Natural system for eliminating salt may point to new antihypertensives

A study of the body system that deals with Americans’ love affair with salt may yield more insight into why so many end up hypertensive and how to better treat them.

A team of scientists from the Medical College of Georgia, the University of Utah and the University of Texas at San Antonio is looking at how the kidneys know you’ve eaten too much salt and what they do to eliminate it. The work is funded by a $11.2 million National Institutes of Health Program Project grant.

Their focus, endothelin, ironically has a bad rep as a “death peptide” because of its shared ancestry with the Israeli burrowing asp that can shut down coronary arteries with one bite.

But the powerful protein produced by the kidney takes direction – good or bad – from its receptors, according to Dr. David Pollock, renal physiologist at MCG’s Vascular Biology Center and director of the program project.

“It’s like politics: all things are local,” said Pollock.  In this case the upright guy tends to be the B receptor, which aids sodium excretion while its roguish sibling A receptor – the same one that shuts down the coronary arteries of asp victims – blocks it. When all goes well, the balancing act regulates the sodium level with the kidneys producing more endothelin and B receptors to eliminate the excess.

However in hypertension models, the B receptor doesn’t work so well, although exactly why is still unclear. “It’s this balance between A’s and B’s that is critical,” Pollock said. “If your balance becomes unbalanced you will have salt-sensitive hypertension.”  That’s why he is looking at the pathways that become activated on a high-salt diet and just what the A receptor is up to.

He and his colleagues are studying rats deficient in B receptors; they are a slightly hypertensive on a regular diet and very hypertensive on a high-salt diet.  More circuitously, the researchers also infused angiotensin, a powerful blood vessel constrictor, into rats causing similar dysfunction of the B receptors.

“We also think without the B receptor function, your A’s go a little bit crazy,” Pollock said. Not only do the A’s constrict, they promote inflammation, which can further damage blood vessels. In fact, a high-salt diet can cause even B receptors to behave badly, said Dr. Jennifer Pollock, MCG biochemist and a project leader.

Across the country, Dr. Donald Kohan, nephrologist and physiologist at the University of Utah, wants to figure out what prompts the kidneys to make more endothelin in the face of a high-salt diet. He is studying kidney cells to examine how endothelin production changes and ideally learn why. The goal, again, is drug therapies to inspire this natural phenomenon.

The results when A receptors go unchecked include stiff, tortuous blood vessels; a thick boggy pumping chamber in the heart; and other major organ damage that includes the kidney.

“The consequences are measurable targets,” said Dr. Edward Inscho, MCG physiologist and a project leader, noting that treatments are available but “preventing it from occurring is something we are not very good at yet.”

To help put the pieces together, Inscho is focusing on how blood vessels that feed directly into kidney filters react to a high-salt diet. Blood, containing salt, continuously flows through the kidneys. The researchers have seen that excess salt increases B receptor expression, which should help the kidneys filter more sodium then get rid of it.

“If you filter more, you have more salt available for excretion,” Inscho said. He wants to know what’s happening with A and B receptors inside the tiny vasculature of the kidneys. He’s using B-deficient rats and drugs that block either receptor to get a better idea about both. The idea is to figure out not just how they normally work but how the system becomes dysfunctional in hypertension.  “I think we are beginning to understand how the B receptor may factor into some other regulatory systems the kidney may use to control filtration,” he said.

Noted Jennifer Pollock, “Your kidneys in theory should be able to lower your blood pressure but because people do remain hypertensive, that means there must a problem with your kidneys as well.” She suspects that endothelin activates production of nitric oxide when it hits the B receptor. Nitric oxide, which dilates blood vessels, prompts the sodium channels in kidney tubules to fold inward.

“The salt can’t get in and so it gets excreted,” Jennifer Pollock said. “We are connecting the dots now.” If they are correct, they have found a new mechanism for controlling salt excretion that is a natural drug target. Since it’s difficult to enhance nitric oxide, it likely will be necessary to find another cue to prompt sodium channels to fold up their tents. She developed a mouse lacking nitric oxide synthase, which prompts nitric oxide production, to help pursue the theory.

Co-investigator Dr. James Stockand in Texas is investigating mechanisms for how endothelin affects transport of sodium in and out of the cell, focusing on proteins known as ion channels. Dr. Jennifer Sullivan, pharmacologist/physiologist at MCG’s Vascular Biology Center, is providing support and expertise with the numerous animal models needed for the grant.

“The future of pharmaceutical therapies is going to be the right balance of different drugs,” said David Pollock.  “Most people with high blood pressure are also taking cholesterol medicine and possibly other drugs. So the future has to be what is the right formula for you and your situation.”

The scientists hope their studies will point the way to these new, targeted options.

By Toni Baker
Medical College of GA

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Nanotechnology may increase longevity of dental fillings

ooth-colored fillings may be more attractive than silver ones, but the bonds between the white filling and the tooth quickly age and degrade. A Medical College of Georgia researcher hopes a new nanotechnology technique will extend the fillings' longevity.

"Dentin adhesives bond well initially, but then the hybrid layer between the adhesive and the dentin begins to break down in as little as one year," says Dr. Franklin Tay, associate professor of endodontics in the MCG School of Dentistry. "When that happens, the restoration will eventually fail and come off the tooth."

Half of all tooth-colored restorations, which are made of composite resin, fail within 10 years, and about 60 percent of all operative dentistry involves replacing them, according to research in the Journal of the American Dental Association.

"Our adhesives are not as good as we thought they were, and that causes problems for the bonds," Dr. Tay says.

To make a bond, a dentist etches away some of the dentin's minerals with phosphoric acid to expose a network of collagen, known as the hybrid layer. Acid-etching is like priming a wall before it's painted; it prepares the tooth for application of an adhesive to the hybrid layer so that the resin can latch on to the collagen network. Unfortunately, the imperfect adhesives leave spaces inside the collagen that are not properly infiltrated with resin, leading to the bonds' failure.

Dr. Tay is trying to prevent the aging and degradation of resin-dentin bonding by feeding minerals back into the collagen network. With a two year, $252,497 grant from the National Institute of Dental & Craniofacial Research, he will investigate guided tissue remineralization, a new nanotechnology process of growing extremely small, mineral-rich crystals and guiding them into the demineralized gaps between collagen fibers.

His idea came from examining how crystals form in nature. "Eggshells and abalone [sea snail] shells are very strong and intriguing," Dr. Tay says. "We're trying to mimic nature, and we're learning a lot from observing how small animals make their shells."

The crystals, called hydroxyapatite, bond when proteins and minerals interact. Dr. Tay will use calcium phosphate, a mineral that's the primary component of dentin, enamel and bone, and two protein analogs also found in dentin so he can mimic nature while controlling the size of each crystal.

Crystal size is the real challenge, Dr. Tay says. Most crystals are grown from one small crystal into a larger, homogeneous one that is far too big to penetrate the spaces within the collagen network. Instead, Dr. Tay will fit the crystal into the space it needs to fill. "When crystals are formed, they don't have a definite shape, so they are easily guided into the nooks and crannies of the collagen matrix," he says.

In theory, the crystals should lock the minerals into the hybrid layer and prevent it from degrading. If Dr. Tay's concept of guided tissue remineralization works, he will create a delivery system to apply the crystals to the hybrid layer after the acid-etching process.

"Instead of dentists replacing the teeth with failed bonds, we're hoping that using these crystals during the bond-making process will provide the strength to save the bonds," Dr. Tay says. "Our end goal is that this material will repair a cavity on its own so that dentists don't have to fill the tooth."

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Male impotence drugs may deserve a second look in women

New studies indicate the three drugs used to treat male impotence also appear to work in females, albeit a little differently, and should give the scientific community pause to take a second look at their potential in the 40 percent of women who report sexual dysfunction, researchers say.

In one of the first studies of the effect of phosphodiesterase Type 5 inhibitors - Viagra®, Levitra® and Cialis® - on the pudendal arteries that supply the penis, vagina and clitoris the blood needed to produce a satisfying sexual experience, Medical College of Georgia researchers showed the drugs relax the artery in male and female rats.

"It shows the drugs need to be investigated more for women and small alterations could make these compounds more effective for women living with these disorders," says Dr. Kyan J. Allahdadi, postdoctoral fellow in physiology at MCG. He's presenting the findings during the 122nd Annual Meeting of the American Physiological Society held in New Orleans April 18-22 as part of the Experimental Biology 2009 scientific conference.

Although there was talk years ago of a pink pill for women to parallel the blue Viagra for men, early clinical trials found essentially no response in women.

MCG researchers decided to look again, first giving a drug to constrict the internal pudendal arteries in male and female rats – as they would be in a non-erect state – then giving doses of each impotency drug to see the impact. The arteries from male rats displayed a relatively standard concentration-dependent relaxation – the more drug they got, the more they relaxed - while in females arteries, there was an initial relaxation then an odd oscillation between relaxation and contraction with subsequent dosing.

While they don't fully understand the swing, the unique female response likely provides more evidence that sexual function is more complex in females, says Dr. R. Clinton Webb, chair of the MCG Department of Physiology and a study author. Scientists define female sexual dysfunction as a multifaceted disorder that includes anatomical, psychological, physiological and social-interpersonal aspects.

MCG researchers have shown part of that complexity may be the smooth muscle cells in the internal pudendal arteries of females communicate, agreeing to contract and relax, while male smooth muscle cells make independent decisions to just relax.

They found one other distinction: females were more sensitive to Viagra®, or sildenafil, while males were most sensitive to Levitra®, or vardenafil.

Previous studies on the effectiveness of these drugs focused on the cavernosal tissue, or penis. The internal pudendal artery actually feeds the penile artery which is buried deep in the penis where numerous caverns enable it to be flaccid when not engorged with blood. Physical stimulation of the area causes the tissue, endothelial cells and nerves to release nitric oxide, a powerful dilator of blood vessels. The system works pretty much the same way in the vagina and clitoris.

"If you have too much constriction or not enough relaxation to allow blood to go through the internal pudendal artery, you are not going to get the net effect of an erection," Dr. Allahdadi says. "That is why we wanted to begin to characterize what was going on in this blood vessel."

Perhaps as importantly, the MCG scientists and others are beginning to believe sexual dysfunction provides an early, or at least visible, clue of vascular disease. Vascular problems, that can result from diabetes, hypertension, high cholesterol and the like, are a major cause of sexual dysfunction in men and women. "You don't feel atherosclerosis but you know darn well if you are not getting an erection," Dr. Webb says. In fact, the MCG scientists are beginning to look at animal models of disease states, such as diabetes, to see what it does to these internal pudendal arteries.

"What we have seen preliminarily is there is big difference in responsiveness in these arteries. The diabetic pudendal arteries are much more sensitive to contraction," Dr. Allahdadi says. They will look at how drugs like Viagra impact that contraction in the days ahead.

In fact MCG scientists suspect one reason that many of the women participants in previous studies of Viagra did not seem to respond is because they did not have vascular problems that could have been circumvented by a drug that relaxes arteries so blood can enter. In men with a healthy vasculature, the drugs likely would still produce a longer erection.

Dr. Rita C. Tostes, associate professor in the MCG Department of Physiology, is a co-author who contributed to the design and analysis of the study.

Toni Baker
Medical College of Georgia

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Not enough vitamin D in the diet could mean too much fat on adolescents

Too little vitamin D could be bad for more than your bones; it may also lead to fatter adolescents, researchers say.

A Medical College of Georgia study of more than 650 teens age 14-19 has found that those who reported higher vitamin D intakes had lower overall body fat and lower amounts of the fat in the abdomen, a type of fat known as visceral fat, which has been associated with health risks such as heart disease, stroke, diabetes and hypertension.

The group with the lowest vitamin D intake, black females, had higher percentages of both body fat and visceral fat, while black males had the lowest percentages of body and visceral fat, even though their vitamin D intake was below the recommended levels. Only one group – white males – was getting the recommended minimum intake of vitamin D.

“This study was a cross-section so, while it cannot prove that higher intake of vitamin D caused the lower body fat, we know there is a relationship that needs to be explored further," says Dr. Yanbin Dong, a molecular geneticist and cardiologist at the MCG Gerogia Prevention Institute.

Dr. Dong, who also co-directs the MCG Diabetes & Obesity Discovery Institute, and Inger Stallman-Jorgensen, a research dietician at the GPI, present their findings this week at the American Heart Association’s Joint 49th Conference on Cardiovascular Disease Epidemiology and Prevention and Nutrition, Physical Activity and Metabolism in Palm Harbor, Fla.

The pair will next study whether it is feasible for teens to take a daily vitamin D supplement in pill form. Those results will help them design a larger study to explore the relationship between vitamin D intake and body fat levels in teens.

“We already know that encouraging teens to get an adequate amount of vitamin D in their diets will help promote a healthy body as they grow and develop,” Ms. Stallman-Jorgensen says. “Now we need to do intervention studies where we give teens vitamin D supplements to determine if there is a cause and effect relationship between vitamin D intake and fat.”

The American Academy of Pediatrics recommends adolescents get at least 400 units of vitamin D per day – either from milk or sun exposure. There are typically 100 units in one 8-ounce glass of whole milk. The recommended daily dose from the sun would require at least 30 minutes of adequate exposure to direct sunlight two or three times a week at peak hours, between noon and 3 p.m.

Ms. Stallman-Jorgensen said there are many reasons teens don't get enough vitamin D, which has been linked to the prevention of diabetes, cancer and cardiovascular disease.

“As humans, our largest source of vitamin D should be the sun. But we don’t spend enough time outdoors to get enough sun exposure and when we do, we’re often covered up and wearing sunscreen," she said. "We can get vitamin D from certain foods, like fatty fish and liver, but it’s not in a lot of foods that we commonly consume. In this country, our milk is fortified with vitamin D. Unfortunately, teens just don’t drink enough milk to get their daily requirements.”

She points out that low sunlight during the winter months reduces the amount of vitamin D the skin produces, and that darker-skinned people obtain less vitamin D from the sun because the extra melanin in their skin filters out more sunlight.

Some people can't tolerate milk because they lack the enzyme that processes lactose, the natural sugar in milk, though "most people can handle it in small amounts,” Ms. Stallman says.

Cultural issues may also be at play, Ms. Stallman-Jorgensen says.

“Most teens want to drink sodas and sugary drinks. It’s not cool to drink milk – they think of it as more of a food for babies,” she said.

Potential study participants had their weekday and weekend diets tracked by researchers seven times during a three-month period. Those who provided at least four diet reports were included in the final group of 659.

Body fat percentages were measured by dual energy X-ray absorptiometry scans, which can measure total body composition. Visceral fat was measured in a subset of 432 teens.

Jennifer Hilliard
Medical College of Georgia

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Prevalence of Disordered Eating Behaviors in Diabetics Probed

Children with diabetes are at an increased risk for developing eating disorders and researchers want to know if it's their disease or treatment that's to blame.

"Diabetes treatment prescribes obsessive food behavior, such as carbohydrate restriction," said Dr. Deborah Young-Hyman, pediatric psychologist in the Medical College of Georgia's Georgia Prevention Institute. "We want to know if those prescribed behaviors contribute to disordered eating and/or whether there are physiological mechanisms which prevent children with diabetes from controlling their eating behavior. For example, treatment with insulin makes you hungry and can cause you to gain weight."

There is some unfortunate synergy: diabetes makes it difficult to control blood glucose and disordered eating behavior does as well, Dr. Young-Hyman said.

Over the next three years, with funding from the American Diabetes Association, she and researchers at Emory and Harvard universities will study 90 children age 10-17 newly-diagnosed with diabetes or transitioning to an insulin pump. They will monitor treatment patterns, weight, psychological adjustment and attitudes about weight and eating. They'll also look at changes in eating patterns and blood sugar levels in response to insulin.

Children and their parents will answer computer-based questionnaires about eating behaviors and psychological adjustment - in the context of their disease and its treatment.

These include questions about parental attitudes, family factors, personality of the child and parents and perceived societal attitudes.

"As they are diagnosed and are adjusting to diabetes treatment, children are already dealing with all sorts of issues that put them at an increased risk for eating disorders. The psychological issues that come with the diagnosis can add to that risk," she said. "There is also the existing drive for thinness that exists in our society, dealing with the diagnosis and management of a long-term illness and the psychological adjustment that comes with that."

Even the insulin the children must take may be a factor. "Large doses can lead to uncontrolled hunger, which can be mislabeled as disordered eating behavior. Patients with type 1 diabetes also lose amylin production - a hormone responsible for gastric emptying and associated with feelings of fullness - that can also lead to increased feelings of hunger," Dr. Young-Hyman said.

Study findings could support a different treatment approach.

"We might come to understand that putting a child or adolescent on an insulin pump sooner rather than later and providing them with a more flexible nutrition regimen could decrease their insulin needs and prevent excess hunger," she said. "If we don't approach weight control as dieting, place less emphasis on food restriction and focus on healthy nutrition and usual eating patterns, we can help patients gain more control over their eating behaviors and their treatment without adoption of maladaptive weight management strategies. Studies indicate that feeling in control of your illness is one of the keys to successful treatment and good psychological adjustment."

Jennifer Hilliard
Medical College of Georgia

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MCG Receives $100,000 Grand Challenges Explorations Grant for Innovative Global Health Research by Dr. Koni

The Medical College of Georgia announced November 5th that it has received a $100,000 Grand Challenges Explorations grant from the Bill & Melinda Gates Foundation. The grant will support an innovative global health research project conducted by Dr. Pandelakis A. Koni titled “Antibody-Dependent Cellular Cytotoxicity Targeted Against HIV-1 Env Glycans.”

Dr. Koni’s project is one of 104 grants recently announced by the Gates Foundation for the first funding round of Grand Challenges Explorations, an initiative to help scientists around the world explore bold, new solutions for health challenges in developing countries. The grants were provided to all levels of scientists in 22 countries and five continents.

To receive funding, Dr. Koni showed in a two-page application how his idea falls outside current scientific paradigms and could lead to significant advances in global health if successful.

His goal is to develop a vaccine against HIV, a virus that is notoriously slippery, constantly mutating itself to avoid being targeted by the immune system. In fact, the dynamic of this virus is one reason vaccines to date have failed, Dr. Koni said. But he thinks there may be chinks in the armor. Like many cells in the body, HIV and HIV-infected cells are sugar-coated. In fact, one role of this complex carbohydrate shield is believed to be protecting HIV from attack. However there are some consistencies in the sugar coating which Dr. Koni believes are critical to the virus and may be good vaccine targets.

As a first step, the immunologist is working to develop antibodies to these segments of the sugar coating with the idea that they are sites of potential vulnerability for the durable virus. "My idea is that these areas are always conserved and are consistent for a reason," said Dr. Koni. While his goal is to develop a protective vaccine, Dr. Koni said if he's successful in his pursuit, the antibodies may provide new targeted treatment strategies as well.

“I congratulate each individual who took the initiative to share their idea with us to help fight the world’s most serious diseases,” said Dr. Tachi Yamada, president of the Gates Foundation’s Global Health Program. “The number of creative approaches we received exceeded our highest aspirations. Projects from this initial pool of grants have the potential to transform health in developing countries, and I will be rooting for their success.”

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Green Tea May Delay Onset of Type 1 Diabetes

A powerful antioxidant in green tea may prevent or delay the onset of type 1 diabetes, Medical College of Georgia researchers say.

Researchers were testing EGCG, green tea's predominant antioxidant, in a laboratory mouse with type 1 diabetes and primary Sjogren's syndrome, which damages moisture-producing glands, causing dry mouth and eyes.

"Our study focused on Sjogren's syndrome, so learning that EGCG also can prevent and delay insulin-dependent type 1 diabetes was a big surprise," says Dr. Stephen Hsu, molecular/cell biologist in the School of Dentistry.

They found it also worked well in their original disease focus.

In the mouse, EGCG reduced the severity and delayed onset of salivary gland damage associated with Sjogren's syndrome, which has no known cure.

"EGCG modulates several important genes, so it suppresses the abnormality at the molecular level in the salivary gland. It also significantly lowered the serum autoantibodies, reducing the severity of Sjogren's syndrome-like symptoms," Dr. Hsu says. Autoantibodies are antibodies the body makes against itself.

Both type 1 diabetes and Sjogren's syndrome are autoimmune diseases, which cause the body to attack itself. Autoimmune disorders are the third most common group of diseases in the United States and affect about 8 percent of the population, says Dr. Hsu. Sjogren's syndrome can occur alone or secondary to another autoimmune disease, such as lupus, rheumatoid arthritis or type 1 diabetes.

The study, published in the Oct. 24 issue of Life Sciences, supports earlier research showing EGCG's impact on helping prevent autoimmune disease.

Researchers treated a control group of mice with water and a test group with a purified form of EGCG dissolved in the drinking water. At 16 weeks, the EGCG-fed mice were 6.1 times more likely to be diabetes-free than the water-fed group, and 4.2 times more likely at 22 weeks.

"Previous studies used another animal model that developed type 1 diabetes only after an injected chemical killed the insulin-producing cells. That may not accurately resemble disease development in humans, because type 1 diabetes is a genetic disease," says Dr. Hsu, the study's corresponding author.

"Our study is significant because we used a mouse model with the genetic defects that cause symptoms similar to human type 1 diabetes and Sjogren's syndrome, so the immune cells attack the pancreas and salivary glands until they are no longer functional."

Another related finding was that even when salivary cells were under attack, they seemed to be rapidly reproducing in the control group. The proliferation was suppressed in the EGCG-fed group.

"It's kind of counterintuitive – why would there be proliferation of the glandular cells occurring when the present cells are not secreting saliva?" says Dr. Kevin Gillespie, first author of the study he conducted for his master's research project at MCG.

The proliferation phenomenon also can be observed in psoriasis, an autoimmune disease affecting the skin and joints, says Dr. Hsu. "Normal skin cells turn over every 30 days or so, but skin cells with psoriasis turn over every two or three days." Dr. Hsu's group previously found that green tea polyphenols, including EGCG, inhibited rapid proliferation in an animal model for human psoriasis.

"We never thought proliferation was going on to this extent in the salivary gland, but we now believe it is tightly associated with Sjogren's syndrome," he says.

The next step is to observe Sjogren's syndrome in human salivary gland samples to determine whether the study findings hold up in humans.

"If the abnormal expression of these genes is the same in humans as in the animal model, then the second stage will be intervention and treatment with a pure form of EGCG," says Dr. Hsu.

"The benefit of using green tea in preventing or slowing these autoimmune diseases is that it's natural and not known to harm the body," says Dr. Gillespie, periodontics chief resident at Fort Gordon's Tingay Dental Clinic. "EGCG doesn't have the negative side-effects that can be associated with steroids or other medications that could otherwise be prescribed."

By Paula Hinely
Medical College of Georgia

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Online Course Gives Physicians Useful Info about Community-Associated MRSA

A new bacterial infection is running rampant in communities because of antibiotic abuse, but ironically it is often misdiagnosed and treated with the wrong antibiotics, says a physician working to stop it.

Physicians regularly mistake the abscesses, or pockets of pus, caused by community-associated MRSA, or CA-MRSA, for spider bites and treat them as such, say Dr. Jim Wilde, pediatric emergency medicine and infectious disease physician at the Medical College of Georgia.

"Don't be fooled into thinking it's a spider bite," he says. "Think MRSA if you see a sore like that on somebody's hand or arm. The problem is that doctors are choosing the wrong oral antibiotics or are just not recognizing it at all."

Now they can log on to a new online lecture through the MCG Division of Continuing Education to learn more about this leading cause of skin and soft-tissue infections in the state.

It's part of a statewide educational campaign sponsored by Georgia United against Antibiotic Resistant Disease, or GUARD, to raise awareness about CA-MRSA.

Doctors and the general public can access the lecture at www.mcg.edu/ce/Online/mrsaonline. Physicians can receive continuing medical education credits for participating.

"The lecture, which is the first online continuing medical education course at MCG, is an excellent opportunity to learn more about this epidemic," says Caro Cassels, director of the continuing education division.

"There is a lot of misinformation and misunderstanding about MRSA, even among practicing physicians," says Dr. Wilde, who directs GUARD. "And we see dozens of cases of CA-MRSA in the emergency room every week here. It is a different type of MRSA than what we've known for the last 40 years and is spreading all over the country very rapidly."

MRSA, or methicillin resistant Staph aureus, cannot be killed by methicillin, a type of penicillin. It is spread by physical contact, not by breathing the same air or coughing. It lives on the skin and can survive on others surfaces for at least 24 hours. Hospital-associated MRSA (HA-MRSA) has been rampant inside hospitals since the early 1960s but was rare among healthy people in the community. CA-MRSA popped up around 2003 and quickly spread nationwide, causing infections primarily in healthy people outside hospitals. Infections caused by either form of MRSA can be treated, but HA-MRSA is much more dangerous. Both are resistant to all beta-lactam antibiotics, which are the most widely used class of antibiotics available.

"And yet, despite the fact that most skin and soft-tissue infections now are caused by CA-MRSA, there are still many doctors who are prescribing these antibiotics," Dr. Wilde says. "We're trying to do is get the word out to everyone in the state to stop using beta-lactams for skin infections."

In addition to the online course, 9,700 primary care physicians received educational packets from GUARD. Each packet contains a CA-MRSA fact sheet, an informational poster, a two-page synopsis of Centers for Disease Control and Prevention recommendations for treating CA-MRSA and a fill-in-the-blank discharge sheet. Dr. Wilde also coordinates a speakers' bureau on CA-MRSA with more than 30 members available to deliver lectures anywhere in the state.

GUARD is the Georgia chapter of the CDC's Get Smart about Antibiotic Use Program. The coalition seeks to reduce antibiotic-resistant disease by decreasing inappropriate antibiotic use. The educational campaign also is sponsored by the Georgia Department of Human Resources.

For more information about the online course and coalition, visit www.ga-guard.org.

By Amy Connell
Medical College of Georgia

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Breast cancer Cells Recycle to Escape Death by Hormonal Therapy

Many breast cancer cells facing potentially lethal antiestrogen therapy recycle to survive, researchers say.

About 70 percent of breast cancer cells have receptors for the hormone estrogen, which acts as a nutrient and stimulates their growth. Patients typically get an antiestrogen such as tamoxifen for five years to try to starve them to death, says Dr. Patricia V. Schoenlein, cancer researcher in the Medical College of Georgia Schools of Medicine and Graduate Studies.

"About 50 to 60 percent of these women really benefit from hormonal therapy," says Dr. Schoenlein. Why others don't has been asked for at least two decades.

One reason may be breast cancer cells switch into a survival mode that normal cells also use when faced with starvation, according to research published in the September issue of Molecular Cancer Therapeutics. Dr. Schoenlein also is reporting on the research during the 2nd World Conference on Magic Bullets (Ehrlich II) Oct. 3-5 in Nürenberg, Germany.

It's called macroautophagy – autophagy means "self eating" – and within a week, breast cancer cells can reorganize component parts, degrade non-essentials and live in this state until antiestrogen therapy is stopped or the cells mutate and resume proliferation in the presence of tamoxifen. "It's like taking your foot off of the gas pedal of your car," says Dr. Schoenlein, corresponding author on the study. "The cancer cell is in idle, unable to grow or replicate. But the cell is smart enough to use component parts generated by macroautophagy for the most necessary things required for survival." She notes that macroautophagy can't be maintained indefinitely; cells can actually self-digest. "This is a time-buying strategy."

Chemotherapeutic drugs are more direct killers but also kill healthy cells and can be tolerated by patients only for relatively short periods. Antiestrogen therapy is more specific, targeting breast cancer cells that express estrogen receptors.

In the laboratory, 20-25 percent of breast cancer cells died when Dr. Schoenlein and colleagues gave antiestrogen continuously over time – similar to how patients get it. More typically, the cells expressed increasing levels of macroautophagy and survived. "They don't grow, but they survive the therapy. They will grow if you take away the therapy." Adding a macroautophagy inhibitor promoted robust cell death.

"We believe targeting the autophagosome function will significantly improve the efficacy of hormonal treatment for estrogen-positive breast cancer," says the researcher. She recently received a three-year, $1.1 million National Cancer Institute grant to pursue that strategy.

She'll now look for ways to block macroautophagy in an animal model, including using chloroquine, a drug used to treat malaria. "We know patients can take it with few side effects," she says. If it works in animals, the drug, in combination with an antiestrogen, could move relatively quickly into human testing.

During autophagy, the internal pH for the recycling center of the reorganized cell gets acidic and chloroquine increases pH. "If you add this particular inhibitor of the recycling center, you alter the pH and block its ability to do what it is supposed to do," says Dr. Schoenlein.

A University of Pennsylvania team led by Dr. Craig Thompson reported in 2007 in The Journal of Clinical Investigation that chloroquine increased death of suicide-resistant lymphoma cells being treated with chemotherapy. Dr. Schoenlein will give chloroquine along with an antiestrogen and measure cell death.

"Most cancers probably use autophagy as a survival mechanism. You can either block the autophagosome with your therapy or you can make the cell eat itself to the point of no return and the cell self-destructs. You have to push it either way," she says. Although there are no known compounds in clinical use to induce self-destruction by autophagy, there is some evidence arsenic trioxide, a compound used in China to treat some aggressive cancers, prompts cancer cells to die from self digestion, she says. That and other compounds will no doubt be studied further, she says.

Dr. Schoenlein believes breast cancer survival during macroautophagy requires high activity of the tumor suppressor protein Rb and low levels of the lipid ceramide. Ceramide is vital but causes cell death at high levels. MCG researcher Erhard Bieberich and colleague Dr. Brian G. Condie at the University of Georgia showed in 2003 that high levels of ceramide kill cells that are unnecessary to the developing brain. The new studies will further explore the roles of Rb and ceramide in breast cancer survival during macroautophagy and determine if chloroquine can change their balance.

By Toni Baker
Medical College of Georgia

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Indian Spice Reduces Size of Hemorrhagic Stroke

By: Amy Connell
Medical College of Georgia
2008 September 22

You might want to make curcumin part of your daily diet.

This active ingredient of the Indian curry spice, turmeric, not only lowers your chances of getting cancer and Alzheimer's disease, but may reduce the size of a hemorrhagic stroke, say Medical College of Georgia researchers.

Second-year medical student Jay McCracken is working with Dr. Krishnan Dhandapani, neuroscientist in the MCG School of Medicine, using animal models to study curcumin's effect on intracerebral hemorrhages, bleeding in the brain caused by ruptured vessels.

Patients with this type of stroke are often treated for symptoms – such as headache and nausea – with medications, but not the stroke itself. Invasive surgery to remove the clot is usually needed, but some patients may not be good candidates, says Mr. McCracken. About 17 percent of strokes are hemorrhagic, according to the American Stroke Association, and usually occur in people with high blood pressure.

"We found that curcumin significantly decreases the size of a blood clot, but we're not sure why it happens," says the Alpharetta native. He thinks it may be because curcumin is a potent anti-inflammatory and antioxidant. For the study, he dissolved the yellow powder, which gives turmeric its color, in corn oil and injected it into the abdomen of an animal model of hemorrhagic stroke three times over three hours. He suspects less may work and is trying to establish the optimal dose and timing.

Timing is critical for patients who often don't know they have had a stroke and may not be seen by a physician for several hours. "Usually, patients can experience other symptoms like seizures, vision or cognitive problems, so they come to the (emergency room) fairly quickly under most circumstances," says Dr. Dhandapani. "Many patients also arrive due to head trauma and are seen within an hour or so. However, treating these injuries, even after an hour, can be tricky."

Patients likely will need to get curcumin intravenously. The researchers believe it may also help prevent strokes; they intend to pursue this line of study with the idea of also making it available in a concentrated tablet form for those at-risk.

Mr. McCracken has worked on this project since May as part of the School of Medicine Dean's Summer Research Fellowship, which enables rising sophomore students to design and participate in cutting-edge basic and/or clinical research. He is among 25 students presenting their findings today from noon to 1 p.m. in the lobby of the Carl T. Sanders Research and Education Building. School of Medicine Dean D. Douglas Miller will recognize students for their work and talk about the importance and role of research.

Mr. McCracken will continue his research through the year. "I like the research, and I think it's good preparation for residency," he says. He hopes to pursue a neurosurgery residency after graduation.

A graduate of the University of Georgia, where he received biochemistry and microbiology degrees, it was a high school football injury that inspired Mr. McCracken to pursue medicine.

"I snapped my ankle, and when I met the orthopedic surgeon, I thought he was so nice and interesting," says Mr. McCracken. "And then, for an anatomy class, we had to interview someone in science or health care, and I chose my surgeon. He let me shadow him, and I thought it was the best thing in the world."

During his first year at MCG, Mr. McCracken found he really enjoyed anatomy, especially neuroanatomy.

"I think it's interesting and challenging," he says. "I've seen patients come in who have terrible tumors or hemorrhages, and neurosurgeons can change their life in a matter of hours. Patients come in expecting three months to live, and surgeons give them years to live. It's amazing."

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