin to restore metabolic balance. Previously healthy with a non-contributory family history, he was diagnosed with new onset diabetes.

Discussion: It has been demonstrated that AAS use, specifically growth hormone, can affect glucose homeostasis through increasing cellular insulin resistance and reducing glucose uptake. Excess growth hormone has been shown to cause symptoms of acromegaly which predisposes up to 40% of patients to diabetes. As trenbolone acetate is not indicated for human use and athletes are known to use supraphysiologic doses of this underground, performance enhancing drug, the correlation of the timing of events and the use of this veterinary growth hormone likely exacerbated an underlying condition or caused this new onset diabetes.

Conclusion: We report a case of a young bodybuilder with no significant past medical history who was diagnosed with new onset diabetes associated with supraphysiologic self-injections of the bovine growth hormone, trenbolone acetate, combined with testosterone. AAS have the potential to induce or exacerbate diabetic conditions due to decreased glucose tolerance and increased insulin resistance.

 

[GirlyMan]

Lab work revealed a serum glucose level of 1166 mg/dl (64.8 mmol/L).

Dude fucked himself up real good. Why'd he do that again?

 

[Michael Scally MD]

Association Between Diagnosed Diabetes and Self Reported Cancer

Diabetes and cancer are two common chronic diseases that exert a serious effect on public health in the U.S. Approximately 25.6 million adults (11.3%) aged 20 years or older were estimated to have diabetes in 2010. Approximately 11.7 million Americans were living with cancer in 2007. Studies have found that diabetes is associated with an increased risk for certain types of cancer, and diabetes may increase the risk of all-cause mortality among people with cancer. To compare the prevalence of cancer between adults without and with diabetes, researchers analyzed a large population–based sample from the Centers for Disease Control and Prevention 2009 Behavioral Risk Factor Surveillance System (BRFSS) in the U.S.


Li C, Balluz LS, Ford ES, Okoro CA, Tsai J, Zhao G. Association Between Diagnosed Diabetes and Self-Reported Cancer Among U.S. Adults. Diabetes Care. Association Between Diagnosed Diabetes and Self-Reported Cancer Among U.S. Adults

OBJECTIVE To assess the association between diagnosed diabetes and self-reported cancer among U.S. adults.

RESEARCH DESIGN AND METHODS We analyzed data for 397,783 adults who participated in the 2009 Behavioral Risk Factor Surveillance System.

RESULTS After adjustment for potential confounders, diabetic men had higher adjusted prevalence ratios for cancer of the prostate (1.1 [95% CI 1.0–1.3]), colon (1.3 [1.0–1.7]), pancreas (4.6 [1.8–11.7]), rectum (2.2 [1.0–4.7]), urinary bladder (1.7 [1.2–2.2]), and kidney (1.9 [1.2–3.0]) than nondiabetic men (all P < 0.05). Diabetic women had higher adjusted prevalence ratios for cancer of the breast (1.1 [1.0–1.3]) and endometrium (1.6 [1.2–2.0]), and leukemia (2.3 [1.3–4.2]) than nondiabetic women (all P < 0.05).

CONCLUSIONS Our results suggest that diabetic adults have higher prevalences of certain cancers than nondiabetic adults.

 

[Michael Scally MD]

Eight Common Genetic Variants Associated with Serum DHEAS Levels

SUMMARY

Dehydroepiandrosterone sulphate (DHEAS), mainly secreted by the adrenal gland, is the most abundant circulating steroid in humans. It shows a significant physiological decline after the age of 25 and diminishes about 95% by the age of 85 years, which has led to speculation that a relative DHEAS deficiency may contribute to the development of common age-related diseases or diminished longevity. Twin- and family-based studies have shown that there is a substantial genetic effect with heritability estimate of 60%, but no specific genes regulating serum DHEAS concentration have been identified to date.

Here, researchers take advantage of recent technical and methodological advances to examine the effects of common genetic variants on serum DHEAS concentrations. By examining 14,846 Caucasian individuals, they show that eight common genetic variants are associated with serum DHEAS concentrations. Genes at or near these genetic variants include BCL2L11, ARPC1A, ZKSCAN5, TRIM4, HHEX, CYP2C9, BMF, and SULT2A1. These genes have various associations with steroid hormone metabolism—co-morbidities of ageing including type 2 diabetes, lymphoma, actin filament assembly, drug and xenobiotic metabolism, and zinc finger proteins—suggesting a wider functional role for DHEAS than previously thought.


________________________________________


Dehydroepiandrosterone sulphate (DHEAS), mainly secreted by the adrenal gland, is the most abundant circulating steroid in humans. It acts as an inactive precursor which is converted initially into DHEA and thereafter into active androgens and estrogens in peripheral target tissues. In humans the serum concentration of circulating DHEAS is 100- to 500-fold or 1000 to 10,000 higher than that of testosterone and estradiol respectively. Unlike DHEA, which is swiftly cleared from the circulation and shows diurnal variation, serum DHEAS concentrations are stable and facilitate accurate measurement and diagnosis of pathology.

DHEAS is distinct from the other major adrenal steroids (cortisol and aldosterone) in showing a significant physiological decline after the age of 25 and diminishes about 95% by the age of 85 years. This age-related decline has led to speculation that a relative DHEAS deficiency may contribute to the development of common age-related diseases or diminished longevity. Low DHEAS concentrations are possibly associated with increased insulin resistance and hypertension, but not with incident metabolic syndrome. It is strongly associated with osteoporosis in women, but not in men. Concurrent change in DHEAS tracks with declines in gait speed, modified mini-mental state examination score (3MSE), and digit symbol substitution test (DSST) in very old women but not in men. Low circulating DHEAS is also strongly associated with cardiovascular disease and mortality in men – but not in women. A recent 15-year follow-up study showed that DHEAS was negatively related to all-cause, all cancers, and other medical mortality, whereas high DHEAS concentrations were protective. This has led to its widespread and uncontrolled use as a controversial anti-ageing and sexual performance supplement in the USA and other western countries without any clear data about efficacy, potential risks or benefits .

Despite these observations, the physiological function of DHEAS and its importance in maintaining health are poorly understood. Although previous twin, and family-based studies, have shown that there is a substantial genetic effect with a heritability estimate of 60%, no specific genes regulating serum DHEAS concentration in healthy individuals have been identified to date. Therefore, the current study meta-analyzed the results of genome-wide association studies (GWAS) performed in a total of 14,846 individuals from seven cohorts to identify common genetic variants associated with serum DHEAS concentrations. The findings not only advance understanding of how serum DHEAS concentration is regulated by genes but also provide clues as to its mechanism of action as well as Mendelian randomisation principles.


Zhai G, Teumer A, Stolk L, et al. Eight Common Genetic Variants Associated with Serum DHEAS Levels Suggest a Key Role in Ageing Mechanisms. PLoS Genet 2011;7(4):e1002025. PLoS Genetics: Eight Common Genetic Variants Associated with Serum DHEAS Levels Suggest a Key Role in Ageing Mechanisms

Dehydroepiandrosterone sulphate (DHEAS) is the most abundant circulating steroid secreted by adrenal glands—yet its function is unknown. Its serum concentration declines significantly with increasing age, which has led to speculation that a relative DHEAS deficiency may contribute to the development of common age-related diseases or diminished longevity. We conducted a meta-analysis of genome-wide association data with 14,846 individuals and identified eight independent common SNPs associated with serum DHEAS concentrations. Genes at or near the identified loci include ZKSCAN5 (rs11761528; p = 3.15×10?36), SULT2A1 (rs2637125; p = 2.61×10?19), ARPC1A(rs740160; p = 1.56×10?16), TRIM4 (rs17277546; p = 4.50×10?11), BMF (rs7181230; p = 5.44×10?11), HHEX (rs2497306; p = 4.64×10?9), BCL2L11 (rs6738028; p = 1.72×10?8), andCYP2C9 (rs2185570; p = 2.29×10?8). These genes are associated with type 2 diabetes, lymphoma, actin filament assembly, drug and xenobiotic metabolism, and zinc finger proteins. Several SNPs were associated with changes in gene expression levels, and the related genes are connected to biological pathways linking DHEAS with ageing. This study provides much needed insight into the function of DHEAS.

 

[Michael Scally MD]

Partial Growth Hormone Deficiency - Adverse Cardiovascular Risk Profile And Increased Carotid Intima-Medial Thickness

Hypopituitary patients on conventional anterior hormone replacement, but not GH, have a twofold increased relative risk of mortality and show clustering of surrogate markers of cardiovascular risk including an elevated total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), fibrinogen, and plasminogen activator inhibitor type-I (PAI-I); high-density lipoprotein cholesterol (HDL-C) is reduced, and insulin sensitivity impaired. Additionally, GH deficiency (GHD) patients have increased truncal fat mass (tFM), and evidence of impaired endothelial function and cardiac performance. It is not surprising, therefore, that the observed excess mortality of hypopituitary patients has been attributed, at least in part, to GHD.

GHD is defined by a peak GH response of <3 mcgg/l to the insulin tolerance test (ITT). Data from healthy adults confirm that a normal GH response to the ITT is significantly higher than this arbitrarily defined cut-off. In patients with putative hypopituitarism as a result of primary hypothalamo-pituitary pathology, a cohort with intermediate GH responses (peak GH 3.1–7.0 mcg/l) can be defined. The clinical impact of this partial GHD (GH insufficiency, GHI) in adults has been partially characterized. GHI adults have increased total FM and tFM, insulin resistance, an adverse lipid profile, and impaired cardiac performance, but are not osteopenic. The current study is the first to comprehensively quantify surrogates of cardiovascular risk in hypopituitary adults with GHI.


Murray RD, Wieringa G, Lawrance JA, Adams JE, Shalet SM. Partial growth hormone deficiency is associated with an adverse cardiovascular risk profile and increased carotid intima-medial thickness. Clin Endocrinol (Oxf) 2011;73(4):508-15. Partial growth hormone deficiency is associated wi... [Clin Endocrinol (Oxf). 2010] - PubMed result

OBJECTIVE: To quantify the relative prevalence of surrogate markers of vascular risk in adults with partial GH deficiency (GH insufficiency, GHI).

CONTEXT: Hypopituitary adults with untreated GH deficiency (GHD) have an excess vascular mortality and demonstrate clustering of adverse vascular risk factors. The vascular risk profile of GHI adults has yet to be comprehensively studied.

DESIGN: A cross-sectional case controlled study.

PATIENTS: Thirty GHD adults, 24 GHI, and 30 age- and sex-matched controls. GHI adults were defined biochemically using two GH stimulation tests (peak GH 3-7 mug/l).

MEASUREMENTS: Serum lipids and apolipoproteins, plasminogen activator inhibitor type-I (PAI-I), C-reactive protein (CRP), lipoprotein (a) [Lp(a)], fibrinogen, blood pressure and carotid intima-medial thickness (IMT).

RESULTS: IGF-I levels of GHI adults were lower than controls (373 +/- 123 vs 295 +/- 104 mug/l; P < 0.001). Total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and triglycerides (TG) values were consistently between those of, but not significantly different from, GHD and control subjects. GHI adults showed significantly elevated PAI-I levels [80 (13-98) vs 50.5 (3-98) ng/ml; P = 0.01], although no there were differences in CRP, Lp(a), and fibrinogen levels compared with control subjects. No differences in systolic or diastolic blood pressure were shown between study groups. In parallel with the increased vascular risk profile of GH-insufficient adults, carotid IMT was significantly increased (0.503 +/- 0.08 vs 0.578 +/- 0.130 mm; P = 0.02). TC, LDL-C, Waist-Hip Ratio (WHR), truncal fat mass, and IMT correlated with IGF-I levels and GH status. TG, K(ITT), and PAI-I additionally correlated with GH status, but not with IGF-I levels.

CONCLUSION: GHI adults are at elevated vascular risk, reflected by adverse surrogate markers and increased carotid IMT. The surrogate risk marker profile parallels GHD adults, but is less divergent from that observed in healthy individuals. No data are yet available as to whether these anomalies will be reflected in an increased vascular mortality in GHI adults.

 

[Michael Scally MD]

[ame=http://www.youtube.com/watch?v=yVkdfJ9PkRQ]YouTube - Pendulum Waves[/ame]

 

[Michael Scally MD]

Delusional Infestation

Delusional infestation is a dermatopsychiatric condition characterized by patients' fixed and false belief that their skin is infested by pathogens. Descriptions of these irritants in the literature have included an assortment of materials. Most common are animate beings such as insects, worms, viruses, fungi, and bacteria. Numerous inanimate materials, such as wood chips, fibers, and little tubes, have also been described. The term delusional infestation encompasses both animate and inanimate materials.

While patients with delusional infestation commonly produce tangible specimens as proof of infestation, no published studies have objectively examined these specimens. Moreover, although delusional infestation has been called an "easy" diagnosis, many patients undergo skin biopsies, even though no study has evaluated their utility. To address this deficit in the literature, researchers retrospectively reviewed the results of physician-obtained biopsies and patient-provided specimens from patients presenting with suspected delusional infestation at Mayo Clinic, Rochester, Minnesota.


Hylwa SA, Bury JE, Davis MDP, Pittelkow M, Bostwick JM. Delusional Infestation, Including Delusions of Parasitosis: Results of Histologic Examination of Skin Biopsy and Patient-Provided Skin Specimens. Arch Dermatol:archdermatol.2011.114. Arch Dermatol -- Abstract: Delusional Infestation, Including Delusions of Parasitosis: Results of Histologic Examination of Skin Biopsy and Patient-Provided Skin Specimens, May 16, 2011, Hylwa et al. 0 (2011): archdermatol.2011.114v1

Objective To review the results of skin biopsies and patient-provided specimens from patients whose assessment was consistent with delusional infestation, including delusions of parasitosis.

Design Retrospective medical record review.

Setting Mayo Clinic, Rochester, Minnesota.

Patients The study population comprised all patients who were seen at Mayo Clinic and had a diagnosis of delusional skin infestation, including delusions of parasitosis, between 2001 and 2007, and who underwent biopsies as part of their dermatologic evaluations or brought samples to their clinical consultations.

Main Outcome Measures The results of examination of these biopsy and patient-provided specimens.

Results A total of 108 patients met inclusion criteria for this study: 80 received biopsies, 80 had self-procured skin specimens, and 52 patients received biopsies and provided specimens. No biopsy specimen (0 of 80) provided evidence to support skin infestation. The most common interpretations in the 80 biopsy specimens were dermatitis in 49 of 80 (61%); excoriation, ulceration, or erosion in 38 (48%); and nonspecific dermal inflammation in 25 (31%). Patient-provided specimens were most frequently assessed by the physician (generally a dermatologist) evaluating the patient, although 20 of the 80 samples (25%) were submitted for pathologic evaluation. Of these 80 specimens, 10 (13%) contained insects. All but 1 of the insects were noninfesting varieties; 1 (1%) was a pubic louse. The remaining findings consisted of cutaneous debris, environmental detritus, or plant material.

Conclusion In patients with suspected delusional infestation, neither skin biopsies nor examination of patient-provided specimens provided objective evidence of skin infestation.

 

[GirlyMan]

YouTube - Pendulum Waves

Crazy ass math art.

 

[Michael Scally MD]

Growth Hormone With An Expanded Genetic Code

Throughout history, natural products have served as a vital source of medicinal agents. However, chemical synthesis is often required to introduce structural changes that lead to improved therapeutic index, pharmacokinetics, potency, stability, delivery, and bioavailability. The more nascent field of protein therapeutics has followed a similar evolutionary path in a more compressed time frame. Animal-sourced protein therapeutics such as insulin and growth hormone have given way to recombinant DNA (rDNA)-based production. More recently, site-directed mutagenesis has allowed the optimization of natural protein sequence and structure for therapeutic and industrial applications. However, compared to chemical synthesis, the structural and functional diversity of native biosynthesis is severely limited. The 20 canonical amino acids derived from strict evolutionary pressure have evolved protein sequences for physiological, but not therapeutic, purposes. Moreover, although solid phase protein synthesis and semisynthesis offers the promise of increased structural diversity, reports of clinical results have yet to emerge, and there are likely to be significant costs associated with manufacturing at scale.

Technology that marries the efficiency and fidelity of rDNA directed protein biosynthesis with the chemical diversity accessible through modern synthetic chemistry has recently been developed. Here we show that this methodology can be applied to the development of an improved human therapeutic. Human growth hormone (hGH) is a proven treatment for pathological short stature and other growth-associated abnormalities. However, while hGH therapy is highly efficacious, it requires daily subcutaneous injection and frequent dose adjustment to minimize adverse effects. Efforts thus far to modify the protein and its formulation have failed to produce a sustained-action hGH with the efficacy, safety, and tolerability of daily subcutaneous injection. Herein researchers report the pharmacological properties of a previously unreported hGH molecule biosynthesized with a genetically encoded nonnative amino acid.


Cho H, Daniel T, Buechler YJ, et al. Optimized clinical performance of growth hormone with an expanded genetic code. Proc Natl Acad Sci U S A. Optimized clinical performance of growth hormone with an expanded genetic code

The ribosomal incorporation of nonnative amino acids into polypeptides in living cells provides the opportunity to endow therapeutic proteins with unique pharmacological properties. We report here the first clinical study of a biosynthetic protein produced using an expanded genetic code. Incorporation of p-acetylphenylalanine (pAcF) at distinct locations in human growth hormone (hGH) allowed site-specific conjugation with polyethylene glycol (PEG) to produce homogeneous hGH variants. A mono-PEGylated mutant hGH modified at residue 35 demonstrated favorable pharmacodynamic properties in GH-deficient rats. Clinical studies in GH-deficient adults demonstrated efficacy and safety comparable to native human growth hormone therapy but with increased potency and reduced injection frequency. This example illustrates the utility of nonnative amino acids to optimize protein therapeutics in an analogous fashion to the use of medicinal chemistry to optimize conventional natural products, low molecular weight drugs, and peptides.

 

[Michael Scally MD]

Skeletal Fluorosis from Brewed Tea

Skeletal fluorosis (SF) is caused by prolonged ingestion or inhalation of fluoride ion (F). Chronic F toxicity leads to increased amounts of poor quality bone and painful calcification and ossification of tendons and ligaments. Most often, SF is explained by well water containing more than 4 mg/liter F; i.e. 4 parts per million (ppm) F. However, SF manifests in some regions of Asia where poor-quality “brick” tea is brewed using the mature leaves, twigs, and berries of the tea plant, Camellia sinensis. Black tea, also from this plant, can be F rich, and its preparations (e.g. brewed tea, instant tea, or “sun tea” steeped at room temperature) are popular in the United States where SF is rare.

Researchers recently reported SF from chronic consumption of 1–2 gallons of instant tea each day by two unrelated middle- age women living in the Midwest. Here, they describe a woman with SF who was an avid drinker of large amounts of brewed tea.


Izuora K, Twombly JG, Whitford GM, Demertzis J, Pacifici R, Whyte MP. Skeletal Fluorosis from Brewed Tea. Journal of Clinical Endocrinology & Metabolism. http://jcem.endojournals.org/content/early/2011/05/18/jc.2010-2891.abstract (Skeletal Fluorosis from Brewed Tea)

Background: High fluoride ion (F?) levels are found in many surface and well waters. Drinking F?-contaminated water typically explains endemic skeletal fluorosis (SF). In some regions of Asia, however, poor quality “brick tea” also causes this disorder. The plant source of brick, black, green, orange pekoe, and oolong tea, Camellia sinensis, can contain substantial amounts of F?. Exposure to 20 mg F? per day for 20 yr of adult life is expected to cause symptomatic SF. High F? levels stimulate osteoblasts and enhance bone apposition but substitute for OH? groups in hydroxyapatite crystals and thereby result in skeletal fragility and perhaps lead to secondary hyperparathyroidism. Beginning in 2005, we showed that daily consumption of 1–2 gallons of instant tea made from this plant can lead to SF.

Aim: We describe a 48-yr-old American woman who developed SF from brewed tea.

Patient and Methods: Our patient had elevated bone mineral density revealed by dual-energy x-ray absorptiometry (spine Z-score, +9.9), severe chronic bone and joint pain, and kyphosis after consuming 1–2 gallons of brewed orange pekoe tea daily for more than three decades. F? levels were high in her serum, urine, and clippings of fingernails and toenails, as well as in our reproduction of her beverage. Renal function was normal. She had vitamin D deficiency. Elevated serum PTH levels were unresponsive to adequate vitamin D supplementation. Pain resolved over several months when she stopped drinking tea and continued ergocalciferol.

Conclusion: Our patient shows that SF can result from chronic consumption of large volumes of brewed tea.