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[Michael Scally MD]

New Insights Into The Role Of Mitochondria In Aging [See: https://thinksteroids.com/community/threads/134303550 ]

The mitochondrial theory of aging postulates that the lifelong accumulation of somatic mitochondrial DNA (mtDNA) mutations leads to mitochondrial abnormalities resulting in a progressive decline in tissue function. Mitochondrial abnormalities and mtDNA mutagenesis are well-established intrinsic instigators that drive multisystem degeneration, stress intolerance, and energy deficits during aging in humans, monkeys, and rodents. Reduced mitochondrial quality and content in multiple tissues is also implicated in several aging-associated conditions, including cancer, obesity, cardiovascular diseases, hypertension, type 2 diabetes, osteoporosis, and dementia, as well as in the pathogenesis of neurometabolic syndromes, psychiatric disorders, end-stage renal disease, and mitochondrial cytopathies. Current treatment strategies for conditions associated with mitochondrial dysfunction address the secondary symptoms but not the deficiency itself. One possible approach to mitigating the primary deficiency is to boost the residual mitochondrial oxidative capacity by increasing functional mitochondrial mass in the affected tissues.

The epidemic emergence of modern chronic diseases largely stems from the adoption of a sedentary lifestyle and excess energy intake. There is incontrovertible evidence from epidemiologic studies that endurance exercise extends life expectancy and reduces the risk of chronic diseases. Endurance exercise is the most potent physiological inducer of mitochondrial biogenesis in skeletal muscle and also has profound effects on metabolism in various other tissues, including heart, brain, adipose tissue, and liver. These adaptations result in improved healthspan, reduced risk of morbidity and mortality, and enhanced quality of life. In this work, researchers used the mtDNA mutator mouse (designated the PolG mouse), a model of progeroid aging that exhibits elevated mtDNA point mutations and systemic mitochondrial dysfunction and phenocopies human aging, to investigate whether endurance exercise can effectively counteract the entrenched multisystem degeneration and mitochondrial dysfunction to mitigate premature aging in these mice.


Safdar A, Bourgeois JM, Ogborn DI, et al. Endurance exercise rescues progeroid aging and induces systemic mitochondrial rejuvenation in mtDNA mutator mice. Proceedings of the National Academy of Sciences. Endurance exercise rescues progeroid aging and induces systemic mitochondrial rejuvenation in mtDNA mutator mice — PNAS

A causal role for mitochondrial DNA (mtDNA) mutagenesis in mammalian aging is supported by recent studies demonstrating that the mtDNA mutator mouse, harboring a defect in the proofreading-exonuclease activity of mitochondrial polymerase gamma, exhibits accelerated aging phenotypes characteristic of human aging, systemic mitochondrial dysfunction, multisystem pathology, and reduced lifespan. Epidemiologic studies in humans have demonstrated that endurance training reduces the risk of chronic diseases and extends life expectancy. Whether endurance exercise can attenuate the cumulative systemic decline observed in aging remains elusive. Here we show that 5 mo of endurance exercise induced systemic mitochondrial biogenesis, prevented mtDNA depletion and mutations, increased mitochondrial oxidative capacity and respiratory chain assembly, restored mitochondrial morphology, and blunted pathological levels of apoptosis in multiple tissues of mtDNA mutator mice. These adaptations conferred complete phenotypic protection, reduced multisystem pathology, and prevented premature mortality in these mice. The systemic mitochondrial rejuvenation through endurance exercise promises to be an effective therapeutic approach to mitigating mitochondrial dysfunction in aging and related comorbidities.

 

[Michael Scally MD]

What is 5b?

Nagata N, Miyakawa M, Amano S, Furuya K, Yamamoto N, Inoguchi K. Design and synthesis of tricyclic tetrahydroquinolines as a new series of nonsteroidal selective androgen receptor modulators (SARMs). Bioorg Med Chem Lett. Design and synthesis of tricyclic tetrahydroquinol... [Bioorg Med Chem Lett. 2011] - PubMed result

Some tricyclic tetrahydroquinolines (THQs) were found to have the potential of a new series of nonsteroidal selective androgen receptor modulators (SARMs). Compound 5b was first designed and synthesized under our hypothesis based on a four-point pharmacophoric requirement of the 3-carbonyl, 18-methyl, 17-hydroxyl, and 13-quaternary carbon groups of dihydrotestosterone (DHT). It was revealed that this compound exhibits not only a strong androgen receptor (AR) agonistic activity (EC(50)=9.2nM) but also the highest selectivity in binding affinity to AR among the steroid hormone receptors. Furthermore, this compound showed a weak virilizing effect with retention of the desired anabolic effect as compared with DHT in vivo.

 

[Michael Scally MD]

Adult Obesity Prevalence in Canada and the United States
http://www.cdc.gov/nchs/data/databriefs/db56.pdf

March 2011

Key findings [Data from the Canadian Health Measures Survey, 2007–2009; the Canadian Heart Health Surveys, 1986–1992; and the U.S. National Health and Nutrition Examination Survey, 1988–1994 and 2007–2008]

The prevalence of obesity among adults in Canada is lower than it is in the United States. [In 2007–2009, the prevalence of obesity in Canada was 24.1%, over 10 percentage points lower than in the United States (34.4%). Among men, the prevalence of obesity was over 8 percentage points lower in Canada than in the United States (24.3% compared with 32.6%) and among women, more than 12 percentage points lower (23.9% compared with 36.2%)]

Among the non-Hispanic white population, the prevalence of obesity is lower in Canada than in the United States, but the difference is not as large as it is when comparing the entire populations.

Between the late 1980s and 2007–2009, the prevalence of obesity increased in both Canada and the United States.

In 2007–2009, the prevalence of obesity among young and middle-aged Canadian women was similar to that observed in U.S. women 20 years earlier.

 

[Michael Scally MD]

Lower Parkinson Risk Seen in Patients on Ibuprofen
http://www.medpagetoday.com/Neurology/ParkinsonsDisease/25157

Individuals who took ibuprofen for long periods were diagnosed with Parkinson's disease at about a 40% lower rate than other participants, two large observational studies showed.

No such relationship was found for other common pain relievers including aspirin or acetaminophen, according to the analysis of six years of data on some 136,000 participants in the Nurses' Health Study and the Health Professionals Follow-Up Study.

The relative risk for incident Parkinson's disease was 0.62 (95% CI 0.42 to 0.93) among participants who reported taking ibuprofen at least twice a week, Xiang Gao, MD, PhD, of Brigham and Women's Hospital in Boston, and colleagues, reported online in Neurology.

But neither the study authors nor other researchers suggested that people should start taking ibuprofen to ward off Parkinson's disease on the basis of these findings.

In an accompanying editorial, James H. Bower, MD, MSc, of the Mayo Clinic in Rochester, Minn., and Beate Ritz, MD, PhD, of the University of California Los Angeles, scoffed at the idea.

They likened the study's finding to earlier results showing that hyperuricemic patients have lower rates of Parkinson's disease.

"Are we ready to tell our patients with Parkinson's disease that they should start taking ibuprofen? Absolutely not. Nor should we tell them to start smoking, drinking coffee, and eating liver paté in hopes of developing gout," Bower and Ritz wrote.

The editorial reminded readers that ibuprofen has significant, well-known risks including liver toxicity and gastric ulcers.

Physicians contacted by MedPage Today and ABC News voiced similar skepticism.

"This represents another in a long line of ... epidemiological studies which purport to demonstrate risk factors for Parkinson's disease," William Weiner, MD, chief of neurology at the University of Maryland's medical center, said in an e-mail. "These studies do not prove that this is a risk factor and only show an association."

David X. Cifu, MD, of Virginia Commonwealth University, suggested that patients "should do the basics of healthy living first."

He also argued that the risk reduction seen in the study, even if causative, is not clinically meaningful.

"[A] 38% improvement on a 0.2% incidence is ridiculous," Cifu declared.

Gao and colleagues had identified 291 cases of incident Parkinson's disease among the 136,197 participants in the two prospective studies of healthcare workers. They compared responses to the studies' detailed questionnaires completed by these individuals with those from other participants.

In addition to the lifestyle-related questionnaires, the two studies also collected data from physical exams and medical histories.

The relative risk of 0.62 associated with ibuprofen reflected adjustments for other factors that affected Parkinson's disease risk, including smoking history, age, caffeine use, alcohol use, lactose intake, and body mass index.

Parkinson's disease incidence also appeared to be related to the amount of ibuprofen taken weekly. Participants who reported taking one or two tablets per week had no reduction in risk (RR 0.95), versus relative risks of 0.40 among those taking three to five tablets weekly and 0.55 with six or more tablets weekly (P=0.01 for trend).

No such relationships were seen for aspirin, acetaminophen, or NSAIDs other than ibuprofen grouped together. Roughly as many participants reported taking these agents as they did ibuprofen.

Limitations of the studies included self-report of ibuprofen use, the fact that the groups studied were not representative of the general population, and the relatively short follow-up period of six years.

A meta-analysis also was performed using these study results, which combined them with findings from six other prospective studies. The meta-analysis included 2,779 Parkinson cases and had data on NSAID use. Ibuprofen was still associated with lower disease risk, whereas other drugs were not.

The relative risk for Parkinson's disease in the pooled data was 0.73 (95% CI 0.63 to 0.85), Gao and colleagues reported.

The editorial noted a further limitation of the meta-analysis, in that few studies separated patients specifically taking ibuprofen as opposed to any NSAID.

The investigators noted that, unlike other NSAIDs and acetaminophen, ibuprofen is an agonist at PPAR-gamma receptors.

David Standaert, MD, PhD, interim chairman of neurology at the University of Alabama at Birmingham, told MedPage Today and ABC News that the findings and the presumed mechanism were both plausible.

He said his own research had suggested that, while Parkinson's disease is probably triggered by a variety of factors, inflammation in the brain is what drives it along. "A simple way to express this is to say that inflammation does not start the fire, but it is responsible for keeping it burning," he said in an e-mail.

But, he added, "the PPAR-gamma mechanism is a reasonable concept as well."

Another class of medications also targets PPAR-gamma -- the glitazone drugs used to treat type 2 diabetes.

A clinical trial based at the University of Rochester is now gearing up to test the PPAR-gamma theory of Parkinson's disease. Patients with early-stage disease will take pioglitazone (Actos) or placebo for 44 weeks. The trial's primary outcome measure will be disease progression according to the UPDRS rating scale.

In their editorial, Bower and Ritz agreed that the mechanism deserved a clinical trial -- and ideally with "a safer PPAR-gamma agonist" than ibuprofen.


Gao X, Chen H, Schwarzschild MA, Ascherio A. Use of ibuprofen and risk of Parkinson disease. Neurology. Use of ibuprofen and risk of Parkinson disease

Background: Neuroinflammation may contribute to the pathogenesis of Parkinson disease (PD). Use of nonsteroidal anti-inflammatory drugs (NSAID) in general, and possibly ibuprofen in particular, has been shown to be related to lower PD risk in previous epidemiologic studies.

Methods: We prospectively examined whether use of ibuprofen or other NSAIDs is associated with lower PD risk among 136,197 participants in the Nurses' Health Study (NHS) and the Health Professionals Follow-up Study (HPFS) free of PD at baseline (1998 for NHS and 2000 for HPFS). NSAIDs use was assessed via questionnaire. Results were combined in a meta-analysis with those of published prospective investigations.

Results: We identified 291 incident PD cases during 6 years of follow-up. Users of ibuprofen had a significantly lower PD risk than nonusers (relative risk [RR], adjusted for age, smoking, caffeine, and other covariates = 0.62; 95% confidence interval [CI] 0.42–0.93; p = 0.02). There was a dose–response relationship between tablets of ibuprofen taken per week and PD risk (p trend = 0.01). In contrast, PD risk was not significantly related to use of aspirin (RR = 0.99; 95% CI 0.78–1.26), other NSAIDs (RR = 1.26; 95% CI 0.86–1.84), or acetaminophen (RR = 0.86; 95% CI 0.62–1.18). Similar results were obtained in the meta-analyses: the pooled RR was 0.73 (95% CI 0.63–0.85; p < 0.0001) for ibuprofen use, whereas use of other types of analgesics was not associated with lower PD risk.

Conclusions: The association between use of ibuprofen and lower PD risks, not shared by other NSAIDs or acetaminophen, suggests ibuprofen should be further investigated as a potential neuroprotective agent against PD.

 

[Michael Scally MD]

The term endocrine disruptors was first coined by Ana Soto and collaborators, who identified a number of developmental effects of EDCs in wildlife and humans. Although EDCs can target various hormone systems, a number of observations concerning reproductive development and sex differentiation, together with early embryonic development and puberty, have focused on EDC interference with sex steroid hormones.

Endocrine disruptors are exogenous compounds with the potential to disturb hormonal regulation and the normal endocrine system, consequently affecting health and reproduction in animals and humans. Endocrine disruptors can interfere with the production, release, metabolism, and elimination of or can mimic the occurrence of natural hormones. Endocrine disruptors may also be derived from natural animal, human, or plant (phytoestrogen) sources; however, for the most part international concern is currently focused on synthetic chemicals and endocrine-disrupting chemicals (EDCs). This concern is further amplified by two factors, the expansion in chemical production, which has now reached 400 million tons globally, and the increased pollution from these chemicals. As such, the impact on human health through known or unknown effects of these chemicals on hormonal systems is great.


Casals-Casas C, Desvergne B. Endocrine disruptors: from endocrine to metabolic disruption. Annu Rev Physiol 2011;73:135-62. Endocrine disruptors: from endocrine to metabolic ... [Annu Rev Physiol. 2011] - PubMed result

Synthetic chemicals currently used in a variety of industrial and agricultural applications are leading to widespread contamination of the environment. Even though the intended uses of pesticides, plasticizers, antimicrobials, and flame retardants are beneficial, effects on human health are a global concern. These so-called endocrine-disrupting chemicals (EDCs) can disrupt hormonal balance and result in developmental and reproductive abnormalities. New in vitro, in vivo, and epidemiological studies link human EDC exposure with obesity, metabolic syndrome, and type 2 diabetes. Here we review the main chemical compounds that may contribute to metabolic disruption. We then present their demonstrated or suggested mechanisms of action with respect to nuclear receptor signaling. Finally, we discuss the difficulties of fairly assessing the risks linked to EDC exposure, including developmental exposure, problems of high- and low-dose exposure, and the complexity of current chemical environments.

 

[Michael Scally MD]

Unhealthy Sleep-Related Behaviors --- 12 States, 2009
Unhealthy Sleep-Related Behaviors --- 12 States, 2009

March 4, 2011 / 60(08);233-238

An estimated 50--70 million adults in the United States have chronic sleep and wakefulness disorders (1). Sleep difficulties, some of which are preventable, are associated with chronic diseases, mental disorders, health-risk behaviors, limitations of daily functioning, injury, and mortality (1,2). The National Sleep Foundation suggests that most adults need 7--9 hours of sleep per night, although individual variations exist. To assess the prevalence and distribution of selected sleep difficulties and behaviors, CDC analyzed data from a new sleep module added to the Behavioral Risk Factor Surveillance System (BRFSS) in 2009. This report summarizes the results of that analysis, which determined that, among 74,571 adult respondents in 12 states, 35.3% reported having <7 hours of sleep on average during a 24-hour period, 48.0% reported snoring, 37.9% reported unintentionally falling asleep during the day at least 1 day in the preceding 30 days, and 4.7% reported nodding off or falling asleep while driving in the preceding 30 days. Continued public health surveillance of sleep quality, duration, behaviors, and disorders is needed to understand and address sleep difficulties and their impact on health. As a first step, a multifaceted approach that includes increased public awareness and education and training in sleep medicine for appropriate health-care professionals is needed; however, broad societal factors, including technology use and work policies, also must be considered.

BRFSS is a state-based, random-digit--dialed telephone survey of the noninstitutionalized U.S. civilian population aged ?18 years, conducted by state health departments in collaboration with CDC (3). Based on Council of American Survey and Research Organizations (CASRO) guidelines, response rates* for 12 states† that used the optional sleep module in 2009§ ranged from 40.0% (Maryland) to 66.9% (Nebraska). Cooperation rates ranged from 55.5% (California) to 83.9% (Georgia).

The following questions from the sleep module were asked: "On average, how many hours of sleep do you get in a 24-hour period? Think about the time you actually spend sleeping or napping, not just the amount of sleep you think you should get (categorized as <7 hours and ?7 hours**)." "Do you snore? (can have been told by spouse or someone else; categorized as yes or no)?" "During the past 30 days, for about how many days did you find yourself unintentionally falling asleep during the day (categorized as none or at least 1 day reported)?" and "During the past 30 days, have you ever nodded off or fallen asleep, even just for a brief moment, while driving (categorized as yes or no)?" Age-standardized (to the projected U.S. 2000 population) prevalence estimates were calculated by state and by selected characteristics; 95% confidence intervals were calculated, and statistical significance (at p<0.05) was determined by t-test.

Among respondents, 35.3% reported sleeping <7 hours on average during a 24-hour period (Table - Unhealthy Sleep-Related Behaviors --- 12 States, 2009 ). Adults aged ?65 years were significantly less likely to report sleeping <7 hours (24.5%) than persons in all other age categories. Non-Hispanic blacks (48.3%) and non-Hispanic persons of other races (38.7%) were more likely to report sleeping <7 hours than non-Hispanic whites (34.9%). No significant differences were observed by sex. Compared with employed adults (37.4%), those unable to work (46.4%) were significantly more likely to report <7 hours of sleep, but retired adults (25.0%) and homemakers and students (30.8%) were less likely. Adults with at least some college education (35.8%) were significantly more likely to report <7 hours of sleep than those with less than a high school diploma (32.0%) as were divorced, widowed, or separated (39.1%) and never married adults (37.9%), compared with married adults (35.1%).

Snoring was reported by 48.0% of respondents (Table - Unhealthy Sleep-Related Behaviors --- 12 States, 2009 ). Persons aged 18--24 years were least likely (25.6%) to report snoring. Hispanics (50.6%) were more likely to report snoring than non-Hispanic whites (46.8%), as were men (56.5%) compared with women (39.6%). Compared with employed persons (50.5%), retired adults (37.9%) and homemakers/students (37.0%) were significantly less likely to report snoring. Persons with less than a high school diploma (51.2%) and with a high school diploma or General Educational Development certificate (GED) (49.9%) were significantly more likely to report snoring than those with at least some college or a college degree (47.0%), as were married persons (49.5%) compared with never married (43.5%) persons.

An estimated 37.9% of adults reported unintentionally falling asleep during the day at least 1 day in the preceding 30 days (Table - Unhealthy Sleep-Related Behaviors --- 12 States, 2009 ). Adults aged 18--24 years (43.7%) and ?65 years (44.6%) were significantly more likely to report this behavior than all other age groups, as were persons from all other racial/ethnic categories compared with non-Hispanic whites (33.4%). No significant difference was observed by sex. Compared with employed persons (33.5%), those who were unemployed (44.0%), unable to work (57.3%), and homemakers/students (39.3%) were significantly more likely to report unintentionally falling asleep during the day. Persons with at least some college education (35.9%) were significantly less likely to report unintentionally falling asleep than those with a high school diploma or GED (39.6%) or less education (43.4%). Never married adults (42.9%) were significantly more likely to report unintentionally falling asleep during the day than married adults (35.9%).

Nodding off or falling asleep while driving in the preceding 30 days was reported by 4.7% of adults (Table - Unhealthy Sleep-Related Behaviors --- 12 States, 2009 ). Persons aged ?65 years (2.0%) were significantly less likely to report this behavior than persons aged 25--34 years (7.2%), 35--44 years (5.7%), 18--24 years (4.5%), 45--54 years (3.9%), and 55--64 years (3.1%). Hispanics (6.3%), non-Hispanic blacks (6.5%), and non-Hispanics of other races (7.2%) all were significantly more likely to report this behavior than non-Hispanic whites (3.2%). Men were more likely (5.8%) to report this behavior, compared with women (3.5%), and employed persons were more likely (5.4%), compared with homemakers and students (2.2%). No significant differences were observed by educational level or marital status.

Persons who reported sleeping <7 hours on average during a 24-hour period were more likely to report unintentionally falling asleep during the day at least 1 day in the preceding 30 days (46.2% versus 33.2%) and nodding off or falling asleep while driving in the preceding 30 days (7.3% versus 3.0%) (Figure - Unhealthy Sleep-Related Behaviors --- 12 States, 2009 ). They also were more likely to report snoring (51.4% versus 46.0%).

Among adults in the 12 states surveyed, reports of <7 hours of sleep ranged from 27.6% in Minnesota to 44.6% in Hawaii. Snoring estimates ranged from 44.8% in California to 54.0% in Hawaii. Estimates of unintentionally falling asleep during the day in the preceding 30 days ranged from 33.0% in Wyoming to 42.8% in Hawaii. Finally, estimates of nodding off or falling asleep while driving in the preceding 30 days ranged from 3.0% in Illinois to 6.4% in Hawaii and Texas.

References

1. Institute of Medicine. Sleep disorders and sleep deprivation: an unmet public health problem. Washington, DC: The National Academies Press; 2006.

2. Ram S, Seirawan H, Kumar SK, Clark GT. Prevalence and impact of sleep disorders and sleep habits in the United States. Sleep Breath 2010;14:63--70.

3. CDC. Public health surveillance for behavioral risk factors in a changing environment: recommendations from the Behavioral Risk Factor Surveillance Team. MMWR 2003;52(No. RR-9) Public Health Surveillance for Behavioral Risk Factors in a Changing Environment Recommendations from the Behavioral Risk Factor Surveillance Team

4. National Highway Traffic Safety Administration and National Center on Sleep Disorders Research. Drowsy driving and automobile crashes. Washington, DC: National Highway Traffic Safety Administration. Available at Drowsy Driving . Accessed February 25, 2011.

5. National Institutes of Health, National Center on Sleep Disorders Research. National sleep disorders research plan. Bethesda, MD: National Institutes of Health; 2003. Available at http://www.nhlbi.nih.gov/health/prof/sleep/res_plan/index.html . Accessed February 25, 2011.

6. Schoenborn CA, Adams PF. Sleep duration as a correlate of smoking, alcohol use, leisure-time physical inactivity, and obesity among adults: United States, 2004--2006. Hyattsville, MD: National Center for Health Statistics; 2008. Available at http://www.cdc.gov/nchs/data/hestat/sleep04-06/sleep04-06.pdf . Accessed February 25, 2011.

7. CDC. Effect of short sleep duration on daily activities---United States, 2005--2008. MMWR 2011;60:239--42.

8. Bixler E. Sleep and society: an epidemiological perspective. Sleep Med 2009;10(suppl 1):S3--6.

9. Strine TW, Chapman DP. Associations of frequent sleep insufficiency with health-related quality of life and health behaviors. Sleep Med 2005;6:23--7.

 

[Michael Scally MD]

The present study reports the identification of Delta6-methyltestosterone in a product named "Jungle Warfare."


Parr MK, Fussholler G, Schlorer N, et al. Detection of Delta6-methyltestosterone in a "dietary supplement" and GC-MS/MS investigations on its urinary metabolism. Toxicol Lett 2011;201(2):101-4. Detection of ?6-methyltestosterone in a "dietary s... [Toxicol Lett. 2011] - PubMed result

Since a few years more and more products have appeared on the market for dietary supplements containing steroids that had never been marketed as approved drugs, mostly without proper labeling of the contents. Syntheses and few data on pharmacological effects are available dated back mainly to the 1950s or 1960s. Only little knowledge exists about effects and side effects of these steroids in humans.

The present study reports the identification of Delta6-methyltestosterone in a product named "Jungle Warfare", which was obtained from a web-based supplement store.

The main urinary metabolites, 17alpha-hydroxy-17beta-methylandrosta-4,6-dien-3-one (Delta6-epimethyl-testosterone), 17alpha-methyl-5beta-androstane-3alpha,17beta-diol (3alpha,5beta-THMT), and 17beta-methyl-5beta-androstane-3alpha,17alpha-diol, as well as the parent compound excreted after a single oral administration were monitored by GC-MS/MS. Delta6-Epimethyltestosterone and 3alpha,5beta-THMT served for long-term detection (still present in the 181-189h urine). 17alpha-Methyltestosterone and its 17-epimer were not detected in the urines (LOD 0.3ng/mL). The highest concentrations were found in the 14-20.5h urine for Delta6-epimethyltestosterone (600ng/mL), and 3alpha,5beta-THMT (240ng/mL) and in the 36-44.5h urine for 17beta-methyl-5beta-androstane-3alpha,17alpha-diol (7ng/mL).

For reference methyltestosterone and epimethyltestosterone were dehydrogenated with chloranil. The characterization of the products was performed by GC-MS(/MS) and NMR.

 

[Michael Scally MD]

In the present study, they examine how GPs deal with a dying patient and with their death. Their goal was to create a model to be used in the training of GPs. This model enables them to reflect on how diverse elements contribute to their own conception of what a good death might be for a patient and themselves.


Verhoeven A, Schuling J, Maeckelberghe E. The death of a patient: a model for reflection in GP training. BMC Family Practice 2011;12(1):8. http://www.biomedcentral.com/content/pdf/1471-2296-12-8.pdf

BACKGROUND: The Dutch government has chosen a policy of strengthening palliative care in order to enable patients to die at home according to their preference. In order to facilitate this care by GPs, we wanted to know how to support them in their training. Therefore we examined the ways in which the death of a patient influences the doctor both at a professional and at a personal level.

METHODS: Based on a qualitative study, we developed a model for reflection for GP trainees on the meaning of the death of patients and its influence on the GP. The qualitative study was done in 2007 and is based on open in-depth interviews and a focus group. We recruited 18 participants who were highly professional GPs and experienced in talking about the death of patients. We invited GPs from a list of experienced GPs, who in addition are also second-opinion GPs for euthanasia (SCEN-physicians) and from a pool of GP trainers, our intention being to include GPs holding a variety of world views. Interviews were audio-taped and transcribed verbatim. A grounded theory approach was used to analyze the results. Themes were first identified independently by three researchers, then after discussion these three sets were rearranged to one list of themes and their mutual relation were determined. A model for the interaction of the GP at professional and at a personal level was formulated.

RESULTS: Forty-three themes emerged from the interviews and focus group. These themes fell into three groups: professional values and experiences, personal values and experiences, and the opinions of the GPs as to what constitutes a good death. We constructed a model of the doctor-patient relationship on the basis of these findings. This model enables GP trainees identifying the unique character of the doctor-patient relationship as well as its reciprocity when the two were confronted by the patient's impending death.

CONCLUSIONS: In dealing with the approaching death of a patient the unique interaction between patient and doctor and the cumulative experiences of doctors with their patients brings about a shift in the GP's own values. The professional development of GP trainees may be facilitated by reflection on the interaction of their own values and beliefs.

 

[Michael Scally MD]

Body Adiposity Index

Dread the weigh-in? Researchers propose a new (scale-free) way to measure obesity (but you still may be too fat)
Dread the weigh-in? Researchers propose a new (scale-free) way to measure obesity (but you still may be too fat) - latimes.com

Move over, BMI. Researchers led by a University of Southern California physician have proposed "a better index of adiposity." This one would require a tape measure and a calculator, but none of the stepping-up-on-the-scale drama featured on NBC's The Biggest Loser and replayed so often in the privacy of our own bathrooms.

The new fat metric is called the Body Adiposity Index, and it's introduced in a study released Thursday in the journal Obesity. It uses a person's height and hip circumference to give a accurate reading of how much of a person's body is made up of fat. That's a measure that physical trainers and some physicians can get by ordering a dual-energy X-ray absorption test (also used to detect osteoporosis) or ahydrostatic underwater weigh-in. But the cost and complexity of taking such measures have made them a rarely-used alternative to good-old BMI.

Dr. Richard N. Bergman, the lead author of the article and a professor of physiology and biophysics at Keck School of Medicine, says the Body Adiposity Index, or BAI, is easy to compute, provides a more precise measure of a patient's ratio of fat-to-lean tissue than the body-mass index (BMI), and offers a standard that researchers could use to make apples-to-apples comparisons of men and women and of people across different ethnic groups.

In an interview, Bergman said he did not think the BAI would topple the BMI from its pedestal, but that, as researchers find links between BAI and health outcomes (such as diabetes, certain cancers, heart disease and stroke), the new measure of fat may become a better way to identify which patients truly have body compositions that put them at risk. In the meantime, he said, it could be a useful measure for doctors to use alongside BMI to counsel their patients.

What prompted him and researchers from the National Institute of Diabetes and Digestive and Kidney health (NIDDK) to explore better ways to measure body fat? "I was upset that BMI is used clinically when in fact, for an individual, it’s rather inaccurate," said Bergman.

Body-Mass Index is a simple but very rough gauge of how fat we are. Calculating BMI requires only a person's height and weight, so researchers have records going back almost 200 years that they can use to plot the steady and, most recently, steep rise in our avoir-du-poids. No surprise, then, that BMI has become the most widely-embraced tool in research on health and nutrition. A search of medical research databases shows that some 45,000 published research studies have used BMI, among other things, to establish links between excess fat and increased health risks such as cancer, cardiovascular disease and diabetes.

As a result, Americans concerned about their weight are as likely to know their BMI number as they do their shoe size--though the weight/height measurement is likely a touchier subject.

The problem is that BMI, while a great tool for charting population trends, is not, in fact, a very good measure of how fat contributes to an individual person's body composition. That shortcoming may be important because advancing research suggests it is body fat--not lean muscle, not healthy bones, and certainly not a BMI number--that increases one's propensity to develop heart disease, type-2 diabetes and other ills. (Much of that research has suggested that visceral fat--blubber that accumulates around the belly--is the most harmful. In light of those findings, Bergman said he and his colleagues were "surprised" to find hip circumference a better way to measure body fat.)

So, it might be more helpful if physicians and public health experts had an easy way to measure just how much fat each of us carries around, and whether that fat plays a distant second fiddle to strong bones and lean muscle, or whether it's become a major player in a person's body composition. Without scales, water tanks or X-ray machines, BAI could provide that.

Bergman and his colleagues settled on the measure using height and hip circumference (throw that tape measure around the hips "at the level of the maximum extension of the buttocks posteriorly in a horizontal plane") after finding that in two studies, it correlated closest with the body composition results gleaned from the more costly X-ray absorption test or the underwater weigh-in tests. The studies looked at large populations of African-Americans and Mexican-Americans, as well as some white European-Americans, and found the BAI consistently correlated with other measures of body composition in all three groups.


Bergman RN, Stefanovski D, Buchanan TA, et al. A Better Index of Body Adiposity. Obesity. Obesity - Abstract of article: A Better Index of Body Adiposity

Obesity is a growing problem in the United States and throughout the world. It is a risk factor for many chronic diseases. The BMI has been used to assess body fat for almost 200 years. BMI is known to be of limited accuracy, and is different for males and females with similar %body adiposity. Here, we define an alternative parameter, the body adiposity index (BAI = ((hip circumference)/((height)1.5)–18)). The BAI can be used to reflect %body fat for adult men and women of differing ethnicities without numerical correction. We used a population study, the “BetaGene” study, to develop the new index of body adiposity. %Body fat, as measured by the dual-energy X-ray absorptiometry (DXA), was used as a “gold standard” for validation. Hip circumference (R = 0.602) and height (R= ?0.524) are strongly correlated with %body fat and therefore chosen as principal anthropometric measures on which we base BAI. The BAI measure was validated in the “Triglyceride and Cardiovascular Risk in African-Americans (TARA)” study of African Americans. Correlation between DXA-derived %adiposity and the BAI was R = 0.85 for TARA with a concordance of C_b = 0.95. BAI can be measured without weighing, which may render it useful in settings where measuring accurate body weight is problematic. In summary, we have defined a new parameter, the BAI, which can be calculated from hip circumference and height only. It can be used in the clinical setting even in remote locations with very limited access to reliable scales. The BAI estimates %adiposity directly.

 

[Michael Scally MD]

Abnormal Liver Function Tests & Chronic Viral Hepatitis

Liver function tests (LFTs) are comprised of a panel of five to eight analytes that are processed inexpensively in large batches. LFTs are one of the most commonly performed “blood tests” in primary care. An abnormal LFT may signify a serious disease that can be identified only through further testing. These conditions include liver diseases, such as primary biliary cirrhosis (PBC), diseases of other organs such as Paget’s disease of bone, and multi-organ diseases such as hemochromatosis. However, the majority of people with an abnormal LFT in primary care settings will not have any such previously undetected disease. They will have either no disease at all, or will be manifesting the effects of alcohol abuse or obesity. The doctor is likely to be aware, or at least suspicious, of these behaviors when ordering LFTs, but this does not exclude the presence of other diseases that may aggravate liver damage. There is thus a real question about which specific further tests, if any, a GP should order when an abnormal LFT result is obtained in a patient with non-specific symptoms, or as a result of routine testing.

In some cases there may be a clear indication for further tests. For example, if the patient has a family history of hemochromatosis then their iron saturation should be measured. In some cases the pattern of LFT abnormality may suggest a diagnosis – for example, an isolated raised unconjugated bilirubin suggests Gilbert’s disease, while a high blood level of alkaline phosphatase (ALP) is indicative of PBC. In most cases however, no unambiguous clinical indication for follow-on testing exists. The literature deals mostly with the pattern of abnormality given a diagnosis, rather than the probability of the various diagnoses given a pattern of abnormal LFTs. It is therefore not surprising that guidelines for GPs confronted by an abnormal LFT in patients with non-specific symptoms or detected fortuitously are inconsistent, or that the way GPs respond has been found to be eclectic. A point on which guidelines do agree is that the LFT panel should be repeated following an abnormal result.

If there is any particular previously unrecognized disease that a patient would wish to have excluded by further testing, then it will have the following features:
1. It is a serious disease;
2. It is treatable in the prodromal phase;
3. Failure to identify the condition can lead to permanent damage;
4. It can be diagnosed with a high specificity by a familiar and inexpensive test;
5. It is among the more prevalent of the serious diseases;
6. It is not a condition such as alcohol misuse or obesity, which can be diagnosed from history and examination.

Chronic viral hepatitis is the prime candidate based on the above criteria. It is a massive problem worldwide and is the most common of the specific liver diseases after alcohol damage. Moreover, chronic viral hepatitis can be reliably confirmed or excluded by means of a relatively inexpensive blood test. The disease has a prodromal period lasting many decades and is eminently treatable if caught early, thereby averting cirrhosis and liver cancer. The purpose of the decision analysis described here is to inform the selection of an efficient strategy for the diagnosis of chronic viral hepatitis. Such a strategy should optimize the tradeoff between detection rate and cost.


Arnold D, Bentham L, Jacob R, Lilford R, Girling A. Should patients with abnormal liver function tests in primary care be tested for chronic viral hepatitis: cost minimisation analysis based on a comprehensively tested cohort. BMC Family Practice 2011;12(1):9. http://www.biomedcentral.com/content/pdf/1471-2296-12-9.pdf

BACKGROUND: Liver function tests (LFTs) are ordered in large numbers in primary care, and the Birmingham and Lambeth Liver Evaluation Testing Strategies (BALLETS) study was set up to assess their usefulness in patients with no pre-existing or self-evident liver disease. All patients were tested for chronic viral hepatitis thereby providing an opportunity to compare various strategies for detection of this serious treatable disease.

METHODS: This study uses data from the BALLETS cohort to compare various testing strategies for viral hepatitis in patients who had received an abnormal LFT result. The aim was to inform a strategy for identification of patients with chronic viral hepatitis. We used a cost-minimisation analysis to define a base case and then calculated the incremental cost per case detected to inform a strategy that could guide testing for chronic viral hepatitis.

RESULTS: Of the 1,236 study patients with an abnormal LFT, 13 had chronic viral hepatitis (nine hepatitis B and four hepatitis C). The strategy advocated by the current guidelines (repeating the LFT with a view to testing for specific disease if it remained abnormal) was less efficient (more expensive per case detected) than a simple policy of testing all patients for viral hepatitis without repeating LFTs. A more selective strategy of viral testing all patients for viral hepatitis if they were born in countries where viral hepatitis was prevalent provided high efficiency with little loss of sensitivity. A notably high alanine aminotransferase (ALT) level (greater than twice the upper limit of normal) on the initial ALT test had high predictive value, but was insensitive, missing half the cases of viral infection.

CONCLUSIONS: Based on this analysis and on widely accepted clinical principles, a "fast and frugal" heuristic was produced to guide general practitioners with respect to diagnosing cases of viral hepatitis in asymptomatic patients with abnormal LFTs. It recommends testing all patients where a clear clinical indication of infection is present (e.g. evidence of intravenous drug use), followed by testing all patients who originated from countries where viral hepatitis is prevalent, and finally testing those who have a notably raised ALT level (more than twice the upper limit of normal). Patients not picked up by this efficient algorithm had a risk of chronic viral hepatitis that is lower than the general population.

 

[Michael Scally MD]

The hallmarks of cancer comprise six biological capabilities acquired during the multistep development of human tumors. The hallmarks constitute an organizing principle for rationalizing the complexities of neoplastic disease. They include sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, and activating invasion and metastasis. Underlying these hallmarks are genome instability, which generates the genetic diversity that expedites their acquisition, and inflammation, which fosters multiple hallmark functions. Conceptual progress in the last decade has added two emerging hallmarks of potential generality to this list reprogramming of energy metabolism and evading immune destruction. In addition to cancer cells, tumors exhibit another dimension of complexity: they contain a repertoire of recruited, ostensibly normal cells that contribute to the acquisition of hallmark traits by creating the tumor microenvironment. Recognition of the widespread applicability of these concepts will increasingly affect the development of new means to treat human cancer.


Hanahan D, Weinberg Robert A. Hallmarks of Cancer: The Next Generation. Cell 2011;144(5):646-74. http://download.cell.com/pdf/PIIS0092867411001279.pdf?intermediate=true

This illustration encompasses the six hallmark capabilities originally proposed in our 2000 perspective. The past decade has witnessed remarkable progress toward understanding the mechanistic underpinnings of each hallmark.

 

[Michael Scally MD]

Recent advances in molecular physiology have identified a number of potential drug targets related to the qualitative and quantitative skeletal muscle changes referred to as sarcopenia in aging humans. Although drug development based on these targets holds great promise, a number of important questions need to be addressed to ensure that appropriate clinical trial designs are used to evaluate these new potential therapies. Important initiatives have been launched to address the challenges of clinical trials in patients with sarcopenia, but additional considerations specific to pharmaceutical development must be addressed in future clinical programs to ensure that studies yield data that not only address the perceived clinical needs, but also meet the regulatory standards of the U.S. Food and Drug Administration (FDA). [NOTE: Any pathway (drug) to combat sarcopenia is the equivalent of promoting anabolic effects. This is where the focus/attention is to be paid for worthwhile future developments.]

Brass EP, Sietsema KE. Considerations in the Development of Drugs to Treat Sarcopenia. J Am Geriatr Soc. Considerations in the Development of Drugs to Trea... [J Am Geriatr Soc. 2011] - PubMed result

Sarcopenia describes reduced skeletal muscle mass and impaired muscle function associated with aging and with a variety of chronic diseases prevalent in the aging population. With increasing understanding of the molecular pathways participating in the structural and functional changes affecting skeletal muscle in these conditions, a number of potential targets for pharmacological interventions to reverse sarcopenia have been identified. The clinical evaluation of therapeutic candidates directed at these targets will require that the efficacy and safety of the drug candidates be adequately evaluated to meet the regulatory standards of the Food and Drug Administration (FDA). Concerns unique to drug development may require different approaches to clinical study design than have been used in the epidemiological research that identified the clinical need for these programs and the intervention trials conducted to date. In addition to being responsive to clinical need as perceived by patients and physicians, clinical trial data must demonstrate to the FDA that the drug provides an objective and clinically meaningful advantage, and must demonstrate to all involved in healthcare decision-making that its benefits justify the associated costs and risks. Potential primary efficacy endpoints for trials of a drug for treatment of sarcopenia include physical performance, falls, fractures, and patient-reported outcomes assessing function and quality of life. Each potential endpoint has advantages and disadvantages from scientific, clinical, and regulatory perspectives that must be carefully considered in the design of trials for sarcopenia treatments.

 

[Michael Scally MD]

Casual Sex: Men, Women Not So Different After All
No, Really. Women Do Enjoy Casual Sex | Smart Journalism. Real Solutions. Miller-McCune.

New research suggests women turn down offers of casual sex for one good reason: They suspect — with some reason — they won’t enjoy it.

By Tom Jacobs

Would you have casual sex with a stranger? How about a close platonic friend?

How about with Johnny Depp?

Getting more interested, ladies? If so, you’re adding to the evidence that some widely accepted beliefs regarding men, women and short-term sexual encounters may be significantly off-base.

In a newly published paper describing a series of studies, University of Michigan psychologist Terri Conley asserts that “when women are presented with proposers who are equivalent in terms of safety and sexual prowess, they will be equally likely as men to engage in casual sex.”

Her research suggests women, like men, are motivated by pleasure-seeking when they enter the sexual arena. It’s just that women are less likely to be satisfied by a short-term encounter, and they know it.

Writing in the Journal of Personality and Social Psychology, Conley describes a series of experiments that refine the results of a seminal 1989 study widely cited in articles and textbooks. That study, by psychologists Russell Clark and Elaine Hatfield, found that when a female college student introduced herself to a male colleague and asked if he wanted to have sex with her, 69 to 75 percent of the guys said yes. When the genders were reversed, not a single woman was interested.

That huge difference has largely been explained in terms of Sexual Strategies Theory, an evolutionary approach that focuses on the desire, conscious or unconscious, to pass one’s genes to the next generation. If that’s our driving impulse, women need to be choosy about their sexual partners; they’re looking for men who are likely to stick around and provide support during their child-rearing years. Men, on the other hand, have an evolutionary incentive to spread their seed as widely as possible.

Although Conley also takes an evolutionary approach, her perspective is significantly different from that much-discussed thesis. She points to a relatively new approach called Pleasure Theory. It asserts “the pursuit of pleasure is the central force that motivates sexual behavior,” and that reproduction is a byproduct of this effort.

“If humans are having pleasurable encounters, enough instances of vaginal intercourse will occur to ensure the survival of the species,” she notes.

In other words, our motivation may be simpler than the first generation of evolutionary psychologists believed. Girls — and boys — just want to have fun, and biology takes care of the rest.

So why did the young men and women in the 1989 study — and in a repeat of that experiment that Conley conducted — react so differently to the offer of casual sex? After conducting a series of follow-up experiments, in which she tweaked Clark and Hatfield’s sexual-invitation scenario in different ways, she came up with an answer sports-conscious men should be able to easily grasp: The playing field isn’t level.

Men, after all, can almost be guaranteed a pleasurable sexual encounter if they’re with someone they find attractive. But Conley points to new, yet-to-be published research by sociologist Elizabeth Armstrong which finds “women orgasm only 35 percent as often as men in first-time sexual encounters.”

“Women’s perception that their heterosexual casual sex partners will be unlikely to give them pleasure is not unwarranted,” Conley states.

This lack of confidence in men as pleasure-givers was indirectly supported by another of Conley’s experiments, which focused on bisexual women. They were “significantly more likely to accept an offer (of a one-night stand) from a woman than from a man,” she reports.

This brings us back to Johnny Depp. In an attempt to learn if gender differences toward casual sex can be eliminated, Conley conducted yet another variation on the basic “Will you go to bed with me?” experiment. Only in this case, the scenario featured one very attractive and one unattractive suitor: Depp and Donald Trump for women, Angelina Jolie and Roseanne Barr for men.

The result: Women were just as likely as men to agree to have sex with the attractive celebrity. They were also “about equally likely” to reject the offer from the unattractive but famous individual.

This suggests a problem with the aforementioned Sexual Strategies Theory. If women were attracted at some deep level to men with the resources to care for them and their prospective children, The Donald would be a catch.

It’s worth noting that gender-specific biology, or at least psychology, does play into this equation. Conley notes that women tend to be more concerned about sexual assault, a fear that makes casual encounters more risky. It’s entirely possible that women, on average, get less pleasure out of casual sexual relations because they are more relaxed, and thus more receptive, when they are with partners they know and trust.

Still, it’s fascinating that when you remove that variable and give women the option of a casual encounter that is likely to be both safe and pleasurable, they are just as receptive as men. This research, Conley concludes, “suggests that women are more similar to men in their reactions to casual sex than would have initially been expected.”


Conley TD. Perceived proposer personality characteristics and gender differences in acceptance of casual sex offers. J Pers Soc Psychol 2011;100(2):309-29. Perceived proposer personality characteristics and... [J Pers Soc Psychol. 2011] - PubMed result

In a highly influential paper, Clark and Hatfield (1989) [See Attached] demonstrated that, whereas men were quite likely to accept a casual sexual offer from a confederate research assistant, women never did so. The current research provides a more in-depth explanation of gender differences in acceptance of casual sex offers via 4 (quasi-) experiments. First, using a person-perception paradigm, I assessed people's impressions of women and men who proposed a casual sexual encounter in the same manner that confederates in Clark and Hatfield did. Women and men agreed that female proposers were more intelligent, successful, and sexually skilled than men who made the same proposals. Second, I demonstrated that the large gender differences from the original Clark and Hatfield study could be eliminated by asking participants to imagine proposals from (attractive and unattractive) famous individuals, friends, and same-gender individuals. Next, I assessed factors associated with likelihood of agreeing to the casual sex proposal. The extent to which women and men believed that the proposer would be sexually skilled predicted how likely they would be to engage in casual sex with this individual. Finally, I examined these factors in the context of actual encounters from the participants' previous experiences, and the results were replicated in this context. Overall findings suggest that the large gender differences Clark and Hatfield observed in acceptance of the casual sex offer may have more to do with perceived personality characteristics of the female versus male proposers than with gender differences among Clark and Hatfield's participants and that sexual pleasure figures largely in women's and men's decision making about casual sex.


Clark RD & Hatfield E. Gender differences in receptivity to sexual offers. Journal of Psychology and Human Sexuality. 1989;2:39-55. [Attached]

 

[Michael Scally MD]

It is impossible to make any sense of these findings since they mix male and female testing!!!

Isotretinoin (ISO), a 13-cis-retinoic acid derivative of vitamin A, is a highly effective therapy for severe nodulocystic acne. Although its mechanism of action is not fully understood, ISO is thought to isomerise to all-trans-retinoic acid (ATRA) ISO, which then interacts with retinoid receptors. The mechanism by which decreases sebum production is not well understood. Few published data describe its effects on hormone physiology in acne patients. In this study, researchers sought to investigate the effect of ISO on various hormone systems in acne patients.


Karadag AS, Ertugrul DT, Tutal E, Akin KO. Isotretinoin influences pituitary hormone levels in acne patients. Acta Derm Venereol 2011;91(1):31-4. Isotretinoin Influences Pituitary Hormone Levels in Acne Patients - Full HTML - Acta Dermato-Venereologica - Content

Besides suppressing sebum production, the exact mechanism of action of isotretinoin in acne vulgaris is not known. Several hormones have been linked to the pathogenesis of acne. In this study, we investigated the effects of isotretinoin on the pituitary-adrenal axis, whose activity may be increased in acne. Various hormone systems were evaluated before and after 3 months of isotretinoin treatment in 47 acne patients. Free triiodothyronine (T3), thyroid-stimulating hormone and thyroid-stimulating hormone receptor antibody levels decreased significantly during isotretinoin treatment (p < 0.001, p < 0.02 and p < 0.02, respectively), as did those of luteinising hormone, prolactin and total testosterone (p < 0.005), as well as morning cortisol and adrenocorticotropic hormone (p < 0.005 and p < 0.05, respectively). We conclude that isotretinoin causes mild suppression of pituitary hormone levels, which may be beneficial for tackling the pathogenesis of acne.

 

[Michael Scally MD]

Low sperm counts linked to fetal effects
Male infertility may stem from in utero chemical exposure
http://www.sciencenews.org/view/generic/id/70484/title/Low_sperm_counts_linked_to_fetal_effects

Scientists report being able to take the measure of a man — or at least his ability to father children — with a $40 pair of measuring calipers. They use the instrument to carefully assay the distance between his genitals and anus.

In a new study, this distance proved a potent predictor not only of sperm count but also of semen quality — the concentration of sperm as well as sperm motility and shape. Of these, sperm count correlated best with anogenital distance, or AGD. In fact, “AGD is now the strongest predictor of sperm count that we know of,” says Shanna Swan, a reproductive epidemiologist in the University of Rochester’s Department of Obstetrics and Gynecology.

No one knows what triggered the reproductive changes for which AGD serves as a marker, Swan says. A number of environmental factors — including a mother’s smoking or obesity — appear able to perturb fetal androgen levels. But in 2005, Swan’s group correlated a diminished AGD in infant boys with a small penis — and both appeared linked to elevated concentrations of chemicals known as phthalates in urine collected from the boys’ mothers during prenatal visits. Phthalates constitute a widely used family of chemicals that serve as solvents and that make certain plastics flexible. Studies show people throughout the industrial world are regularly exposed to them.

The share of reproductively challenged men that Swan’s team turned up in the new study was large. Based on semen measurements, one in four of the 126 apparently healthy men who were tested appeared subfertile at best — and possibly infertile, Swan and her colleagues report online March 4 in Environmental Health Perspectives. The men in this group had sperm concentrations at or below 20 million per milliliter, a cutoff that Swan says doctors often use to determine whether men who haven’t been able to father a child warrant referral to a fertility clinic.

Animal studies show that AGD is controlled early in prenatal development by sex hormones, especially androgens such as testosterone, notes Richard Sharpe of Queen’s Medical Research Institute in Edinburgh. “AGD therefore offers a lifelong readout of fetal androgen exposure — and just for this critical period of vulnerability,” which he says roughly corresponds to weeks eight through 14 of human gestation.

His group linked shortened AGD in rodents with reduced sperm counts, birth defects affecting the genitals and smaller male organs. But there remained the nagging question of whether AGD provided a similarly important readout of androgen exposure in early human development.

“We now know it does,” Swan says.

The evidence emerged among residents of Rochester, N.Y., who took part in the first study of semen quality among healthy U.S. men. “These were kids in college,” Swan says. “They volunteered to be tested just because they wanted to make $75,” the compensation for participating.

Those whose anogenital distance was below the median for their build were 7.3 times as likely to be in the subfertile group as were those whose AGD was above the median, Swan says. Her team’s analyses found less than one-tenth of a percent likelihood that this association might be due to chance.

“Up until now, nobody has really understood what might be the impacts of a shortened AGD on quality of life,” says Philip Landrigan, director of the Children's Environmental Health Center at the Mount Sinai School of Medicine in New York City. “So this observation that a short AGD is correlated with low sperm count is new stuff and, I think, very important.”

One reason: Getting useful measures of sperm is complicated because numbers fluctuate with a host of factors, including season, ambient temperature and how long a man has been abstinent. “The beauty of measuring AGD,” Landrigan says, “is that once it’s established [in the womb], it remains stable — as long as you adjust for the overall size of the man.” This gives doctors “a new way to screen men — a new tool in their quiver.”

Data since 1992 have pointed to low and falling sperm counts among men throughout much of the developed world. “And we’ve been touting for years that this may have its origins in fetal life,” Sharpe says. “But we’ve lacked the direct evidence.” The new Rochester data, he says, now offer an explanation for low sperm counts in a large share of young men.

Sharpe’s team also has shown that fetal exposure to some phthalates can shorten AGD in rats and diminish their adult sperm production. The sperm changes traced back to a reduced proliferation of Sertoli cells in the fetal testes. “Ultimately,” he says, “the number of Sertoli cells will determine how many sperm you can make in adulthood.”


Mendiola J, Stahlhut RW, Jorgensen N, Liu F, Swan SH. Shorter Anogenital Distance Predicts Poorer Semen Quality in Young Men in Rochester, New York. Environ Health Perspect. Environmental Health Perspectives: Shorter Anogenital Distance Predicts Poorer Semen Quality in Young Men in Rochester, New York

Background: In male rodents, anogenital distance (AGD) provides a sensitive and continuous correlate of androgen exposure in the intrauterine environment and predicts later reproductive success. Some endocrine disrupting chemicals can alter male reproductive tract development, including shortening AGD, in both rodents and humans. Whether AGD is related to semen quality in human is unknown.

Objectives: To examine associations between AGD and semen parameters in adult males.
Methods: We used multiple regression analyses to model the relationships between sperm parameters and two alternative measures of AGD (anus to the posterior base of the scrotum [AGDAS], and to the cephalad insertion of the penis [AGDAP]), in 126 volunteers in Rochester, NY.

Results: AGDAS, but not AGDAP, was associated with sperm concentration, motility, morphology, total sperm count and total motile count (p-values 0.002-0.048). Men with AGDAS below (compared to above) the median were 7.3 times more likely (95% CI 2.5, 21.6) to have a low sperm concentration (<20x106/ml). For a typical study participant, sperm concentrations were 34.7 x106/ml and 51.6 x106/ml at the 25th and 75th percentiles of (adjusted) AGDAS.

Conclusions: In our population, AGDAS was a strong correlate of all semen parameters and a predictor of low sperm concentration. In animals, male AGD at birth reflects androgen levels during the masculinization programming window and predicts adult AGD and reproductive function. Our results suggest, therefore, that the androgenic environment during early fetal life exerts a fundamental influence on both AGD and adult sperm counts in humans, as demonstrated in rodents.

Diagram of the male genitalia showing the three anogenital distance measurements taken: anogenital distance 1 (AGD1), the distance from the anterior of the penis to the center of the anus; anogenital distance 2 (AGD2), the distance from the posterior of the penis to the center of the anus; and anoscrotal distance (ASD), the distance from the posterior of the scrotum to the center of the anus.

 

[Michael Scally MD]

Non-Steroidal Anti-Inflammatory Drugs Linked to Increased Risk of Erectile Dysfunction
Non-steroidal anti-inflammatory drugs linked to increased risk of erectile dysfunction

ScienceDaily (Mar. 2, 2011) — Men who take non-steroidal anti-inflammatory drugs three times a day for more than three months were found to be 2.4 times* more likely to have erectile dysfunction compared to men who do not take those drugs regularly, according to a Kaiser Permanente study published online in The Journal of Urology.

While previous research showed a trend toward this same finding, this observational study used electronic health records, an automated pharmacy database and self-reported questionnaire data to examine NSAID use and ED in an ethnically diverse population of 80,966 men aged 45 to 69 years throughout California.

After controlling for age, race, ethnicity, smoking status, diabetes, hypertension, heart disease, high cholesterol and body mass index, the researchers found that ED was just 1.4 times more likely -- a modest risk -- among regular NSAID users compared to men who did not take the drugs regularly. This association was consistent across all age groups.

"This study is a great example of how we work to understand the safety and effectiveness of what we recommend for our patients. We went into this study thinking we would find the opposite effect: that NSAIDs would have a protective effect because they protect against heart disease, which is also linked to ED," said study senior author Steven J. Jacobsen, MD, PhD, an epidemiologist and director of research for Kaiser Permanente Southern California. "The next step is to dive a bit deeper to understand the underlying physiology of what might be happening with these drugs."

Erectile dysfunction is a common problem in many middle-aged and elderly men. According to the National Institutes of Health, approximately 5 percent of 40-year-old men and between 15 and 25 percent of 65-year-old men experience ED on a long-term basis.

However, the researchers caution that men should not stop taking NSAIDs based on this study.
"There are many proven benefits of non steroidals in preventing heart disease and for other conditions. People shouldn't stop taking them based on this observational study. However, if a man is taking this class of drugs and has ED, it's worth a discussion with his doctor," Jacobsen said.


Gleason JM, Slezak JM, Jung H, et al. Regular Nonsteroidal Anti-Inflammatory Drug Use and Erectile Dysfunction. J Urol. 2011;185:1388-93. Regular Nonsteroidal Anti-Inflammatory Drug Use an... [J Urol. 2011] - PubMed result

PURPOSE: Previous data suggest a potential relationship between inflammation and erectile dysfunction. If it is causal, nonsteroidal anti-inflammatory drug use should be inversely associated with erectile dysfunction. To this end we examined the association between nonsteroidal anti-inflammatory drug use and erectile dysfunction in a large, ethnically diverse cohort of men enrolled in the California Men's Health Study.

MATERIALS AND METHODS: This prospective cohort study enrolled male members of the Kaiser Permanente managed care plans who were 45 to 69 years old beginning in 2002. Erectile dysfunction was assessed by questionnaire. Nonsteroidal anti-inflammatory drug exposure was determined by automated pharmacy data and self-reported use.

RESULTS: Of the 80,966 men in this study 47.4% were considered nonsteroidal anti-inflammatory drug users based on the definitions used and 29.3% reported moderate or severe erectile dysfunction. Nonsteroidal anti-inflammatory drug use and erectile dysfunction strongly correlated with age with regular drug use increasing from 34.5% in men at ages 45 to 49 years to 54.7% in men 60 to 69 years old with erectile dysfunction increasing from 13% to 42%. The unadjusted OR for the association of nonsteroidal anti-inflammatory drugs and erectile dysfunction was 2.40 (95% CI 2.27, 2.53). With adjustment for age, race/ethnicity, smoking status, diabetes mellitus, hypertension, hyperlipidemia, peripheral vascular disease, coronary artery disease and body mass index, a positive association persisted (adjusted OR 1.38). The association persisted when using a stricter definition of nonsteroidal anti-inflammatory drug exposure.

CONCLUSIONS: These data suggest that regular nonsteroidal anti-inflammatory drug use is associated with erectile dysfunction beyond what would be expected due to age and comorbidity.

 

[Michael Scally MD]

According to a study published online March 1 in the journal Academic Emergency Medicine, "levels of previously undiagnosed or poorly controlled diabetes are higher than expected in the US population," as evidenced by survey resulted gathered from emergency department (ED) personnel. After collecting "glycated hemoglobin (HbA1c) data from 313 patients attending a single ED during eight 24-hour periods," researchers found "a higher than expected number of patients (n=38; 14%) with previously undiagnosed diabetes," as well as a number of patients with poorly controlled glycated hemoglobin levels. Have you had your HbA1c checked?


Menchine MD, Arora S, Camargo CA, Ginde AA. Prevalence of Undiagnosed and Suboptimally Controlled Diabetes by Point-of-care HbA1C in Unselected Emergency Department Patients. Academic Emergency Medicine. Prevalence of Undiagnosed and Suboptimally Controlled Diabetes by Point-of-care HbA1C in Unselected Emergency Department Patients - Menchine - 2011 - Academic Emergency Medicine - Wiley Online Library

Objectives: The objective was to estimate the glycemic control of patients with known diabetes and to assess the prevalence of undiagnosed diabetes in an unselected emergency department (ED) population. Secondary objectives include evaluating the prevalence of undiagnosed diabetes in high-risk groups of ED patients such as Hispanic patients, African Americans, and patients with body mass index (BMI) ? 30 kg/m2.

Methods: A convenience sample of adult ED patients was screened for diabetes using a National Glycohemoglobin Standardization Program–certified point-of-care (POC) glycated hemoglobin (HbA1C) meter at a single academic medical center during eight 24-hour periods. Diabetes was defined as HbA1C ? 6.5%, consistent with new American Diabetes Association (ADA) guidelines.

Results: Of the 1,611 patients evaluated in the ED during the study period, 313 were included in the study sample. Of these, 15% reported a history of diabetes, 42% of whom were suboptimally controlled. An additional 14% of the study sample was found to have previously undiagnosed diabetes. In our limited sample, the prevalence of previously undiagnosed diabetes in Hispanics, African Americans, and patients with BMI ? 30 kg/m2 was 14, 27, and 22%, respectively.

Conclusions: Patients in our sample had a high prevalence of suboptimally controlled and undiagnosed diabetes. New POC HbA1C devices and simplified diagnostic criteria for diabetes significantly enhance the possibility of ED-based screening programs. Future research should validate our findings in a broader array of EDs and study the acceptance of such ED-based diabetes screening programs.

 

[Michael Scally MD]

Type 2 diabetes is a progressive disease, characterized by a gradual deterioration in glycaemic control because of the continuing loss of ?-cell function. Thus, combinations of glucose-lowering drugs are often needed to maintain blood glucose at target values: glycated hemoglobin (HbA1c) per Diabetes Control and Complications Trial (DCCT) <7% or per International Federation of Clinical Chemistry and Laboratory Medicine <53 mmol/mol. The development and commercialization of new classes of drugs for diabetes has increased the treatment options and made the management of hyperglycaemia more complex. The selection of glucose lowering treatments should take into account patient-specific factors (e.g. age, duration of diabetes, body weight, waist circumference, associated cardiovascular risk factors), as well as mechanistic effects of various drugs on the main target organs involved in the pathogenesis of type 2 diabetes (e.g. liver, skeletal muscle, adipose tissue, ?-cell, intestine, kidney). In this review, they specifically focus on the place of the new incretin therapies, glucagon-like peptide (GLP)-1 receptor agonists and dipeptidyl peptidase (DPP)-4 inhibitors, in type 2 diabetes treatment.


Charbonnel B, Cariou B. Pharmacological management of type 2 diabetes: the potential of incretin-based therapies. Diabetes, Obesity and Metabolism 2011;13(2):99-117. Pharmacological management of type 2 diabetes: the potential of incretin-based therapies - Charbonnel - 2010 - Diabetes, Obesity and Metabolism - Wiley Online Library

Management guidelines recommend metformin as the first-line therapy for most patients with type 2 diabetes uncontrolled by diet and exercise. Efficacy with metformin therapy is usually of limited duration, which necessitates the early introduction of one or two additional oral agents or the initiation of injections, glucagon-like peptide-1 (GLP-1) agonists or insulin. Although safe and effective, metformin monotherapy has been associated with gastrointestinal side effects (?20% of treated patients in randomized studies) and is contraindicated in patients with renal insufficiency or severe liver disease. Patients treated with a sulphonylurea are at increased risk for hypoglycaemia and moderate weight gain, whereas those receiving a thiazolidinedione are subject to an increased risk of weight gain, oedema, heart failure or fracture. Weight gain and hypoglycaemia are associated with insulin use. Thus, there is an unmet need for a safe and efficacious add-on agent after initial-therapy failure. Evidence suggests that incretin-based agents, such as GLP-1 receptor agonists and dipeptidyl peptidase-4 inhibitors, can successfully achieve glycaemic targets and potentially provide cardiovascular and ?-cell-function benefits. This review will examine current approaches for treating type 2 diabetes and discuss the place of incretin therapies, mainly GLP-1 agonists, in the type 2 diabetes treatment spectrum.

 

[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.

 

[Michael Scally MD]

[For recently filed FINASTERIDE lawsuit, see: https://thinksteroids.com/community/posts/750587 ]


Sperm DNA damage is associated with male infertility and an increased risk for spontaneous abortions. Low-dose finasteride has a mild adverse effect on sperm parameters in healthy men but this adverse effect may be amplified in infertile men. A 48-year-old man on low-dose finasteride for androgenic hair loss presented for evaluation of secondary infertility of 4 years duration. Further investigations revealed normal semen parameters. The sperm DNA fragmentation index (DFI) done one year ago was elevated at 30%. Finasteride was discontinued and the %DFI decreased to 21% and eventually 16.5% 6 months later. There is no literature on the association between low-dose finasteride and %DFI. The researchers hypothesize that low-dose finasteride may exert a negative influence on sperm DNA integrity resulting in increased miscarriages.


Tu HY, Zini A. Finasteride-induced secondary infertility associated with sperm DNA damage. Fertil Steril. Finasteride-induced secondary infertility associat... [Fertil Steril. 2011] - PubMed result

OBJECTIVE: To report a case of low-dose finasteride-induced secondary infertility with associated elevated sperm DNA fragmentation index (DFI) and otherwise normal semen parameters. DESIGN: Case report. SETTING: University hospital.

PATIENT(S): A 48-year-old man on low-dose finasteride and his 37-year-old wife with normal menses and normal gynecologic exam. INTERVENTION(S): Determination of sperm DFI and discontinuation of low-dose finasteride.

MAIN OUTCOME MEASURE(S): Sperm DFI. RESULT(S): The sperm DFI done a year earlier was 30%. This value was unchanged when repeated 2 months later. The patient was advised to stop finasteride. Three months after discontinuing the finasteride, the DFI decreased to 21% and subsequent DFI after another 3 months improved to 16.5%. To date, there is still no documented full-term pregnancy or live birth.

CONCLUSION(S): The significant reduction in DFI within 3 months of finasteride cessation and continued improvement suggests a causal link between finasteride and sperm DNA damage. We hypothesize that low-dose finasteride may exert a negative influence on sperm DNA integrity, resulting in increased pregnancy losses. We suggest that in infertile men using finasteride, sperm DFI should be measured in addition to semen parameters, and a trial of discontinuation of finasteride may be warranted.