Medical Research Today

Old Age Is a Too-Easy Culprit for Sudden Decline (Johns Hopkins Medical School)

2010-03-13T11:51:00.000-08:00

Ahmet Hoke

Looking back to events that began two years ago, Emilie Daly can now recognize the subtle signs that her health was not right. It began, she now realizes, with an occasional tingling in her feet. Sometimes her legs felt weak. Then she started having trouble opening jars and turning the faucet.

At first, Daly didn’t pay much attention. She was 86, after all. “That’s just what happens when you get old,” she told herself. But over the next few months, her entire body grew weaker. “I couldn’t feed myself, write, stand, dress myself,” says Daly.

As her health declined, Daly’s son and daughter-in-law, Ned and Kitty Daly, took her to several doctors, and eventually, she was admitted to the hospital. But the doctors found nothing wrong that could account for Daly’s symptoms beyond “old age,” and they referred her to a rehabilitation facility, where she remained for several months.

By then, Daly had started to wonder whether her advancing years could really account for her condition. “I couldn’t even lift a pencil,” she says. Such frailty is not a normal consequence of aging. Kitty Daly, too, had not given up hope. She continued to seek the advice of various health professionals. Eventually, she spoke to a neurologist who suggested that Daly might have a condition called chronic inflammatory demyelinating polyneuropathy, or CIDP, and referred her to Johns Hopkins.

After examining Daly and reviewing her medical history, neurologist Ahmet Hoke agreed with her referring physician that she almost certainly had CIDP. The disease occurs when the immune system attacks the myelin sheath, the fatty covering that coats and protects nerve cells. As the damage progresses, nerve function declines, and the muscles stimulated by those nerves weaken. Daly’s symptoms, Hoke concluded, were strong signs that her body was experiencing such a reaction.

First, the tingling and numbness in her fingers and toes—technically called paresthesias—were not normal symptoms of “old age,” says Hoke. Another clue was the fact that her weakness began in her feet and legs and ascended upward, “textbook classic” of CIDP, says Hoke. To confirm his diagnosis, Hoke also performed a nerve conduction study, a test used to evaluate how well nerves conduct electrical signals. The test showed that Daly did indeed have CIDP.

Hoke prescribed a series of intravenous immunoglobulin treatments—basically, large doses of antibodies intended to reboot the immune system. After two rounds of the therapy, Daly says, her health had returned.

Daly has since resumed the active life she led before the onset of her illness, driving herself to the grocery store, playing duplicate bridge, and going to the fitness center three times a week.

“We often attribute weakness and frailty in older people to old age,” says Hoke. “But if these conditions develop rapidly, we should suspect something else. Just because somebody is elderly, you shouldn’t stop thinking about treatable causes.”

For more information: 410-955-9441

Strokes Happen in Young as Well as Old (Johns Hopkins Medical School)

2010-03-11T15:31:00.000-08:00

It's well worth the risk of surgery to correct moya moya disease in children, says Ahn.

One morning, a 15-year-old girl stumbled down the stairs of her family’s Baltimore home, walked crookedly to the couch and lay down. When her father asked her what was wrong, she did not reply. He assumed his daughter was “faking it” to get out of going to school. Only later that evening, when she was unable to move one side of her body or speak properly, did he realize that something was seriously wrong.
The girl had had a stroke.

Although the teenager recovered, “the father felt terrible,” says pediatric stroke specialist Lori Jordan, who treated the girl after she was taken to The Johns Hopkins Hospital. “He just kept saying that he didn’t know that kids could have strokes.”

Jordan, who has heard that misconception all too often, tries to correct it by speaking about pediatric stroke at medical conferences for groups of paramedics, nurses and physicians. Pediatric stroke, she says, is at least as common as brain tumors in children. At least three out of every 100,000 children have a stroke each year. In newborns, the rate is about one out of 4,000.

“Parents see symptoms that they would recognize as stroke in adults, but they don’t in children,” says Jordan. On average, a child who has had a stroke is not presented for medical care for about 20 hours. Doctors, too, often miss the diagnosis. In an Australian study, children who had experienced a stroke were diagnosed on average 10 hours after being admitted to the hospital.

The sooner a child is brought to the hospital, the sooner doctors can provide the special care that will help protect the brain and avert a subsequent stroke, says Jordan, who co-directs the Johns Hopkins Pediatric Stroke and Neurovascular Center. The center’s team of neurologists, neurosurgeons, interventional neuroradiologists, hematologists, cardiologists and intensive care physicians diagnose and treat about 100 pediatric stroke patients each year. They have extensive experience treating patients with sickle cell disease and heart disease, two of the most common underlying causes of pediatric stroke.

In addition, the center specializes in a surgical procedure for patients who have moyamoya disease. The rare condition, affecting only about one in a million people, stems from blocked arteries at the base of the brain. These children naturally progress to have repeated strokes, says neurosurgeon Edward Ahn. In operating on children with moyamoya disease, Ahn isolates the superficial temporal artery from the scalp and grafts it onto the brain’s cortex. The procedure, he explains, stimulates the growth of healthy new vessels that can deliver blood to the afflicted brain region.

The surgery itself poses a risk of stroke, notes Ahn. However that risk—about 4 percent—is significantly less than the almost inevitable chance of stroke that children with moyamoya disease face otherwise.

Still, despite all the medical care available for pediatric stroke patients, scientists have a lot to learn about the condition, says Jordan. She and her Johns Hopkins colleagues are involved in several multicenter studies of pediatric stroke, including one aimed at determining the causes of hemorrhagic stroke and another focused on improving methods for monitoring brain function. They are also planning to participate in multicenter studies looking at the role that infection and inflammation may play in pediatric stroke. Soon they'll examine the use of clot-busting drugs in young stroke patients.

In the field of neurology, says Jordan, “pediatric stroke research is exploding.”
For information: 410-955-4259

Yale Study Offers Insight into Possible Cause of Lymphoma

2010-03-07T15:37:00.000-08:00


	David Schatz

New Haven, Conn. — The immune system’s powerful cellular mutation and repair processes appear to offer important clues as to how lymphatic cancer develops, Yale School of Medicine researchers report this week in Nature.
“The implications of these findings are considerable,” said David Schatz, a Howard Hughes Medical Institute investigator, professor of immunobiology at Yale, and senior author of the study. “It now seems likely that anything that compromises the function of these DNA repair processes could lead to widespread mutations and an increased risk of cancer.”
The lymph system is made up of infection-fighting B cells. Schatz and his colleagues examined the somatic hypermutation (SHM) process, which introduces random mutations in B cells’ antibody genes to make them more effective in fighting infection.
SHM occurs in two steps: First, a mutation initiator, or activation-induced deaminase (AID), causes genetic mutations. Second, DNA repair enzymes spot the changes and begin making “sloppy” repairs, which lead to yet more mutations. The two steps combined, Schatz said, present a major risk to genomic stability.
Interestingly, these same repair enzymes recognize mutations in many other types of genes in the B cells, but they fix the genes in a precise, or, “high fidelity,” manner.
Up until now it was thought the risk to genomic stability was avoided for the most part because the first step of the SHM process only happened in antibody genes. But this study found that AID acts on many other genes in B cells, including genes linked to lymphatic cancer and other malignancies.
“And then we had another surprise,” Schatz said. “Most of these non-antibody genes do not accumulate mutations because the repair, for whatever reason, is precise, not sloppy.”
What this means, Schatz said, is that researchers studying lymphatic cancer must understand both the first and the second step—the original mutations and then the repair process.
“If the precise, or high fidelity, repair processes break down, this would unleash the full mutagenic potential of the initial mutation, resulting in changes in many important genes,” Schatz said. “We hypothesize that exactly this sort of breakdown of the repair processes occurs in the early stages of the development of B cell tumors.”

Brain Surgery's GPS (Johns Hopkins Medical Center)

2010-03-04T15:33:00.000-08:00

By: Judy F. Minkove

New technology at Johns Hopkins Bayview Medical Center gives neurosurgeons--and patients--an edge

Johns Hopkins Bayview’s Neurosurgery Chair Alessandro Olivi, with nurse coordinator Allison Godsey. Says Olivi, “This technology helps us verify positions and detect potential complications.”

More than a century ago at Hopkins, Harvey Cushing, widely regarded as the greatest neurosurgeon of the 20th century, performed the first successful operation for brain tumors. Seventy years later, CT scans would revolutionize brain surgery again. Still, brain tumor patients needed postsurgical scans to see if all the growth had been removed. If not, the patient had to schedule additional surgeries, raising risks for infection and other complications.
Now, Johns Hopkins Bayview Medical Center has found a better way. Since last November, the hospital’s two new neurosurgical operating rooms have been sharing a coveted “intraoperative” CT scanner that gauges a surgery’s progress with razor-sharp precision during and immediately following procedures—while the patient is still prepped for surgery. This eliminates the need to move the patient out of the OR and into the radiology department. If a correction is needed, the patient is ready to be moved right back into surgery.
Hopkins Bayview is the first hospital on the East Coast and the second in the United States to offer this hardware and software working together in connected operating rooms. “There’s a lot of excitement among our neurosurgeons about this,” says lead CT tech Patrick Tyler. “We used to be able to get 60 percent to 70 percent of tumors out during surgery. With this new technology, the doctors project capturing 98 percent of all tumors.”
“Intraoperative CT will make us more effective and provide more safety to patients in the OR,” says Alessandro Olivi, Hopkins Bayview’s neurosurgery chair. “It will be useful when we place catheters into the brain or screws in the spine. It will help to verify their position and make sure that bleeding from the brain has been completely stopped before we take the patient away from the OR.”
Learning this technology was no small feat. Months earlier, the hospital sent a multidisciplinary team to Carondelet Neurological Institute in Tucson, where the only other iCT in the country is housed. Led by former Hopkins Bayview neurosurgery resident Eric Sipos, who is now medical director at the Arizona Institute, the training has also built professional relationships. As time goes on, teams at both hospitals will be able to merge outcomes data to evaluate the effect of the new technology on patients’ experiences.
Brand new technology also debuted recently at Hopkins Bayview’s adjoining new endovascular operating room, aiding surgeons as they treat a wide range of complex vascular conditions. The fixed, ceiling-mounted system in a sterile surgical environment means combination cases can be performed at one time, which is better for the patient—instead of using an interventional radiology suite and then having another procedure in the operating room.
The only drawback to these new developments, says Tyler, is that it puts additional pressure on his staff of about a dozen techs to work longer hours—a small price to pay, he adds, for better outcomes.

Asthma: from mouse to man and back again (Yale Medical School)

2010-03-02T15:40:00.000-08:00

Bench-to-bedside approach yields important insights into a common disorder

It all started with a mouse, says Jack A. Elias, M.D., chair of the Department of Internal Medicine and an expert on lung diseases. A few years ago, Elias, the Waldemar Von Zedtwitz Professor of Medicine, discovered that mice he had engineered to develop asthma had high levels of a very unusual enzyme. The enzyme, chitinase, is more commonly found in plants and lower organisms, where it breaks down chitin (pronounced “ky-tin”), an abundant and sturdy sugar polymer that gives insect and crustacean shells their resilience and strength. In humans, chitinases are thought to provide a first line of defense against fungi and some parasitic worms that also bear outer coats containing chitin.

Jack Elias (left) and Geoffrey Chupp have discovered a protein that regulates the immune response, and hence the severity of inflammation and cell damage, in asthma and other conditions.

That result was intriguing, because environmental exposure to indoor pollutants such as fungi and dust mites has been blamed for the growing incidence of asthma over the last decades. Translating the chitinase finding quickly from mice into humans, Elias and Geoffrey L. Chupp, M.D., associate professor of medicine and director of the Yale Center for Asthma and Airway Disease (YCAAD) soon discovered that people with severe asthma have high levels of a chitinase-related protein, YKL-40, in their blood. Then, they found that YKL-40 plays a central role in regulating the immune response and driving the lung inflammation that is at the root of asthma. The work could lead to new methods for diagnosing and treating asthma, a disease that affects an estimated 20 million Americans, including 9 million children.
In the mouse experiments, YKL-40 was not the original protein of interest for Elias. It is not a true chitinase; YKL-40 can bind to chitin, but it lacks the enzymatic activity required to break down the tough polymer. However, as reported in The New England Journal of Medicine in 2007, YKL-40 was known to circulate in the blood, and it could be measured with a simple test. “We saw this chitinase relative and thought ‘the cousin may actually be prettier than the girl we’d been dating,’ ” Elias said, describing the investigators’ early attraction to YKL-40 as a potential blood marker of asthma.
Enter Chupp, a skilled researcher whom Elias had recruited to Yale in 1997. Chupp had taken on the challenge of building up a clinical research program on lung diseases to parallel the basic research effort Elias had organized at the medical school.
The result was YCAAD, an active clinic that draws referrals from all over Connecticut and surrounding states. Besides receiving the best available treatment, Chupp says, all the patients at YCAAD get the opportunity to contribute to research. So far, he has enrolled more than 500 subjects into a well-characterized cohort of asthma sufferers, many of whom have a severe form of the disease.
Because of the presence of YCAAD, when YKL-40 popped up in the mouse studies, Chupp had everything ready to go to apply the findings to human disease. After measuring YKL-40 levels in blood samples from 200 patients, the researchers found that the protein was elevated in people with asthma, and its levels were highest in those with severe disease. The same held true in two other patient groups they tested, from Wisconsin and Paris. Levels of YKL-40 in the blood and lungs of these patients correlated with the use of medication to control asthma, with how often people were hospitalized and with the appearance of irreversible lung damage. For the first time, the severity of airway scarring could be measured by looking at a blood sample.
The next question was whether high levels of YKL-40 caused asthma symptoms or merely signaled the damage wrought by the disease. To find out, Chupp looked for differences in the genetic makeup of people with high or low YKL-40. The results, reported earlier this year, also in The New England Journal of Medicine, show that people who have a particular version of the YKL-40 gene tend to have a higher blood level of YKL-40, and along with that, a greater risk of getting asthma.
Those results were suggestive, but still did not prove that YKL-40 caused any of the pathological changes of asthma. To settle that question, Elias and Chupp went back to mice, genetically engineering them to have either none of the mouse equivalent of YKL-40, or too much. The result, they say, was clear. Animals lacking the protein were resistant to developing the type of inflammation that causes asthma, while animals with extra protein had an overactive immune response and more severe disease.
Further work revealed that YKL-40 is part a novel regulatory pathway governing the level of inflammation in asthma and in other conditions. The protein works by slowing the rate at which activated immune cells die off.
“We believe YKL-40 is a kind of a rheostat that sets the level of inflammation,” Elias explains. “If you’re a normal healthy person with a normal to low level of the stuff, when you have inflammation, it clears normally, but if you’re a person with high levels of YKL-40, you end up with a more robust and chronic response and the consequences are therefore worse.”
The latest findings suggest that not only is the protein a potential disease reporter, but also a likely target for new therapies. The YKL-40 story is a perfect model of how the interplay of animal and human research can speed basic discoveries to the clinic, Elias says. The work proceeded so rapidly because Yale’s group of asthma experts functions as an integrated unit. “We have master clinicians on one side and master scientists on the other side and the two constantly interact with each other,” he explains. “We believe that you have to bounce back and forth to move things forward.”

Surgery Sooner Rather Than Later May Be Best for Drug-Resistant Epilepsy (Johns Hopkins Medical School)

2010-02-27T15:22:00.001-08:00

George Jallo and Fred Lenz:

When medications aren’t controlling seizures, there are alternatives.

Many epilepsy patients spend years searching for a drug that can control their seizures, a quest that can lead them to try a dozen or more different medications. Until recently, many of those patients and their doctors considered surgery a last resort: Patients receiving surgery for epilepsy have had the condition, on average, for 22 years.

Now some epilepsy specialists are shifting their view; they say that patients with certain forms of the disorder, whose seizures cannot be controlled with medication should not wait that long before considering surgery. “Seizure surgery is really not a last option,” says neurologist Greg Bergey, director of the Johns Hopkins Epilepsy Center. “There’s more of an appreciation that surgery can render people seizure free and should be considered after several years if medications do not provide seizure control.”

Not having seizures managed isn’t a reasonable option, says neurosurgeon Fred Lenz. The health consequences include memory loss, an increased risk of accidents and reduced life expectancy.

What’s brought the change in philosophy about surgery, Lenz explains, arises from a growing body of research on the 20 percent to 40 percent of epilepsy patients who fall into the “intractable” category—most with the form called temporal lobe epilepsy.

In one set of studies, results suggest that patients whose seizures persist even after they’ve tried as few as two or three different epilepsy drugs are unlikely to find effective medication. “The odds of improving your chances on the third or fourth or fifth drug are vanishingly small,” says Lenz.

Still other research examines how patients fare after surgery for temporal lobe epilepsy. In the typical procedure, surgeons remove the small, focal portion of brain tissue that generates a patient’s seizures. Some 60 percent to 90 percent of patients who undergo an operation no longer have disabling seizures, even though some may still need to take anti-epilepsy medication.

Technical advances have influenced most neurosurgeons’ views on epilepsy surgery. The ability to image seizures in the brain through MRI and PET has improved dramatically in recent years. In addition, epilepsy specialists now have improved methods to analyze the electrical activity of a patient’s seizures using advanced digital recording technology. “And the quality of the technology has improved a lot,” says Lenz. “We can now localize seizures’ focal points in the brain with a definition we never had before.”

Hopkins neurosurgeons perform about 45 epilepsy operations per year, about one quarter of them pediatric cases. The latter reflects a pediatric shift to the sooner-is-better-than-later approach for children with intractable seizures, says pediatric neurosurgeon George Jallo, who’s operated on children as young as 1 year. (In contrast to adults’ temporal lobe seizures, most children’s seizures arise in the frontal lobe or other non-temporal areas.) “Children tend to do great,” Jallo says. “They generally recover better than adults.”

That said, surgery isn’t appropriate for every epilepsy patient. It generally works best on those whose seizures originate in a relatively small focal area of the brain, says Lenz. Patients with more diffuse seizures or with seizures that come from multiple regions or both sides of the brain are often not good surgical candidates.

As in any form of brain surgery, there are risks, including stroke, hemorrhage and infection. “Patients need to assess these and the likely benefits carefully with a neurologist before considering surgery,” advises neurologist Gregory Krauss. Still, for many patients, he adds, the consequences of continued uncontrolled seizures far outweigh any risks.

For more information: 410-955-6406

Cartilage Replacement Using The Body's Own Cells: Fast, Affordable And A Perfect Fit

2010-02-25T10:39:00.000-08:00

Injuries to joints and cartilage can have serious consequences, including osteoarthritis. Cartilage degeneration in joints is a widespread disease in Germany and worldwide. Prof. Dr. Prasad Shastri is an expert in tissue engineering (TE), tissue construction and tissue cultivation using the body's own cells. He is Professor of Biofunctional Macromolecular Chemistry at the Centre for Biological Signalling Studies (BIOSS), a Cluster of Excellence at the University of Freiburg, where he has been researching for the last year. Together with peers from Maastricht and Nashville, he has developed a fast and cost-efficient method for producing sufficient amounts of bone and cartilage tissue using the body's own cells.

Damage to larger joints such as knees, feet, hips and shoulders is often the beginning of a painful process during which mobility continues to decrease. Because cartilage cannot regenerate after the body has stopped growing, defects caused by injuries and "wear and tear" cannot be absorbed by producing new cartilage. Genetic engineering and molecular biology have now made it possible to remove healthy cartilage cells and grow these outside the body in special solutions. This cartilage tissue is then applied to the defective cartilage where it attaches and grows. Repairing cartilage and bone damage using the body's own cells is still a difficult process. Cultivating the body's own tissue is still time-consuming and expensive, and much time is needed until the implant has reached its desired functionality. In their article published in the renown American journal PNAS, Dr. Prasad Shastri and his co-authors present a strategy for the "de novo engineering" of cartilage and bone tissue which requires only three weeks.

The scientists even successfully generated large pieces of bone tissue using Agarose gel, a common biomaterial in biochemistry. The gel is injected into the double membrane surface on bones, using this space as a biological reactor. According to the main argument in the article, the resulting lack of oxygen (hypoxia) in that confinement induces and stimulates the development of bone tissue and cartilage. Studies have shown that the cultivated cartilage tissue adapts well to its new environment and shows no signs of calcification even after nine months.

Source: Albert-Ludwigs-Universitat Freiburg

Why Do People Become Lactose-Intolerant? Scientists Turn to DNA in an Attempt to Answer Why Adults Develop Trouble Digesting Milk But Can Eat Ice Cream (from the Wall Street Journal)

2010-02-19T06:46:00.000-08:00

By Shirley S. Wang

Most of us drank milk every day when we were young without a problem. Then, sometime in our teens or early 20s, we start to feel bloated or have discomfort after consuming a lot of milk, typically two or more glasses at a time.
Scientists have discovered that most people develop some degree of lactose intolerance as they get older. Why we lose this ability to break down lactose, the key sugar found in milk, is a puzzle that researchers have been trying to figure out. The National Institute of Child Health and Human Development, part of the National Institutes of Health, will hold its first conference on the topic next week.
It is unusual for people to lose the ability to digest a nutrient as they age. But most people stop making large quantities of "lactase"—the enzyme that breaks down lactose—after childhood, says Eric Sibley, an associate professor of pediatrics at the Stanford University School of Medicine, who has been studying why people develop lactose intolerance as they get older.

So Young Lee/Journal of Biological Chemistry 2002

Most people stop making large amounts of lactase—the enzyme that breaks down lactose, pictured above—as they age.

Most people continue to produce some lactase, but at much-diminished levels. After they reach their individual threshold and can no longer break down lactose, it passes intact through the intestine until it reaches the colon, where it is finally fermented by the bacteria that reside there. As the bacteria do their job, they produce gas as a byproduct, which causes discomfort and pain as well as symptoms such as cramping and diarrhea.

Training the Bacteria

Some people, after diagnosing themselves, cut out regular consumption of dairy—which can potentially make symptoms worse when they do consume it. The bacteria in the gut can become less efficient at processing lactose if they aren't continually asked to do it. Conversely, people can train the bacteria to tolerate more dairy if they consume it regularly.
By understanding which genes and proteins are responsible for turning off lactase production, scientists are hoping they can then flip a genetic switch to turn the system back on—but only in the intestine. The hope is one day to be able to "program the intestine to take on the ability to maximally use nutrients," says Dr. Sibley.
This type of complex localized gene therapy isn't likely to be used in run-of-the-mill lactose-intolerant individuals, who can just watch the amount of dairy that they consume or take enzyme supplements. Instead, says Dr. Sibley, it could be used to treat children with serious digestive diseases, such as short bowel syndrome, get the nutrients they need.
Dairy products that have gone through some processing, such as cheese and ice cream, tend to have less lactose because the fermentation process breaks some of it down. But those with an intolerance should keep an eye out for lactose that has been added to products like cookies by reading the food label, says Gilman Grave, acting director of the National Institute of Child Health and Human Development's Center for Research for Mothers and Children.
A separate group of individuals have an allergic reaction to milk that isn't related to lactose. Instead, they are allergic to a protein in cow's milk and tend to have more blood in their stool and abdominal pain, instead of bloating. The allergy typically fades after childhood.
For years, doctors thought that lactose intolerance primarily affected individuals from certain parts of the world, such as Asia and Africa. But newer evidence suggests the opposite is true. Most adults develop lactose intolerance. Only a minority—those descended from herding cultures in northern Europe and parts of Africa—have a mutation that allows them continue to break down lactose into adulthood. The misperception likely developed in part because so many Americans are of northern European descent and have the mutation.
"A lot of people are self-diagnosing themselves with being lactose-intolerant just because they're a member of a certain ethnicity, and they may not be," Dr. Grave says.
Dr. Sibley, who holds a doctorate in biochemistry and also is a pediatric gastroenterologist at Lucile Packard Children's Hospital at Stanford, has spent more than 15 years in the lab investigating genes and proteins that tell the lactase system to shut down production.
To track whether the lactase gene is turned on or off, Dr. Sibley borrowed the firefly's "luciferase" gene, which is responsible for lighting up the firefly's tail. Light is emitted when the gene is turned on.
In the lab, Dr. Sibley and his colleagues take fragments of DNA from regions they think are important to lactase production and graft them into the luciferase gene. They then implant the combination gene into human intestine cells in a dish and allow them to grow. If the DNA fragment indeed starts the lactose production process, it turns the gene on. Thanks to the graft, the turned-on gene emits light, which can be measured.
Using these methods, Dr. Sibley figured out what section of DNA appeared to be responsible for turning the lactase system on and off. In cells from people descended from northern Europeans, a single genetic mutation was associated with the continued ability to tolerate lactose.
They then took cells with those mutations, and in a dish, showed that they increased luceriferase production, which suggests the mutation does change the cell's behavior. These findings were published in 2003 in the journal Human Molecular Genetics.
With the small segment of the African population that is lactose-tolerant, the mutations appear to be slightly different but are located in the same region of the DNA.

Multiple Proteins

Dr. Sibley and his colleagues have also identified several key proteins that must be bound to specific regions of the lactase gene and in the right combinations in order to turn on the gene. One protein they are currently studying, called PDX-1, appears to suppress lactase production in cells in the dish. But when the group generated mice that don't make PDX-1, lactase production was only slightly increased. This suggests that there are multiple proteins working together to suppress lactase and that PDX-1 alone isn't enough to turn the system off completely, says Dr. Sibley.
They also are working to figure out which segment of the DNA sequence tells the lactase gene to produce lactase in certain cells of the intestine but not others, and when the system should be turned off. The ultimate goal of this line of research would be to be able to turn on genes in cells in the intestine that don't naturally produce it, says Dr. Sibley.
Individuals who are worried they are lactose-intolerant can do a self-test by cutting out dairy for two weeks and seeing if their symptoms subside, says Dr. Sibley. There is also a breathalyzer test that measures the amount of hydrogen in the breath, which is a byproduct that bacteria produce if they are breaking down lactose. Most individuals don't need it to be diagnosed with lactose intolerance, according to Dr. Sibley.
For most individuals, lactose intolerance doesn't mean they should permanently cut out all dairy. Studies have shown that people who are lactose intolerant can drink one to two glasses of milk a day without symptoms, says Dr. Grave, who encourages all people without allergies to drink this amount. Many people say their symptoms actually improve when they regularly drink milk, perhaps because the bacteria in the colon break down lactose more efficiently or the number of bacteria build up, he says.
Another reason to drink milk: calcium. If children in particular don't get the amount of calcium they need, their growth and skeletal health may be compromised, says Dr. Grave. A New Zealand study showed that kids on a dairy-free diet get only one-third of their needed daily calcium and had a higher fracture rate, compared with kids who consumed dairy.
It is certainly possible to get calcium from other foods, but people would have to eat vast amounts of it in order to get the same amount found in dairy, says Dr. Grave. For instance, you would have to eat many servings of spinach in order to absorb the same amount of calcium you would get in one cup of milk.
Write to Shirley S. Wang at shirley.wang@wsj.com

Molecular Pathways Linked to Sex, Age Affect Outcomes in Lung Cancer

2010-02-15T10:46:00.000-08:00

By Duke Medicine News and Communications
The biology of lung cancer differs from one patient to the next, depending on age and sex, according to scientists at Duke University Medical Center.

The findings, appearing in the Journal of the American Medical Association, may help explain why certain groups of patients do better than others, even though they appear to have the same disease.

“Our study supports two key findings: First, the biology of lung cancer in women is dramatically different from what we see in men. Women, in general, have a less complex disease, at least in terms of the numbers of molecular pathways involved. We also discovered that there is a subset of elderly patients would probably benefit from treatments that we’ve normally reserved for younger patients,” says Anil Potti, MD, an oncologist in the Duke Institute for Genome Sciences & Policy (IGSP), and the senior author of the study.

Potti says that in the past, physicians have had to rely on very rough measures to categorize patients’ lung cancers, factors such as the size of the tumor, the tissue type and the degree to which the cancer had spread.

“But this new information tells us that we can analyze patients’ disease much more discretely,” says Potti. He says the information could also be used to enrich the selection process in clinical trials designed to evaluate new drugs aimed at specific molecular targets.

Physicians have long observed that over time, women with lung cancer tend to do a little better than men, and that younger patients do better than older ones. Potti found that women tend to have only a few cancer-promoting pathways activated in their tumors, where men may have twice as many.

Potti and a team of researchers in the IGSP studied clinical data and accompanying genomic information obtained from tumors of 787 patients with predominantly early stage non-small cell lung cancer (NSCLC), the most common form of the disease. They gathered tumor samples and corresponding microarray data showing which genes were activated in the tumors, then selected twelve of the most common molecular pathways that become dysregulated in NSCLC.

The goal was to identify any patterns linking the pathways to age, sex and time to recurrence. They sorted the patients by age and sex and then again into low- and high-risk groups, based on five-year, recurrence-free survival.

They found that certain molecular pathways were more frequently activated in some groups than others and that certain pathway patterns were associated with better long-term survival in patients with lung cancer. Specifically, they found that:
High-risk patients -- those with the shortest time to recurrence -- were significantly more likely to have increased activation of the pathways responsible for tumor metastasis and necrosis, when compared with low-risk patients.
High-risk patients 70 or older were found to have higher activation of pathways regulating blood supply and invasiveness.
In comparing high-risk women to high-risk men, they found that men were more likely to have a much more complex pattern of multiple pathways being activated than women with the same type of lung cancer.

The study also identified a subset of patients over age 70 who had a low-risk profile, meaning the molecular pathways activated in their tumors would likely give them a better chance at long-term survival. Potti says that’s important because people over age 70 are generally not included in many clinical trials and physicians often hesitate to offer them the option of conventional chemotherapy.

“The thinking has been that they may not withstand the treatment or benefit from it much. But now we know that it probably makes sense to consider treating this population, by risk-stratifying the disease,” says Potti.

Potti says it is likely that there are additional cancer-promoting pathways that are involved in the development and progression of NSCLC and adds that these findings must be validated in other studies. But he said the set of 12 known oncogenic pathways they chose to study are significant “because we already have drugs that can regulate many of them.”

“People still don’t realize how bad a disease this is,” says Jeffrey Crawford, MD, a study co-author and the chief of medical oncology at Duke. “Lung cancer kills more than 150,000 patients each year in the U.S. -- more than breast, prostate, colon and ovarian cancer combined. Unfortunately, there is a patient dying from lung cancer every three minutes in this country. So being able to better understand the disease and stratify patients by their individual molecular profiles means we can do a much better job pairing the right drug with the right patient.”

The study was funded by grants from the Emilene Brown Cancer Research Fund, the Harold and Linda Chapman Lung Cancer Fund, the Jimmy V Foundation, the American Cancer Society and the National Cancer Institute.

Duke colleagues who contributed to the study include lead authors William Mostertz, Marvaretta Stevenson, Chaitanya Acharya, Isaac Chan, Kelli Walters, Wisut Lamlertthon, William Barry, Jeffrey Crawford and Joseph Nevins.

How To Recognize A Heart Attack, Or Avoid One All Together

2010-02-14T10:31:00.000-08:00

Not everyone who suffers aheart attack clutches their chest and falls to the floor. "I woke up and felt like a pill was stuck in my throat," says Betsy, a 68-year-old patient from Upper Providence. "I was taking antibiotics at the time and really didn't think much of it," she adds. "So I tried drinking water and when the "stuck" feeling didn't go away after 45 minutes, I thought something might be wrong."

"My son took me to the Emergency Room and yes, now I realize I should have called 9-1-1 immediately." After the ER staff ran an EKG (a test that measures the electrical activity of the heart), they told Betsy she was having a heart attack. "Next thing I knew, they took me right to the cardiac cath lab and inserted a stent to open up my artery. After two days in the hospital, I came home and started cardiac rehab three times a week for about the last 5 weeks."

Betsy's recovery also involved making important changes to her lifestyle like quitting smoking, "which I really didn't want to do, but I had to," watching her cholesterol, and making time for daily exercis whether it's walking or using free weights.

"What's amazes me most is that I didn't even realize I was having heart attack. Had I waited much longer, things may have turned out very differently."

Betsy is one of an estimated 650,000 Pennsylvanians, ages 35 and over, who have been told by a doctor that they've had a heart attack. In the January 2010 Patient Poll conducted by the Institute for Good Medicine at the Pennsylvania Medical Society, 34 percent of those surveyed said they'd know they were having a heart attack because their chest and arms would hurt.

Not necessarily so, says C. Richard Schott, MD, a Philadelphia-area cardiologist and Pennsylvania Medical Society member. "Pain isn't always an indictor. Any new pressure or discomfort in the upper body can signal a heart attack."

Warning Signs

Dr. Schott urges patients to pay close attention to these heart attack warning signs:

-- Pressure or discomfort in the chest/upper body

-- Discomfort radiating to the left arm, jaw, back, neck or stomach

-- Shortness of breath

-- Sweating, nausea, dizziness

If you experience one or more of these symptoms, it's best to call 9-1-1 right away. "Err on the side of caution and assume it may be a heart attack. The longer you wait, the more damage is done to your heart." Dr Schott also notes, "And the only ride you should take to the ER is in an ambulance they can alert the cardiac team in advance of your arrival and, if your heart stops, emergency personnel can begin treatment immediately."

Who's at risk?

Betsy's smoking, age, and sedentary job put her at risk for a heart attack. Here's what else matters:

1. Family History If your father had heart problems before age 55 or your mother had problems before age 65, or if your brothers or sisters have had heart attacks, talk with your doctor and be especially careful to minimize other risks.

2. Smoking Heart health is only one of many reasons to quit.

3. Cholesterol Cholesterol abnormalities, meaning both high LDL (bad cholesterol) and low HDL (good cholesterol), in some cases, can be controlled through diet and exercise. Often, however, medication may be needed.

4. High Blood Pressure Hypertension (chronic high blood pressure), is a condition with few or no self-evident symptoms. It may be controllable through diet and exercise and, as with cholesterol levels, with medication.

5. Diabetes If you have diabetes, you have a much higher risk of heart attacks which may occur with atypical symptoms. It is extremely important to work with your doctor to manage your diabetes.

6. Physical inactivity -- Regular, moderate-to-vigorous physical activity can help control blood cholesterol, diabetes, and obesity, as well as help lower blood pressure and reduce your risk of heart attack.

Prevention

Beyond recognizing and responding to heart attack symptoms, Dr. Schott says that he and his member colleagues encourage patients to take steps now to prevent heart attacks or repeat heart attacks.

"The same advice applies, whether you've had a heart attack or would like to keep your heart healthy:

-- Don't smoke.

-- Manage your blood pressure and cholesterol.

-- Eat healthy and exercise daily.

Betsy fortunately got the message about a healthier lifestyle and we've worked together to help her make those important changes. But she did the hard work." James Goodyear, MD, president of the Pennsylvania Medical Society sums up, "Our job as physicians is not just to treat sick patients. We're here to work with our patients to provide the information and support they need to prevent illness and improve their health in the long run."

January 2010 Patient Poll background

Conducted: January 2010

Margin of Error: 5.67 percent

Eligibility: Pennsylvania adults age 21 or older

Survey Consultants: Taylor Brand Group, Lancaster, Pa., and Greenfield Online, Connecticut.

Question: Please answer true or false to the following statements:

Heart disease can start while you are still a teenager. True = 95.5%; False = 4.5%

A little alcohol is good for the heart. True = 71.9%; False = 28.1%

Two eggs contain more than the daily recommended allowance for cholesterol intake. True = 49.7%; False = 50.3%

If you ever have a heart attack, you'll know because your chest and arms will hurt. True = 33.7%; False = 66.3%

The patient-doctor relationship has been the priority of the Pennsylvania Medical Society since its founding in 1848. While there are many issues being debated about health system reform, the physician members will continue to focus on better health for all Pennsylvanians.

Source: Pennsylvania Medical Society

Targeted Therapy Prolongs Life in Patients with HER2-Positive Breast Cancer

2010-02-13T10:42:00.001-08:00

By Duke Medicine News and Communications
Lapatinib plus trastuzumab are significantly better than lapatinib alone in extending the lives of breast cancer patients whose tumors are HER2-positive, according to Kimberly Blackwell, MD, associate professor of medicine at Duke University Medical Center.

Blackwell presented the findings today at the CTRC-AACR San Antonio Breast Cancer Symposium.

Blackwell says the combination-targeted therapy gave patients more than a four-month survival advantage over those who took lapatinib alone. She says the findings may be the first step toward a chemotherapy-free future.

"This is the first time that a pair of targeted therapies has been shown to be superior to any intervention that paired a targeted therapy with a hormonal or chemotherapy based approach," she said.

The results stem from a large, Phase III clinical trial where investigators randomized 296 patients with metastatic breast cancer to receive either lapatinib (also known as Tykerb) alone or lapatinib plus trastuzumab (Herceptin) once a day.

All participants had metastatic disease that had continued to spread even after treatments with several interventions that included trastuzumab plus chemotherapy.

Blackwell says trastuzumab binds to and blocks part of the HER2 growth factor that appears on the surface of some breast cancer cells while lapatinib binds to a second growth factor, EGFR, and part of HER2 that sits below the cell surface. "It's sort of a double whammy, disabling the HER2 protein in two places instead of one."

Women who enrolled in the single-agent arm of the study and whose cancer continued to spread after four weeks were allowed to cross over to the other arm of the study to continue on the combined approach.

Fifty-two percent of the women enrolled in the lapatinib-only arm of the study crossed over to the combination arm. The median overall survival following treatment with lapatinib plus trastuzumab was 60.7 weeks compared to 41.4 weeks for those who took only lapatinib.

Other researchers involved in the study include Hal Burstein, from the Dana Farber Cancer Institute; George Sledge, from Indiana University Cancer Center; Steven Stein, Catherine Ellis, and Michelle Casey, of GlaxoSmithKline; Jose Baselga, of Vall d’Hebron University Hospital, Barcelona, Spain; and Joyce O’Shaughnessy from Baylor Sammons Cancer Center, Texas Oncology, PA, US Oncology, Dallas.

Allegheny General Hospital Study Demonstrates Safety And Potential Efficacy Of Oral Allergy Treatment

2010-02-13T10:37:00.001-08:00

An oral allergy treatment administered in drops under the tongue is a safe and effective alternative to injections for adults who are allergic to ragweed pollen, according to a study published in the Journal of Allergy and Clinical Immunology by allergic disease specialist at Allegheny General Hospital.

Widely used in Europe, but not yet approved by the U.S. Food and Drug Administration, sublingual allergen immunotherapy (SLIT) can be a more convenient and tolerable treatment approach that leads to greater patient compliance, said David Skoner, MD, director of AGH's Division of Allergy, Asthma and Immunology and a co-lead investigator in the study.

"The study's findings mark a step forward in gaining approval for sublingual administration of allergy medication," said Dr. Skoner, "We believe a large number of patients would greatly benefit from having access to this new oral treatment to ease their symptoms."

"The sublingual method so far has been safe, and the adherence rate should be better because no injections are involved and the medication is administered at home," said co-investigator Deborah Gentile, MD, Director of Research in AGH's Division of Allergy, Asthma and Immunology.

The AGH study, "Sublingual Immunotherapy in Patients with Allergic Rhinoconjunctivitis Caused by Ragweed Pollen," involved 115 patients in Pittsburgh, Madison, Wisc., Iowa City and Evansville, Ind. They were randomly assigned to a medium or high dose of standardized glycerinated short ragweed pollen extract or to a placebo. Participants kept diaries to monitor their symptoms over the course of 17 weeks during the ragweed pollen season.

The frequency of daily symptoms, as well as the need for additional medication to treat symptoms, both dropped significantly for those taking the high-dose medication, versus those taking a placebo. The frequency of adverse events was similar between the placebo and treatment groups.

The researchers concluded that SLIT was safe and can reduce symptoms in ragweed-sensitive patients, though more trials are needed to definitively establish the method's efficacy.

Shortcomings of previous trials with the sublingual method included small patient populations, high withdrawals and short treatment duration. Questions remaining on SLIT include treatment schedules, optimal doses and cost-effectiveness.

Other researchers involved in the study were Robert Bush, MD of the University of Wisconsin School of Medicine and Public Health; Mary Beth Fasano, MD, University of Iowa Hospitals and Clinics; Anne McLaughlin, MD, of Wellborn Clinical Research Center in Evansville, Ind., and Robert E. Esch, PhD, of Greer Laboratories Inc., Lenoir, NC.

Source: Allegheny General Hospital

Napping may not be such a no-no (Harvard Health Letter)

2010-02-13T10:27:00.000-08:00

Research is showing that the daytime snooze may have benefits and not interfere with nighttime sleep.

The nap has long been the troubled stepchild of the unassailably hygienic and universally admired good night's sleep. At work, if you get caught napping, it could get you into trouble or, more mildly, sully your reputation for diligence. In studies, naps have been linked to ill health, although usually as a consequence, not a cause. And in sleep recommendations, naps have taken a back seat — or been cast as a threat to nighttime sleep. On its Web site, the American Academy of Sleep Medicine tells people to "avoid taking naps if you can."

But lately, naps have been shedding some of their bad-for-you image. Researchers are finding benefits. A few employers have become accommodating of the quick snooze. And some research suggests that instead of fretting about napping more as we get older, we should plan on adding daytime sleep to our schedule as a way to make up for the normal, age-related decay in the quality of our nighttime sleep.

Getting over the hump

Naps, of course, can be an antidote to daytime sleepiness, and we get sleepy during the day for a wide variety of reasons. There is, in fact, a biological clock located in a cluster of cells in the hypothalamus of the brain. Those cells orchestrate the circadian (that is, daily) ups and downs of many physiological processes (body temperature, blood pressure, secretion of digestive juices), including sleep and wakefulness. As you might expect, the usual circadian pattern is wakefulness during the day followed by gradually increasing sleepiness in the evening, but it's also common to have a little "hump" of midafternoon sleepiness programmed into the circadian schedule. An afternoon nap is one way to accommodate that hump.

In 2008, British researchers reported results of a study that compared getting more nighttime sleep, taking a nap, and using caffeine as ways to cope with the afternoon hump. The nap was the most effective.

Another factor in daytime sleepiness is the number of hours you've been awake. After about 16 consecutive hours without sleep, most of us will start to feel tired. Ideally, this homeostatic sleep drive, as it is called, is in sync with the one set by our circadian rhythm, so they're mutually reinforcing. But if you work a night shift, or have problems sleeping at night, your 16-hour allotment of wakefulness may begin — and end — earlier, which can set you up for grogginess in the late afternoon or early evening. A short nap won't completely reset the timer, but it can buy you some time before the grogginess sets in again.

How to take a good nap

Keep it short. The 20- to 30-minute nap may be the ideal pick-me-up. Even just napping for a few minutes has benefits. Longer naps can lead to sleep inertia — the post-sleep grogginess that can be difficult to shake off.

Find a dark, quiet, cool place. You don't want to waste a lot of time getting to sleep. Reducing light and noise helps most people nod off faster. Cool temperatures are helpful, too.

Plan on it. Waiting till daytime sleepiness gets so bad that you have to take a nap can be uncomfortable and dangerous if, say, you're driving. A regular nap time may also help you get to sleep faster and wake up quicker.

Time your caffeine. Caffeine takes some time to kick in. A small Japanese study published several years ago found that drinking a caffeinated beverage and then taking a short nap immediately afterward was the most restful combination because the sleep occurred just before the caffeine took effect. We're not so sure about that approach — the mere suggestion of caffeine, in the form of coffee taste or smell, wakes us up. Regardless of the exact timing, you need to coordinate caffeine intake with your nap.

Don't feel guilty! The well-timed nap can make you more productive at work and at home.

On the job

Since 2000 or so, researchers at Harvard and elsewhere have conducted dozens of experiments that have shown that sleep improves learning, memory, and creative thinking. In many cases, the edifying sleep has come in the form of a nap. For example, several studies have shown that if people are asked to memorize something — say, a list of words — and then take a nap, they'll remember more of it than they would have if they hadn't taken the nap. Even catnaps of six minutes (not counting the five minutes it takes to fall asleep on average) have been shown to make a difference in how well people retain information.

Robert Stickgold, a Harvard sleep researcher, says napping makes people more effective problem solvers. His research group has shown that taking a nap seems to help people separate important information from extraneous details. If the nap includes REM sleep — the phase during which dreaming occurs — people become better at making connections between seemingly unrelated words.

Stickgold says his and others' findings argue for employer policies that actively encourage napping, especially in today's knowledge-based economy. Some companies have set up nap rooms, and Google has "nap pods" that block out light and sound.

Understandably, employers are concerned about abuse: employees catching up on sleep they should be getting on their own time. But there may be a place for "strategic napping," especially among people who work a night shift. Results from a New Zealand study published in 2009 showed that air traffic controllers working the night shift scored better on tests of alertness and performance if they took advantage of a planned nap period of 40 minutes. Researchers in the Harvard Division of Sleep Medicine are working with fire departments to improve sleep policies. One of their recommendations is that firefighters on the night shift take a nap in the late afternoon before their shift starts.

Can be a sign of trouble

Daytime sleepiness, and napping to relieve it, can also be a sign of a health problem. Daytime sleepiness is one symptom of Parkinson's disease, for example. In studies of older people, regular napping has been associated with diabetes, depression, and chronic pain, presumably because those conditions adversely affect nighttime sleep. Indeed, it only stands to reason that napping might be a coping mechanism for those who can't sleep well at night, no matter the age or the reason. Sleep problems, daytime grogginess, fatigue, a desperate need to nap — all are noteworthy, and suitable topics of conversation with your doctor.

Bad nighttime sleep may be a cause of napping, but what's less clear is whether the reverse is true: does napping cause bad nighttime sleep? That's been the belief, but a couple of studies haven't found an association between napping and complaints about nocturnal sleep. In fact, a few studies have shown that napping, and the ability to nap, are more common in older adults who sleep well at night than in those who don't. And it's been suggested that a nap might be an appropriate adaptation for older people who, as a rule, sleep an hour less per night than younger people and wake up earlier.

Out in the cold (Harvard Health Letter)

2010-02-12T23:16:00.000-08:00

No doubt cold weather can be hard on your health, but there may be a silver lining or two.

Winter and its chilly temperatures are a mixed blessing when it comes to human health. We might not appreciate it at the time, but cold temperatures perform a great public health service by killing off disease-mongering insects and microorganisms, and one of the big worries about climate change is that winter will lose its pestilence-fighting punch. Although it's a bit theoretical, cold weather may also help us slim down by stimulating metabolically active brown fat. And in Scandinavia and Russia, many people actively seek out the cold: wintertime swimming in frigid water is believed to do health wonders, and there's some science (not much, but some) suggesting that it might be so.

But there's also a dark side to consider. Numerous studies have shown that death rates peak this time of year. Blood pressure increases during the winter, and, by some reckonings, 70% of the wintertime increase in the death rate can be traced back to heart attacks, strokes, and other cardiovascular causes of death. And, of course, flu season is a winter event, and flu viruses spread more readily once the air is dry and chilly.

Winter darkness, in a literal sense, may make matters worse. Sun-exposed skin makes vitamin D, a vitamin that seems to have all kinds of health benefits. During the winter, when days are short and the sun is at a low angle, levels of the vitamin in the body tend to dip. Cold temperatures and low vitamin D levels: that may be a bad combination.

The shunt and shiver

If it's not too cold, our bodies adapt to cold temperatures pretty well. When we encounter cold air or water, the lacy network of blood vessels in the skin constricts, and blood is hastily shunted to the interior. That response adds to the insulating power of the skin because there's less heat lost from blood circulating near the surface. It also protects vital organs against the falling temperature. But we pay a price for the rerouting: diminished blood flow makes fingers, toes, and other peripheral parts of the body (the nose, the ears) vulnerable to frostbite, which occurs when the fluids in and around tissue freeze. Under the right conditions, blood vessels in the skin will open and close in an oscillating pattern, so skin temperatures rise temporarily, especially in the fingertips.

Shivering is another familiar defense mechanism against falling body temperatures. The rapid, rhythmic muscle contractions throw off heat that helps the rest of the body stay warm. The body may recruit more and more muscles as the temperature drops, so shivering can get intense and very uncomfortable. Voluntary movement — stomping your feet, swinging your arms — is another way to generate heat, and depending on the circumstance, may cancel out the need to shiver. It's not a total gain, though, because exercise also increases blood flow to the skin, so some body heat escapes.

Body type explains some of the varying reactions to cold weather. Taller people tend to get cold faster than shorter people because a larger surface area means more heat loss. And fat's reputation as an insulating material is well deserved, although for warmth during the winter, you want it to be the subcutaneous fat layered under the skin, not the visceral fat that collects in the abdomen.

Cold reaction

In cold temperatures, blood is shunted from the periphery to the interior.

Warming up to cold

Most of us spend the winter trying to stay warm and avoid getting cold, but a little bit of exposure may not be such a bad thing. It's been suggested, for example, that moderately cold temperatures could be good for the vasculature because it trains blood vessels in the skin to be responsive. (An added benefit: rosy cheeks.)

Brown fat is the heat-producing, calorie-burning fat that babies need to regulate their body temperatures. Most of it disappears with age, but PET scans have shown that adults retain some brown fat. Years ago, Finnish researchers reported that outdoor workers had more brown fat than indoor workers. Dutch researchers reported findings in The New England Journal of Medicine in 2009 that showed that moderately cool temperatures of 61? F activated brown fat in 23 of 24 study volunteers. No one is suggesting that cold weather be used for dieting purposes (not yet anyway). But when we get chilled this winter, we may take some consolation that at least we're firing up those brown fat cells.

Using cold temperatures for medical purposes is taken quite seriously in other countries. "Whole-body cryotherapy" was developed in Japan to treat pain and inflammation from rheumatic and other conditions. Patients spend one to three minutes in a room cooled to -166? F. And people in Finland, Russia, and elsewhere are passionate about winter swimming having health benefits. Several years ago, Finnish researchers reported the results of a study of 10 women who for three months took cold-water plunges (20 seconds in water just above freezing) and submitted to whole-body cryotherapy sessions. Blood tests were unremarkable except for a two- to threefold jump in norepinephrine levels minutes after cold exposure. Norepinephrine is a chemical in the nervous system that wears many hats, including, possibly, a role in pain suppression. (Spikes in norepinephrine levels may also explain the rise in blood pressure that occurs in cold weather).

Cold ain't so hot

But before heading north in search of a more healthful clime, or ringing in the New Year with a polar bear swim, you may want to think about the toll that cold and winter takes.

Research documenting wintertime increases in blood pressure goes back decades. French researchers rounded out the record in 2009 with findings that showed the cold-weather increase in systolic blood pressure (the top number) was especially pronounced in those ages 80 and older. Cold may trigger the fight-or-flight response: blood pressure goes up because the heart pumps faster and blood vessels tense up.

Cold weather and respiratory disease, including flu, also go hand in hand. Research has shown that cold spells are reliably followed by upticks in the number of deaths from respiratory disease. Some of this may have to do with a few infectious organisms, like flu viruses, thriving in colder temperatures, but there's also evidence that exposure to cold temperatures suppresses the immune system, so the opportunities for infection increase. A study published in The New England Journal of Medicine in the late 1970s famously debunked the belief that the common cold is linked to cold exposure, but British cold researchers have maintained that there is a cold–to–common cold connection. Their hypothesis: cold air rushing into the nasal passages makes infections more probable by diminishing the local immune response there.

Altered leptin signaling in diet-induced obesity

2010-02-11T18:40:00.000-08:00

by Boman Irani

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Beer May Be Good For Your Bones

2010-02-10T06:30:00.000-08:00

Jeanna Bryner

LiveScience Managing Editor

LiveScience.com jeanna Bryner

If you downed one too many while watching the Super Bowl, here's at least one reason to hold your head high: Drinking beer can be good for your health.

But seriously, a new analysis of 100 commercial beers shows the hoppy beverage is a significant source of dietary silicon, a key ingredient for bone health.

Though past research has suggested beer is chockfull of silicon, little was known about how silicon levels varied with the type of beer and malting process used. So a pair of researchers took one for the team and ran chemical analyses on beer's raw ingredients. They also picked up 100 commercial beers from the grocery store and measured the silicon content.

The silicon content of the beers ranged from 6.4 mg/L to 56.5 mg/L, with an average of 30 mg/L. Two beers are the equivalent of just under a half liter, so a person could get 30 mg of the nutrient from two beers. And while there is no official recommendation for daily silicon uptake, the researchers say, in the United States, individuals consume between 20 and 50 mg of silicon each day.

However, other studies show that consuming more than one or two alcoholic beverages a day may be, overall, bad for health.

The take-home message for the casual drinker: "Choose the beer you enjoy. Drink it in moderation," lead researcher Charles Bamforth of the University of California, Davis, told LiveScience. "It is contributing silicon (and more) to your good health."

Bamforth and his colleague Troy Casey, both of the university's Department of Food Science and Technology, detail their findings in the February issue of the Journal of the Science of Food and Agriculture.

The silicon levels of beer types, on average:

* Indian Pale Ale (IPA): 41.2 mg/L

* Ales: 32.8 mg/L

* Pale Ale: 36.5 mg/L

* Sorghum: 27.3 mg/L

* Lagers: 23.7 mg/L

* Wheat: 18.9 mg/L

* Light lagers: 17.2 mg/L

* Non Alcoholic: 16.3 mg/L

Their research showed the malting process didn't affect barley's silicon content, which is mostly in the grain's husk. However, pale-colored malts had more silicon than the darker products, such as the chocolate, roasted barley and black malt, which all have substantial roasting. The scientists aren't sure why these darker malts have less silicon than other malts.

Hops were the stars of the beer ingredients, showing as much as four times more silicon than was found in malt. The downside: Hops make up a much smaller portion of beer compared with grain. Some beers, such as IPAs are hoppier, while wheat beers tend to have fewer hops than other brews, the researchers say.

"Beers containing high levels of malted barley and hops are richest in silicon," Bamforth said. "Wheat contains less silicon than barley because it is the husk of the barley that is rich in this element. While most of the silicon remains in the husk during brewing, significant quantities of silicon nonetheless are extracted into wort and much of this survives into beer."

(Wort is the sweet liquid that comes from mashing the grains and eventually becomes beer.)

Got beer?

While the researchers are not recommending gulping beer to meet your silicon intake needs, their study does add to others on the potential health benefits of this cold beverage.

The type of silicon in beer, called orthosilicic acid, has a 50 percent bioavailability, meaning that much is available for use in the body. Some foods, like bananas are rich in silicon but only 5 percent is bioavailable. This soluble form of silica found in beer could be important for the growth and development of bone and connective tissue, according to the National Institutes of Health.

Past research has suggested that moderate beer consumption may help fight osteoporosis, a disease characterized by low bone mass and deterioration of bone tissue.

Another past study involving nearly 1,700 women reported last year in the journal Nutrition showed participants who were light to moderate beer drinkers had much better bone density than non-drinkers. The researchers suggested the beer's plant hormones, not the alcohol, could be responsible for the bone boost.

LiveScience.com chronicles the daily advances and innovations made in science and technology. We take on the misconceptions that often pop up around scientific discoveries and deliver short, provocative explanations with a certain wit and style. Check out our science videos, Trivia & Quizzes and Top 10s. Join our community to debate hot-button issues like stem cells, climate change and evolution. You can also sign up for free newsletters, register for RSS feeds and get cool gadgets at the LiveScience Store.

Study links sugary soft drinks to pancreas cancer

2010-02-08T05:40:00.001-08:00

Mon Feb 8, 2010 12:00am EST

* Regular soda drinkers had 87 percent higher risk

* Theory is that sugar fuels tumors

WASHINGTON, Feb 8 (Reuters) - People who drink two or more sweetened soft drinks a week have a much higher risk of pancreatic cancer, an unusual but deadly cancer, researchers reported on Monday.

People who drank mostly fruit juice instead of sodas did not have the same risk, the study of 60,000 people in Singapore found.

Sugar may be to blame but people who drink sweetened sodas regularly often have other poor health habits, said Mark Pereira of the University of Minnesota, who led the study.

"The high levels of sugar in soft drinks may be increasing the level of insulin in the body, which we think contributes to pancreatic cancer cell growth," Pereira said in a statement.

Insulin, which helps the body metabolize sugar, is made in the pancreas.

Writing in the journal Cancer Epidemiology, Biomarkers & Prevention, Pereira and colleagues said they followed 60,524 men and women in the Singapore Chinese Health Study for 14 years.

Over that time, 140 of the volunteers developed pancreatic cancer. Those who drank two or more soft drinks a week had an 87 percent higher risk of being among those who got pancreatic cancer.

Pereira said he believed the findings would apply elsewhere.

"Singapore is a wealthy country with excellent healthcare. Favorite pastimes are eating and shopping, so the findings should apply to other western countries," he said.

But Susan Mayne of the Yale Cancer Center at Yale University in Connecticut was cautious.

"Although this study found a risk, the finding was based on a relatively small number of cases and it remains unclear whether it is a causal association or not," said Mayne, who serves on the board of the journal, which is published by the American Association for Cancer Research.

"Soft drink consumption in Singapore was associated with several other adverse health behaviors such as smoking and red meat intake, which we can't accurately control for."

Other studies have linked pancreatic cancer to red meat, especially burned or charred meat.

Pancreatic cancer is one of the deadliest forms of cancer, with 230,000 cases globally. In the United States, 37,680 people are diagnosed with pancreatic cancer in a year and 34,290 die of it.

The American Cancer Society says the five-year survival rate for pancreatic cancer patients is about 5 percent.

Some researchers believe high sugar intake may fuel some forms of cancer, although the evidence has been contradictory. Tumor cells use more glucose than other cells.

One 12-ounce (355 ml) can of non-diet soda contains about 130 calories, almost all of them from sugar. (Editing by John O'Callaghan)

Strengthening the pelvic floor

2010-02-03T21:33:00.000-08:00

Kegel exercises

The standard advice is to pretend as if you are passing gas. Women are sometimes advised to imagine that they are tightening the vagina around a tampon. In general, you should feel like you are pulling in the anal area.

It can be difficult to isolate the pelvic floor muscles. People contract their leg and abdominal muscles instead. It can help to put your hand on your belly so you can sense when you are contracting your abdominal muscles when you shouldn’t be.

The advice to practice pelvic muscle exercises during urination has been discarded. An article on urinary stress incontinence in women in the March 6, 2008, New England Journal of Medicine said this:

“Performance of pelvic floor exercises is not recommended during voiding, because frequent interruptions of voiding may cause voiding dysfunction, and the ability to stop the flow of urine intermittently does not confirm that the exercises are performed correctly.”

The second part of that statement seems especially important. An article on treatment of urinary incontinence in Uptodate, an online publisher of in-depth review articles on medical topics, has this to say:

“Instructions to interrupt urination on regular basis or do [Kegel] exercises ‘one hundred times per day’ are unphysiologic and doomed to failure.”

Biofeedback

Both men and women can sometimes learn to do Kegels more effectively with biofeedback. Monitors are placed inside the vagina or rectum (or both, if you are a woman). As you attempt to do Kegels, you watch a computer screen to see if you are activating the correct muscles. Just one session of biofeedback can help people learn to perform Kegels correctly. Others may need five or six biofeedback sessions.

Electrical stimulation

If you are unable to activate your pelvic floor muscles, electrical stimulation therapy can help. A small electrode is placed inside the vagina or rectum. That electrode is used to deliver an electric current that causes the pelvic muscles to contract. The current can be set at different strengths and time intervals. Electrical stimulation therapy can be done with at-home machines or in a doctor’s office.

Sacral nerve stimulation is another form of electrical stimulation therapy. A wire with a small electrode tip is implanted inside the body so the tip is near the sacral nerve in the lower spine. There’s a device at the end of the wire that generates small electrical impulses. Those impulses activate the sacral nerve, which controls bladder function.

Magnetic stimulation

Magnetic stimulation is similar, conceptually, to electric stimulation, but a pulsed magnetic field is used to activate pelvic floor muscles instead of an electric current. Treatment with a magnetic stimulation device called Neocontrol involves sitting in a chair that sends magnetic pulses into the body. Magnetic stimulation can also be delivered by magnets applied externally near the sacral nerve roots. Uptodate sounds a cautionary note:

“Trials of these devices have been uniformly small, included heterogeneous patient groups, and may have been incompletely blinded or had no control group.”

Vaginal cones

These small, plastic cones are placed in the vagina. They come in different shapes and weights, and women are usually instructed to begin with the lightest one first. The idea is to use the pelvic floor muscles to keep the cone in place. Vaginal cones are, in effect, a sort of low-tech biofeedback device.

Pessaries

Pessaries are inserted into the vagina and positioned so they support the urethra. They come in various shapes, but are basically circular with a knob that pushes gently against the urethra. Strictly speaking, the purpose of a pessary isn’t to strengthen the pelvic floor or activate its muscles. The notion is to provide additional physical support to the urethra.

Fatty Liver Disease Next Big Problem for Obese and Inactive People MU scientist says the problem can be overcome with exercise

2010-02-02T20:56:00.000-08:00

It is known that low aerobic fitness is a strong predictor of early death. Now, a University of Missouri researcher has linked low aerobic capacity to a decreased ability to metabolize fat in the liver. Using rats bred over several generations for lower aerobic capacity and decreased ability to metabolize fat, the researchers showed that the rats’ livers are more susceptible to chronic disease, injury and dysfunction later in life. However, despite their genetic predisposition, the study found that exercise lowered the risk factors.

“Fatty liver disease will be the next big metabolic disorder associated with obesity and inactivity,” said John Thyfault, PhD, assistant professor in the MU School of Medicine’s Departments of Internal Medicine and Nutrition and Exercise Physiology. “It also is a significant contributor to type 2 diabetes.”

Low aerobic fitness can partially be linked to genetics but is mainly an end product of physical inactivity. The links between low aerobic fitness and metabolic disease in studies like this highlight the importance of being physically active, which can sustain or improve aerobic fitness across our lifespan, said Thyfault, who also is a health scientist at Harry S. Truman Memorial Veterans Hospital.

In contrast, the same study examined rats that were bred over several generations for high aerobic fitness. Those rats were protected from liver problems. A healthy liver is much better protected from fibrosis, the precursor to non-alcoholic liver cirrhosis. A higher aerobic capacity also means a better functioning heart, lungs, muscles and a lower risk for chronic diseases and early mortality.

“Your personal aerobic fitness is not something you will see in the mirror, but it is an important predictor of your long-term health,” Thyfault said. “The most important part of physical activity is protecting yourself from diseases that can be fatal or play a significant role in increasing the risk factors for other metabolic diseases. Too much fat in the liver also can lead to hyperglycemia.”

Using sedentary rats genetically bred to be low capacity runners allowed researchers to biochemically study the connection between low aerobic capacity and increased fat in the liver. Their main finding was that low aerobic capacity was linked to reduced mitochondrial content and function in the liver, which made the liver more susceptible to fat storage. The researchers believe the rats used in the study mimic the pathology of human chronic metabolic disease better than animal models where single genes are altered.

The study will be published in the Physiological Society’s Journal of Physiology. Jamal Ibdah, MD, PhD, Raymond E. and Vaona H. Peck Chair in Cancer Research and senior associate dean for research in the MU School of Medicine, collaborated on the study.

Low Serotonin Eyed as Mechanism for SIDS

2010-02-02T13:47:00.000-08:00

By Crystal Phend, Senior Staff Writer, MedPage Today
Published: February 02, 2010
Reviewed by Dori F. Zaleznik, MD; Associate Clinical Professor of Medicine, Harvard Medical School, Boston.

Low brainstem levels of serotonin and the enzyme that makes it could underlie sudden infant death syndrome (SIDS), researchers suggested.
In an autopsy study, SIDS cases showed 26% lower serotonin levels in two major components of the medulla's serotonin system -- the raphé obscurus (P=0.05) and paragigantocellularis lateralis (P=0.04) -- compared with age-adjusted controls who died from known causes.
These brainstem circuits control breathing, blood pressure, and heart rate during sleep, Hannah C. Kinney, MD, of Children's Hospital Boston, and colleagues reported in the Feb. 3 issue of the Journal of the American Medical Association.

A baby with an abnormality in control of these systems might not be able to respond to a life-threatening challenge like asphyxia by rousing from sleep or turning its head the researchers explained.

Action Points
Explain to interested patients that this study supports serotonin as part of the mechanism of SIDS, but how this can be exploited in prevention of SIDS remains to be seen.

SIDS occurs in the "critical first year of life, when homeostatic systems are still maturing," they noted.

Mary McClain, RN, MS, of Boston University Medical Center, who counsels families that have lost a baby to SIDS, commented that these findings help establish the biological basis for urging parents to place their babies on their backs to sleep.

The researchers obtained tissue samples from autopsies of 41 children who died from SIDS, seven who died acutely from known causes (including a car accident, drowning, pneumonia, and unsuspected congenital heart disease), and five who died in the hospital with chronic conditions causing hypoxia-ischemia.

SIDS cases had mean serotonin levels of 31.4 pmol/mg of protein in the paragigantocellularis lateralis, compared with 40.0 pmol/mg among the controls who died acutely (P=0.04).

Levels averaged 55.4 versus 75.5 pmol/mg of protein, respectively, in the raphé obscurus (P=0.05).

These abnormalities in the medulla did not appear to involve the catecholamine system. Catecholamine levels were similar between SIDS cases and controls.

Nor was there evidence for excessive degradation of dopamine or neurotransmitter turnover in SIDS cases, supporting the idea that the key abnormality is reduced synthesis of serotonin, the researchers said.

Another marker of serotonin function -- tryptophan hydroxylase (TPH2), the key enzyme involved in synthesis of serotonin -- also supported this conclusion, with 22% lower levels in the raphé obscurus in SIDS than in controls (P=0.03).

Serotonin receptor binding was 29% to 55% lower in three medullary nuclei that receive serotonin projections, notable for a decrease in binding with older age in SIDS cases, but not controls, the researchers noted.

Given similar findings in three previous investigations, this "may reflect a progressive decrease with age in those infants with the 'SIDS abnormality,'" they wrote. Or it's possible that those with a "stronger abnormality take longer to outgrow the risk period for SIDS and continue to die at older ages," Kinney's group wrote.

Likewise, serotonin receptor binding in infants who died from SIDS was significantly lower in those without known risk factors for SIDS, such as sleeping face down, "suggesting that additional risk factors are necessary to precipitate death when the medullary serotonin system is less compromised," they added.

Although repetitive apnea and agonal impaired gasping before death have been reported in some SIDS cases, chronic impaired oxygenation in the hospitalized children in the study produced a very different serotonin pattern than that seen in SIDS.

Children who died with chronic hypoxia conditions had 55% higher serotonin levels in the raphé obscurus (P=0.02) and 126% higher levels in the paragigantocellularis lateralis (P=0.002) than the SIDS cases.

They also had 640% higher dopamine levels in the raphé obscurus than the SIDS cases (P=0.006).

This suggested "that the primary mechanisms underlying serotonin abnormalities in SIDS are not mediated by chronic hypoxia-ischemia," Kinney's group wrote.

The researchers cautioned that their neurotransmitter measurements may have been off somewhat due to prolonged postmortem intervals.

They also warned that the study was limited by inability to perform these measurements at the synapse in postmortem tissues and by the small sample of controls.

The study was supported by the First Candle/SIDS Alliance, CJ Martin Overseas Fellowship (National Health and Medical Research Council of Australia), CJ Murphy Foundation for Solving the Puzzle of SIDS, CJ Foundation for SIDS, National Institute of Child Health and Development, and the Developmental Disabilities Research Center at Children's Hospital Boston.
The researchers reported no conflicts of interest.
McClain provided no information on conflicts of interest.

Primary source: Journal of the American Medical Association
Source reference:
Duncan JR, et al "Brainstem serotonergic deficiency in sudden infant death syndrome" JAMA 2010; 303: 430-37.

Educational game in development will focus on the science of drug addiction (University of Missouri School of Medicine)

2010-02-01T20:53:00.000-08:00

While video games sometimes get a bad rap for enticing children and teens to spend hours in front of a glowing screen, one University of Missouri School of Medicine researcher has the chance to prove games can be beneficial in the classroom.

Joel Epstein, PhD, MU associate professor of psychiatry and researcher at the Missouri Institute of Mental Health in St. Louis, recently received a four-year $1 million grant from the National Institute on Drug Abuse (NIDA), part of the National Institutes of Health, to develop a video game focused on what happens in the brain and the body when a person uses drugs.

Epstein, the recipient of two previous NIDA grants for developing multimedia programs that educate children on the dangers of substance abuse, views this project as a progression of his 17 years of work with the MIMH. First there were videos, then interactive CD-ROMs that were distributed to 19,000 schools across the country, and now, a video game.

“We’ve always done something a bit different than kids are used to and they’ve responded really well to it,” Epstein said. “I think the more you can engage them in the learning process, the more likely it is that the information you’re trying to convey to them will be retained.”

As someone who worked as a freelance computer programmer while earning his doctorate in clinical psychology, Epstein is especially qualified to lead a creative team at MIMH in developing the video game software.

During the development phase, Epstein will work with St. Louis teachers to ensure that the game fits seamlessly into state curriculum standards and meets educational objectives. Focus groups with some important stakeholders – the fourth- and fifth-grade students who make up the target audience – will help developers determine how the game should look and function. The final result will be a single curriculum with two different versions of software, one competitive and one socially collaborative, to test how boys and girls respond to these different types of presentations.

Pretesting children to determine their knowledge about the science of addiction, their attitudes toward drug use and their attitudes toward science in general will help gauge the game’s success. Once the children have played the game, researchers will conduct several follow-up tests to see if playing time has had any impact on these variables.

“My hope is that we can create a unique, memorable and effective learning experience,” Epstein said. “The students will be so engaged in the storyline of the game that they’ll also be engaged in the content we’re trying to get across.”

Click here to view and download Epstein’s previous multimedia programs that teach students about the science of addiction.

Other current projects at the Missouri Institute of Mental Health include:
MIMH is evaluating the Youth Suicide Prevention and Early Intervention program for the Missouri Department of Mental Health. Activities will include outcome evaluation and assessment of suicide prevention trainings conducted by approximately 14 regional centers. Funding for the prevention and intervention program is provided by the Substance Abuse and Mental Health Services Administration (SAMHSA).
Faculty with the MIMH Child and Family Division will evaluate the Safe Schools Healthy Students program for the Hazelwood School District in St. Louis. Safe Schools Healthy Students is a national initiative designed to reduce violence and substance use and improve mental health for students attending elementary and secondary schools. Funding is provided by the U.S. Department of Education, the Substance Abuse and Mental Health Services Administration and the Department of Justice.
MIMH faculty, along with researchers at Saint Louis University and Southern Illinois University Edwardsville are conducting a study examining substance abuse and mental health issues in the metropolitan St. Louis Bosnian community. The study is funded by a one-year grant from the Missouri Foundation for Health (MFH) and is part of a multi-year effort supporting both broad-based and targeted projects addressing mental health and substance abuse issues.
MIMH, in conjunction with the Missouri Department of Mental Health, has received a more than $13 million grant from SAMHSA to create an early intervention program in medical settings for people with risky behaviors. These behaviors include excessive use of alcohol or tobacco, use of illegal drugs, or abuse of prescription medications.

Patient-Centered Medical Homes in Ontario (From the New England Journal of Medicine)

2010-01-31T10:53:00.000-08:00

Walter W. Rosser, M.D., Jack M. Colwill, M.D., Jan Kasperski, R.N., M.H.Sc., and Lynn Wilson, M.D.

As the United States debates health care reform, the conceptof “patient-centered medical homes” is receiving increasingattention.¹ Many experts believe that medical homes with multidisciplinaryteams and financial incentives for providing comprehensive carewill lead to improvements in health, increase efficiency, andreduce costs of care while making practice more attractive forprimary care physicians. Lessons regarding the implementationof medical homes and their ability to accomplish these goalscan be gleaned from Ontario’s experience with Family HealthTeams (FHTs).

Back in 1969, Canada adopted a universal health insurance program.The federal government provided partial funding, and each provincedeveloped its own health care system under national guidelines.At first, the system was well funded, and most Ontarians weresatisfied. Family physicians practiced solo or in small groupsand were paid on a fee-for-service basis. But by the mid-1980s,family doctors struggled to keep up with practice demands. Risingcosts and either static or falling incomes pressured physiciansto increase the number of patient visits, which, many observersbelieve, negatively affected both the quality of care and physicians’personal lives. Interest in family medicine declined, and theproportion of Ontario medical graduates entering the field fellto 24% in 1998, though the health care system was based on theexpectation that 50% of physicians would be in family practice,Canada’s only primary care specialty.

In the early 1990s, the chairs of Ontario’s five universitydepartments of family medicine became increasingly concernedthat the payment system rewarded high-volume practices ratherthan broad, patient-centered care.²^,³ In response, a government-appointedcommittee identified a “basket” of services that family practicesshould provide. After physicians and politicians had been persuadedof its merits, the FHT was introduced in 2004. The FHT modelis designed to expand the capacity of primary care through developmentof interdisciplinary teams and to improve the breadth and qualityof care through incentives provided by a blended payment model.Today, about 720 physicians in 150 FHTs serve more than 1 millionpatients.

The model is flexible, and no two FHTs are the same. A typicalpractice includes at least seven family physicians and a multidisciplinaryteam that provides a broad range of services and 7-day-a-weekaccess to care. Physicians sign a contract with the Ministryof Health to provide the basket of services and agree to theremuneration package. Patients wishing to receive care froman FHT must register with the Ministry and select a physicianat a given practice. There is no certification process for FHTs,but electronic data, such as results of screening for coloncancer, document the services and provide information for reimbursementby the Ministry.

Primary care services focus on patient advocacy and coordinationof care. Specifically included are episodic and acute care;mental health care; chronic disease care; evidence-based prevention;education for self-care; care in the hospital, at home, andin the community; support for the terminally ill; and arrangementsfor around-the-clock response for urgent problems. In essence,the FHT serves as the focus for all patient care, providingthe majority of care and coordinating that provided by specialistsand by other community resources. Not every physician deliversevery service, but each group must be organized to do so. Thepatient’s physician sees to it that appropriate services areprovided.

Physicians have responsibility for a defined panel of patientsand are assisted by other health professionals, such as nurses,nurse practitioners, psychologists, pharmacists, social workers,and health educators. A typical physician panel includes about1400 patients, smaller than a typical U.S. practice. Inclusionof a nurse practitioner adds 800 patients to the expected practicesize. The Ministry provides salaries for the other health professionalsand funding for an electronic record system meeting Ministryrequirements.

Physician payment is based on age- and sex-based capitationthat is calculated from Ontario’s fee-for-service experience.Additional fees are provided for services deemed to requireadded emphasis — visits for infants, for instance, orpatients over 75 years of age. Physicians receive fees for proceduresand for visits to hospitals, homes, and nursing homes. Gradedbonuses are provided for achieving prevention goals for one’spatient panel. Family doctors receive a bonus of $100 to $300for every new patient, depending on the complexity of that patient’sneeds. The physician forfeits 1 month’s capitation fee whena patient seeks care elsewhere. About 60% of physicians’ incomescome from capitation and 40% from other fees and bonuses. EachFHT has a governing board with community representatives andis responsible for ensuring that standards are met, but standardsof care are established by physicians.

Primary care reform in Ontario took more than a decade fromconceptualization to implementation. Although many physicianswere initially skeptical about its potential for success, as-yet-unpublishedstudies document high levels of patient and physician satisfaction.When the Ministry recently sought to delay expansion to 200FHTs, protests by patient groups and physicians led to cancellationof the delay.

The use of interdisciplinary teams expands the range of servicesprovided and reduces overload for individual physicians. Sinceincome is not based primarily on physician visits, practicescan explore broader roles for team members and may use telephone,e-mail, and group visits to enhance efficiency. The total numberof visits per patient has not declined, but more visits appearto be occurring with team members other than the primary physician.One study has shown that control of hypertension is better amongpatients in FHTs than among those in fee-for-service practices.⁴ The use of integrative electronic record systems appears toimprove efficiency and communication, and we believe that qualityincentives have made participating physicians more proactivein providing preventive services and providing care managementfor chronically ill patients. A full evaluation of this model’seffects on health outcomes, quality measures, and costs willbe completed in 3 to 5 years. One effect that is already obviousis an increase of approximately 40% in physicians’ incomes:the average net income for a family physician has increasedfrom $180,000 (Canadian) in 2004 to $250,000 within FHTs, butit has not risen substantially in the fee-for-service sector.

Most Ontario teaching practices are FHTs and emphasize the valuesof patient-centered care in both family medicine residency programsand undergraduate medical education. The percentage of Ontariomedical school graduates entering family medicine has increasedfrom 25% in 2004 to 39% in 2009 (as compared with an increasefrom 24% to 29% in other Canadian provinces). Anecdotal informationsuggests that the first choice of Ontario’s family medicineresidents is now to practice in FHTs. Family physicians whowere initially skeptical are now seeking to participate.

Per capita, Canada has one third fewer active physicians thanthe United States, 15% more primary care physicians, and halfas many specialists. Consequently, the heavy responsibilitiesof Canadian specialists promote shared care with family physicians,and specialists rarely see patients without referral. In theUnited States, only 30% of visits to specialists occur throughreferrals,⁵ and patients are likely to see multiple specialists.Canada’s physician mix has helped to contain costs, but thegovernment recognizes that it faces shortages of both primarycare and specialist physicians. Its goal is for every personto have a family physician. Ontario’s large investment in FHTssignifies its commitment to enhancing the capacity and qualityof primary care.

Could medical homes be implemented in the United States? Formany in primary care, Ontario’s model represents the type ofpractice they always hoped to have. Already, many managed careorganizations and some integrated delivery systems are headedin that direction. But multiple insurers in a region, ratherthan a single payer, would have to invest in the medical homefor it to be viable for most primary care practices.

U.S. health care reform legislation anticipates a strong foundationof primary care — but that foundation is crumbling. Havingfaced similar problems, Ontario continues to convert fee-for-servicepractices to patient-centered medical homes, so far with positiveresults, including more graduates entering family medicine.Its experience can provide useful lessons for the United Statesas it addresses its primary care crisis.

Financial and other disclosures provided by the authors areavailable with the full text of this article at NEJM.org.

Source Information

From the Department of Family Medicine, Queen’s University, Kingston, ON, Canada (W.W.R.); the Department of Family and Community Medicine, University of Missouri School of Medicine, Columbia (J.M.C.); the Ontario College of Family Physicians, Toronto (J.K.); and the Department of Family and Community Medicine, University of Toronto, Toronto (L.W.).

This article (10.1056/NEJMp0911519) was published on January 6, 2010, at NEJM.org.

References

The patient centered medical home: history, seven core features, evidence and transformational change. Washington, DC: Robert Graham Center, November 2007. (Accessed January 5, 2010, at http://www.graham-center.org/online/etc/medialib/graham/documents/publications/mongraphs-books/2007/rgcmo-medical-home.Par.0001.File.tmp/rgcmo-medical-home.pdf.)
Forster J, Rosser W, Hennen B, McAuley R, Wilson R, Grogan M. New approach to primary medical care: nine-point plan for a family practice service. Can Fam Physician 1994;40:1523-1530. [Web of Science][Medline]
Rosser WW, Kasperski J. Organizing primary care for an integrated system. Healthc Pap 1999;1:5-21. [Medline]
Tu K, Cauch-Dudek K, Chen Z. Comparison of primary care physician payment models in the management of hypertension. Can Fam Physician 2009;55:719-727. [Free Full Text]
Valderas JM, Starfield B, Forrest CB, Sibbald B, Roland M. Ambulatory care provided by office-based specialists in the United States. Ann Fam Med 2009;7:104-110. [Free Full Text]

MU Researcher Developing New Preventive Agent for Stopping Spread of HIV

2010-01-29T20:43:00.000-08:00

Tests show EFdA is much more effective than other microbicides

Nearly 30 years after the discovery of the virus that causes AIDS, contracting the disease is no longer a quick death sentence. While high-tech therapies help patients live longer, healthier lives, one University of Missouri researcher is fighting HIV on another level — with a microbicide that stops the virus in its tracks.

Stefan Sarafianos, PhD, assistant professor of microbiology and immunology in the MU School of Medicine, and his collaborators Michael Parniak, PhD, at the University of Pittsburgh and Hiroaki Mitsuya, MD, PHD, at the National Institutes of Health have shown that the molecule EFdA can be used as a highly effective microbicide to prevent HIV transmission. They are in the process of patenting the chemical compound, which is up to 60,000 times more powerful than any other drug currently used for the treatment of HIV infection.

EFdA is a nucleoside reverse transcriptase inhibitor, meaning it targets the main HIV enzyme responsible for viral replication. In laboratory tests, human cells treated with EFdA can still become infected with HIV, but the compound stops the virus from replicating and spreading. Then, the immune system rids cells of the invader.

“The immune system has the capability to kill a little of the virus in the background, so it becomes manageable,” Sarafianos said. “Infection is the result of an overwhelming attack of the virus, but if you manage to keep the viral load low, the body has mechanisms to defend itself and clean up the virus on its own.”

With HIV vaccine efforts at an impasse, increased emphasis is placed on the discovery of alternate strategies to prevent HIV infection. Internationally, researchers are focused on developing microbicides that contain the same or related antiretroviral drugs used as treatments for people infected with HIV. Scientists hope the drugs can double as preventive agents in the form of vaginal gels and creams, empowering women to protect themselves when their partners refuse to use condoms.

One of the most popular drugs, tenofovir, is being tested as a microbicide in gel form. When EFdA is tested head-to-head with tenofovir in lab trials, there’s no competition, Sarafianos said.

“EFdA provides a much longer-term barrier to HIV infection, up to days whereas other microbicides last hours,” Sarafianos said. “EFdA also has a low toxicity against normal cells, and it is active against a broad spectrum of HIV subtypes.”

Sarafianos co-investigator Michael Parniak, a professor of microbiology and molecular genetics, has spent more than 15 years studying and developing antiviral drugs for HIV/AIDS. His work in this area has resulted in eight patents issued or pending. Along with EFdA, he is developing the antiviral drug UC781, which is currently in clinical trials as a microbicide to prevent HIV transmission.

Parniak calls EFdA the most potent HIV inhibitor discovered so far.

“To me, this is the molecule that should and will move forward as a microbicide,” Parniak said. “A combination of EFdA and UC781 would be a powerhouse, a one-two punch pretty much guaranteeing significant blockage of HIV transmission.”

Just as an EFdA and UC781 combination could someday knockout HIV, Sarafianos and Parniak posses a dynamic and complementary working relationship. Parniak, who specializes in virology, is the principal investigator for the microbicidal use of EFdA, while Sarafianos is the biochemical expert and principal investigator for work to understand EFdA’s mechanism of action — he understands precisely how EFdA works against the virus.
Sarafianos, Parniak and Hiroaki Mitsuya, head of the experimental retrovirology section at the NIH and inventor of several approved HIV drugs, recently submitted a patent disclosure. The scientists now have one year to apply for a patent to use EFdA, originally synthesized by the Japanese company Yamasa, to minimize the sexual transmission of HIV. Once patented, the microbicide could be integrated into a product already commonly used for protection during sexual intercourse, such as a spermicide or other form of birth control.

“If we can reduce the transmission of HIV, we can finally get a handle on overall infection spread,” Parniak said. “If we could reduce HIV transmission by only 30 percent or 40 percent, that would make a huge difference.”

According to estimates by the World Health Organization and UNAIDS, 33 million people were living with HIV at the end of 2007. That same year, some 2.7 million people became newly infected, and 2 million died of AIDS, including 270 000 children.

In the distant future, EFdA could also evolve into a treatment for patients already infected with HIV. In a study conducted by Parniak at the University of Pittsburgh, EFdA effectively treated rhesus monkeys infected with simian immunodeficiency virus (SIV) who showed end-stage simian AIDS symptoms. Monkeys with end-stage SAIDS typically die within a few weeks; the EFdA-treated animals lived for more than six months, a positive predictor that EFdA could have a similar effect in humans.

Parniak attributes much of EFdA’s potential to the novel mechanism of action discovered by Sarafianos’ lab at MU.

“He’s so excited about research, that he recharges me every time,” Parniak said of their weekly conversations to share data. “He’s one of our brightest young investigators and a real gem for Mizzou.”

The investigators’ EFdA research is funded by seven grants. Funding sources include multiple NIH grants, a grant from the American Foundation for AIDS Research and indirect federal funding of Sarafianos’ lab in MU’s Christopher S. Bond Life Sciences Center.

More on the Stroke Belt study (From the Harvard Health Letter)

2010-01-28T20:05:00.000-08:00

Maria Glymour and her colleagues at the Harvard School of Public Health conducted their study of the Stroke Belt by using data from the 1980, 1990, and 2000 censuses and mortality data from the National Center for Health Statistics for those same years. One of the strengths of their study was the use of “hard” mortality data, which is based on official death certificates.

They defined the Stroke Belt as being the states of North Carolina, South Carolina, Georgia, Alabama, Mississippi, Tennessee, and Arkansas. These are the seven states included in the federal government’sStroke Belt elimination project.

Using the census and mortality data, the researchers created four “exposure” categories, with the exposure being either birth in the Stroke Belt or residence in a Stroke Belt state as an adult. The exposure groups stack up like this:

Born in the Stroke Belt, adulthood in the Stroke Belt (double exposure)
Born in the Stroke Belt, adulthood out of the Stroke Belt (out-migrants)
Not born in the Stroke Belt, adulthood in the Stroke Belt (in-migrants)
Not born in the Stroke Belt, adulthood out of the Stroke Belt (no exposure)

Crude rates

Once the exposure groups were set, the researchers then calculated the number of stroke deaths per 100,000 people — the crude stroke mortality rate — for each of them. Here are the results:

	1980	1990	2000
Stroke Belt birth, Stroke Belt adulthood (doubly exposed)	122	83	74
Stroke Belt birth, non-Stroke Belt adulthood (out-migrants)	115	89	88
Non-Stroke Belt birth, Stroke Belt adulthood (in-migrants)	63	43	39
Non-Stroke Belt birth, non-Stroke Belt adulthood (nonexposed)	78	52	47

Here is the same information just for whites:

	1980	1990	2000
Stroke Belt birth, Stroke Belt adulthood (doubly exposed)	97	68	66
Stroke Belt birth, non-Stroke Belt adulthood (out-migrants)	86	65	66
Non-Stroke Belt birth, Stroke Belt adulthood (in-migrants)	60	41	40
Non-Stroke Belt birth, non-Stroke Belt adulthood (nonexposed)	75	51	46

And for blacks:

	1980	1990	2000
Stroke Belt birth, Stroke Belt adulthood (doubly exposed)	211	128	96
Stroke Belt birth, non-Stroke Belt adulthood (out-migrants)	146	115	116
Non-Stroke Belt birth, Stroke Belt adulthood (in-migrants)	112	66	37
Non-Stroke Belt birth, non-Stroke Belt adulthood (nonexposed)	112	68	58

Note that in almost every category, the stroke mortality rate is higher for blacks. The lone exceptions are the so-called in-migrants — people who moved to the Stroke Belt after living elsewhere.

Glymour and her colleagues pointed out that excess stroke mortality from Stroke Belt exposure, either at birth or as an adult, declined from 1980 to 2000 in every category. The biggest decline was among blacks who were “doubly exposed” (from a rate of 211 stroke deaths per 100,000 people in 1980 to a rate of 96 stroke deaths per 100,000 in 2000).

More refined numbers

But these are crude mortality rates that don’t take into account sex and age. The researchers made those adjustments. They also expressed the stroke risk as an odds ratio relative to the nonexposed group. In simplified terms, that means calculating how much greater the stroke risk was for people who had spent time in the Stroke Belt (birth, adulthood, or both) compared with the stroke risk for those who were neither born nor lived there as adults — the nonexposed in the charts above.

So, for example, in the chart below, 45% means a 45% greater chance of having a stroke than the nonexposed group. Here are those results for whites:

	1980	1990	2000
Stroke Belt birth, Stroke Belt adulthood (doubly exposed)	45%	29%	34%
Stroke Belt birth, non-Stroke Belt adulthood out (out-migrants)	31%	20%	20%
Non-Stroke Belt birth, Stroke Belt adulthood (in-migrants)	8%	7%	11%

For blacks:

	1980	1990	2000
Stroke Belt birth, Stroke Belt adulthood (doubly exposed)	55%	47%	34%
Stroke Belt birth, non-Stroke Belt adulthood out (out-migrants)	20%	11%	9%
Non-Stroke Belt birth, Stroke Belt adulthood (in-migrants)	13%	49%	1%

The highest group for whites and blacks are the doubly exposed, although by 2000, there is no racial difference: the stroke death rate is 34% higher for both whites and blacks. It’s also interesting that the stroke risk for out-migrant blacks is lower than it is for out-migrant whites in all three years.

Glymour and her colleagues acknowledge that their study cannot answer perhaps the most interesting question: Why is there a Stroke Belt in the first place? Genetic explanations don’t seem to work, because the Stroke Belt effect is true for both blacks and whites, although it’s usually less pronounced in whites. Behaviors or perhaps environmental toxins of some sort are more likely explanations, but nobody knows for sure.

This study does raise new questions about timing and whether there might be something about being born and spending your early childhood (place of birth and place of early childhood are not the same but census information shows that they are closely related) in the American Southeast that leads to a greater chance of having a fatal stroke later in life.

Does stroke risk begin with the stork? (From the Harvard Health Letter)

2010-01-27T18:50:00.000-08:00

Early life exposures, including those in the womb, may increase stroke risk later in life.

When we think about the risk factors for having a heart attack or stroke, the rogues' gallery includes poor eating habits, being overweight, having high blood pressure or elevated LDL cholesterol levels, and, of course, smoking. As adults, many of us fight the good fight against these risk factors in hopes of staving off cardiovascular calamity. Countless studies show that if we follow through, the efforts pay off, although obviously there are no guarantees. Unknown risk factors, and those that experts are less certain about, may have harmful effects, even as we dutifully work at minimizing the certified ones. And genetic predisposition can certainly trump even the most sterling health habits.

Also out of our control are all the exposures we experience in childhood — or even earlier, as developing fetuses in the womb. The notion of early-life exposures resulting in disease much later on is quite familiar. Was anyone really surprised by study results reported in 2009 that children exposed to secondhand smoke are more likely to develop lung cancer than those who aren't? But, as a rule, we don't think of tracing strokes (or heart attacks) back to when we were wee things or in utero. Yet there are some tantalizing clues that groundwork for our cardiovascular troubles is laid early in life and not simply a matter of adult behaviors and genetic inheritance. For example, Harvard researchers believe that early-life exposures of some kind may help explain one of the great riddles of American epidemiology, the Stroke Belt.

The Stroke Belt

Strokes occur when the blood supply to the brain is cut off by a clot in an artery or when an artery breaks open, so blood spills into the brain. Either way, it's serious business. Year after year, stroke comes after heart attack and cancer on the list of the leading causes of death in the United States.

In the southeastern part of the country, stroke cuts an even larger swath through the population. Residents of North Carolina, South Carolina, Georgia, Alabama, Mississippi, Arkansas, and Tennessee (Louisiana sometimes is included, too) are 20% to 50% more likely to die from a stroke than those who live elsewhere in the country. This Stroke Belt, as it has come to be called, has existed since at least the 1940s, and the excess mortality isn't confined to any one group: men, women, blacks, and whites from the region are more likely than other Americans to die from stroke.

Researchers have poked around in the data for decades, trying to tease out explanations for the geographic difference. Socioeconomic status, access to medical care, more people in those states having traditional stroke risk factors like high blood pressure or diabetes — none of these characteristics adequately explains the greater number of fatal strokes.

Several years ago, M. Maria Glymour, an assistant professor at the Harvard School of Public Health, started investigating whether the Stroke Belt mystery could be solved by looking at early-life exposures, not just snapshots of the risk profiles of adults. In a 2007 paper cleverly titled "Is the ‘stroke belt' worn from childhood?" she and her colleagues found that people who lived in the Stroke Belt as children were 25% more likely to have a stroke in adulthood than those who had never lived there, and that their risk was actually a bit higher than people who lived in the region as both children and adults.

In 2009, Glymour reported findings from a follow-up study that used a larger database, which puts the statistics on a firmer footing. The gist of the results was similar. This time, though, people with "double exposure" — birth and adulthood in the Stroke Belt — had the highest stroke mortality rate. Still, people born in the Southeast who moved away seemed to lug the Stroke Belt risk with them, although the risk was greater for whites than for blacks. If you're interested in reading more about this study, we've posted some details on our Web site at www.health.harvard.edu/healthextra.

Low birthweight an explanation

The Stroke Belt isn't the only geographic "hot spot" for stroke mortality that can't be explained by differences in genes or lifestyle. British researchers have also found higher stroke mortality rates in certain parts of northern England and in Wales.

The question that comes to mind is perhaps the most important one: what exactly are the exposures early in life that might increase our stroke risk later on? British researchers have zeroed in on low birthweight, poverty, and poor maternal health and nutrition as likely suspects. It's possible that our circulatory systems are affected in subtle ways by what we ate as children, undocumented environmental exposures, even psychological stresses. In utero exposures may affect how blood vessels develop or change the inflammatory response in enduring ways, so strokes are more easily triggered and atherosclerotic plaque in arteries more abundant. There are any number of possibilities — and no firm answers.

This research into the prenatal and childhood origins of stroke doesn't mean we should give up on cardiovascular disease prevention in adults. Far from it. Depending on our childhoods, we may need to try even harder. But it is another reason to think of adult lifestyle changes as risk reducers and a way to improve the odds, not as efforts that will wipe the slate clean.