Mayo Clinic Finds Seizure Generation in Brain is Isolated from Surrounding Brain Regions

Mayo Clinic researchers found that the part of the brain generating seizures in individuals with epilepsy is functionally isolated from surrounding brain regions. The researchers hope this finding could be a clinical biomarker to help identify individuals with abnormal brain function. This study was presented at the American Epilepsy Society's annual meeting in San Antonio on Dec. 4.

Epilepsy is a disorder characterized by the occurrence of two or more seizures. It affects almost 3 million Americans.

"The synchronization of local and distributed neuronal assemblies underlies fundamental brain processes like perception, learning and cognition," says Gregory Worrell, M.D., Ph.D., a Mayo Clinic epileptologist and an author of this study. "In neurological disease, neuronal synchrony can be altered, and in epilepsy the synchrony plays an important role in the generation of seizures."

Mayo Clinic researchers investigated neuronal synchrony by studying intracranial EEG (electroencephalogram) recordings from patients with epilepsy and control subjects with facial pain. Researchers discovered that the control patients had greater average synchrony than patients with focal epilepsy (when seizures are produced in a small part of the brain, not the entire brain). When implanted electrode pairs bridged seizure-generating brain and other brain regions, the synchrony was significantly less than between other electrode pairs in the epileptic brain and the control brain. The team also found that with greater activity in the seizure-generating region, there was less synchrony with neighboring tissue outside that region.

"Our study shows us that the part of the brain generating seizures is isolated from the surrounding brain regions," says Dr. Worrell. "This finding could serve as a clinical biomarker of an abnormal brain, and it can also be useful in epilepsy surgery and brain stimulation treatments, as well as helping us understand how seizures are generated." Other scientists involved in this research include C. Warren, Ph.D.; S. Hu; S. Stead, M.D., Ph.D.; B. Brinkmann, and M. Bower, Ph.
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Mayo-Led Researchers Discover Genetic Variants Modifying Breast Cancer Risk

Individuals with disrupting mutations in the BRCA1 gene are known to be at substantially increased risk of breast cancer throughout their lives. Now, discoveries from an international research team led by Mayo Clinic researchers show that some of those persons may possess additional genetic variants that modify their risk. These new findings enhancing individualized medicine appear in the current Nature Genetics.

"These findings should be useful in helping determine individual risk for breast cancer in BRCA1 carriers," says Fergus Couch, Ph.D., Mayo investigator and senior author of the study. "It also provides insights into hormone-receptor-negative breast cancer in the general population."

Genetic mutations in the BRCA1 gene give carriers of these mutations an increased risk for developing breast cancer. To determine if any genetic variations would modify or alter this risk among large populations of the mutation carriers, the researchers conducted genome-wide association studies (GWAS) that ultimately spanned 20 research centers in 11 different countries.

They first studied 550,000 genetic alterations from across the human genome in 1,193 carriers of BRCA1 mutations under age 40 who had invasive breast cancer and compared the alterations to those in 1,190 BRCA1 carriers of similar age without breast cancer. The 96 single nucleotide polymorphisms (SNPs) discovered were subsequently studied in a larger sample population of roughly 3,000 BRCA1 carriers with breast cancer and 3,000 carriers without cancer. Researchers found five SNPs associated with breast cancer risk in a region of chromosome 19p13.

Further studies of those SNPs in 6,800 breast cancer patients without BRCA1 mutations showed associations with estrogen-receptor-negative disease, meaning cancer in which tumors don't possess estrogen receptors. In another GWAS involving 2,300 patients, the five SNPs also were associated with triple-negative breast cancer, an aggressive form of the disease accounting for about 12 percent of all breast cancer. Triple-negative tumors don't express genes for estrogen or progesterone receptors or Her2/neu. The researchers also found that these SNPs were not related to risk for ovarian cancer in BRCA1 mutations carriers.

By locating these risk-modifying SNPs, the researchers have provided a target for better understanding the mechanisms behind the development of breast cancer. Furthermore, when combined with other risk-modifying SNPs that remain to be identified in ongoing studies by this group, it may be possible to identify certain BRCA1 carriers who are at lower risk of cancer and, also, carriers at particularly elevated risk of cancer who may decide to change their approach to cancer prevention.

Support for the research came from the Breast Cancer Research Foundation, Susan G. Komen for the Cure, the National Institutes of Health, and Cancer Research UK. In addition to first author Antonis Antoniou, Ph.D., of Cambridge University, over 180 individuals and several consortia contributed to the research and are co-authors.
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St. John's Wort Not Helpful Treatment for Irritable Bowel Syndrome, Mayo Clinic Researchers Say

A Mayo Clinic research study published in the January issue of The American Journal of Gastroenterology finds that St. John's wort is not an effective treatment for irritable bowel syndrome (IBS). While antidepressants are frequently used to treat IBS, to date, no study has examined the success of using the herbal supplement St. John's wort in treating IBS.

"Our study investigated if herbal antidepressants such as St. John's wort could benefit irritable bowel disease patients," says Yuri Saito, M.D., M.P.H., a gastroenterologist and lead physician scientist on the study. "Several of the chemical neurotransmitters that are in the brain are also in the colon. Therefore, it's been thought that antidepressants may affect sensation in the colon in a similar way to how they affect sensation in the brain. Our goal was to evaluate the usefulness of St John's wort in treating IBS."

In this placebo-controlled trial, 70 participants with IBS were randomized where half the patients received St. John's wort and the other half received a placebo for three months. In all, 86 percent of the participants were women, and the median age was 42 years. After three months of observing symptoms such as stomach pain, diarrhea, constipation and bloating, Mayo researchers found that the placebo group had a better response than the group taking the herbal supplement, St. John's wort.

"Because people tend to struggle with IBS for several years, patients are really looking for inexpensive, over-the-counter treatments such as St. John's wort," says Dr. Saito. "Unfortunately, our study showed that St. John's wort was not successful in helping IBS patients."

St. John's wort is an herbal supplement derived from the St. John's wort plant. It has been shown to be helpful in several medical conditions such as depression as well as other pain syndromes. Research has shown it to be as effective as conventional, prescription anti-depressants in treating mild to moderate depression.

"The challenge with IBS is that there is no cure, no one treatment tends to be wholly effective and some treatments come with significant side effects," explains Dr. Saito. "However, well-designed studies of herbal supplements are important so that physicians and patients can make informed decisions about which supplements to recommend or try. Studies of alternative treatments are generally lacking and patients are forced to use a "trial and error" approach to over-the-counter treatments for their IBS."

IBS is a common disorder that affects the colon and commonly causes cramping, abdominal pain, bloating, gas, diarrhea and constipation. Approximately 58 million people struggle with IBS, mostly women.

Each year, Mayo Clinic physicians treat thousands of people with IBS. Read more information on treatment for irritable bowel syndrome at Mayo Clinic.

Mayo Clinic's Division of Gastroenterology and Hepatology has been ranked #1 in the U.S. News & World Report Honor Roll of Top Hospitals since the rankings began 20 years ago.

Other members of the Mayo Clinic research team included Enrique Rey, M.D.; Ann Almazar-Elder; W. Scott Harmsen; Alan Zinsmeister, Ph.D.; G. Richard Locke , M.D.; and Nicholas Talley, M.D., Ph.D.
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Mayo Clinic Offers Perspective on Health Care Reform in New England Journal of Medicine

Mayo Clinic's perspective about how to get high-value health care is the focus of a Perspectives article in the New England Journal of Medicine, published online on Sept. 23, 2009, and in the print issue on Oct. 1, 2009.

"We must hold physicians and other providers accountable for providing high-value health care, defined in terms of both quality and cost," say Denis Cortese, M.D., president and CEO of Mayo Clinic and Jeff Korsmo, executive director of the Mayo Clinic Health Policy Center. To help achieve this goal, Cortese and Korsmo recommend basing a portion of Medicare payments to physicians and hospitals on value scores (measurable good outcomes, safety and service delivered at a lower cost), rewarding those providers who deliver high-value care and providing an incentive for others to improve.

In their essay, Dr. Cortese and Korsmo emphasize other key points to achieve true patient-centered health care reform including:

•Coordinating patient care services across people, functions, activities, sites, and time

•Reducing conflict of interest so physicians have less of a personal financial incentive to order unnecessary tests or procedures

"It should also be noted that researchers from the Dartmouth Institute for Health Policy and Clinical Practice have studied regional variation in health care quality and spending," says Korsmo. "They have documented that more care does not necessarily translate into better care. The research suggests that the United States could reduce health care costs by 30 percent or more if all regions practiced to the standard of the best-performing medical centers." The article can be viewed online.

Note: The New England Journal of Medicine also published a Mayo Clinic survey on physicians' beliefs and health care reform in the Sept. 14 issue. It can be viewed online.
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Mayo Clinic Proceedings: Common Blood Disorder May Not be Linked to as Many Serious Diseases, as Previously Thought

A symptomless blood disorder, monoclonal gammopathy of undetermined significance, known as MGUS, is not linked to as many serious diseases as previously thought. This finding may save patients from undergoing unnecessary workup and treatment according to a study published in the August 2009 issue of Mayo Clinic Proceedings.

MGUS has long been thought to be a precursor of serious disease, such as multiple myeloma, primary amyloidosis and Waldenström macroglobulinemia. However, for years physicians have reported possible association of MGUS with many more diseases. As a result, some patients with MGUS who had these disorders were subjected to investigations and sometimes additional treatments as a precaution.

MGUS is a fairly common disorder, affecting roughly 3 percent of the U.S. population. This study was supported in part by grants from the National Institutes of Health and the U.S. Public Health Service.

In this study, researchers looked at the records of 17,398 patients, all of whom were uniformly tested for the presence or absence of MGUS. Among the 17,398 samples tested, 605 cases of MGUS were identified. The researchers then looked at the incidence of over 16,000 different diagnosis codes in those with MGUS and those without. They identified 14 real disease associations, while 61 disease associations with MGUS were determined to be likely coincidental.

In addition to multiple myeloma, the associations deemed real include vertebral and hip fractures and osteoporosis. "In addition to the article, we have made available on the journal Web site an appendix that has the raw data on all 16,062 hospital diagnosis codes which we think will be valuable to other researchers in the field," says S. Vincent Rajkumar, M.D., of Mayo Clinic's Department of Hematology and senior author on the study.

A peer-review journal, Mayo Clinic Proceedings publishes original articles and reviews dealing with clinical and laboratory medicine, clinical research, basic science research and clinical epidemiology. Mayo Clinic Proceedings is published monthly by Mayo Foundation for Medical Education and Research as part of its commitment to the medical education of physicians. The journal has been published for more than 80 years and has a circulation of 130,000 nationally and internationally. Articles are available online at www.mayoclinicproceedings.com.
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Mayo Clinic Identifies Two Genes as Potential Therapeutic Targets for Multiple Sclerosis

Early research holds promise for new therapies and better prediction of patient outcomes

A Mayo Clinic study has found that two genes in mice were associated with good central nervous system repair in multiple sclerosis (MS). These findings give researchers new hope for developing more effective therapies for patients with MS and for predicting MS patients' outcomes. This study will be presented at the Congress of the European Committee for Treatment and Research in Multiple Sclerosis in Dusseldorf, Germany, on Sept. 11, 2009.

"Most MS genetic studies have looked at disease susceptibility — or why some people get MS and others do not," says Allan Bieber, Ph.D., a Mayo Clinic neuroscientist and author of this study. "This study asked, among those who have MS, why do some do well with the disease while others do poorly, and what might be the genetic determinants of this difference in outcome."

Mayo Clinic provides care for nearly 2,500 patients with MS each year. MS is a disease of the central nervous system that includes the brain, spinal cord and nerves. MS is called a demyelinating disease because it results from damage to myelin, the insulating covering of nerves. It occurs most commonly in those between the ages of 20 and 40, and is the most frequent neurological disorder in young adults in North America and Europe. Approximately 330,000 people in the United States have MS. Symptoms include loss of muscle coordination, strength, vision, balance and cognition.

Dr. Bieber and a team of Mayo Clinic researchers used two different strains of mice with a chronic, progressive MS-like disease. One strain progressed to paralysis and death. The other underwent the initial damage induction phase of the disease and then spontaneously repaired the damage to the central nervous system and retained most neurologic function. Using the powerful genetic mapping techniques that are available for mice, the team mapped two strong genetic determinants of good disease outcome.

"It's possible that the identification of these genes may provide the first important clue as to why some patients with MS do well, while others do not," says Dr. Bieber. "The genetic data indicates that good central nervous system repair results from stimulation of one genetic pathway and inhibition of another genetic pathway. While we're still in the early stages of this research, it could eventually lead to the development of useful therapies that stimulate or inhibit these genetic pathways in patients with MS."

According to Dr. Bieber, the research suggests that there may be a small number of strong genetic determinants for central nervous system repair following demyelinating disease, rather than a larger number of weak determinants.

"If that's true, it may be possible to map the most important genetic determinants of central nervous system repair in patients with MS and define a reparative genotype that could predict patients' outcomes," says Moses Rodriguez, M.D., a Mayo Clinic neurologist and director of Mayo Clinic's Center for Multiple Sclerosis and Central Nervous System Demyelinating Diseases Research and Therapeutics. "Such a diagnostic tool would be a great benefit to patients with MS and is consistent with the concepts of 'individualized medicine.'"

Also on the Mayo Clinic research team was Kanitta Suwansrinon, M.D.
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Mayo Clinic Study Finds Celiac Disease Four Times More Common than in 1950s

Undiagnosed celiac disease associated with nearly quadrupled mortality

Note: We rec'd this 6/29/09 so it's not "new" news, but it got stuck in our to be posted folder and there it has languished... until now. It's interesting and relevant, so we're sharing it with you even though it's late on the off-chance that you missed it... - hhh

Celiac disease, an immune system reaction to gluten in the diet, is over four times more common today than it was 50 years ago, according to findings of a Mayo Clinic study published this month in the journal Gastroenterology.

The study also found that subjects who did not know they had celiac disease were nearly four times more likely than celiac-free subjects to have died during the 45 years of follow-up.

"Celiac disease has become much more common in the last 50 years, and we don't know why," says Joseph Murray, M.D., the Mayo Clinic gastroenterologist who led the study. "It now affects about one in a hundred people. We also have shown that undiagnosed or 'silent' celiac disease may have a significant impact on survival. The increasing prevalence, combined with the mortality impact, suggests celiac disease could be a significant public health issue."

In patients with celiac disease, the presence of a protein called gluten from wheat, barley or rye triggers an immune system attack, damaging the villi in the small intestine. Villi are fingerlike projections that increase the intestine's surface area for nutrient absorption. Celiac disease symptoms may include diarrhea, abdominal discomfort, weight loss, anemia, unexplained infertility, loss of teeth or even premature or severe osteoporosis.

The Mayo Clinic research team tested blood samples gathered at Warren Air Force Base (AFB) in Wyoming between 1948 and 1954 for the antibody that people with celiac disease produce in reaction to gluten. They compared those blood test results with those from two recently collected sets from Olmsted County, Minn. One matched the ages of those from the 1948–1954 testing at the time of the blood draw, and the other matched their birth years. Researchers found that young people today are 4.5 times more likely to have celiac disease than young people were in the 1950s, while those whose birth years matched the Warren AFB participants were four times more likely to have celiac disease.

"Celiac disease is unusual, but it's no longer rare," says Dr. Murray. "Something has changed in our environment to make it much more common. Until recently, the standard approach to finding celiac disease has been to wait for people to complain of symptoms and to come to the doctor for investigation. This study suggests that we may need to consider looking for celiac disease in the general population, more like we do in testing for cholesterol or blood pressure."

Dr. Murray says the study findings highlight the need for increased awareness of celiac disease, both among physicians and patients. "Part of the problem is that celiac disease symptoms are variable and can be mistaken for other diseases that are more common, such as irritable bowl syndrome," he says. "Some studies have suggested that for every person who has been diagnosed with celiac disease, there are likely 30 who have it but are not diagnosed. And given the nearly quadrupled mortality risk for silent celiac disease we have shown in our study, getting more patients and health professionals to consider the possibility of celiac disease is important."

In addition to Dr. Murray, authors of the study, which was conducted in collaboration with the University of Minnesota Medical School and the Medical Follow-Up Agency, Washington, D.C., include Alberto Rubio Tapia, M.D.; Robert Kyle, M.D.; Edward Kaplan, M.D.; Dwight Johnson, M.D.; William Page, Ph.D.; Frederick Erdtmann, M.D.; Tricia Brantner; W. Ray Kim, M.D.; Tara Phelps; Brian Lahr; Alan Zinsmeister, Ph.D.; and L. Joseph Melton III, M.D.
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Study Results Raise Questions About Vertebroplasty for Patients With Osteoporotic Spinal Compression Fractures

A new study led by Mayo Clinic researchers has found that relief of pain from vertebral compression fractures, as well as improvement in pain-related dysfunction, were similar in patients treated with vertebroplasty and those treated with simulated vertebroplasty without cement injections. The article, "A Randomized Controlled Trial of Vertebroplasty for Osteoporotic Spine Fractures," was released today in the New England Journal of Medicine.

Vertebroplasty is a widely applied procedure in which medical cement is injected into the spine to relieve pain and improve function in patients who have osteoporotic fractures. This study, funded by the National Institutes of Health, was the first of its kind, using a double-blinded research model to examine the impact of vertebroplasty.

"Though the medical community has been using vertebroplasty for many years, there were no research results to prove whether the efficacy of the treatment relates to the cement injections, patient expectations, or other factors," says the study's leader, David Kallmes, M.D., a Mayo Clinic physician who specializes in radiology and neurosurgery.

"The cement is a permanent medical implant, and there is some concern that it places patients at future risk for additional spinal fractures."

Researchers from eight medical centers in the United States, United Kingdom and Australia enrolled a total of 131 patients in the trial. The baseline characteristics of pain and function were similar in the vertebroplasty group containing 68 patients and the control group containing 63 patients. Within days of treatment, both groups showed similar improvements in function and pain. Researchers continue to follow study participants, and one year results will be released at a later date.

"We aren't saying the vertebroplasty doesn't work, because it somehow does," says Dr. Kallmes. "But both sets of patients experienced significant improvements in pain and function a month following the procedure, whether they received cement injections or not. Improvements may be the result of local anesthesia, sedation, patient expectations, or other factors."

"Patients should seek medical advice from their care provider before making a decision about treatment options," Dr. Kallmes advises.

Other centers involved in the research included the University of Washington, Seattle; Nuffield Orthopaedic Centre NHS Trust, Oxford, UK; St. George Hospital, University of New South Wales, Sydney, Australia; Gartnavel General Hospital, Glasgow, UK; Department of Social Medicine, Bristol, UK; Nottingham University Hospital NHS Trust, UK; and Western General Hospital, University of Edinburgh, UK. University of Washington researcher Jerry Jarvik, M.D., coordinated the data gathering and analysis for the project.

Dr. Kallmes says that several related research projects are in progress at Mayo Clinic, including a study of kyphoplasty, which uses a balloon to make space for cement injections, as well as an unblinded trial to measure the impact of local anesthesia on pain.
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Mayo Researchers Help Discover Genetic Cause for Primary Biliary Cirrhosis

Researchers have discovered a novel molecular path that predisposes patients to develop primary biliary cirrhosis, a disease that mainly affects women and slowly destroys their livers. Primary biliary cirrhosis has no known cause.

The finding, significant because it is a first step toward developing a targeted treatment and a cure, will be published in the June 11, 2009, issue of the New England Journal of Medicine.

"Now that we better understand the molecular basis of primary biliary cirrhosis, we can look for ways to specifically fix those elements," says Konstantinos Lazaridis, M.D., a Mayo Clinic hepatologist and a senior researcher in the study.

Currently, treatments for primary biliary cirrhosis can slow progression of the disease, which affects 1 in 2,500 Americans, 90 percent of them women. However, about half of patients do not respond to medical therapy. For some patients, a liver transplant cures the condition. But not all patients qualify for a transplant, and some transplant recipients experience a recurrence within five to 10 years.

The study was conducted at the University of Toronto using blood samples of patients collected at several medical centers in Canada and at Mayo Clinic's campus in Rochester, Minn., through its Primary Biliary Cirrhosis Genetic Epidemiology Research Resource. This resource comprises the biospecimens of hundreds of primary biliary cirrhosis patients and individuals who do not have the disease (controls) --matched for age, sex, race and state of residence. Mayo Clinic and the University of Toronto are among the largest treatment centers in North America for primary biliary cirrhosis.

The University of Texas MD Anderson Cancer Center in Houston provided historical controls and conducted the statistical analysis of the study.

The genetic link to primary biliary cirrhosis has been well-established by previous studies. "Indeed, mothers, sisters and daughters in the same family have a significantly higher tendency to develop the disease compared with the general population," says Dr. Lazaridis.

To learn more about the cause of the illness, researchers designed a three-phase study to identify genetic markers associated with the disease. In phase one, researchers conducted a genome-wide association analysis, comparing the genotypes of 536 patients with primary biliary cirrhosis to those of 1,536 people who did not have the disease. Researchers looked at more than 300,000 single-nucleotide polymorphisms (SNPs), the most common genetic variations, among the approximately 11 million known to be present in the human genome.

"There were significant differences between the patients with primary biliary cirrhosis and the control group," says Dr. Lazaridis. As a result, researchers narrowed their focus to 16 SNPs significantly linked to primary biliary cirrhosis.

In phases two and three, researchers conducted "replication" and "fine-mapping" studies to confirm the initial results and to further detail the genetic variations most closely linked to primary biliary cirrhosis.

Researchers discovered that variants of two genes, interleukin 12A (IL12A) and interleukin 12RB2 (IL12RB2), were strongly associated with primary biliary cirrhosis. These two genes constitute a pathway of the immune system. Potential therapeutic manipulation of this pathway provides new possibilities for more effective treatments of these patients, says Dr. Lazaridis.

Researchers also confirmed that the human leukocyte antigen (HLA) region of the genome is linked to primary biliary cirrhosis, an association which had been identified in previous research.

"Although both the HLA region and the IL12 pathway are equally involved with susceptibility to primary biliary cirrhosis, HLA is very complicated to dissect genetically, with multiple pathways," says Dr. Lazaridis. "It will be difficult to modulate with the intention to treat, while IL12 is a single pathway and thus more amenable to treatment."

The reliability of the newly discovered association is very strong; statistically, there's about a one in 10 trillion chance that the pathway isn't linked to primary biliary cirrhosis, Dr. Lazaridis noted.

"That strong association is remarkable, given that the researchers started by looking at 300,000 genetic markers across approximately three billion base pairs that comprise our entire genetic material," he says. "Needle in a haystack doesn't begin to convey the challenge of this search."

Dr. Lazaridis describes this finding as the "end of the beginning" in learning more about the predisposing genetic factors to primary biliary cirrhosis. The newly discovered IL12 pathway does not account for all instances of primary biliary cirrhosis. There is more work to be done on additional genetic links, and exactly how IL12A and IL12RB2 contribute to primary biliary cirrhosis remains unknown. But researchers now have, for the first time, the knowledge to begin to develop targeted treatments and better predict outcomes for some patients with primary biliary cirrhosis.
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