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Worldwide, children have been increasingly developing Type 1, or juvenile, diabetes. Why the disease is becoming more prevalent remains unknown, but some recent studies suggest cow's-milk proteins in baby formula may increase the risk for diabetes in infants at increased genetic risk for the disease.

To investigate whether a cow's-milk-free diet for babies could prevent Type 1 diabetes, Columbia Health Sciences researchers are participating in a multicenter, 10-year trial to reduce Type 1 diabetes in the genetically at risk. The study, which is actively recruiting participants, follows results from pilot studies in Finland that found cow's-milk proteins may foster the creation of juvenile diabetes by spurring the development of antibodies that destroy insulin-producing cells. Columbia enrolled the first three babies in the U.S. part of the trial earlier this month.

Dr. Holly Schachner, assistant professor of clinical pediatrics in P&S, assistant director for pediatric diabetes in the Naomi Berrie Diabetes Center, and principal investigator for Columbia's component of the trial, says the randomized double-blind study will involve 8,000 babies worldwide—300 of whom will be studied at Columbia. Babies included in the study, deemed at increased risk for Type 1 diabetes, have a mother, father, or sibling with Type 1 diabetes.

Each mother in the study will be encouraged to breastfeed her baby from birth. For babies who require supplemental nutrition for the first six months, half will get a formula with cow's-milk protein and the other half will get a formula free of cow's-milk protein. Researchers will perform several blood tests in the first two years, followed by yearly tests in the last eight years to see if the babies consuming cow's milk protein are more likely to develop antibodies to human islet cells and to develop diabetes.

The National Institutes of Health, the Juvenile Diabetes Research Foundation, and the American Diabetes Association are supporting the research.

— Matthew Dougherty

Women who have BRCA1/2 gene mutations, which make them more likely to get breast and ovarian cancer, face difficult cancer prevention choices. They can elect to undergo surgery to remove their breasts, ovaries, or both, take drugs, or receive a combination of medication and surgery.

Now researchers from Columbia Health Sciences, led by Dr. Victor R. Grann, associate clinical professor of medicine at P&S and in public health at the Mailman School of Public Health, have found that a current analysis of data from 1998 through 2001 on prophylactic surgery—either mastectomy or ovary removal—reveals greater survival benefits than what had been estimated from studies done in 1997 and 1998.

The researchers also report that ovary removal and mastectomy together offer the best survival strategy, but when quality of life is considered, ovary removal and tamoxifen together appear to be the better option. They also found that preventive strategies offer greater benefits to women who undertake them early, near age 30.

Dr. Grann and his colleagues used a computer model to analyze cancer patient data from recent medical literature, a National Cancer Institute database issued in 2001 with data from 1973 to 1998, and a 1999 survey of quality of life preferences for different prevention strategies. The findings were reported in the May 15 Journal of Clinical Oncology.

"In the future we can update this model as new information becomes available in the continuing effort to help women with these mutations choose the best strategy," Dr. Grann says.

He has begun investigating whether it is cost effective for insurance companies and the government to pay for these surgical procedures. Initial indications show the cost of the procedures is relatively small compared with the survival benefit they provide.

The research was supported in part by grants from the American Cancer Society, the Sindab African American Breast Cancer Project, the Avon Foundation Breast Cancer Research and Care Program, and the Breast Cancer Alliance.

— Matthew Dougherty

The inflamed joints and damaged bones of rheumatoid arthritis appear to be heavily influenced by the activation of a cell surface receptor, called RAGE, located in the joints of patients, according to researchers at P&S. Led by Dr. Ann Marie Schmidt, associate professor of surgery, the researchers found that blocking the receptor prevents much of the inflammation and damage, and certain alleles of RAGE may increase disease severity.

RAGE is a receptor on a range of inflammatory and vascular cells. Molecules such as S100/calgranulins bind to RAGE and trigger extracellular signaling pathways, thereby amplifying inflammation. While investigators knew that S100/calgranulins, abundant in the joints of arthritis patients, bound to RAGE, it was unknown if RAGE-S100/calgranulin binding played a role in rheumatoid arthritis.

Now in a mouse model of rheumatoid arthritis, Dr. Schmidt and colleagues have shown the RAGE-S100/calgranulin interaction increases the severity of the joint inflammation and bone damage. When RAGE-S100/calgranulin binding was blocked in the arthritic mice, the joints produced fewer inflammatory molecules, had less swelling and fewer deformities, and suffered less bone and cartilage destruction than controls.

The researchers also found the protein product of the 82S allele of RAGE binds S100/calgranulins more easily and may be associated with more severe disease in humans. Human phagocytes that expressed the 82S RAGE released more inflammatory molecules than cells with the 82G version after binding S100/calgranulins.

The researchers are hoping to design a study in which they follow patients with rheumatoid arthritis over time to determine if the 82S allele correlates with severity of symptoms. The research was published in the May issue of Genes and Immunity and was funded by the Surgical Research Fund of P&S, the U.S. Public Health Service, and the National Arthritis Foundation.

"The research may lead to better treatments of rheumatoid arthritis," Dr. Schmidt says. "And we may be able to tailor the course of therapy to a patient based on their genetic profile, including that of their RAGE allele."

— Susan Conova