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

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)

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

	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)

By: Judy F. Minkove 

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

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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)

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)

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

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)

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

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

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

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

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)

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)

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

by Boman Irani

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The prevalence of obesity has increased alarmingly in the developed world over the last 20-30 years as cheap, highly palatable, fat-rich foods have become readily available. Since it is unlikely that our gene pool has significantly changed over this time, it is likely that environmental factors are the main culprit underlying the current obesity epidemic. As with obesity in most humans, the development of diet-induced obesity in rodents is inherited as a polygenic trait. Thus, the obesity-prone rat is an excellent experimental model, especially for the study of interactions between brain pathways that regulate energy intake, expenditure and storage, and hormones such as leptin, a signal from adipose tissue that informs the brain of the amount of fat in the body. We have used this model to determine the degree to which a raised threshold for sensing leptin’s negative feedback from increasing fat stores contributes to the obesity that develops in these animals when they are fed a high fat diet. We found that these rats, which we have selectively bred to be obesity-prone, do have such a raised threshold, also known as leptin resistance. This resistance is due to a reduced number of receptors for leptin on specialized nerve cells in the hypothalamus, which are key regulators of food intake and body weight. When we assessed these nerve cells individually in a dish, they exhibited exquisite sensitivity to leptin. Importantly, there were major differences between the leptin responsiveness of nerve cells from obesity-prone rats and those from obesity-resistant rats. These and other studies from our laboratory confirm that genetically inherited leptin resistance can be one predisposing factor in the development of obesity in animals fed high fat diets. Such studies provide insights into potential ways to treat or prevent human obesity.

Diet-induced obesity in rats shares several features with human obesity. These include reduced sensitivity to leptin, a key hormonal signal from fat tissue that informs the brain of increasing fat stores. Leptin circulates in the blood and enters the brain, where it exerts an inhibitory effect on food intake and an excitatory effect on energy expenditure when fat stores increase. We previously showed that rats selectively bred for their genetic propensity to become obese have an inborn elevation in their threshold for sensing and responding to the anorectic effects of leptin. This appears to be an important cause of their predisposition to become obese when fed a high fat diet.
Over the last 3 years, I have carried out research in Dr. Barry Levin’s laboratory, comparing leptin signaling in rats selectively bred to be either obesity-prone or obesity-resistant. I first performed a detailed comparison of leptin binding in the brains of these rats (Figure 1) and found significant reductions in the arcuate (ARC), ventromedial (VMN) and dorsomedial (DMN) hypothalamic nuclei of obesity-prone rats. These nuclei play critical roles in the regulation of energy homeostasis, i.e. the balance between energy intake vs. energy expenditure and storage. Importantly, the reduced leptin binding was present before the obesity-prone rats were made obese on a high fat diet, suggesting that their reduced binding is genetically inherited and not due to dietary content or the development of obesity. Thus, the reduced responsiveness of obesity-prone rats to the negative feedback effects of leptin is likely to be due to a reduced number of receptors for this hormone on neurons in these key hypothalamic areas. For this reason, I carried out studies that used calcium imaging techniques in freshly dissociated neurons to demonstrate that individual ARC and VMN neurons respond to low levels of leptin in a concentration-dependent fashion. Importantly, I found that neurons from obesity-prone rats respond quite differently to leptin than do those from obesity-resistant rats suggesting that the leptin resistance of the former is present in individual hypothalamic neurons.

Figure 1: Pseudocolor image of binding of 125I Leptin to its receptors in the arcuate (ARC), ventromedial (VMN) and dorsomedial (DMN) hypothalamic nuclei of a rat brain

Some human studies suggest that when mothers are obese, this predisposes their offspring to a higher risk of obesity. Because such human epidemiological studies rarely identify the mechanisms promoting offspring obesity, we have used the obesity-prone rat to identify factors that promote obesity in offspring of obese mothers. We first showed that maternal genotype was a critical factor. Thus, offspring of mothers that were bred for their obesity-prone genotype became more obese as adults if their mothers were obese during gestation and lactation. Offspring of obesity-resistant mothers did not become obese as adults, even when their mothers were made obese with highly palatable diets. Besides being more obese, offspring of genetically obese dams had abnormal development of brain neurotransmitter pathways that are critically involved in regulation of energy homeostasis. This suggests that there are important interactions between the perinatal environment and genetic background in the development of these pathways. We are currently assessing the leptin sensitivity of individual neurons to test the hypothesis that maternal obesity in genetically predisposed individuals increases offspring obesity by further impairing leptin sensitivity of their ARC and VMN neurons.
In summary, our data strongly support our previous findings, which show that a genetic predisposition to develop diet-induced obesity is associated with a raised threshold for detecting leptin signaling that is due to reduced numbers of leptin receptors on neurons in brain areas critical to the regulation of energy homeostasis. Such data suggest that drugs, which increase the number of these receptors, might be an effective way to prevent and treat the development of obesity. Lastly, we are optimistic that understanding the mechanisms by which the obese perinatal environment elicits permanent metabolic changes in offspring (e.g., altered leptin signaling) will provide a basis for future interventional studies in humans.
Boman Irani earned his PhD in 2005 from the Department of Medicinal Chemistry at the University of Florida under the supervision of Dr. Carrie Haskell-Luevano. He is currently carrying out his postdoctoral research under the guidance of Dr. Barry E. Levin in the Department of Neurology and Neurosciences, UMDNJ-New Jersey Medical School

Beer May Be Good For Your Bones

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.

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Study links sugary soft drinks to pancreas cancer

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)