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Conventional yearly mammograms that are effective for most women may not be adequate to catch breast cancer in women with BRCA 1 and 2 mutations, according to new research by Dr. Freya Schnabel, associate professor of clinical surgery and her colleagues in breast surgery.

Almost half of the women in the study discovered a lump in their breasts less than 12 months, and sometimes only three months, after a routine mammogram gave them a negative result.

"Women with BRCA 1 and 2 mutations have a great risk of developing breast cancer, but it can be quite challenging to catch cancers early in younger women who are mutation carriers because mammography is a less sensitive tool in younger women," Dr. Schnabel says. "We're finding that simple conventional screening is probably inadequate to screen women who are mutation carriers."

Women with mutations in one of the BRCA genes have an approximately 80 percent chance of getting breast cancer during their lives. For these women, doctors generally recommend that regular mammograms begin much earlier than usual, but there is no consensus on exam frequency. Most women with the mutations get yearly exams, as is recommended for all women over age 50.

In the new study, Dr. Schnabel and her colleagues looked back into the medical charts of women who were screened for BRCA mutations at the medical center's Comprehensive Breast Center between 1995 and 2002. Of 13 women with mutations, 46 percent were diagnosed with an aggressive form of breast cancer during the 12 months between mammograms. Half of these women (3 out of 6) found their cancers less than 3 months after their last mammogram.

"It's disconcerting to tell a woman she's okay, and then two, four, or five months later they have breast cancer," Dr. Schnabel says. "It really calls into question the screening process. It also may indicate that the cancer is very aggressive.

"For all women, early detection is critical for survival. With the current availability of other imaging methods, including ultrasound and MRI, serious consideration should be given to utilizing everything at our disposal to give mutation carriers the best chance for early detection," Dr. Schnabel says, although she adds more research is needed before any specific protocol can be recommended.

The study is published online in advance of print at the Cancer website.

–Susan Conova

Israeli women with a history of pre-eclampsia, a potentially life-threatening increase in blood pressure during pregnancy, are at increased risk of cancer, particularly breast cancer, according to a study by researchers at Columbia's Mailman School of Public Health and Hadassah-Hebrew University in Jerusalem.

Women in the study who had pre-eclampsia had a 30 percent higher risk of cancer in general and a 40 percent higher risk for breast cancer.

"We don't think that pre-eclampsia causes cancer," says Dr. Susan Harlap, a physician–epidemiologist and the study's senior author. "But it raises some interesting thoughts. Pre-eclampsia has been a huge puzzle for years, and by focusing on both diseases at once we may be able to get a better picture of what causes pre-eclampsia."

The study contradicts other large studies conducted in European and U.S. women that found pre-eclampsia is associated with a decrease in cancer risk. Dr. Harlap says environmental and genetic factors unique to the Israeli population may underlie the differences among the studies. But the new study's longer follow-up time may also be a factor.

"Pre-eclampsia is a disease of pregnant women, so it typically occurs in women in their 20s. Cancer is a disease of older women. If you follow pre-eclampsia women for 10 to 15 years, as the other studies did, the women are only in their 40s and their probability of having cancer is much smaller," she says.

The new study followed, for an average of 29 years, 37,000 Israeli women who delivered babies in three large hospitals in West Jerusalem between 1964 and 1976. The results were published March 5 on the British Medical Journal Web site.

"We can't extend our findings in Israeli women to other populations," Dr. Harlap says, "but we have cast doubt on the general view that pre-eclampsia is associated with a reduced risk of cancer."

Dr. Harlap's study is part of a broader life course studies program in the Department of Epidemiology that examines how a wide range of environmental and genetic factors that come into play throughout life increase or decrease the risk of disease.

Dr. Harlap led an international team of scientists, including Dr. Ora Paltiel from the Braun School of Public Health and Community Medicine at Hadassah-Hebrew University in Jerusalem, and first author of the study. The research was funded by the NIH.

–Susan Conova

Vitamin A and iron deficiencies are independent risk factors for anemia in malnourished preschool children, according to a study by Columbia University Medical Center researchers and colleagues.

Anemia, defined by the World Health Organization and Unicef as a hemoglobin count of less than 110 grams per liter, is a condition in which a lack of red blood cells limits the ability of blood to carry oxygen. The disorder is an important health problem for malnourished children because it is associated with delayed psychomotor development and growth retardation. The main cause of anemia in preschool children worldwide is iron deficiency, but other factors that may contribute to anemia include vitamin A deficiency and systemic inflammation.

The relative contribution of these factors has not been well characterized, however, so the researchers, led by Dr. Mary Gamble, assistant professor of environmental health sciences at the Mailman School of Public Health and first author of the paper, conducted a study of 367 preschool children in the Republic of the Marshall Islands (RMI), which is comprised of 29 atolls in Micronesia. Previously, these investigators reported that the prevalence of vitamin A deficiency among preschoolers in the RMI is among the highest in the world. In the present study, inflammation was not found to be a significant risk factor for anemia.

"The study points out the importance of treating multiple micronutrient deficiencies in developing countries, rather than the more typical approach of treating them individually," Dr. Gamble says. The findings were published online March 31 in the European Journal of Clinical Nutrition.

The study was supported in part by the Pacific Health Research Institute, Unicef, the Fergussen Foundation Hawaii, the Hawaii Community Foundation, Ministry of Health and Environment, Republic of the Marshall Islands, NIH and USAID.

–Matthew Dougherty

Columbia University Medical Center researchers have determined that mutations in a specific gene are a common cause of a form of familial epilepsy. In this form of epilepsy, autosomal dominant partial epilepsy with auditory features (ADPEAF), seizures are often accompanied by changes in hearing, such as buzzing or ringing sounds or distortions in volume.

Two years ago, the researchers, led by Dr. Ruth Ottman, professor of epidemiology in the Mailman School of Public Health and deputy director for research at the Gertrude H. Sergievsky Center, found that mutations in the gene LGI1 cause ADPEAF. Now, the researchers have found that LGI1 mutations are present in about half of the families in which two or more members have epilepsy associated with auditory symptoms. They found mutations in three families in addition to the five they previously reported. All together seven of the 14 families they have studied – not including the original family they used to describe the syndrome – have had mutations. The findings were published in the April 13 issue of Neurology.

In the families with mutations, some people who inherit a mutation never develop epilepsy. The investigators estimated that "penetrance," or the probability that someone with a mutation will develop epilepsy, is about 54 percent. The researchers believe their new estimate is more accurate than their previous estimate of 71 percent because the new study corrected for biases more effectively.

The researchers were not able to find clinical symptoms of ADPEAF that would predict which families have an LGI1 mutation. However, in two of the families they studied, some people with an LGI1 mutation had a different form of epilepsy – idiopathic generalized epilepsy. ADPEAF is a form of focal epilepsy, in which seizures begin in a specific brain region, the lateral temporal lobe. In contrast, in idiopathic generalized epilepsies, seizures affect the whole brain or both hemispheres from the outset.

"These results are really surprising and interesting because focal and generalized epilepsies are thought to be caused by separate genes," says Dr. Ottman. More research is needed to determine if LGI1 mutations raise the risk for both focal and generalized epilepsy or if these families have mutations in unidentified genes in addition to LGI1.

The research was supported by the NIH.

–Matthew Dougherty

A new study in mice identifies one of the missing steps in how Alzheimer's develops and suggests a possible new treatment strategy, according to researchers at Columbia University Medical Center and Weill Cornell Medical College and their colleagues. The research was published in the April 16 issue of Science.

The researchers, led by Dr. Shi Du Yan, associate professor of clinical pathology, Dr. Joyce W. Lustbader, senior research scientist in obstetrics and gynecology, and Dr. Hao Wu at Weill Cornell, created a crystal form of two molecular components, a protein and a peptide, of the disease. The crystal form enables researchers to study the molecular structure, which helps in understanding the function and ways to inhibit such components. "The crystal complex is the first demonstration that beta-amyloid peptide binds to a protein called ABAD and accumulates inside the mitochondria in brain cells," Dr. Lustbader says.

Many researchers believe that Alzheimer's occurs when beta-amyloid clusters in and ultimately kills brain cells by causing the production of destructive free radicals in the mitochondria. In the new study, the investigators demonstrated that transgenic mice, which produced too much ABAD in a beta-amyloid rich environment, showed exaggerated neuronal oxidative stress and impaired memory.

"Our findings suggest that one way to treat Alzheimer's would be to develop a drug that prevents the beta-amyloid peptides from binding with ABAD, which might prevent the cascade of damage that Alzheimer's typically leads to," says Dr. Yan, who is also a member of the Taub Institute for Research on Alzheimer's Disease and the Aging Brain and of the surgical science division in surgery. She says that ABAD is an important enzyme for fatty acid metabolism and, therefore, it would not be desirable to block ABAD itself.

The research was supported by the National Institute on Aging.

–Matthew Dougherty

Researchers know that sleep deprivation acts as a brake on the brain, slowing alertness, reaction time and memory. But until recently, scientists have looked at the brain section by section, rather than as a whole, to see which areas are most affected by lack of sleep.

Now, Columbia University Medical Center researchers, taking a more holistic approach, have used functional magnetic resonance imaging (fMRI) in two recent studies to determine which brain areas change their activity levels together to form a network associated with sleep deprivation, according to Dr. Yaakov Stern, professor of clinical neuropsychology, director of the Cognitive Neuroscience Division of the Gertrude H. Sergievsky Center and the Taub Institute for Research on Alzheimer's Disease and the Aging Brain, and senior author of both studies.

In the latest study, Dr. Stern, Dr. Christian Habeck, postdoctoral research scientist in the Taub Institute, and colleagues examined the effects of sleep deprivation on the short-term memory of 19 young adults who went two days without sleep. The study participants were tested before and after the sleep deprivation with a visual recognition task.

The participants were asked to memorize a large set of geometrical shapes and then identify which shapes they were already shown and which they were seeing for the first time. The researchers identified a network of brain areas whose activity levels dropped after sleep deprivation and correlated that drop in activity level with diminished memory performance.

"Although further research is needed, our findings suggest which brain regions need to be stimulated during sleep deprivation to overcome the cognitive effects of sleep loss," Dr. Habeck says.

The study findings might be useful as a screening tool to indicate which individuals would be able to withstand sleep deprivation better than others. The researchers found that the people whose memory performance decreased the most during sleep deprivation also had lower memory test scores before the sleep deprivation began. The research was published March 28 online in the journal Cerebral Cortex.

The U.S. Defense Advanced Research Projects Agency funded the research.

–Matthew Dougherty