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.”

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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.”