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Stem Cell Research in Cardiology

Stem cell will create countless new legal issues in coming years.

The following article from Reuters, taken from Yahoo News, describes recent developments in stem cell research in cardiology:

By Maggie Fox, Health and Science Editor

WASHINGTON (Reuters) - A nutritious cocktail helped human embryonic stem cells thrive and repair the damaged hearts of rats, U.S. researchers reported on Sunday.

The experiment provides the best evidence yet that the powerful but controversial stem cells might be used to repair the ravages of heart attacks and heart failure, the researchers said.

Biotechnology company Geron Corp said it would try to develop the cells into a product. "We're developing our cardiomyocyte product, GRNCM1, to address the large unmet need in heart failure," said Dr. Thomas Okarma, president and chief executive officer of Geron.

Stem cells are the body's master cell, acting as a source for the various cells and tissues in the body. Those taken from days-old embryos, called embryonic stem cells, are the most malleable and can produce all of the cell types.

Their use is controversial because some people oppose the destruction of a human embryo. U.S. President George W. Bush has kept strict limits on federal funding of human embryonic stem cell research. There are no restrictions on privately funded researchers.

Okarma said embryonic stem cells were the only human stem cells that had been shown to form cardiomyocytes -- heart muscle cells.

Because embryonic stem cells are so immature, it is very difficult to control what kinds of cells they produce, and the fear is that a tooth could grow inside a heart, for instance.

"We got stem cells to differentiate into mostly cardiac muscle cells, and then got those cardiac cells to survive and thrive in the damaged rat heart," said Dr. Chuck Murry of the University of Washington's Institute for Stem Cell and Regenerative Medicine, who worked on the study.

But the cells died when they injected them into the hearts of the rats, the researchers reported in the journal Nature Biotechnology.

"This problem is not unique to our system. Death of transplanted cells is slowing research progress in cell therapy for diabetes, Parkinson's disease and muscular dystrophy, among other diseases," they wrote.

So the team developed what they dubbed a "survival cocktail" that included various proteins and other compounds to stop the cells from dying.

It worked. When they caused heart attacks in the rats and then injected the new heart muscle cells, every graft survived and integrated into the hearts of the rats.

They beat in rhythm and improved the heart function of the rats, they reported.

"This is one of the most successful attempts so far using cells to repair solid tissues -- every one of the treated hearts had a well-developed tissue graft," Murry said.

This is key to treating someone after a heart attack, known medically as a myocardial infarction, said Dr. Michael Laflamme, who also worked on the study.

"This sort of treatment could help the heart rebound from an infarction and retain more of its function afterwards," Laflamme said in a statement.

An estimated 865,000 people have heart attacks in the United States every year and more than a third eventually develop heart failure, a chronic condition in which the heart fails to pump blood properly. A third of heart failure patients die within two years.

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A Nation in Pain or Addiction?

Injury attorneys have long been aware of America's increasing problem with prescription pain medicines and the article below, pulled off Yahoo News this morning, confirms that a new national dialogue on this subject is in order. Legal addiction has become a major problem for the United States:

MYRTLE BEACH, S.C. - People in the United States are living in a world of pain and they are popping pills at an alarming rate to cope with it.

The amount of five major painkillers sold at retail establishments rose 90 percent between 1997 and 2005, according to an Associated Press analysis of statistics from the Drug Enforcement Administration.

More than 200,000 pounds of codeine, morphine, oxycodone, hydrocodone and meperidine were purchased at retail stores during the most recent year represented in the data. That total is enough to give more than 300 milligrams of painkillers to every person in the country.

Oxycodone, the chemical used in OxyContin, is responsible for most of the increase. Oxycodone use jumped nearly six-fold between 1997 and 2005. The drug gained notoriety as "hillbilly heroin," often bought and sold illegally in Appalachia. But its highest rates of sale now occur in places such as suburban St. Louis, Columbus, Ohio, and Fort Lauderdale, Fla.

The world of pain extends beyond big cities and involves more than oxycodone.

In Appalachia, retail sales of hydrocodone -- sold mostly as Vicodin -- are the highest in the nation. Nine of the 10 areas with the highest per-capita sales are in mostly rural parts of West Virginia, Kentucky or Tennessee.

Suburbs are not immune to the explosion.

While retail sales of codeine have fallen by one-quarter since 1997, some of the highest rates of sales are in communities around Kansas City, Mo., and Nashville, Tenn., and on New York's Long Island.

The DEA figures analyzed by the AP include nationwide sales and distribution of drugs by hospitals, retail pharmacies, doctors and teaching institutions. Federal investigators study the same data trying to identify illegal prescription patterns.

An AP investigation found these reasons for the increase:

The population is getting older. As age increases, so does the need for pain medications. In 2000, there were 35 million people older than 65. By 2020, the Census Bureau estimates the number of elderly in the U.S. will reach 54 million.

Drugmakers have embarked on unprecedented marketing campaigns. Spending on drug marketing has gone from $11 billion in 1997 to nearly $30 billion in 2005, congressional investigators found. Profit margins among the leading companies routinely have been three and four times higher than in other Fortune 500 industries.

A major change in pain management philosophy is now in its third decade. Doctors who once advised patients that pain is part of the healing process began reversing course in the early 1980s; most now see pain management as an important ingredient in overcoming illness.

Retired Staff Sgt. James Fernandez, 54, of Fredericksburg, Va., survived two helicopter crashes and Gulf War Syndrome over 20 years in the Marine Corps. He remains disabled from his service-related injuries and takes the equivalent of nine painkillers containing oxycodone every day.

"It's made a difference," he said. "I still have bad days, but it's under control."

Such stories should hearten longtime advocates of wider painkiller use, such as Russell Portenoy, head of New York's Beth Israel pain management department. But they have not.

"I'm concerned and many people are concerned," he said, "that the pendulum is swinging too far back."

Consider:

More people are abusing prescription painkillers because the medications are more available. The vast majority of people with prescriptions use the drugs safely. But the number of emergency room visits from painkiller abuse has increased more than 160 percent since 1995, according to the government.

Spooked by high-profile arrests and prosecutions by state and federal authorities, many pain-management specialists now say they offer guidance and support to patients but will not write prescriptions, even for the sickest people. The increase in painkiller retail sales continues to rise, but only barely. There was a 150 percent increase in volume in 2001. Four years later, the year-to-year increase was barely 2 percent.

People who desperately need strong painkillers are forced to drive a long way -- often to a different state -- to find doctors willing to prescribe high doses of medicine. Siobhan Reynolds, the widow of a New Mexico patient who needed large amounts of painkillers for a connective tissue disorder, said she routinely drove her late husband to see an accommodating doctor in Oklahoma.

Perhaps no place illustrates the trends and consequences for the world of pain better than Myrtle Beach, a sprawling community of strip malls, hotels and bars perched along a 60-mile strip of sand on the Atlantic Ocean. The metro area, which includes three counties, is home to 350,000 people but sees more than 14 million tourists annually, drawn to its warm water, golf courses and shopping.

During the eight-year period reflected in government figures, oxycodone distribution increased 800 percent in the area of Myrtle Beach, partly due to a campaign by Purdue Pharmaceuticals of Stamford, Conn. The privately held company has pleaded guilty to lying to patients, physicians and federal regulators about the addictive nature of the drug.

Use of other drugs soared in the area, too: Hydrocodone use increased 217 percent; morphine distribution went up 180 percent; even meperidine, most commonly sold as Demerol, jumped 20 percent.

It is no small wonder that federal authorities suspected the area was home to a notorious "pill mill," or a clinic that dispenses prescription medication without verifying that it's needed.

The U.S. attorney for South Carolina secured a 58-count indictment in June 2002 against seven physicians and one employee of the Comprehensive Care and Pain Management Center, a nondescript storefront on Myrtle Beach's main drag.

Tipped off by local pharmacists concerned about an increase in the volume of painkiller prescriptions, the federal investigation created a furor in the medical profession. The owner, D. Michael Woodward, was sentenced to 15 years in the case and has relinquished his license.

A second physician, Deborah Bordeaux, had worked at the clinic less than two months before quitting in disgust. Bordeaux, now serving a two-year prison term, was threatened with a 100-year sentence if she did not help the prosecution.

Officials with the Justice Department and the DEA would not discuss what some activists say is a "war on doctors."

Reynolds, the widow who drove her late husband hundreds of miles for his pills, became an activist after the Myrtle Beach indictments. She contributed money to appeal some of the criminal convictions in South Carolina and started the Pain Relief Network, an advocacy organization for people living in pain. She believes the doctors sent to prison were railroaded.

"It was a witch hunt," she said.

Bordeaux's husband, Edworth Swaim, agrees. A retired U.S. Postal Service employee, Swaim believes his wife was sentenced to two years because she would not turn on her former colleagues. Even though Bordeaux had worked at the clinic less than two months and eventually sued over what she alleged was rampant Medicare fraud, he said she did not stand a chance of avoiding prison.

"She wasn't guilty of anything, so she wasn't going to plead to anything," Swaim said. "She was absolutely railroaded, made an example of. I can't tell you how angry I am."

Myrtle Beach physicians are not convinced that the "Myrtle Beach Eight," as they became known, were innocent.

A Myrtle Beach internist who also works in addiction medicine, Brian Adler, said physicians were flooded with patients seeking pain medicine after the clinic was shut down.

The community has a slightly higher-than-average number of older people and relatively high numbers of people between 21 and 64 who describe themselves as disabled.

"There's a significant problem with narcotics in this area," Adler said. After the pain management clinic closed, "all those folks were like rats, scurrying from a burning building, trying to get their fix."

Other physicians were concerned about patients with legitimate needs for painkillers. The federal bust raised the stakes.

When radio commentator Rush Limbaugh settled a federal case charging him with illegally obtaining painkillers, he did not get prison time. Neither did NFL star Brett Favre, who publicly acknowledged an addiction to Vicodin that he obtained legally.

To pain management specialists, they were being blamed for everyone's addiction.

The DEA cites 108 prosecutions of physicians during the past four years; 83 pleaded guilty or no contest, while 16 others were convicted by juries. Eight cases are pending, and one physician is being sought as a fugitive.

In congressional testimony, the agency's deputy assistant administrator, Joseph T. Rannazzisi, estimated that fewer than 1 percent of the nation's physicians -- under 9,000 -- illegally provide prescription drugs to patients. He told lawmakers it is far more common for people to illegally obtain prescription drugs from friends and family members.

"It is not merely illegal but could feed or lead to an addiction and place that loved one in a life-threatening situation," Rannazzisi said.

It is impossible to reliably measure painkiller abuse.

A 2004 government study estimated between 2 million and 3 million doses of codeine, hydrocodone and oxycodone are stolen annually from pharmacies, distributors and drug manufacturers. The AP's analysis only included retail sales and did not include estimates of diverted pharmaceuticals.

John Charles, director of medical affairs at the Grand Strand Regional Medical Center in Myrtle Beach, practices pain management. A few years ago, Charles said, he took a drastic step to reduce his potential legal risks: He stopped prescribing painkillers.

The decision gave him peace of mind, but he does not expect there to be less of a need for painkillers or physicians who prescribe them.

"People with cancer are surviving longer, elderly people are living longer," Charles said. "So, physicians are walking a fairly fine line. We're walking a narrow path. And I think we'll continue to see it for a while."

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More Fun with Allstate

As you may have seen in earlier blogs, Allstate's Nevada Counsel has got himself into a lot of trouble with the Nevada Supreme Court and a number of District Courts and has incurred high sanctions.

I received this email update from Peter Chase Neumann, one of the attorneys keeping the heat on Allstate:

In the wrongful death case of Duncan Estate vs. Peri and Stratton, the Trial Court, Dept 4, granted plaintiff's motion for new trial on 2-13-06. Order was based, inter alia, on misconduct of Emerson.

Emerson and the counsel for the co-defendant, Mr. Kolvet, appealed.

On April 4, 2007 the Supreme Court dismissed their appeal, for their failure to obtain a judgment on the defense verdict, prior to appealing. (Court had no jurisdiction to entertain appeal).

Emerson's pet. for rehearing denied by supreme court May 18, 2007.

The case now set for re-trial 12 months hence, Sept. 15, 2008.

On July 24, 2007 plaintiffs filed a Motion to Impose Sanctions on Emerson and his client, Stratton.

On Aug 7, 2007, Emerson filed Opposition thereto.

Today, Aug 15, 2007, plaintiffs filed their REPLY thereto.

(If anyone wants a copy of the Reply email me or comment via this blog and I'll get it to you. -Steve)

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Melanoma Rates Continue to Rise

This from D. Garth Sullivan, Esq. at Indox Consulting. Mr. Sullivan writes to attorneys every week with news from legal-medical frontiers:

The incidence of melanoma has steadily increased in the United States, and from 1995 to 2004, the rate of melanoma rose by more than 1% per year. The rising increase in melanoma is not specific to 1 age group, but the incidence was particularly noted among young adults and the elderly, explained Martin A. Weinstock, MD, PhD, professor of dermatology and community health at Brown University, in Providence, Rhode Island, and chief dermatologist at Veterans Affairs Medical Center in Providence. He was speaking last week at a plenary session at the American Academy of Dermatology's Summer Academy Meeting 2007.

"Of the 10 leading types of cancer, other than keratinocyte carcinomas, only kidney cancer and melanoma rates are increasing," Dr. Weinstock told Medscape in an interview.

There are several possible reasons for the increased incidence in younger and older individuals, said Dr. Weinstock. "Possible changes in diagnostic criteria, increased surveillance, and increased UV exposure may all account for it."

Data from a population based study published in 2006 found that despite public education campaigns to reduce sun exposure, there was little improvement in sun-protection practices and reducing sunburns among youths between 1998 and 2004. (Cokkinides V et al. Pediatrics 2006;118:853-864). According to the survey, which examined trends on sunburns, sun protection, and attitudes related to sun exposure among individuals aged 11 to 18 years, 69% of participants reported having been sunburned during the summer in 2004. This rate was only slightly less than the 72% reported in 1998.

However, when the data were broken down by age, there was a significant decrease in the percentage of youngsters aged 11 to 15 years who reported sunburns, while there was a nonsignificant increase among the 16- to 18-year-olds. The proportion of participants who reported using sunscreen on a regular basis in 2004 was also significantly higher than in 1998 (39% vs 31%).

"A [Centers for Disease Control and Prevention] CDC survey also reported that adults were getting more sunburns in 2004, as compared with 1999," said Dr. Weinstock.

The results of this survey (CDC. MMWR Morb Mortal Wkly Rep. 2007;56:524-528) indicated that sunburn prevalence among all participants rose from 31.8% in 1999 to 33.7% in 2004. Men were reported to have a higher prevalence of sunburn than women during 3 survey years: 35.8% vs 28% in 1999, 37% vs 30.2% in 2003, and 37% vs 30.3% in 2004. The incidence of sunburn was also reported among ethnic and racial groups usually considered to be at low risk of getting sunburn, such as American Indians/Alaska Natives (30.4% for men, 21.5% for women), black Hispanics (12.4% for men, 9.5% for women in 2004), and Asians/Pacific Islanders (16% for men and women).
While the study found only a small 2% increase in the percentage of adults who reported getting sunburned during that time period, it also showed that the occurrence of sunburns was not declining.

Dr. Weinstock also reviewed the effectiveness of different interventions in changing sun-exposure behaviors. One study conducted in Australia evaluated the efficacy of delivering solar UV forecasts and supporting communications in promoting personal sun-protection practices on weekends (Dixon HG et al. Health Educ Behav. 2007;34: 486-502). The researchers involved in the study did not find any significant changes in behaviors such as the use of hats and sunscreen or sun avoidance that was related to solar-UV forecasts.

On the other hand, another study found that found that a multicomponent community-based intervention was able to successfully increase sun-protection behaviors in children entering sixth to eighth grades. The program involved a variety of role models that included school personnel, coaches, pediatricians, teen peer advocates and lifeguards, all of whom actively encouraged the youths to practice appropriate sun-protection practices (Olson AL et al. Pediatrics. 2007;119:e247-256).

Dr. Weinstock also pointed out that there are benefits from UV exposure, in that it is needed to fuel vitamin D production. "Most physical activity also takes place outdoors," he said. "Therefore, it is important that dermatologists do not tell their patients to avoid the sun completely because of the importance of physical activity and its preventive effect against numerous illnesses, as well as obesity."

When people do engage in outdoor activities, they need to protect themselves from overexposure to UV radiation. "There are 3 public health messages that I focus on," said Dr. Weinstock, "the first being that the healthiest color for your skin is the one you were born with."

The belief that suntans make a person more physically attractive is a primary motive for suntanning behavior. "If you have fair skin and try to make it tan, you are setting yourself up for a problem," he explained. "There is a whole psychology of pursuing a tan, and that is not a good thing. I would focus intervention efforts on changing that perception.

"The second message is that supplements are a safer source of vitamin D than UV radiation, if you need more vitamin D," said Dr. Weinstock. "It is a safer to take vitamin supplements than spend more time in the sun getting excessive UV exposure."

Third, when it comes to protecting the skin, Dr. Weinstock advocates "Slip, slop, slap," which is to slip on a shirt, slop on the sunscreen, and slap on a hat. "This sun-protection message has been adopted by the American Cancer Society as a way of encouraging protection from harmful UV radiation without interfering with physical activity," he said.

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Relationship Between Low LDL and Cancer

This from an email to me yesterday from Indox Consulting. More contradictions in medical research:

Results from a new analysis, initially designed to determine whether there was a correlation between the extent to which statins lowered low-density lipoprotein (LDL)-cholesterol levels and liver and muscle toxicity, suggests that the cardiovascular benefits of achieved levels of LDL cholesterol might be offset by an increased risk of cancer. In an analysis of patients enrolled in large, randomized statin trials, investigators observed a "significant and linear relationship" between achieved LDL levels and the risk of new cancer cases.

"The statin trials have clearly shown that statin therapy, overall, reduces cardiovascular risk," said senior investigator Dr Richard Karas (Tufts-New England Medical Center, Boston, MA). "These findings don't change that. They're based on the same studies. But a component of that, perhaps one of the costs of that, is a relationship between the LDL lowering and cancer risk."


Speaking with heartwire, Karas said the cancer association was a surprise and initially wasn't even on his group's radar. The Boston researchers conducted their analysis examining the relationship of the degree of LDL-cholesterol lowering to liver toxicity and rhabdomyolysis in 23 randomized, controlled trials assessing statin therapy, including, among others, the Scandinavian Simvastatin Survival Study (4S), West of Scotland Coronary Prevention Study (WOSCOPS), Long-term Intervention with Pravastatin in Ischemic Disease (LIPID) study, the Heart Protection Study (HPS), and the more recent trials of intensive vs moderate lipid-lowering therapy such as Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE-IT), TNT, and Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL).

Investigators also studied the effect of drug dosage on liver and muscle toxicity. In the first analysis, no matter how investigators looked at the extent of LDL reduction, as a relative or absolute reduction or achieved LDL-cholesterol levels, they observed no relationship between how much the cholesterol was lowered and the risk of liver or muscle toxicity. In the second analysis, however, when they looked at muscle toxicity on the basis of the dose of the drugs, they found that the higher the dose of statins used in the study, the higher the risk of toxicity to the liver.

"Overall, statins are very safe, but the safety implication here is that it does matter how you lower LDL-cholesterol levels," said Karas. "In other words, the high-dose statins are associated with a higher risk of side effects. This does then have implications for how we practice medicine, the question being, and it's just a question, as to whether or not we might be better off using multiple medications, all at modest doses, to try to get the cholesterol targets that we want to get to, to minimize side effects and maximize the benefit."

Considering these findings worthy of publication, the group submitted the manuscript to the Journal of the American College of Cardiology, but, as noted in an editorial comment by journal editors Dr Anthony DeMaria and Ori Ben-Yehuda, the researchers were asked to include cancer in the analysis because "this was the other major side effect often feared from statin therapy." Of the 23 statin therapy trials, 13 studies included the number of patients with newly diagnosed cancer. Overall, there was no significant relationship between percent and absolute reductions in LDL-cholesterol levels. There was, however, a highly significant inverse relationship between achieved LDL-cholesterol levels and rates of newly diagnosed cancer (R2 = 0.43, p = 0.009). The researchers found one additional incident of cancer per 1000 patients with low LDL levels when compared with patients with higher LDL levels. The new cancers were not of any specific type or location.

To heartwire, Karas said the findings are paradoxical in light of recent meta-analyses concluding there is no significant increase in the risk of cancer with statin therapy. Karas stressed, however, that the new findings are observational, hypothesis generating, and in no way definitive. "This is an association at this point," he said. "It might have nothing to do with cause and effect. The best analogy is to say that I have a dog, and every time an airplane goes over my house, my dog goes out into the backyard and barks at the plane. That airplane has never landed in my yard. Now we could say there is a very strong association between my dog barking and planes not landing in my yard, but there certainly is no cause and effect. "Even if the risk of cancer is increased with statin use, Karas said clinicians would have to balance the magnitude of that risk with the benefits of statin therapy."

Dr Thomas Pearson (University of Rochester School of Medicine, NY), who was not affiliated with the study, told heartwire that the results should be interpreted carefully.

"In many ways it is déjà vu all over again," said Pearson. "In the 1970s, there were several papers describing higher risks from cancer in those with the lowest cholesterol levels. This is from the prestatin era. Old-time clinicians will tell you that monitoring cholesterol levels is useful, such that when they start to fall, you should look for a cancer. Indeed, the MRFIT study looked at this and showed the shorter the interval between the cancer diagnosis and the blood test, the lower the cholesterol."

For this reason, said Pearson, one should assume the very low cholesterol levels in patients with cancer on statins are due to a cancer-low cholesterol link rather than a statin-cancer association.

In his editorial, LaRosa points out that no single form of cancer predominates, "so the effect of low achieved LDL would have to have been one that stimulates neoplasia in a variety of tissues." In addition, the effect of low LDL-cholesterol levels would have to be unusually rapid, given that most statin trials lasted five years or less, in producing new cancers.



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