The discovery of an inflammatory mediator key to the blinding effects of diabetic retinopathy is pointing toward a potential new treatment, Medical College of Georgia researchers said.
Interleukin-6, known to contribute to the debilitating joint inflammation of rheumatoid arthritis, also helps ignite inflammation of the retina, a first step in a disease that is the leading cause of blindness is working-age adults, MCG researchers reported online in Investigative Ophthalmology & Visual Science.
The finding has the scientists looking at whether an interleukin-6 antibody, which is showing success in treating rheumatoid arthritis, can halt inflammation in mice with diabetic retinopathy. "We expect that this neutralizing antibody can be used to treat diabetic retinopathy in the future," said Dr. Wenbo Zhang, assistant research scientist in MCG's Vascular Biology Center. Drs. Zhang and Modesto Rojas, senior postdoctoral fellow, are co-first authors on the paper.
Angiotensin II, a powerful constrictor of blood vessels, is typically associated with the kidneys where it plays a vital role in regulating blood pressure. The scientists suspect angiotensin II helps promotes wound healing and regulation of pressure within small blood vessels in the eye.
However in diabetes, angiotensin II levels increase in the eye -- probably in response to high glucose levels -- and help promote inflammation, spurring remodeling of blood vessels and tissue destruction, Dr. Rojas said. "Vascular inflammation is one of the first steps to inducing the changes in the retina."
MCG scientists have shown interleukin-6 is a needed accomplice whose previously undetectable levels in the eye also increase, said Dr. Ruth Caldwell, cell biologist a the Vascular Biology Center and the Charlie Norwood Veterans Affairs Medical Center and the study's corresponding author.
With the help of interleukin-6, angiotensin II induces white blood cells to stick to the endothelial cells lining blood vessels of the retina, which slows blood flow. The white blood cells also start producing inflammatory and vascular growth factors that cause blood vessel walls to leak and thicken, further constricting blood flow. Retinal cells start dying from the reduced blood and oxygen supplies that result. In response, the body prompts growth of new blood vessels, presumably to help but instead causing more vision impairment.
If the trigger, high glucose, was temporary, these natural responses might help clear damaged cells and protect the eye. "Inflammation is a compensatory mechanism that gets activated as a survival mechanism," Dr. Rojas said. "If it continues, the effect is bad."
"We have known for along time if patients keep their blood sugar under perfect control, they don't have these problems, but that's hard," Dr. Caldwell adds. "That is why it's such a difficult disease."
To examine interleukin-6's role in the destruction, the researchers injected angiotensin II into the vitreous portion of the eyes of mice missing the gene for the inflammatory factor as well as normal mice. The extra angiotensin did little to the retinal vessels of mice lacking interleukin-6 but vessels in the normal mouse retina mimicked the inflammatory reaction found in diabetic retinopathy. When they reintroduced interleukin-6 to the genetically altered mice, the damage mimicked that of the normal mice. "So when we knock out interleukin-6, we can block the effects of angiotensin II," Dr. Caldwell said.
The scientists want to see whether the interleukin-6 antibody can be used to prevent damage by giving it shortly after the onset of diabetes in rodents and as a treatment by using it later in the disease process.
The research was funded by the National Institutes of Health, the Department of Veterans Affairs and postdoctoral fellowship awards from the Juvenile Diabetes Research Foundation International and the American Heart Association.
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Anti Inflammation therapy for Retinal Disease
Chlamydial Infections can't be prevented by just screening girls alone
Chlamydial Inclusion BodiesDespite the fact they were screened every three months and treated when infected, the proportion of infected girls did not change over the course of the study. On entering the study, 10.9 percent of the young women were infected. After 18 months of participation, 10.6 percent were infected; 10.4 percent were infected at the four-year mark.
Eighty-four percent of repeated infections were reinfections. In spite of being so highly motivated that they kept diaries of their sexual encounters and interacted at least quarterly with the study staff, some of the young women had unprotected sex with either an untreated partner or a new partner and subsequent infection occurred. The researchers determined that 13 percent of repeated infections were due to failure of antibiotics to cure an earlier infection; considering all infections, antibiotic treatment was 92.1 percent effective.
"The rate of infection we found in the 365 Indianapolis girls we followed is similar to the rates reported by other researchers for girls in Denver and Baltimore, so it is likely that our important new findings on reinfection can be generalized to urban teenage girls in other cities," said Byron E. Batteiger, M.D., professor of medicine at the IU School of Medicine, an infectious disease specialist who is the first author of the study.
The researchers obtained a biological sample from as many sex partners of the study participants as possible to determine if the boys were chlamydia infected. "We were able to test 22.6 percent of all the partners that the girls named in the study. We determined that 26.2 percent of the participating boys were infected -- a very high level of infection in this pool of young men to whom young women in the study were exposed," noted Dr. Batteiger.
Current national recommendations call for routine chlamydia screening of women based on age and history of sexual activity. There is no similar recommendation for screening young men.
"The high rate of reinfection we found in our study strongly suggests there may be some real limits on what we can do to control chlamydia without doing a better job of controlling chlamydia in young men," said J. Dennis Fortenberry M.D. M.S., professor of pediatrics at the IU School of Medicine, an adolescent medicine physician who is the senior author of the study.
"We also need to make sure that sexually active teens are aware of fact that unlike some other diseases, having chlamydia and being successfully treated for it does not give the individual immunity from reoccurrence," said Dr. Fortenberry, who urges physicians to repeatedly screen adolescents for the disease.
Chlamydia is the most common bacterial sexually transmitted infection and is associated with an increased risk of pelvic inflammatory disease, ectopic pregnancy, tubal infertility, and increased susceptibility to human immunodeficiency virus infection. Chlamydia is more common in sexually active teens than in any other age group.
In addition to Dr. Batteiger and Dr. Fortenberry, co-authors of the study are IU School of Medicine faculty members Wanzhu Tu, Ph.D.; Susan Ofner, M.S.; Barbara Van Der Pol, Ph.D.; Diane R. Stothard, Ph.D.; Donald P. Orr, M.D.; and Barry P. Katz, Ph.D. In addition to their IU affiliations, Dr. Tu is a Regenstrief Institute investigator, Dr. Orr and Dr. Katz are Regenstrief Institute affiliated scientists and Dr. Van Der Pol is with the Marion County Department of Health. Dr. Stothard, formerly with the IU School of Medicine, is presently affiliated with Eli Lilly and Company. The study was funded by the National Institutes of Health.
The IU School of Medicine is located on the Indiana University-Purdue University Indianapolis campus.
Early Scents Really Do Get 'Etched' In The Brain
Common experience tells us that particular scents of childhood can leave quite an impression, for better or for worse. Now, researchers reporting the results of a brain imaging study online on November 5th in Current Biology, a Cell Press publication, show that first scents really do enjoy a "privileged" status in the brain."We found that the first pairing or association between an object and a smell had a distinct signature in the brain," even in adults, said Yaara Yeshurun of the Weizmann Institute of Science in Israel. "This 'etching' of initial odor memories in the brain was equal for good and bad smells, yet was unique to odor." Sounds did not have the same effect, the research showed.
In the study, the researchers presented adults with a visual object together with one, and later with a second, set of pleasant and unpleasant odors and sounds while their brains were imaged by functional magnetic resonance imaging (fMRI). A week later, the researchers presented the same objects inside the fMRI and tested participants' associations of those images with the scents and smells.
The researchers found that people remembered early associations more clearly when they were unpleasant, regardless of whether they were smelled or heard. The images, however, revealed a unique activation in particular brain regions in the case of their first olfactory (but not auditory) associations. That signature held regardless of whether the odors or sounds were pleasant or unpleasant. The researchers even found that they could predict what a person would remember later based on the activity in their brains on day 1.
Yeshurun explained that it makes good sense to remember unpleasant memories as a kind of evolutionary "risk management." But the findings show that there is also something particularly special about early memories of smells.
That wasn't really unexpected, Yeshurun said -- it is after all a phenomenon that has long fascinated authors, poets, and scientists alike. Still, the results did hold some surprises.
"We expected a unique representation of initial or 'first' olfactory associations but did not expect that it would materialize even in cases where the behavioral evidence did not indicate a stronger memory," Yeshurun said. "In our paradigm, initial and later olfactory associations were remembered equally well, but only first associations had the unique brain representation."
In terms of understanding the brain, the findings suggest that activity in two brain regions, known as the hippocampus and amygdala, together can render a memory "special."
Although any application of the findings would be far off, Yeshurun said the results could suggest ways to strengthen particular memories. "Perhaps more importantly, it may help us generate methods to better forget early and powerful memories, such as trauma," she said.
The researchers include Yaara Yeshurun, Hadas Lapid, Yadin Dudai, and Noam Sobel, of the Weizmann Institute of Science, in Rehovot, Israel.
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