Medscape.com, by Lisa Nainggoian, October 22, 2010 (Sheffield, United Kingdom) — Among men who have coronary heart disease, mortality was doubled in those with low testosterone levels compared with those who had normal levels, a new observational study has shown. Dr Chris J Malkin (Royal Hallamshire Hospital, Sheffield, UK) and colleagues report their findings in Heart. [1]

“This is the fourth epidemiologic study to have shown that low testosterone is a marker of early mortality,” senior author Dr Kevin S Channer (Royal Hallamshire Hospital, Sheffield, UK) told heartwire . “But most crucially, it is the first in men with vascular disease; all of the other epidemiologic follow-up studies of testosterone have excluded this patient population.”

In an accompanying editorial [2], Drs Ronald CW Ma and Peter CY Tong (Prince of Wales Hospital, Shatin, Hong Kong) describe the history of studies on testosterone and cardiovascular disease and say the new trial “adds to the emerging picture” by making it clear that the link between reduced testosterone and increased mortality extends to subjects with established cardiovascular disease.

Channer says a long-term (5 to 10 years) prospective randomized placebo-controlled trial of testosterone replacement therapy is now needed in patients with heart disease, to assess its effects on mortality: “If you replace the testosterone, can you push that Kaplan-Meier survival curve back to the normal line?”

The editorialists agree. While Ma and Tong say there are some risks from testosterone–it might increase the risk of prostatic diseases and erthrocytosis, and exacerbate sleep apnea–overall, “The encouraging results from clinical studies so far support investigating the effects of testosterone supplementation on cardiovascular disease in larger clinical trials.”

20% of Men Were Testosterone-Deficient

To examine the effect of testosterone levels on survival, Malkin et al followed 930 consecutive men with coronary disease referred for angiography for a two-year period from June 2000, with a mean follow-up of almost seven years. The main variables were all-cause and vascular mortality and the presence of testosterone deficiency.

The overall prevalence of biochemical testosterone deficiency was 20.9% using a measure of bioavailable testosterone <2.6 nmol/L; 16.9% using total testosterone <8.1 nmol/L; and using either measure it was 24%.

Adjusted all-cause and vascular mortality was more than doubled among those with low bioavailable testosterone (HR 2.2. p<0.0001 for all-cause mortality; HR 2.2, p=0.007 for vascular mortality) compared with those who had normal levels of the hormone.

Low serum testosterone was one of only four variables found to influence time to all-cause and vascular mortality in multivariate analyses (HR 2.27), along with the presence of left ventricular dysfunction (HR 3.85), aspirin therapy (HR 0.63), and beta-blocker therapy (HR 0.45).

“In patients with coronary disease, testosterone deficiency is common and impacts negatively on survival. Prospective trials of testosterone replacement are needed to assess the effect of treatment on survival,” the authors conclude.

Testosterone Not Like Female HRT, No Money for a Big Trial

Channer explains that testosterone replacement therapy can be given in a number of ways. Testosterone is not suitable for oral therapy, because “It undergoes high first-pass metabolism through the liver,” he explains. But it is available in slow-release injection formulations, as a three-month depot injection, as transdermal patches, and as a gel. He says his team has had some problems with the skin patch because it causes a rash and men tend not to like it, but they have had more success with the three-month depot injections, which they have been able to keep people on for a year. However, “We desperately need some other formulations,” he says.

He is keen to stress that testosterone is a whole different ballgame from female hormone replacement therapy: “Men are given testosterone, the same hormone as they make themselves, and we monitor levels and titrate to physiologic levels. This is not like female hormones, where women were given doses of a drug and the physicians didn’t know whether they were physiological, super-physiological, or what; it’s totally different.”

But he does not hold his breath when it comes to a big trial. He and his colleagues have had every request for funding for such a large study turned down, he says, adding: “The problem is that none of the drug companies that make testosterone are big enough to fund such a study, because it would cost millions.”

Concerns Dismissed: Testosterone “Like Thyroid Hormone”

Channer also doesn’t understand what he sees as reticence from some quarters when testosterone as a potential therapy is discussed. “I’ve struggled to understand why endocrinologists don’t just accept that replacing testosterone is the same as replacing thyroid hormone, for example, what’s the matter with that?”

And he dismisses any concerns arising from a US National Institutes of Health study in elderly men, which was stopped early because testosterone treatment was associated with an increased risk of cardiovascular events; the paper was published in the New England Journal of Medicine earlier this year.

“We were very surprised that NEJM published that paper. The end points were very soft indeed,” he comments. “Yes, there were a few more deaths, but these were elderly men and you wouldn’t expect in the duration of that study for the testosterone to have had that kind of effect. We’ve been doing studies for 15 years with testosterone in men with known heart disease, angina, and heart failure, and we haven’t had any [serious] adverse reactions.”

Neither the authors nor the editorialists report any conflict of interest.

References

  1. Malkin CJ, Pugh PJ, Morris PD, et al. Low serum testosterone and increased mortality in men with coronary heart disease. Heart 2010 DOI: 10.1136/hrt.2010.195412
  2. Ma RCW and Tong PCY. Testosterone levels and cardiovascular disease. Heart 2010;96:1787-1788.

FORBES.com, October 25, 2010, by Randolph E. Schmid  –WASHINGTON — The ability to taste isn’t limited to the mouth, and researchers say that discovery might one day lead to better treatments for diseases such as asthma.

It turns out that receptors for bitter tastes are also found in the smooth muscles of the lungs and airways. These muscles relax when they’re exposed to bitter tastes, according to a report Sunday from researchers from the University of Maryland College of Medicine in Baltimore in the online edition of the journal Nature Medicine.

That surprised Dr. Stephen B. Liggett, a lung expert who noted that bitter tastes often are associated with poisonous plants, causing people to avoid them.

Liggett said he expected the bitter-taste receptors in the lungs to produce a “fight or flight” reaction, causing chest tightness and coughing so people would leave the toxic environment.

“But that’s not what we found,” Liggett said.

Instead, when scientists tested some nontoxic bitter compounds on mice and on human airways in the laboratory, the airways relaxed and opened more widely.

The compounds “all opened the airway more profoundly than any known drug that we have for treatment of asthma or chronic obstructive pulmonary disease,” Liggett said.

“That’s the fun of science, when you find something you didn’t expect,” he said in a telephone interview.

Liggett, who hopes to begin tests in humans within a year, said that eating bitter tasting foods or compounds would not help in the treatment of asthma. Instead, he said, to get a sufficient dose people will need to use aerosolized compounds, which can be inhaled.

Fortunately there are thousands of compounds known to have a bitter taste, such as quinine and many drugs, he said. So researchers can begin testing them to determine which have the best result without few or no side effects.

The presence of bitter taste receptors on the hair-like cilia in the airways was reported last year by Michael J. Welsh of the University of Iowa. It was suggested that the cilia might react by moving to push a noxious aerosol out of the airways, and Liggett said that may be the case.

But the new research by Deepak A. Deshpande and Liggett centers on receptors in the smooth muscles, rather than the cilia. The lung receptors were limited to bitter tastes, Liggett said, and did not include the ability to sense salty, sour, sweet and savory tastes, which the tongue can detect.

Unlike the taste receptors in the tongue, the ones in the airways react to the taste but do not send signals to the brain.

The research was supported by the U.S. National Heart, Lung and Blood Institute.

An attractive material: Neodymium (shown here) is one of the rare-earth elements that are key to making very strong magnets for compact electric motors.
Credit: Hi-Res Images of Chemical Elements

 

The rest of the world is trying to find alternatives to these crucial materials

MIT Technology Review, October 25, 2010, by Adam Aston  —  For three weeks, China has blocked shipments of rare-earth minerals to Japan, a move that has boosted the urgency of efforts to break Beijing’s control of these minerals. China now produces nearly all of the world’s supply of rare earths, which are crucial for a wide range of technologies, including hard drives, solar panels, and motors for hybrid vehicles.

In response to China’s dominance in rare-earths production, researchers are developing new materials that could either replace rare-earth minerals or decrease the need for them. But materials and technologies will likely take years to develop, and existing alternatives come with trade-offs.

China apparently blocked the Japan shipments in response to a territorial squabble in the South China Sea. Beijing has denied the embargo, yet the lack of supply may soon disrupt manufacturing in Japan, trade and industry minister Akihiro Ohata told reporters Tuesday.

Rare earths are comprised of 17 elements, such as terbium, which is used to make green phosphors for flat-panel TVs, lasers, and high-efficiency fluorescent lamps. Neodymium is key to the permanent magnets used to make high-efficiency electric motors. Although well over 90 percent of the minerals are produced in China, they are found in many places around the world, and, in spite of their name, are actually abundant in the earth’s crust (the name is a hold-over from a 19th-century convention). In recent years, low-cost Chinese production and environmental concerns have caused suppliers outside of China to shut down operations.

Alternatives to rare earths exist for some technologies. One example is the induction motor used by Palo Alto, California-based Tesla Motors in its all-electric Roadster. It uses electromagnets rather than permanent rare-earth magnets. But such motors are larger and heavier than ones that use rare-earth magnets. As a rule of thumb, in small- and mid-sized motors, an electromagnetic coil can be replaced with a rare-earth permanent magnet of just 10 percent the size, which has helped make permanent magnet motors the preferred option for Toyota and other hybrid vehicle makers. In Tesla’s case, the induction motor technology was worth the trade-off, giving the car higher maximum power in more conditions, a top priority for a vehicle that can rocket from zero to 60 mph in 3.7 seconds. “The cost volatility going into the rare-earth permanent magnets was a concern,” says JB Straubel, Tesla’s chief technology officer. “We couldn’t have predicted the geopolitical tensions.”

More manufacturers are following Tesla’s lead to shun the rare-earth materials, although the move means sacrificing space and adding weight to vehicles. A week after the China dust-up began, a research team in Japan announced they had made a hybrid vehicle motor free of rare-earth materials, and Hitachi has announced similar efforts. BMW’s Mini E electric vehicle uses induction motors, and Tesla is supplying its drive trains to Toyota’s upcoming electric RAV 4. Given the volatility of rare-earth supplies, and the advantages induction motors offer in high performance applications, “It makes sense for car companies to give serious thought to using induction motors,” says Wally Rippel, senior scientist at AC Propulsion. Rippel previously worked on induction motor designs at Tesla and GM, where he helped to develop the seminal EV1.

As automakers explore alternative motors, researchers in the U.S. and elsewhere are also trying to devise replacements for rare-earth materials, and political efforts are advancing to boost supplies of rare earths from outside of China.

In the U.S., the Chinese dominance of rare-earth mineral production has prompted a surge of funding focused on developing permanent magnets that use less, if any, rare-earth materials, such as nearly $7 million from the Advanced Research Projects Agency for Energy (ARPA-E). In one of these projects, University of Nebraska researchers are working to enhance permanent magnets made with an alloy iron and cobalt, or FeCo. This class of materials is sold today, but delivers half or less of the power of the best rare-earth-based magnets. The Nebraska researchers will focus on ways to dope the structural matrix of these alloys with traces of other elements, thereby rearranging their molecular geometry to create stronger, more durable permanent magnetic materials.

Working alongside the Nebraska researchers in the same ARPA-E program, researchers at the University of Delaware are advancing nanocomposites that use far less of the valuable rare-earth materials, but that have been shown theoretically to generate magnetic strengths twice as powerful as today’s best permanent magnets. The lab is mixing particles, just 20 to 30 nanometers in size, of rare-earth magnetic materials with a non-rare-earth complement (tin cobalt). Prior efforts to make this material have been unable to precisely align the nanoparticles, diminishing their magnetic performance substantially. Instead of concocting the material in bulk, like mixing batter, the team is developing a process to control the particles’ alignment by assembling them in regular arrays.

GE Global Research, in Niskayuna, New York, is pursuing nanocomposites similar to those being developed in Delaware, also with ARPA-E funding. Using methods developed in-house, the project aims to build a new material through the alignment of nanopowders. “These materials are intrinsically unstable,” so controlling their assembly is at the frontier of nanoscale manufacturing processes, says Luana Iorio, a manager at GE’s High Temperature Alloys and Processing Laboratory, who leads the research. GE estimates its nanocomposites could deliver 35 percent greater magnetic strength than today’s best permanent magnets, while using 40 percent of the rare earths, by volume. Within two years, Iorio hopes, the project will be able to create samples of the new material a few centimeters in diameter.

Yet since it may take years for these efforts to bear fruit, the hunt for non-Chinese sources of the minerals is attracting attention in the near term. In California, Molycorp Minerals is looking to reopen rare-earth mines that closed in 2002, amidst low pricing and environmental concerns. In recent weeks, bills have been floated in the U.S. House and Senate aimed at reviving the rare-earth supply chain in the U.S., including mining, refining, and manufacturing. A third bill, in the House, is narrower, focusing on offering loan guarantees to restart mining.