Testosterone replacement and prostate cancer: Is therapy safe?

For men with low testosterone, taking supplements can mean greater libido, energy and muscle. It also goes against decades of medical thinking.

05 april 2009--Manny Hamelburg, 68, a retired businessman, had fought prostate cancer for years. First, he tried radiation, then a drug with side effects that nearly killed him, and finally Lupron, a drug that blocks production of testosterone, the hormone that can fuel prostate cancer.

The cancer disappeared. But life was miserable.

Without normal levels of testosterone, Hamelburg says, he had no energy, and "zero libido for seven years. I was like a eunuch. I was chemically castrated. Sex was just hugs."

So three years ago, with his cancer undetectable and his oncologist and urologist cautiously on board, the Holbrook, Mass., man made a decision that many doctors consider anathema: He took testosterone supplements.

"The cancer hasn't come back," Hamelburg says, "but my libido has, my sense of being alive. It's like a fog cleared. It's being aware of things, being more vibrant."

For decades, the idea of giving testosterone to a man who had had prostate cancer was forbidden -- "verboten" in the words of Hamelburg's urologist, Dr. Abraham Morgentaler of Beth Israel Deaconess Medical Center. "It would have been considered heresy, or malpractice," Morgentaler says.

That thinking is changing, due in part to Morgentaler and his new book, "Testosterone for Life."

Morgentaler argues that although depriving tumors of testosterone does make them shrink, other evidence is beginning to suggest that it may be safe to give testosterone to men who have been successfully treated for prostate cancer and who appear to be cancer free.

One revolutionary aspect of Morgentaler's theory is the observation that prostate cancer is often found in men with low testosterone levels, not high ones, underscoring the idea that taking it may not be an added risk. It's not surprising that Morgentaler -- who has received honorariums and research funding from companies selling testosterone-related products -- has generated such controversy with his ideas.

"To say that testosterone replacement therapy is safe because we have no evidence it's harmful is making an assertion on faith, not facts," said Dr. Ian Thompson, chairman of the department of urology at the University of Texas Health Science Center at San Antonio, echoing the view of other doctors who disagree with Morgentaler.

But amid often-confusing testosterone research results, there are hints that Morgentaler and like-minded physicians may be on to something. In the test tube, prostate cancer cells have been shown to grow faster when testosterone is added, but only up to a point. Then the growth plateaus, even if more testosterone is added.

In 2006, Morgentaler co-wrote a study on 345 men with low testosterone. The study -- published in the journal Urology and not industry funded -- showed prostate cancer risk was higher in men with the lowest testosterone, a finding supported by a handful of other small-scale studies using human subjects.

That was contrary to findings suggested by the Physicians' Health Study in 1996, a discrepancy doctors cannot fully explain. And in February, an analysis of data from 18 studies around the world involving nearly 4,000 men with prostate cancer, and more than 6,000 without, showed no correlation between high testosterone levels and cancer risk. The study was published in the Journal of the National Cancer Institute.

Understanding the pros and cons of testosterone replacement is not easy.

An estimated 2 million to 6 million American men have low testosterone, and the benefits of replacement therapy can be huge: revival of sagging libido, better mood, more energy, more muscle, better bone density, more red blood cells.

But there are also risks, in large part because many seemingly healthy men have undetected prostate cancer, which could be stimulated by taking testosterone. Studies suggest that prostate cancer is lurking in as many as 25% or more of men 50 and older. Only when a man has a "clean" biopsy -- an invasive procedure in which snippets of the prostate are surgically removed and tested -- can a doctor confidently say the man doesn't have cancer.

As an extra measure of safety, Morgentaler says, he biopsies men older than 50 before he prescribes testosterone for them. But most doctors don't, says Dr. Marc Garnick, a cancer specialist at Beth Israel Deaconess Medical Center and editor in chief of Harvard Medical School's publication "Perspectives on Prostate Disease."

Even with apparently healthy men, "Nobody has proven that it is completely safe" to give testosterone," says Dr. Philip Kantoff, head of the Prostate Cancer Program at the Dana-Farber Cancer Institute.

So, what's a guy to do?

The traditional recommendations are to steer clear of testosterone supplementation if you have prostate or breast cancer; or if you meet one of several criteria: your physician can feel a nodule on the prostate during a digital rectal exam, your PSA (a marker of potential cancer) score is higher than 3 nanograms per deciliter, your hematocrit (the proportion of blood volume occupied by red blood cells) is greater than 50%, or you have untreated sleep apnea, severe urinary tract symptoms or heart failure. These standards are set by the Endocrine Society, a professional group of doctors who study and treat patients with hormones.

And if you have had prostate cancer that appears to be gone? Proceed with caution.

"Most physicians consider testosterone replacement therapy contraindicated for men with a history of prostate cancer," says Dr. Matthew Smith, director of genitourinary medical oncology at Massachusetts General Hospital Cancer Center.

But if you do wish to explore testosterone supplements, it's smart, given the controversy, to get a second opinion. Grill your doctors on how serious your prostate cancer was to start with -- that is, how high your PSA was, and how many gland segments contained cancer.

Also, keep being monitored for cancer recurrence.

Hamelburg is glad he eventually opted for testosterone. "My body was my enemy," he says. "Now, I just feel like a man again."

Coffee 'eases exercise pain'

The subjects were asked to perform a high-intensity cycling regime

05 april 2009--“Coffee before gym session ‘takes the pain out of exercise,’” The Daily Telegraph has reported. The newspaper says that Professor Motl from the University of Illinois, who has studied the relationship between coffee and exercise for years, has demonstrated in new research that coffee consumption can reduce the pain of high-intensity exercise. This is thought to be due to its effect on receptors in the body, which normally alert the brain to muscle strain.

The study involved giving 24 fit young men either caffeine pills or placebo pills before intense cycling. Taking a moderate amount of caffeine prior to exercise reduced the perception of muscle pain. However, there are several limitations to this study, including its small size and its use of subjects that might not represent the average person’s fitness level.

It is potentially harmful to take any substance to reduce pain during exercise because pain can signal when exercise is too intense. Toning things down to a more reasonable level would be more beneficial than trying to block out the pain in the body.

Where did the story come from? This research was conducted by Rachael Gliottoni, Robert Motl and colleagues of the Department of Kinesiology and Community Health, University of Illinois at Urbana-Champaign, and the Center for Sport and Health Sciences, Iceland University of Education. No sources of funding were reported for this research. The study was published in the International Journal of Sport Nutrition and Exercise Metabolism, a peer-reviewed medical journal.

What kind of scientific study was this? This was an experimental study that aimed to investigate the effect of moderate doses of caffeine on the intensity of quadricep muscle pain during high-intensity cycling.

Following on from results of previous studies, which have demonstrated that caffeine reduces muscle pain in normally low-caffeine consumers, the researchers expected caffeine to be associated with a reduction in pain intensity when compared with a placebo, and that the effect would be greatest in those who normally drink minimal amounts of caffeine.

The researchers recruited a group of 24 male college students who were regular exercisers. To be eligible for this study, these men had to be of above-average fitness, be non-smokers, be of an average body weight, and have no self-reported hypersensitivity to caffeine.

Before preliminary testing, the participants completed a seven-day caffeine consumption questionnaire, and their medical history was assessed. They were then divided into two groups, depending on caffeine consumption: 12 who drank ≤100 mg/day and 12 who drank ≥400mg per day.

Testing took place on three occasions: one preliminary test and two experimental tests. Tests were on separate days, conducted in the early morning and one week apart. Prior to the test, participants abstained from caffeine and food for 12 hours, and alcohol for 24 hours. On the two test days, participants ingested either 5mg/kg caffeine capsules (equivalent to consuming approximately two-and-a-half to three 8-oz cups of ground roasted coffee) or placebo capsules. The 30-minute exercise tests were performed one hour after tablet consumption when caffeine levels were believed to be at their peak.

All participants performed an exercise test on a computer-driven cycle that could measure peak oxygen consumption. After inserting a mouthpiece to collect expired gases, participants performed a five-minute warm-up at 25 watts. The initial work rate for the exercise test was 50 watts, and the work rate continuously increased at a rate of 24W/min until each participant said he was exhausted.

Lung respiratory measurements were taken every 25 seconds, and heart rate, perceived exertion and intensity of muscle pain were recorded every five minutes. Intensity of quadriceps muscle pain was assessed using a numbered scale: 0 = no pain at all, 0.5 = very faint pain (just noticeable), 1 = weak pain, 2 = mild pain, 3 = moderate pain, 4 = somewhat strong pain, 5 = strong pain, 7 = very strong pain, and 10 = extremely intense pain (almost unbearable). Work rate was gradually reduced, trying to maintain a constant expired gas concentration.

Results were compared by caffeine use (low vs. high) and by capsule taken (caffeine vs. placebo).

What were the results of the study? There was a larger reduction in work rate over time in the low caffeine user group compared to high users, but there was no difference according to the type of capsule taken.

There was no difference in oxygen consumption during exercise between the two groups, nor when the two different capsules were taken.

For quadricep pain intensity rating, there was a statistically significant difference between caffeine and placebo consumption prior to exercise, with caffeine causing a reduction in reported pain intensity. This effect was the same for both those who normally drank low caffeine and those who drank high amounts of caffeine.

What interpretations did the researchers draw from these results?

The researchers conclude that both low and high habitual caffeine drinkers report a significant and moderate reduction in quadricep muscle pain intensity, after taking a moderate dose of caffeine. However, their theory that the effect was greater among low consumers of caffeine was not supported.

Although this study demonstrated that taking a moderate amount of caffeine prior to 30 minutes of intense cycling exercise reduced reported pain levels, there are several important points to consider:

• This was a very small study, with only 24 participants. Although other studies investigating this question have been conducted (but not analysed in this appraisal article), the small sample size of this study means that the differences in results may have occurred only by chance.
• The study involved a select group of healthy young men with ‘above average fitness’, therefore these participants cannot be considered to be comparable to the general population.
• The self-reported measure of quadricep pain intensity, although a validated scale, is a subjective response. This means similar levels of pain could be rated quite differently between participants.
• The study only examined the effects during two, 30-minute intense cycling bouts. It cannot assess the longer-term benefits or adverse effects of such intense exercise on a regular basis, nor the effects of a longer cycling bout in a single session. Also, whether the pain-reducing effect of caffeine would be maintained under long-term regular use is not clear.

Importantly, caution should be taken by individuals thinking of drinking coffee, or taking anything else, to try and ‘take the pain out of exercise’. In people not accustomed to exercising, excessive muscle or joint pain during exercise should be an indication that the exercise level is too intense. Toning things down to a mild-to-moderate level would benefit the person’s health and fitness more than trying to block out pain sensations in the body. The stimulant effects of drinking high quantities of caffeine should also be noted.

Polypill can 'halve' heart risk

A single pill containing a combination of drugs could lower heart risk

05 april 2009--Most national newspapers have reported on a study of a ‘polypill’ that can “halve” the risk of heart disease and stroke. The Daily Telegraph said the new “five-in-one pill can significantly reduce the risk of heart disease and stroke in even healthy patients, and could save tens of thousands of lives a year”. The Independent says that the pill “costs pennies”.

The study was carried out in India as a twelve-week trial in 2,053 people (aged 45 to 80 years old) who had no known cardiovascular disease, but had at least one risk factor, such as diabetes or smoking. Some of the participants were given one “Polycap” daily, while others took different combinations of the polypill’s constituent drugs (including cholesterol-lowering drugs, aspirin, and blood pressure drugs).

The trial was well-conducted, and its findings are promising. It indicates that the formulation of this particular polypill is at least as effective as the drugs given separately (other than its effect on lipids). Whether or not it actually reduces mortality from strokes and heart disease will need to be demonstrated by larger trials.

Where did the story come from?

The trial was conducted by doctors from The Indian Polycap Study (TIPS) and funded by the makers of the Polycap, Cadila Pharmaceuticals. The study was published in the peer-reviewed medical journal The Lancet.

What kind of scientific study was this? This was a phase II randomised controlled trial of the Polycap, a new capsule pill that combines several existing drugs that are known to reduce the risk of coronary heart disease and stroke by improving lipid profiles, blood pressure and clotting factors in the blood.

The Polycap contains

• thiazide (12.5mg)
• atenolol (50mg)
• ramipril (5mg)
• simvastatin (20mg) to lower cholesterol
• aspirin for thinning the blood (100mg)

These include aspirin, a statin, three blood pressure-lowering drugs, and folic acid.

It was, in part, a ‘non-inferiority’ trial, which means that it firstly tested whether the Polycap was no worse at improving risk factors than each drug given separately. Once the non-inferiority of the Polycap combination was confirmed, it was compared with pills containing one drug, two drugs and three drugs to observe the effect of different polypills.

The researchers recruited 2,053 people without cardiovascular disease from 50 health centres across India. The participants were aged 45 to 80 years old, and each of them had one risk factor, which included either type 2 diabetes, high blood pressure (more than 140mm Hg systolic or 90mm Hg diastolic), being a smoker within the past five years, having a large waist-to-hip ratio (a measure of abdominal obesity), or having abnormal lipids (LDL-cholesterol more than 3.1mmol/L or HDL-cholesterol less than 1.04mmol/L).

The participants were also not taking any of the study drugs, or they had more extreme levels of risk factors, abnormal liver function, asthma or were pregnant.

The participants were randomly split into nine groups, and each group were given a different treatment for 12 weeks. Of these, 412 were randomised to one Polycap daily. The other eight groups took other combinations of the constituent drugs in a similar capsule, to allow comparison. These other groups took identical-looking capsules containing one of the following:

• Aspirin
• Hydrochlorothiazide
• Hydrochlorothiazide and ramipril
• Hydrochlorothiazide and atenolol
• Ramipril and atenolol
• Hydrochlorothiazide, ramipril and atenolol
• Hydrochlorothiazide, ramipril, atenolol and aspirin simvastatin

After obtaining written informed consent, there was a three-week lead-in period while the participants’ condition at the beginning of the trial was recorded. The researchers then recorded the participants’ blood pressure and heart rate to test for the effects of medication to lower blood pressure. The participants also had blood tests for LDL-cholesterol, and a urine test for the antiplatelet effects of aspirin.

Records were made at four, eight, twelve and sixteen weeks. The rates of discontinuation of drugs was also recorded as a safety measure.

The researchers analysed the nine groups according to the groups that they had been originally allocated.

What were the results of the study?

The results were reported for the nine different formulations. The main result was that groups taking the Polycap had a reduction in systolic blood pressure of 7.4mmHg and diastolic blood pressure of 5.6mmHg. The blood pressures achieved were lower than in groups that did not receive drugs to lower blood pressure.

The blood pressure reduction was the same whether aspirin was included in the Polycap or not. The more blood pressure drugs were used, the greater the reductions in blood pressure (2.2/1.3mm Hg with one drug, 4.7/3.6mm Hg with two drugs, and 6.3/4.5mm Hg with three drugs).

The Polycap reduced LDL cholesterol by 0.70mmol/L, which was less than taking simvastatin on its own (0.83mmol/L, 0.72–0.93; p=0.04). Both these reductions were greater than that in the groups that were not given simvastatin.

The Polycap was no worse than the other combinations that contained aspirin in terms of showing the antiplatelet (blood thinning) effects of aspirin.

Tolerability of the Polycap was similar to that of other treatments, and there was no evidence that increasing the number of active components in one pill increased intolerability.

What interpretations did the researchers draw from these results? The researchers simply say that the Polycap formulation “could be conveniently used to reduce multiple risk factors and cardiovascular risk”. They also say that they are unable to clarify why the Polycap was less effective at lowering LDL-cholesterol than when the statin, simvastatin, was used alone.

What does the NHS Knowledge Service make of this study? This important study has been widely reported because it is the first to have tested the multiple effects of a combination pill for reducing heart and stroke risk factors in people without known cardiovascular disease. The researchers emphasise that it cannot be assumed that the effects of any type of polypill are equal to the effects of its individual components, and that each polypill needs testing individually.

This study has demonstrated that combination pills can reduce risk factors for heart disease and stroke to a similar extent as the component medications. Whether or not these pills fulfil the potential to reduce mortality from strokes and heart disease will need to be clarified with further research.

There are a few other points to note:

• Other groups of researchers around the world are investigating polypills with different formulations. Each formulation would need to be tested individually to assess its pharmacological properties.
• The researchers say that because this formulation containing 20mg of simvastatin did not reduce cholesterol as well as simvastatin on its own, it may lead to combination pills that contain alternative doses or alternative statins.
• As the study was carried out in India, it is not known whether the drugs studied would have a similar effect on other ethnic groups.

The researchers calculate the expected reduction in risk of stroke and heart attack based on the improvement in risk factors (cholesterol, blood pressure and platelet function) shown in their trial by multiplying the risk ratios together. This gives an expected reduction of 62% in the rate of coronary heart disease and 48% in the rate of stroke, over five years. However, it is not yet known if this reduction can be achieved in practice.

Statins cut risk of DVT

Sitting still for extended periods during long-haul flights can cause DVT

05 april 2009--Taking a common heart drug “halves the risk of death from DVT,” reports the Daily Express. The newspaper says that a commonly prescribed statin pill “slashes the risk of the killer condition deep vein thrombosis by more than half.”

These results come from research into use cholesterol-lowering statin drug by apparently healthy people. In this publication researchers focused on the role the drug plays in preventing venous thromboembolism (the development of clots in the veins of the legs or lungs). DVT can be caused by sitting still during long-haul air travel or being confined to bed for long periods.

The well-conducted study provides good evidence that the statin can reduce risk of DVT in apparently healthy people, and that this effect is not simply a result of statins reducing the chance of heart-related illness, which can raise the risk of DVT. The researchers imply that this research offers a new reason for prescribing the drug.

However, the participants in this study had to meet a number of criteria, and although apparently healthy, they were all at higher risk of a cardiovascular event than the general population. The results may not apply to the wider population, and more research will be needed before statins can be widely used to prevent DVT as suggested.

Where did the story come from? This research was conducted by Dr Robert Glynn and colleagues from Brigham and Women’s Hospital in Boston, Universidade Federal de Sao Paulo, McGill University Health Centre in Montreal, and other academic and medical institutions in Denmark, Argentina and Scotland.

The research was funded by the AstraZeneca pharmaceutical company, and by a grant from the National Institutes on Aging. It was published in the peer-reviewed medical journal, the New England Journal of Medicine.

What kind of scientific study was this? This study was a large randomised controlled trial that reported on the effects of statin use on occurrence of venous thromboembolism (deep vein thrombosis and pulmonary embolism). Apparently healthy individuals were randomly allocated to receive rosuvastatin (20mg daily) or a placebo.

This study used data from the large ‘Jupiter trial’, which was originally set up to assess the role of rosuvastatin for primary prevention of cardiovascular events in people with higher C-reactive protein (CRP) levels. CRP is a protein that is produced in reaction to inflammatory processes in the body, and it is thought to be a marker of increased risk of diabetes and cardiovascular diseases. The occurrence of venous thromboembolism was a secondary outcome from this initial Jupiter study.

Although statins such as rosuvastatin are used for managing cholesterol levels, it is also thought that they reduce inflammation, with observational studies showing a 22% to 50% cut in risk. This study is one of the first randomised studies to report on any possible anti-inflammatory effects of statins.

A total of 17,802 people were randomised within this study. To be eligible for inclusion, they had to meet the following criteria:

• Be aged at least 50 years for males or 60 years for females.
• Have no known cardiovascular diseases at an initial screening visit.
• Have a low-density lipoprotein (LDL) cholesterol level of less than 3.4 mmol/L, and a high-sensitivity C-reactive protein (CRP) level of 2.0 mg/L or more.

Between March 2003 and December 2006, participants were randomised into either an active group, receiving a daily 20mg dose of rosuvastatin, or a placebo. They were followed-up for an average of 60 months after randomisation, with regular visits to the study team for interim interviews that assessed the occurrence of outcomes.

Any reported venous thromboembolism was confirmed using a venous ultrasonogram or venogram for DVT. For confirmation of pulmonary embolism, angiograms, computed tomographic scans or ventilation–perfusion scans were used.

The Jupiter trial on rosuvastatin was stopped in March 2008 because evidence of efficacy of the statin’s effectiveness was convincing. Events up to this date were included in the analysis. To account for the fact that thromboembolism often occurs around the time of cardiovascular events, the researchers performed separate analyses for venous thromboembolism and for primary cardiovascular events.

What were the results of the study? A pulmonary embolism or DVT occurred in 94 participants, with 34 in the statin group and 60 in the placebo group. Rosuvastatin reduced the combined risk of these outcomes by 43% (HR 0.57, 95% CI 0.37 to 0.86). There was a similar-sized effect of statin on prevention of either a primary cardiovascular event or a venous thromboembolism (HR 0.56, 95% CI 0.47 to 0.68).

Venous thromboembolism was more common in those people over 70 years with a high BMI and large waist circumference. Cholesterol levels at time of entry to the study (baseline) did not have any effect on the efficacy of the drug. The researchers do not discuss the side effects of statin use in this publication.

What interpretations did the researchers draw from these results? The researchers report that 20mg of rosuvastatin a day reduces the risk of symptomatic venous thromboembolism in apparently healthy people. They say that this reduction in risk appears to be an independent benefit of statin use, in that it does not depend on the reduction in risk of heart attacks or strokes.

They go on to say that as a result of this newly observed benefit of statins, the research goal should be widened from preventing arterial thrombosis to preventing venous thromboembolism and death too.

This randomised control trial found that daily rosuvastatin reduces the risk of venous thromboembolism: the study was large and well-conducted and offers robust evidence for the successful treatment of DVT with this drug.

This study only assessed the role of statin treatment in outcomes of symptomatic venous thromboembolism. The researchers say that because asymptomatic venous thromboembolism is common too, the study may have underestimated the beneficial effects of the drug by not assessing this outcome as well.

It should be noted that the selection of participants who took part in this study make it harder to apply the findings to the general population. In particular:

• Only people with higher levels of CRP were entered into this study, meaning that although none of them had yet had a cardiovascular event, they were at a higher risk of having one than the general population.
• In both the rosuvastatin and placebo groups, 37.6% of the subjects were obese, with a BMI of more than 30.
• 41.7% of the participants had metabolic syndrome, another marker of increased risk.

It should also be noted that despite higher-than-average risk of venous thromboembolism, the absolute number of events in this group of people was low, with only 94 episodes among all the 17,802 participants.

In general, this large randomised trial confirms previous findings from observational studies, but also raises further questions about who exactly should be offered treatment with these drugs. Further analysis of the subgroups results from this study, as well as repeated trial in groups with normal CRP levels will be required before new indications for statin use can be confirmed.

Elan, Wyeth abandon top dose of Alzheimer's drug

LONDON, 04 april 2009– Irish drugmaker Elan and its U.S. partner Wyeth have decided to stop testing the highest dose of their experimental Alzheimer's drug bapineuzumab in final-stage Phase III studies, they said Thursday.

The decision to discontinue the 2.0 mg/kg dose followed a review of cases of vasogenic edema, or fluid build-up in the brain.

"Our review of the safety data and the feedback from the Safety Monitoring Committee made it clear that continued development of the highest dose was not advisable," said Elan President Carlos Paya.

Testing of the 0.5 mg/kg and 1.0 mg/kg doses in two Phase III trials will continue as planned.

Shares in Elan were flat in a sharply higher market in early trade.

Brain Cells Give New Clues to Alzheimer's

04 april 2009 -- By uncovering a mechanism that causes damage to brain synapses during Alzheimer's disease, researchers might have found a key to reducing or preventing nerve degeneration for these patients.

According to a report in the April 3 issue of Science, researchers at the U.S.-based Burnham Institute for Medical Research have shown that beta-amyloid protein "multimers" create excessive nitric oxide. This free radical then reacts with the protein Drp1, causing the fragmentation of mitochondria -- the cell's energy storehouses -- in the brain, a violent process that causes the neurodegeneration linked to Alzheimer's disease.

When mitochondria break apart, the reaction damages synapses leading to nerve cell death. As brain synapses are vital for learning and memory, any damage or malfunction of these message-carrying connections can lead to Alzheimer's and dementia. Multimers had also been previously linked to Alzheimer's disease.

"By identifying Drp1 as the protein responsible for synaptic injury, we now have a new target for developing drugs that may slow or stop the progression of Alzheimer's," study leader Dr. Stuart A. Lipton, director of the Del E. Webb Center for Neuroscience, Aging and Stem Cell Research, said in a news release issued by the Burnham Institute.

Grapefruit Breakfast Shares Blame in Leg Thrombosis

Woman had a perfect storm of risk factors leading to limb-threatening emergency

04 april 2009 -- A defective gene, a long car ride, a daily contraceptive dose and grapefruit for breakfast added up to a limb-threatening medical emergency for a woman in a case reported in the April 4 issue of The Lancet.

Lucinda A Grande, M.D., of St. Peter Hospital in Olympia, Wash., and colleagues report on the case of a 42-year-old woman who limped into the emergency department with a badly swollen and bluish left leg and signs of phlegmasia caerulea dolens threatening gangrene. Immediate ultrasound revealed a deep vein thrombosis extending from the external iliac vein distal to the calf. Emergency personnel began intravenous heparin, and surgeons quickly performed catheter-directed thrombolysis using recombinant tissue plasminogen activator. Radiography revealed a stenosis in the left common iliac vein, and a stent was placed.

By evening, the swelling had gone down and normal color had returned to the woman's leg, the authors note. With further study, it was determined the woman had factor V Leiden mutation (a hypercoagulability disorder) and was taking an estrogen contraceptive, which also increases blood coagulability. Physicians theorized that sitting in the car for 90 minutes the previous day crimped the blood vessel, and the grapefruit the woman had been eating as part of a new diet augmented the action of the ethinylestradiol in the contraceptive by inhibiting the enzyme CYP3A4, further increasing coagulability.

"Our patient had a constellation of potential risk factors for venous thrombosis; a heightened hypercoagulable state from increased ethinylestradiol serum concentration due to her three days of grapefruit for breakfast may well have tipped the balance," the authors write.

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Three Popular Diets Studied for Effects on Lipid Profile

South Beach and Ornish diets may reduce low-density lipoprotein cholesterol

04 april 2009-- The maintenance phases of the South Beach and Ornish diets reduce levels of low-density lipoprotein cholesterol, whereas levels are increased by the maintenance phase of the Atkins diet, according to research published in the April issue of the Journal of the American Dietetic Association.

Michael Miller, M.D., of the University of Maryland School of Medicine in Baltimore, and colleagues conducted a study of 18 adults who all completed a four-week maintenance phase of the three diets with a four-week washout period in-between, and who were assessed for the effects of the diets on lipids, endothelial function and C-reactive protein.

When the subjects were on the South Beach and Ornish diets, low-density lipoprotein cholesterol was reduced by 11.8 percent and 16.6 percent, respectively, versus an increase of 8.1 percent on the Atkins diet, the investigators found. When the researchers used brachial artery testing to measure flow-mediated vasodilatation, they found there was an inverse correlation with intake of saturated fat.

"These data suggest that during weight maintenance, less favorable biological effects are observed during a simulated, high-fat Atkins diet when compared to the South Beach and Ornish diet," the authors write. "The findings support additional study in subjects with visceral obesity and the metabolic syndrome, in whom an increased risk of coronary disease at baseline may be accentuated with chronic consumption of a diet that exhibits unfavorable effects on lipids and endothelial function."

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Catheter-Based Therapies May Benefit Stroke Patients

Option appears safe and effective after ischemic stroke in patients not eligible for IV thrombolysis

04 april 2009-- In some patients who aren't candidates for intravenous thrombolysis, catheter-based therapy (CBT) provides an optional treatment for acute ischemic stroke, according to research published in the April 1 issue of Catheterization and Cardiovascular Interventions.

James T. DeVries, M.D., of the Ochsner Heart and Vascular Institute in New Orleans, and colleagues analyzed data from 26 patients with acute ischemic stroke who underwent CBT, including intra-arterial thrombolysis, balloon angioplasty, stent placement, guidewire thrombus disruption, mechanical embolectomy, or combinations of these. Patients were ineligible for intravenous thrombolysis.

In 88 percent of the patients, culprit artery recanalization was successfully accomplished. In-hospital adverse events -- mostly intracerebral hemorrhage -- occurred in 15 percent of patients. Half of the patients achieved a modified Rankin score of two or less, indicating mild disability, the researchers found.

"Our data suggest that CBT for severe, disabling acute stroke is an important and effective treatment for selected patients not eligible for intravenous thrombolysis," the authors conclude. "The 'time is brain' paradigm requires that 24 hour a day, 365 days a year 'CBT stroke teams' are available for patients with acute stroke who are not candidates for intravenous thrombolysis. To that end, it will be necessary to create multidisciplinary teams consisting of experienced carotid stent operators and stroke specialists to improve the quality of care and outcomes for patients presenting with acute stroke."

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Effects of disease severity on autobiographical memory in semantic dementia revealed in new study

Milan, Italy, 3 april 2009 - In a study conducted by the Laboratory of Neuropsychology of the Université de Caen Basse-Normandie and published by Elsevier in the April 2009 issue of Cortex (http://www.elsevier.com/locate/cortex), researchers studied for the first time autobiographical memory in a group of semantic dementia (SD) patients according to disease progression. They highlighted that at early stages of the disease those patients could recall recent memories, but also lasting memories from their youth which tend to disappear as dementia evolves. Mechanisms at the root of this autobiographical memory impairment result from storage deficits combined with faulty retrieval strategies.

Semantic dementia is a neurodegenerative disease characterized by a semantic memory breakdown; this type of memory concerns meanings and understandings about the world, e.g. "Paris is the capital of France" as well as personal semantics. Despite their important semantic deficits, these patients show preserved abilities concerning daily living activities and can recall recent specific personal events, with episodic details, at least at the beginning of the disease. This observation is interesting because it suggests that episodic autobiographical memory referring to both recent and old memories, particular to each individual at the source of personal continuity over time, is preserved in early SD.

Two groups of 7 patients each were studied. One group consisted of SD patients with mild cognitive impairment and the other consisted of patients with moderate cognitive impairment. An autobiographical memory test, called the TEMPau task, was used which assessed general and specific memories across the entire lifetime. Results indicated for the mild subgroup, preserved performances for the most recent time period and a relative preservation of a reminiscence bump, which concerns the surge of vivid and important self-defining episodic memories acquired between 18 and 30 years. In the moderate subgroup, performances were impaired whatever the time period including the most recent one. These results highlight that, with disease severity, episodic memories tend to vanish regardless of their recency.

The implications of these findings are particularly interesting from both theoretical and clinical viewpoints. First, they confirm that the relative preservation of episodic memories in early SD is not just a matter of recency, as frequently proposed. Second, they should provide new avenues on the development of specific methods of rehabilitation of new and old semantic concepts based on episodic autobiographical memory from the last 12 months and the reminiscence bump.

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Notes to Editors:

The article is "Patterns of autobiographical memory impairment accoding to disease severity in semantic dementia" by Vanessa Matuszewsky, Pascale Piolino, Serge Belliard et al and appears in Cortex, Volume 45, Issue 4 (April 2009), published by Elsevier in Italy.The article is published in a special issue dedicated to the Cognitive Neuroscience of Drawing".

Full text of the article featured above is available to members of the media upon request. Please contact the Elsevier press office, newsroom@elsevier.com. To schedule an interview, contact Dr. Beatrice Desgranges, desgranges-b@chu-caen.fr.

Supervised exercise therapy can lead to improvements in COPD symptoms

Article by LA BioMed researcher confirms the benefits of pulmonary rehabilitation

LOS ANGELES, 3 april 2009– Those suffering from chronic obstructive pulmonary disease (COPD) often complain that exercise is too exhausting and leaves them breathless. An article in the current issue of the New England Journal of Medicine reports that supervised exercise through pulmonary rehabilitation can actually reduce their feelings of breathlessness, increase their tolerance for exercise and improve their quality of life.

The article's lead author is Richard Casaburi, Ph.D., M.D., a senior investigator at the Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center (LA BioMed). He directs the institute's Rehabilitation Clinical Trials Center, a facility that focuses on COPD research. Dr. Casaburi surveyed previous studies on pulmonary rehabilitation for COPD and found that supervised exercise therapy improves aerobic function of the muscles, which helps reduce the breathlessness that is common in COPD.

"These findings are a clear indication that pulmonary rehabilitation can improve the quality of life for those living with COPD," said Dr. Casaburi. "The studies also indicate that pulmonary rehabilitation results in decreased anxiety and depression for COPD patients because they find they can exercise more, and they enjoy the feeling that they have mastered something important in their lives."

COPD, a group of lung diseases that includes chronic bronchitis and emphysema, is the fourth leading cause of death in the United States. The article in the Journal reports that it is on course to be the third most common cause of death worldwide by 2020.

Once a disease primarily of men, it now kills roughly equal numbers of men and women in the U.S. In 2000, COPD was responsible for 8 million physician office visits, 1.5 million emergency department visits and 726,000 hospitalizations (about 13% of all hospitalizations in the U.S.).

While the benefits of pulmonary rehabilitation programs for COPD are well-documented, the Journal article reports that access to this type of therapy is limited, especially among lower-income, minority and rural populations.

"A major stumbling block in providing pulmonary rehabilitation for COPD has been the lack of adequate funding for it," said Dr. Casaburi. "That should begin to change next January, when Medicare starts providing coverage for pulmonary rehabilitation for COPD."

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Copies of the report, titled "Pulmonary Rehabilitation for Management of Chronic Obstructive Pulmonary Disorder," may be obtained by contacting Laura Mecoy, 310.546.5860, or lmecoy@issuesmanagement.com

Recognizing cognitive impairment key to keeping older adults at home

Training medical professionals to identify red flags

INDIANAPOLIS, 3 april 2009 – Doctors, nurses and others who provide health care to older adults are often so focused on acute medical problems that they may miss symptoms of cognitive impairment. A unique educational summit to be held in April and May in Indianapolis focuses on the problem and will enhance the skills of these health-care providers in recognizing and managing cognitive impairment. The goal is to enable older adults to remain in their homes.

According to Malaz Boustani, M.D., associate professor of medicine at the Indiana University School of Medicine and a Regenstrief Institute research scientist, more than half of Americans with cognitive impairment are not recognized as having the conditions when they go to a hospital and more than three-quarters are not recognized as having cognitive impairment by their primary care physicians. The result is that less than 10 percent receive medications appropriate to their level of cognitive impairment and approximately one-quarter receive medications which are inappropriate.

"Medical professionals who care for older adults are faced with the problems of the real world – providing the best care to patients with multiple acute and chronic diseases under time constraints and reimbursement pressures. We hope with this summit to provide these committed individuals with tools that will help them to identify the red flags of cognitive impairment – to recognize delirium as an urgent medical syndrome, to reduce exposure to inappropriate medications, and to enable them to employ non-pharmacological methods to manage the special needs of both the patient and his family caregiver," said Dr. Boustani.

Dr. Boustani, who is a center scientist with the IU Center for Aging Research, is also the research director for the Indianapolis Discovery Network for Dementia. IDND, fostered by the research of the Regenstrief Institute, is an expanding group of researchers, clinicians, caregivers and community advocates who are working to enhance dementia care in the nation's twelfth largest city. IDND is a national model for how members of the community, caregivers, clinicians and researchers can work together to improve the delivery of dementia care.

Nearly 360 health-care providers from throughout Indiana will participate in the multi-session summit, which is funded by a $75,000 grant from Pfizer Pharmaceuticals to the Medical Education Group of Community Home Health Services. CHHS, which provides home health-care services, has partnered with IDND to sponsor the summit. In late 2007, IDND launched RAPID-PC – Recognizing and Assessing the Progression of Cognitive Impairment and Dementia in Primary Care, a highly successful program.

"We hope that this summit will serve as both a local resource and a national model which will spawn similar educational opportunities to help doctors, nurses and others who take care of older adults in their homes to better deal with their often unrecognized mental health needs," said Jessie Westlund, R.N. of Community Home Health Services, part of Community Health Network.

"Recognizing and properly treating cognitive impairment will only become more important as our population ages. If we can identify and handle it appropriately, we can help keep older adults in their homes and out of long-term care facilities longer, a goal which benefits older adults and saves health-care dollars," said Dr. Boustani.

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(Note to editors: This event is not open to the public. Interested reporters may attend summit sessions on April 14, 15, 16 or May 5, 6, 7. To request press credentials call 317-274-7722.

Diabetes drug class linked to vision-threatening complication

Philadelphia, PA, 3 april 2009– Treatment with the glitazone class of diabetes drugs leads to a "modest" increase in the risk of diabetic macular edema (DME)—a common complication that can lead to vision loss, reports a study in the April issue of the American Journal of Ophthalmology (http://www.elsevier.com/locate/ajo), published by Elsevier.

Using a database of about 170,000 patients with diabetes, Drs. Donald S. Fong and Richard Contreras of Southern California Permanente Medical Group analyzed the link between glitazones and the development of DME. Diabetic macular edema is a common diabetes complication, with swelling and fluid build-up in the retina leading to progressive visual loss.

The researchers identified 996 patients who were diagnosed with DME during 2006. Overall, patients who took glitazones were 2.6 times more likely to develop DME than patients not taking these drugs. Even after further adjustment for other factors, DME risk remained 60 percent higher for glitazone users.

Previous studies have linked glitazones to problems related to fluid retention and edema (swelling), including heart failure. Fluid retention from heart failure or other diseases can worsen DME. Most of the glitazone users in the study were taking pioglitazone (Actos). Other studies have linked rosiglitazone (Avandia)—the only other approved glitazone drug—to a possible increase in the risk of myocardial infarction.

Although the study is not the first to suggest a link, it provides confirmation in a very large sample of diabetic patients that glitazones are "modestly associated" with DME. Drs. Fong and Contreras concluded, "When treating patients with DME, ophthalmologists should consider the role of the glitazone class of drugs."

"Ocular complications are an overlooked safety issue of systemic drugs," commented Dr. Thomas J. Liesegang, Editor-in-Chief of AJO, "Safety is as important as the efficacy of a drug. However, long term safety is not currently monitored because the approval process is based on smaller, shorter term clinical trials. Safety necessarily requires monitoring of treatment in larger groups of people over longer periods of time. This monitoring is often neglected and should be required of all therapies."

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About the American Journal of Ophthalmology

The American Journal of Ophthalmology is a peer-reviewed, scientific publication that welcomes the submission of original, previously unpublished manuscripts directed to ophthalmologists and visual science specialists describing clinical investigations, clinical observations, and clinically relevant laboratory investigations. Published monthly since 1884, the full text of the American Journal of Ophthalmology and supplementary material are also presented on the Internet at www.AJO.com

Medication may improve portal hypertension

A therapeutic agent called sorafenib dramatically improved the condition of rats with portal hypertension

03 april 2009--In a new study, a therapeutic agent called sorafenib dramatically improved the condition of rats with portal hypertension. The drug is already approved in several countries for treatment of kidney and liver cancer, and it may be time to consider it for patients suffering from advanced portal hypertension, the authors suggest. Their findings are in the April issue of Hepatology, a journal published by John Wiley & Sons on behalf of the American Association for the Study of Liver Diseases (AASLD). The article is also available online at Wiley Interscience (www.interscience.wiley.com).

Portal hypertension is the most significant complication for patients with liver cirrhosis. It can become serious and life-threatening, and we do not have many effective ways to treat it. Researchers have considered antiangiogenic drugs, which inhibit the growth of new blood vessels, since such vascular formation is a hallmark of portal hypertension, as they have previously demonstrated. One such drug is sorafenib, a powerful multikinase inhibitor that can be taken orally.

Researchers, led by Mercedes Fernandez from the Institute of Biomedical Research IDIBAPS of Barcelona, examined the effects of sorafenib on rats with portal hypertension induced by partial portal vein ligation or bile duct ligation.

"Our present study is the first to determine if the multiple kinase inhibitor sorafenib causes beneficial effects on the splanchnic, intrahepatic and systemic circulations, and on portosystemic collateral vessels in two different experimental models of portal hypertension," they report.

The rats in the study took sorafenib orally every day for two weeks. They showed no signs of toxicity or adverse effects and the researchers noted numerous improvements in their condition. They had an 80 percent decrease in the growth of new blood vessels and marked lessening of circulation in the areas around the liver. The treatment also decreased portal pressure by 25 percent, and liver fibrosis and inflammation improved.

"Taking into account the limitations of translating animal study results into humans, we believe that our findings will be stimulating for consideration of sorafenib as an effective therapeutic agent in patients suffering from advanced portal hypertension," the authors conclude.

An accompanying editorial by Vijay Shah of the Mayo Clinic and Jordi Bruix of Barcelona notes the promise of the findings by Mejias and colleagues. "It is obvious that a new avenue for pharmacologic intervention in patients with cirrhosis has emerged," they write.

They encourage the evaluation of antiangiogenesis therapy in patients with cirrhosis and portal hypertension, though saying it "will need a very careful approach." Researchers will have to determine the optimal dosage that maintains efficacy while remaining tolerable and safe for patients. They must also consider the impact on cardiac function.

"The challenge is there and it is time to move ahead," Shah and Bruix conclude.

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Article: "Beneficial Effects of Sorafenib on Splanchnic, Intrahepatic and Portocollateral Circulations in Portal Hypertensive and Cirrhotic Rats." Mejias, Marc; Garcia-Pras, Ester; Tiani, Carolina; Miquel, Rosa; Bosch, Jaime; Fernandez, Mercedes. Hepatology; April 2009.

Editorial: "Antiangiogenic Therapy: Not Just for Cancer Anymore." Shah, Vijay; Bruix, Jordi. Hepatology; April 2009.

Compassion fatigue: Impact on healthcare providers of caring for the terminally ill

INDIANAPOLIS, 02 april 2009 – Compassion fatigue in nurses, doctors and other front line cancer-care providers significantly impacts how they interact with patients, with patient families, with other healthcare workers, and with their own family, according to analysis by Indiana University School of Medicine and Regenstrief Institute researchers published in the March issue of the Journal of Health Psychology.

"The healthcare field is becoming more aware of the profound emotional disturbances that occur in healthcare providers when they witness the suffering and pain of their patients in the face of an incurable disease, such as cancer. Healthcare providers are often partners in this journey, and the understanding of the effects of caring for the terminally ill on the caregiver is limited," the researchers wrote. They reviewed 57 studies to identify the prevalence of compassion fatigue among cancer-care providers, how to detect it and means of prevention and treatment.

"Individuals who are drawn into healthcare careers may be more likely to develop compassion fatigue, based on their drive for perfection and to do their best for their patients. If you work in an environment where despite your very best efforts patients for whom you provide care will not survive, there is a set up for developing a sense of 'there is nothing I can do anymore,'" says the study's principal investigator Caroline Carney Doebbeling, M.D., associate professor of medicine and of psychiatry at the IU School of Medicine and a Regenstrief Institute research scientist.

The term compassion fatigue was first coined in the 1990s to describe a syndrome experienced by a healthcare provider caring for individuals facing dire consequences as a result of their disease. Going beyond empathy or "feeling bad" for the person, it effects the nurse, doctor or other member of the healthcare team in a way that he or she often develops a distance from the patient as a way of self-protection.

Symptoms of compassion fatigue include chronic tiredness and irritability, lack of joy in life, engagement in behaviors which are fine in moderation, such as drinking, at a destructive level. Like individuals who have post traumatic stress disorder (PTSD), those with compassion fatigue often re-experience the deaths of their patients, according to Dr. Carney Doebbeling.

Compassion fatigue can lead individuals to protect or insulate themselves by loss of compassion, cynicism, boredom, decreased productivity, more sick days and ultimately higher turnover.

"How do you deal with compassion fatigue if you see patients every single day?" asks Dr. Carney Doebbeling. "In order to provide the best care to patients, the system, beginning with training in nursing and medical schools and residency, has to do a better job of helping those who go into cancer care learn what to expect and how to deal with it. On the job we need to create supportive work environments where supervisors and colleagues are aware that those who care for the sickest of the sick may be vulnerable to the triggers that could bring about compassion fatigue."

While compassion fatigue has not been labeled a psychiatric disorder, it can lead to depression and anxiety disorders, according to Dr. Carney Doebbeling, a member of the Indiana University Melvin and Bren Simon Cancer Center, who is an internist and a psychiatrist as well as a health services researcher.

"We are taught in medicine to be brave and to be strong, but there should also be a time and place for emotional expression, and perhaps even for crying. Doctors, nurses and other members of the healthcare team must be steady sources of support for patient. But when the patient encounter is over, at the end of the day, the doctor or nurse or social worker or clerk needs to be able to process everything they have seen and experienced. We need to support people who work with the sickest of the sick," she said.

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Co-authors of "Cancer-care Providers Compassion Fatigue: A Review of the Research to Date and Relevance" are Nadine Najjar, M.Sc., of the Regenstrief Institute; Louanne W. Davis, PsyD, of the Roudebush Veterans Affairs Medical Center and the I.U. School of Medicine; and Kathleen Beck-Coon, M.D., of Mindfulness at the Center, the IU Simon Cancer Center and Clarian West Integrative Care Center.

Chronic insomnia with short sleep duration is a significant risk factor for hypertension

Findings suggest that chronic insomnia is a major public health concern, and its diagnosis and appropriate treatment should become the target of public health policy

Westchester, Ill., 02 april 2009 — A study in the April 1 issue of the journal SLEEP is the first to demonstrate that chronic insomnia with objectively measured short sleep time is an independent and clinically significant risk factor for hypertension.

Results indicate that participants with insomnia and an objectively measured, severely short sleep duration of less than five hours had a risk for hypertension that was 500 percent higher than participants without insomnia who slept more than six hours. People with insomnia and a moderately short sleep duration of five to six hours had a risk for hypertension that was 350 percent higher than normal sleepers.

In contrast, neither insomnia with a normal sleep duration of more than six hours nor a short sleep duration without a sleep complaint was associated with a significant risk for hypertension. This suggests that there is an additive or synergistic effect on hypertension risk when insomnia occurs in combination with a short sleep duration.

According to lead author Alexandros N. Vgontzas, MD, director of the Sleep Research and Treatment Center at the Penn State College of Medicine in Hershey, Pa., one of the study's strengths is that sleep duration was measured objectively by overnight polysomnography.

"It should be emphasized that many times the amount that we feel we slept is different from the actual amount," said Vgontzas. "Thus self-reported sleep duration cannot replace measured sleep duration."

The study involved a random sample of 1,741 men and women in central Pennsylvania with an average age of 49 years. Eight percent were classified as having chronic insomnia with symptoms persisting for at least one year; 22 percent were poor sleepers with a moderate to severe complaint of difficulty falling asleep, staying asleep, early final awakening or unrefreshing sleep; and 70 percent were normal sleepers. Twenty-one percent had a severely short sleep duration of less than five hours; 23 percent had a moderately short sleep duration of five to six hours; and 56 percent had a normal sleep duration of more than six hours.

Although the cross-sectional nature of the study did not allow for causality to be determined, the authors note that large amounts of clinical and research data indicate that it is most likely that insomnia leads to hypertension. Previous reports have shown that insomnia with short sleep duration is associated with the hypersecretion of cortisol, increased catecholaminergic activity, increased heart rate and 24-hour metabolic rate, and impaired heart rate variability. All of these conditions may lead to hypertension and other cardiovascular events.

Because the study sample is representative of the general population, the authors estimate that eight percent to 10 percent of the U.S. population may be at risk for hypertension and other significant medical complications related to chronic insomnia.

According to Vgontzas, the study indicates that people with insomnia should seek evaluation and treatment from their medical provider. Although the results suggest that people with insomnia have a lower risk for physical problems if their sleep duration is normal, they still are at risk for depression and may suffer from the behavioral effects of insomnia.

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A media fact sheet about insomnia is available from the AASM at http://www.aasmnet.org/Resources/FactSheets/Insomnia.pdf.

Information about insomnia for patients and the public is available from the AASM at http://www.sleepeducation.com/Disorder.aspx?id=6.

As good as it gets: Octogenarian muscles don't get stronger with exercise

Lesson learned: Start exercising earlier

BETHESDA, Md. 02 april 2009--Octogenarian women were unable to increase muscle mass after a 3-month weight lifting program targeted at strengthening the thigh muscle, according to a new study from the Journal of Applied Physiology. The results are surprising because previous studies have found resistance training capable of increasing muscle mass, even for people who are into their 70s. An increase in muscle size translates to an increase in strength.

Still, the Ball State University study contained some good news: The octogenarians were able to lift more weight after the training program, likely because the nervous system became more efficient at activating and synchronizing muscles.

The American Physiological Society published the study, "Improvements in whole muscle and myocellular function are limited with high-intensity resistance training in octogenarian women." The researchers are Ulrika Raue, Dustin Slivka, Kiril Minchev and Scott Trappe. You can read the full study by going to: http://jap.physiology.org/cgi/reprint/91587.2008v1?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&author1=Trappe%2C+S&andorexactfulltext=and&searchid=1&FIRSTINDEX=0&sortspec=relevance&resourcetype=HWCIT

Aim: Strengthen Octogenarian Thigh Muscle

The experiment involved six women, all in their 80s, all of whom lived independently and came to the laboratory three times a week for three months. The women exercised on a machine designed to strengthen the thigh (quadriceps) muscle. They did three sets of 10 lifts, with a 2-minute rest period between sets.

The researchers measured the size of the women's thigh muscle using an MRI, before the exercise program began and after it ended. They also took biopsies from the thigh muscles, which they used to track muscle changes at the cellular level.

The biopsies included both fast-twitch and slow-twitch muscle fibers. Fast-twitch muscles are high powered and explosive and are associated with anaerobic exercise. Slow-twitch are associated with aerobic tasks, including endurance exercise such as marathons.

Fast-twitch muscles are important in posture and balance and so may be of particular importance for the elderly, who are more prone to falls. When people do not use their muscles during a period of convalescence or with a sedentary lifestyle, the fast twitch muscles lose functionality and atrophy more quickly than slow-twitch.

From the muscle biopsies, the researchers isolated single muscle strands, both fast-twitch and slow-twitch. They measured the strength, speed and power of each fiber and examined the genetic profile of these strands.

No change in muscle strength

As a result of the exercise program, the octogenarians were able to increase the amount they could lift with their quadriceps by 26%. That was the good news. The bad news was that the pre- and post-training MRIs showed that the training did not change their muscle size. This was surprising because an earlier study had found that 70-year-old women gained 5% muscle mass with resistance training.

The biopsy results confirmed the MRI results: there was no change in the size of the individual muscle strands, pre-training versus post-training. This confirms that the increase in the amount the women could lift with the quadriceps was unrelated to improvement in muscle strength. Instead, the results were probably due to improvements in how efficiently the nervous system was able to activate and synchronize the muscles.

In an earlier study, the researchers found that the muscles of octogenarian men also failed to gain strength with the exercise program. Together, the studies show that the muscles of octogenarian men and women are far less responsive to improving with exercise, even compared to people only 10 years younger.

"The message of the study is that exercise is good for octogenarians, just not as good as we thought it would be," Dr. Trappe said. The study also suggests that it is better to build as much muscle mass as possible earlier in life to ensure more muscle strength in later life. "We should do all we can to educate people to build up the muscle before 80," he said.

Next steps

Muscle atrophy relates not only to aging, but to people whose muscles are immobilized for a period and even for astronauts who spend long periods of time in space. Dr. Trappe, who also does research on astronauts, next wants to begin to uncover the physiological basis for why the muscles of octogenarians do not gain strength with resistance exercise.

His team may be able to build on two intriguing findings from the current study:

• while the octogenarian women had many fewer muscle fibers, the fibers they did have were large and healthy looking
• the genes involved in muscle growth are present in the resting muscle of the octogenarians at much higher levels compared to young people.

These results suggest that the octogenarian muscle is already operating at peak capacity and may not have the potential for better performance, Dr. Trappe said. If these mechanisms can be understood, it may be possible to find ways to strengthen older muscles.

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Editor's Notes: To arrange an interview with Dr. Trappe, please contact Christine Guilfoy at cguilfoy@the-aps.org or (301) 634-7253.

Physiology is the study of how molecules, cells, tissues and organs function to create health or disease. The American Physiological Society (APS) has been an integral part of this scientific discovery process since it was established in 1887.

ACC: Combo Treatment Beneficial in Atrial Fibrillation

Clopidogrel plus aspirin reduces major vascular events, but may increase hemorrhage risk

02 april 2009-- In atrial fibrillation patients for whom vitamin K-antagonist therapy such as warfarin is not indicated, adding clopidogrel to aspirin reduces the risk of major vascular events but increases the risk of major hemorrhage, according to a study published online March 31 in the New England Journal of Medicine to coincide with the American College of Cardiology's 58th Annual Scientific Sessions held March 29 to 31 in Orlando, Fla.

Stuart J. Connolly, M.D., of McMaster University in Hamilton, Ontario, Canada, and colleagues randomly assigned 7,554 patients to receive either daily clopidogrel at a dosage of 75 mg, or placebo, in addition to aspirin.

After a median follow-up of 3.6 years, the researchers found that the rate of major vascular events was lower in the combination group than in the aspirin-alone group (6.8 percent per year versus 7.6 percent per year, respectively). They found that the difference was primarily due to a decreased rate of stroke (2.4 percent per year versus 3.3 percent per year). But the investigators also found that the combination group had a higher rate of major bleeding (2 percent per year versus 1.3 percent per year).

"The purpose of the ACTIVE-A trial was to determine if the addition of clopidogrel to aspirin would reduce major vascular events and stroke in patients with atrial fibrillation, at an acceptable risk of increased hemorrhage," Connolly said in a statement. "If you treated 1,000 patients over the course of three years by adding clopidogrel to aspirin, you would prevent 28 strokes, 17 of which would be fatal or disabling, and you would prevent six heart attacks. This would occur at a cost of 20 major hemorrhages."

The study was supported by Sanofi-Aventis and Bristol-Myers Squibb; several study authors disclosed financial relationships with both companies.

Abstract
Full Text

Protein-Folding Problem May Help Spur Alzheimer's

02 april 2009-- A dysfunction in protein folding contributes to nerve cell death in Alzheimer's disease, a finding that could help lead to new treatments, Dutch researchers report.

The presence of tangles of misfolded proteins is believed to contribute to Alzheimer's disease, the experts explained. A process known as the "unfolded protein response" typically protects cells from the toxic effects of accumulated misfolded proteins. But prolonged activation of the unfolded protein response -- such as that seen in Alzheimer's patients -- may result in cell death.

The researchers at the VU University Medical Center in Amsterdam and the University of Amsterdam believed that unfolded protein response contributed to brain damage through its effects on the accumulation of hyperphosphorylated tau, a major component of tangles in the brains of people with Alzheimer's.

The study revealed that markers of the unfolded protein response were expressed in areas of tau accumulation in Alzheimer's patients. The unfolded protein response-related proteins were expressed early, in pre-tangle neurons, but were absent in tangle neurons.

The findings suggest that "unfolded protein response activation occurs at an early stage of neurofibrillary degeneration and ... that the prolonged activation of the [unfolded protein response] is involved in both tau phosphorylation and neurodegeneration in [Alzheimer's disease] pathogenesis ... Future studies will address the therapeutic opportunities of this pathway for the treatment of [Alzheimer's disease] and other tauopathies," the researchers wrote.

The study was published in the April issue of The American Journal of Pathology.

ACC: Polypill May Reduce Cardiovascular Risk

Combo treatment with anti-hypertensive drugs, a statin and aspirin suggests favorable results

01 april 2009-- A polypill -- a combination of three blood-pressure-lowering drugs at low doses, with a statin, aspirin and folic acid -- could significantly reduce cardiovascular events in otherwise healthy patients, according to an article published online March 30 in The Lancet to coincide with the American College of Cardiology's 58th Annual Scientific Session held March 29 to 31 in Orlando, Fla.

Salim Yusuf, M.D., of McMaster University in Hamilton, Ontario, Canada, and colleagues randomly assigned 2,053 Indian patients aged 45 to 80 who were free of heart disease but had one risk factor to receive either a polypill containing low doses of thiazide, atenolol, ramipril, simvastatin and aspirin or aspirin alone, simvastatin alone, hydrochlorthiazide alone, three combinations of the two blood-pressure-lowering drugs, three blood-pressure-lowering drugs alone, or three blood-pressure-lowering drugs plus aspirin.

The researchers found that the polypill reduced systolic blood pressure by 7.4 mm Hg and diastolic blood pressure by 5.6 mm Hg, which was similar when three blood-pressure-lowering drugs were used, with or without aspirin, compared with groups not receiving blood-pressure-lowering drugs. They also found that the polypill reduced low-density lipoprotein (LDL) cholesterol by 0.70 mmol/L, which was less than that with simvastatin alone.

"Our findings emphasize that the effects of the polypill cannot be assumed to equal the combined effects of its individual components," the authors write. "Every preparation of a combination pill needs to be tested to assess its pharmacokinetic and pharmacodynamic effects, before it is used in larger studies examining clinical outcomes. The substantial preservation of the lowering of blood pressure, heart rate, LDL cholesterol, and 11-dehydrothromboxane B2 with the Polycap suggests that it has the potential to greatly reduce cardiovascular disease."

The study was supported by Cadila Pharmaceuticals, Ahmedabad, India; one of the authors disclosed a financial relationship with Cadila.

Abstract
Full Text (subscription or payment may be required)

As CT Radiation Accumulates, Cancer Risk May Rise

By Steven Reinberg
01 april 2009-- Cumulative exposure to radiation from CT scans can increase the risk for cancer by as much as 12 percent, Harvard University researchers report.

Widely used as a diagnostic tool, CT scans provide detailed images of organs, allowing more accurate diagnoses of conditions such as cancer. But CT involves a higher radiation dose than most other imaging tests.

"People should be aware that cumulative radiation risks do add up when they have numerous CT scans," said lead researcher Dr. Aaron Sodickson, assistant director of emergency radiology at Brigham and Women's Hospital in Boston.

Almost 69 million CT scans were done in the United States in 2007, up from 62 million the year before, according to a report from the Medical Information Division of IMV Ltd., a marketing research firm.

Generally, people should not worry about the risk of cancer associated with CT scans, Sodickson said. "Patients getting a small number of CT scans, they really shouldn't be very concerned at all."

However, people who are having a lot of CTs need to think more carefully and talk with their doctor to determine whether additional scans add value to their care because the risks can add up over time, he said. "We found cancer risks up to 12 percent" higher for people who had 38 scans, he said.

The report is published in the April issue of Radiology.

For the study, Sodickson's team looked at the medical records of 31,462 people who had undergone a total of 190,712 CT scans over 22 years. About 33 percent had five or more scans, 5 percent had more than 22, and 1 percent had more than 38.

In all, 15 percent of the people in the study had received cumulative radiation doses of more than 100 millisieverts (mSv), the same level of radiation as 1,000 chest X-rays. Four percent had received more than 250 mSv, and 1 percent had gotten more than 399 mSv.

For about 7 percent of the study participants, their cumulative radiation exposure increased their cancer risk by 1 percent above the U.S. cancer risk rate of 42 percent. For the 315 people who had received the most radiation, their risk of cancer increased 12 percent, the researchers calculated.

Dr. E. Stephen Amis Jr., chairman of the radiology department at Montefiore Medical Center in New York City, agrees that the dangers are there, but he said most patients should not be concerned.

"Patients should discuss with their physician," Amis said, suggesting they ask such questions as: "Do I really need this test? Have you considered the risk of radiation weighted against the benefit of the diagnostic acumen of the study?"

And if you really need the test, he said, you should have it.

"People should not be lying awake at night wondering when they are going to get their cancer -- after one or two or five or six CT scans -- if they needed to have them done," he said.

"On the other hand, if you have a chronic problem like passing kidney stones, and every time you show up at the emergency department every six months, they get another CT scan rather than doing a less-dangerous [test] that doesn't use radiation, like ultrasound, you are being mis-served, and CT is being overused," Amis said.

The results of Sodickson's study echo those of another study presented last May at the annual meeting of the Society for Academic Emergency Medicine.

In that study, researchers led by Dr. Timothy Bullard, chief medical officer and a practicing emergency room physician at Florida's Orlando Regional Medical Center, suggested that the long-term buildup of radiation from repeated emergency room X-rays and CT scans might be placing some people at an increased risk for developing cancer.

Poor balance a bad sign in Alzheimer's patients

NEW YORK ,01 april 2009– A simple balance test may help doctors predict a decline in memory and brain function in people with Alzheimer's disease, research shows.

In a study, researchers found that Alzheimer's patients with an abnormal one-leg balance test experienced greater decline in brain function over 2 years than those with a normal one-leg balance test.

"Our results reinforce, in an Alzheimer's disease population, the growing evidence suggesting a link between physical performances and cognitive decline," study chief Dr. Yves Rolland, of the University of Toulouse III, France, noted in a written statement.

"If these results are confirmed by other data, the one-leg balance test could be adopted in clinical practice to identify Alzheimer's disease patients at high risk of rapid cognitive decline," the researcher added.

According to a report of the study published in the Journal of Alzheimer's Disease, 686 patients with Alzheimer's disease were evaluated by a geriatrician every six months for up to two years, and their degree of cognitive impairment was measured.

At the same time, a "one-leg balance" test was given, where a participant was asked to stand on one leg for as long as possible. The test was considered abnormal when the participant was unable to stand on one leg for 5 seconds or more.

At the outset, roughly 15 percent of the study subjects had an abnormal one-leg balance test and these patients were significantly older and had significantly more severe cognitive impairment.

In analyses taking into account factors that might influence the results, the researchers found that subjects with an abnormal one-leg balance test had significantly greater decline in memory and thinking at 12, 18, and 24 months.

For example, the average decline on the Mini-Mental State Examination at 24 months was 9.2 points when balance impairment was present, compared with just 3.8 points with no balance impairment.

"The one-leg balance test is a stress test that may characterize subjects with low cognitive reserve," Rolland and colleagues conclude.

SOURCE: Journal of Alzheimer's Disease, March 2009.

"Watchful waiting" safe for some prostate cancers

By David Douglas

NEW YORK , 01 april 2009 – Carefully selected men with "low-risk" prostate cancer can safely delay treatment and opt instead for active surveillance, researchers report in the April issue of The Journal of Urology.

With active surveillance, or "watchful waiting," patients with early prostate tumors are monitored regularly and only treated if their cancer progresses.

"Active surveillance with delayed treatment, if necessary, for select patients appears to be safe" and associated with a low risk of the cancer spreading, the researchers conclude.

Despite the potential survival advantages associated with prostate cancer treatment, senior investigator Dr. Bertrand Guillonneau told Reuters Health, "there is still a large number of patients who are over-treated and who will suffer from prolonged side effects that impair their quality of life."

"Active surveillance, based on strict criteria," added Guillonneau, "might be a way to sort out patients with growing tumor that requires treatment from quiescent tumor that will not progress."

To study the safety of active monitoring instead of immediate treatment of men with low-risk prostate cancer, Guillonneau, of Memorial Sloan-Kettering Cancer Center, New York, and colleagues studied 268 men younger than age 75 years.

All of the men had been given multiple treatment options but ultimately chose active surveillance over immediate treatment. The men had early "low-risk" disease, based on their prostate specific antigen (PSA) level and initial biopsy findings.

The men had a second "restaging" biopsy immediately before active surveillance began and no treatment in the following 6 months. They subsequently underwent physical exams and PSA tests every six months with biopsies recommended every 1 to 2 years.

Of that initial pool of men electing active surveillance of their cancer, 43 eventually chose treatment or had evidence of cancer progression prompting recommendation of treatment by their physician. Following delayed treatment (radiation or surgery,) all but one were cured of their cancer. The remaining 219 patients remained on active surveillance without evidence that their disease had spread.

At 2 years the probability of staying on active surveillance was 91 percent. At 5 years, it was 75 percent.

"Our study indicates that 75 percent of the patients who are real candidates for active surveillance will still fulfill the same criteria 5 years later, demonstrating the absence of noticeable (disease) progression," Guillonneau said.

"These patients should still be closely monitored," he concluded, "but it seems likely, for many of them, the prostate cancer will not ultimately develop and will not require any kind of active and therefore morbid treatment."

SOURCE: The Journal of Urology, April 2009.

Study: Plavix plus aspirin helps prevent strokes

By MARILYNN MARCHIONE

ORLANDO, Fla.,01 april 2009 – Taking the blood thinner Plavix along with aspirin helped prevent strokes and heart attacks in people with a common heartbeat abnormality that puts them at high risk of these problems, doctors reported Tuesday.

The treatment is for atrial fibrillation, a rhythm disorder that 2.2 million Americans have. It occurs when the upper parts of the heart quiver instead of beating properly. This allows blood to pool and form clots that can travel to the brain, causing a stroke.

The usual treatment is the blood thinner warfarin, sold as Coumadin and in generic form. But finding the right dose is tricky — too little and patients can have a stroke; too much and they can have life-threatening bleeding. Patients on the drug must go to the doctor often for blood tests to monitor their dose.

For these reasons, as many as half of patients take aspirin instead of warfarin, even though aspirin is much less effective at preventing strokes.

Dr. Stuart Connolly of McMaster University in Hamilton, Ontario, led a study testing whether adding clopidogrel, sold as Plavix by French-based Sanofi-Aventis SA, could help.

The study involved 7,554 patients in the United States and 32 other countries who were not able or chose not to take warfarin. All were treated with aspirin; half also were given Plavix.

After nearly four years of followup, the dual drug treatment lowered a combined measure — heart attacks, heart-related deaths, strokes and blood clots — by 11 percent. There were 924 of these problems in patients on aspirin alone but only 832 in those also getting Plavix.

However, the combination treatment raised the risk of serious bleeding — 251 cases versus 162 for those on aspirin alone.

Doing the math, patients still come out ahead on the combination, Connolly said. For every 1,000 patients treated for three years, it would prevent 28 strokes and six heart attacks, and lead to 20 bleeding cases. Bleeding often is treated with transfusions and is not as likely to prove fatal.

"For the first time in 20 years, there's a new treatment for atrial fibrillation," Connolly said.

Results were presented Tuesday at an American College of Cardiology conference and published online by the New England Journal of Medicine.

The study was sponsored by Sanofi, and Connolly and other authors have consulted for the company. Plavix costs about $4 a day.

"Warfarin was, and remains, first-line therapy — this does not change that," said Dr. Richard Page, cardiology chief at the University of Washington School of Medicine in Seattle and an American Heart Association spokesman.

But for those who can't tolerate it, the Plavix-aspirin combo gives a better option than aspirin alone, he said. Page has consulted for Sanofi in the past.

On Saturday, other doctors at the cardiology conference reported on another potential treatment for atrial fibrillation — an experimental heart device called the Watchman aimed at preventing clots from reaching the brain. A federal Food and Drug Administration panel meets to consider it on April 23.