Stem cell transplant advance 'thrilling'

U.S. scientists use embryonic tissue from humans to repair hearts in rats

Aug 27, 2007 04:30 AM

Joseph Hall

health reporter

In a major scientific advance, U.S. researchers have used human embryonic stem cells to repair damaged heart tissue in rats that had suffered cardiac arrests.

The "thrilling" accomplishment, released in a study yesterday, seems to overcome two of the most persistent and perplexing hurdles that have thwarted use of the promising embryonic cells for organ repair.

"One was how to coax the human embryonic stem cell to turn into (heart) cells," says Dr. Charles Murry, director of cardiovascular biology at the University of Washington's Institute for Stem Cell and Regenerative Medicine. The other was to keep them alive after transplantation.

"Embryonic stem cells can turn into hundreds of different cell types and the trick was to turn them into the cell type of interest, to the exclusion of all this other stuff. It's like getting the roulette ball to go into the right slot in the wheel."

The study was published yesterday in the journal Nature Biotechnology.

Janet Rossant, deputy scientific director of the non-profit Canadian Stem Cell Network, says the ability to make large numbers of heart cells and to have them live after transplant "are big steps forward."

But Rossant, a scientist with the federal funding agency Canadian Institutes of Health Research, says the paper has not shown that the implanted heart tissue is functioning as existing tissue would, or that the new cells will survive in the long term.

"There's still a lot of questions remaining before taking that forward to therapy," she says. "But it's certainly an interesting step forward."

Embryonic stem cells appear soon after conception and can transform themselves into any tissue in the body.

The study authors also created a concoction of compounds that helped the newly created heart cells survive once they'd been transplanted into the damaged rat organs.

Typically, new cardiac cells died after past implantations, due to inflammation, the lack of a vascular network to feed them and their inability to integrate with existing organ tissues.

"We used to just squirt them (the cells) in a saline solution and say, `See you boys,' and hope for the best," Murry says. "That was pretty dismal."

After 18 months of work, Murry's team came up with a cocktail of six ingredients that would allow the new cells to take root and thrive once they'd been injected into the damaged hearts.

The concoction included a cellular glue-like substance – known as Matrigel – that allowed the new cells to attach themselves to the existing heart tissue.

In the past, failure to properly attach meant transplanted cells did not receive the "survival signals" that are passed via different messenger enzymes between their connected counterparts.

The "pro-survival cocktail," which was injected into the heart along with the cells, also included compounds that shovelled energy to the implanted cells and protected them against the harsh, inflammatory environment that exists after a heart attack.

But coaxing the embryonic stem cells to become heart cells in the first place involved an entirely different bag of tricks.

Sifting through a slew of biochemical factors that were known to be involved in heart formation, researchers came up with a formula that greatly increased the yield of heart tissue from the stem cells.

"Typically one tenth of 1 per cent of the (stem) cells would make heart muscle, maybe 1 per cent on a really good day," Murry says. "Now we're getting 38 to 50 per cent of the cells turning into heart muscle."

In total, the combined procedures increased the proportion of successful cell grafts from 15 per cent to 100 per cent in the rodents, who went through lab-induced heart attacks.

The size of those grafts went from "tiny clusters of cells" under the old methods to upwards of 10 per cent of the damaged heart region under the new.

Murry hopes to bring the research into clinical human trials within three years, but will test it on pigs or other large mammals first.

He says it may have applications for stem cell therapies on other organs that have similar production and transplantation hurdles.

"The problem with cell death in cell transplantation (for example) is something that has plagued repair of all solid tissues so far," Murry says. "It's our hope that this will be useful outside of the heart as well."

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Tests Confirm First Human Case of West Nile Virus in State

HARRISBURG -- State Health Secretary Dr. Calvin B. Johnson reported this year’s first confirmed human case of West Nile virus in Pennsylvania. The individual, a 56-year-old Clearfield County man, is recovering and has been discharged from the hospital.

“Every case of human infection from West Nile is a reminder that we can take precautions to help reduce the risk of illness,” Dr. Johnson said. “The chance of contracting West Nile virus from an infected mosquito is small, and your chances of becoming seriously ill are even smaller. However, it is important to remember that everyone -- particularly older adults and people with compromised immune systems – should take simple steps to reduce their risk.”

Secretary Johnson recommended these simple precautions to prevent mosquito bites, particularly for those most at risk:

· Make sure screens fit tightly over doors and windows to keep mosquitoes out of your home;

· When possible, reduce outdoor exposure at dawn and dusk, the times of day when the mosquitoes that transmit West Nile virus are most active, during the warmer months of the year (usually April through October);

· Consider wearing long-sleeved shirts, long pants and socks when outdoors, particularly at dawn and dusk, or in areas known for having large numbers of mosquitoes;

· Use insect repellents according to the manufacturer’s instructions. Effective repellents contain DEET. Consult a doctor if you have concerns about the use of repellent on young children, as repellent is not recommended for children under the age of two months. Two other insect repellants, Picaridin (KBR 3023) and oil of lemon eucalyptus, a plant based repellent, were tested against mosquitoes and provided protection similar to repellents with low concentrations of DEET.

Pennsylvanians also can reduce the risk of West Nile virus by eliminating the places where mosquitoes breed. Mosquitoes can breed in standing water that is present for four or more days.

“The Department of Environmental Protection and our county partners are working hard to eliminate mosquitoes and mosquito breeding sites in public areas, but we need homeowners to help,” DEP Secretary Kathleen McGinty said. “If there is standing water on your property, remember our advice: ‘dump it, drain it, treat it.’”

McGinty suggested some simple steps that can be taken around the house:

Dispose of tin cans, plastic containers, ceramic pots, discarded tires, or any object on your property that could collect standing water.

Drill holes in the bottom of recycling containers left outdoors.

Have roof gutters cleaned every year, particularly if the leaves from nearby trees have a tendency to clog the drains.

Turn over plastic wading pools and wheelbarrows when not in use.

Don’t let water stagnate in birdbaths.

Aerate ornamental pools or stock them with fish.

Clean and chlorinate swimming pools and remove standing water from pool covers.

Use landscaping to eliminate standing water that collects on your property.

Standing water that cannot be eliminated should be treated with Bti products, which are sold at outdoor supply, home improvement, and other stores. Bti is a naturally occurring bacterium that kills mosquito larvae but is safe for people, pets, aquatic life and plants.

West Nile virus is spread to people and animals by infected mosquitoes. Usually, the infection does not result in any illness. Older adults and persons with compromised immune systems are at greatest risk of becoming ill after a West Nile infection.

The disease can take two forms. The milder form is known as West Nile fever. In addition to fever, people with this form of the disease may also experience headache, body aches, skin rash, and swollen lymph glands. The more severe form of West Nile infection is known as encephalitis (an inflammation of the brain). People with encephalitis may experience high fever, headache, neck stiffness, disorientation, tremors, convulsions, paralysis, and coma. Dr. Johnson advises anyone with any of these symptoms to immediately contact their health care provider.

There is no specific treatment for West Nile virus. For severe cases, hospitalization is needed and illness can be associated with long-term disabilities and death.

Since it was first identified in Pennsylvania in 2000, West Nile virus has been found in all areas of the state and has returned each summer. Pennsylvanians should presume that West Nile virus is present throughout the state during the warmer periods of the year and should take appropriate precautions.

In 2006 there were nine human cases of West Nile virus and two related deaths. In 2005 there were 25 human cases and two related deaths. In 2004 there were 15 cases of human West Nile virus, resulting in two fatalities.

For more information about West Nile virus, including current test results for mosquitoes, birds and horses, visit the West Nile virus website at www.westnile.state.pa.us or call the Department of Health at 1-877-PA HEALTH.

http://www.solanconews.com

Avandia should stay on shelves, U.S. panel says

DAVID ANDREATTA

From Tuesday's Globe and Mail

July 31, 2007 at 9:28 AM EDT

The widely used diabetes drug Avandia should stay on the market in the United States with a warning about increased risks of heart diseases, a panel of medical experts recommended to the U.S. Food and Drug Administration yesterday, in a decision that went against the urging of one federal scientist that the medicine be withdrawn.

The FDA is expected to follow the recommendation, although officials said it will need some time to make a final decision.

It was the latest development in the continuing saga of Avandia, a controversial drug manufactured by GlaxoSmithKline PLC that was the third most commonly prescribed oral pharmaceutical last year for the roughly 1.8 million Canadians with Type 2 diabetes.

The FDA was expected to follow the panel's recommendation, even though one of its own scientists testified earlier that the medicine should be pulled from the market because of increased heart risks.

Health Canada, which has confirmed that 19 Canadians have suffered fatal heart problems while using Avandia since its approval here in March, 2000, is conducting its own analysis of the drug.

The medicine's benefits are still deemed to outweigh its risks, an agency spokesman said.

Alastair Sinclair said a preliminary review of the 19 deaths suggests a possible link between the drug and six of the fatalities. In all, the agency has received 243 reports of adverse cardiovascular reactions to the drug, including 31 heart attacks, but said that they had not established a link between the cardiovascular problems and the drug.

"Medical and scientific information is continuously evolving, and the results of the advisory panel will be considered in Health Canada's assessment of Avandia, as will the findings of a number of scientific studies," Mr. Sinclair said.

The panel was convened by the FDA two months after a study published in The New England Journal of Medicine linked the drug to a 43 per cent higher chance of having a heart attack among sufferers of Type 2 diabetes.

Glaxo executives argued before the panel that there is no increased risk, citing its own studies of the drug.

"The number of heart attacks across all sources of data is small, the data are inconsistent, and the totality of evidence does not show a difference between Avandia and the most commonly prescribed anti-diabetic agents," read a summary of the company's defence to the committee.

According to IMS Health Canada, a private firm that collects information on the prescription drug market, nearly 1.2 million prescriptions for the drug were filled in Canada last year at a retail value of about $156 million.

Warnings of heart risks associated with Avandia have been around since it was authorized for mass distribution in Canada and the United States. Just four months after the drug was approved here, a group of physicians in British Columbia sounded the alarm about Avandia, citing side effects that included weight gain and a spike in so-called bad cholesterol.

"It was doing things that were known to be associated with adverse cardiovascular outcomes," said Jim Wright, a professor of pharmacology at the University of British Columbia and managing director of Therapeutics Initiative, the independent organization of physicians that raised the concern in a newsletter to doctors.

"There really is no evidence that the benefits outweigh the harm," Dr. Wright said in a telephone interview. "There was lots of time for [Health Canada] at that point to have done a trial and they didn't do it."

A year later, in July, 2001, Glaxo was reprimanded by the FDA about its promotion of Avandia and for playing down safety concerns. The company subsequently fired off letters to doctors warning them of risks of heart failure.

In a letter to Canadian doctors dated Nov. 13, 2001, Glaxo warned that Avandia could cause fluid retention, which, the company wrote, "can exacerbate or lead to congestive heart failure."

Canadian diabetes experts yesterday cautioned against reacting too hastily to the developments south of the border.

Lawrence Leiter, head of the division of endocrinology at St. Michael's Hospital in Toronto, said the drug is effective at lowering blood sugar and pointed to studies showing that half of all diabetics in Canada do not have their blood sugar under control.

"We don't want to unnecessarily lose a drug that can be very useful," Dr. Leiter said. "Right now, we have conflicting data."

Whitney Binns, spokeswoman for the Canadian Diabetes Association, recommended that diabetics on Avandia consult their doctors about the appropriate course of action and said the organization trusted that Health Canada would advise the diabetic community of its findings shortly.

http://www.theglobeandmail.com