Tag Archives: Medical College of Georgia

Study provides new treatment targets for deadly brain swelling

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High-efficiency transporters that work like a shuttle system to constantly move ions into and out of neurons appear to slam into reverse following a stroke or other injury and start delivering instead too much water, scientists have found.

It’s called spreading depolarization, a wave of death that can follow a stroke or traumatic brain injury, as neurons and their extensions, called dendrites, become bloated, dysfunctional and vulnerable, said Dr. Sergei Kirov, neuroscientist in the Department of Neurosurgery and director of the Human Brain Lab at the Medical College of Georgia at Georgia Regents University.

While swelling is clearly a result of trauma to the brain, just how water gets into neurons was largely a mystery.

In a study published in The Journal of Neuroscience, Kirov and his colleagues report that a handful of these ion transporters – known to tote some combination of sodium, potassium and chloride – appear to be a missing link in how excess water gets inside.

“They act as molecular water pumps. This is a new way of thinking,” said Kirov. He and Dr. Nanna MacAulay, associate professor in the Department of Cellular and Molecular Medicine at the University of Copenhagen, are co-corresponding authors on the study, which is highlighted in the journal. These transporters also provide new drug targets for treating deadly edema.

Some water is routinely needed by neurons to carry out basic metabolic functions, but despite what some medical textbooks say, neurons are not freely permeable to water, Kirov said. “You need some molecular mechanism for water to enter or leave,” he said. The transporters, which are known to snatch up water and ions from outside the neuron, appeared a plausible option to Kirov.

At rest, neurons have a lot of potassium inside and a lot of sodium outside. This differential distribution of ions polarizes the neuron, creating a negative electrical charge inside. The unequal amount of sodium and potassium inside and outside is actively maintained through the operation of sodium-potassium pumps.

The differential distribution of sodium and potassium also is essential for neurons to generate electrical signals, called action potential, and communicate with other neurons or cells so humans and animals can think or move or otherwise function.

When action potential is generated, a neuron goes through a process called depolarization, which alters its electrical charge so it becomes positive inside. Sodium channels open and small amounts of sodium move inside and channels rapidly close. The whole thing happens mega-rapidly.

During the repolarization that follows, the opposite happens: potassium channels open and small amounts of potassium move out of the neuron and those channels close. Once again, the sodium-potassium pumps push the ions back in their correct location. It’s a continuous, efficient process in the healthy brain.

But a traumatic brain injury, stroke, brain bleed or even a migraine can result in unrelenting, pathological spreading depolarization in which large amounts of sodium move inside and large amounts of potassium move out of neurons. Sodium-potassium pumps quickly get overwhelmed trying to straighten things out and neurons and their extensions, called dendrites rapidly find themselves in trouble.

While a swollen ankle may be uncomfortable, a swelling brain can quickly become deadly in the closed confines of the skull. “The normal balance of potassium and sodium during spreading depolarization is almost completely off so the normal function of the cell is off and it is at increased risk of dying,” Kirov said.

Kirov’s team used powerful two-photon laser scanning microscopy to study the function of transporters in slices of mouse brain and in mice. They watched the spreading depolarization and resulting swelling and documented how the edema was dramatically diminished by drugs that blocked the action of the transporters.

He notes that drugs he used in the lab can’t be used in humans, but like the transporters, they provide direction. “We need to develop better agents that will be safe in human patients that we can give for a short period of time and reduce swelling,” Kirov said of next steps in the research. Today, in severe cases of brain swelling, neurosurgeons will remove a piece of the skull to give the brain more room and ideally reduce permanent damage.

Kirov notes that astrocytes, another brain cell type that support neurons, have natural water channels, called aquaporins, so that water typically can more easily move in and out, but neurons don’t have these well-defined channels. “That was the puzzle,” Kirov said.

The research was supported by the National Institutes of Health, the American Heart Association and the Thorberg’s Foundation.

Bleed for your Team: Fall Blood Update

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Fall has fallen and with it the end of the Bleed for your Team Blood Drive is fast approaching.

With only one week left to donate as much blood as they (safely) can, which team will give the most for residents of the CSRA?

When last we checked in on our college competitors, the College of Dental Medicine had edged out a slight lead over their Medical College of Georgia rivals.

Have the tables turned in favor of the Medical Masters since our last Bleed for your Team update? Or will Team Tooth prove once and for all that they are, in fact, the better bleeders?

Find out here.


Frontline treatments show best results for unexplained infertility

A breast cancer drug with promise for improving the chance that couples with unexplained infertility can have a baby without increasing their risk of multiple births apparently does not deliver, according to a comparative study.

“The question was could we reduce the risk of twins and triplets without negatively impacting the total number of women who can conceive?” said Dr. Michael P. Diamond, reproductive endocrinologist and Chairman of the Department of Obstetrics and Gynecology at the Medical College of Georgia at Georgia Regents University.

In a study published in the New England Journal of Medicine, researchers showed pregnancy rates and live birth rates were significantly lower in women treated with letrozole, an aromatase inhibitor that enables ovulation, than those receiving the frontline drugs gonadotropin or clomiphene. As an example, live birth rates were 32.3 percent in women taking gonadotropin and 18.7 percent with letrozole.

The cancer drug has been used off-label for infertility for several years because of anecdotal reports that it could help women conceive with less risk of multiple births. Diamond participated in another study published last summer, also in NEJM, that showed letrozole was better than clomiphene at improving rates of ovulation, conception, pregnancy and live birth in women with polycystic ovary syndrome. PCOS affects 5-10 percent of reproductive-age women whose major infertility problem is that they don’t ovulate.

But letrozole’s success in women with PCOS does not hold up when the cause of infertility is unclear. While patients with unexplained infertility taking letrozole did have a significantly lower number of multiple births than those taking gonadotropins, those rates were comparable to clomiphene, said Diamond, the new study’s corresponding author. Letrozole therapy did result in a significantly reduced number of multiple births compared with gonadotropin, but its rates were two-and-a-half times higher than clomiphene’s.

“The conclusion for couples with unexplained infertility is that clomiphene probably still remains the first-line therapy,” Diamond said of the widely used drug that enables production of more eggs and the hormones that support them.

Women taking gonadotropin, which is given by shot rather than by tablet like the other two drugs, had the highest rate of pregnancy and live births, but it also had the highest multiple birth rate, Diamond noted. Gonadotropin therapy resulted in 24 sets of twins and 10 sets of triples. Letrozole and clomiphene therapy produced only twins, which generally result in fewer complications during pregnancy and after birth than triplets. There were no significant differences among the three treatment arms in resulting birth defects or newborn complications.

The study looked at 900 women age 18 to 40 with unexplained infertility at 12 centers across the nation through the Cooperative Reproductive Medicine Network of the Eunice Kennedy Shriver National Institute of Child Health and Human Development.

A third of patients were randomly assigned to receive up to four cycles of ovarian stimulation with gonadotropin, clomiphene or letrozole; there was no placebo group. Researchers obtained an investigational new drug application with the Food and Drug Administration for the study since letrozole is currently only approved for breast cancer treatment.

Like clomiphene, letrozole actually tricks the body into making more estrogen. Clomiphene, which is a selective estrogen receptor modulator, binds to estrogen receptors when estrogen levels are high so the brain gets the message to make even more, Diamond said. The pituitary gland gets stimulated by the hypothalamus, and patients make follicle stimulation hormone, which enables the eggs to mature, and more luteinizing hormone, which stimulates ovulation, enabling the mature egg to be released for fertilization. Letrozole produces similar results by blocking estrogen production, Diamond said.

“In a typical monthly cycle, there is usually one follicle and one egg that develop to the point of ovulation,” Diamond said. “What happens with the fertility drugs, you are overriding the mechanisms which usually only lead to development of one dominant follicle and release of one egg.”

Women are diagnosed with unexplained infertility if they have been trying for a year to get pregnant and there are no obvious problems such as lack of ovulation, an abnormal uterus or evidence of inflammation, such as endometriosis. Some of the women may have already had a previous child.

Yale University provided data coordination for the study. Diamond is also GRU’s senior vice president for research.

Study looks at whether daily limb compressions reduce dementia

A new study is looking at whether short, daily bouts of reduced blood flow to an arm or leg can reduce the ravages of dementia.

It’s called remote conditioning, and researchers say it activates natural protective mechanisms in the brain that should help about half of dementia patients.

The approach uses a blood pressure cuff-like device to temporarily restrict blood flow to an appendage repeatedly for a few minutes each day, which increases blood flow to other body areas, including the brain, said Dr. David Hess, Chairman of the Department of Neurology at the Medical College of Georgia at Georgia Regents University.

Increased flow activates endothelial cells lining blood vessels, calling to action a series of natural protective mechanisms that can be effective wherever blood travels, Hess said. Interestingly, the mechanisms seem most active in areas of impaired flow, such as those deep inside the brain, where most dementia has its roots.

“The most powerful way to protect the brain is to cut off blood flow to it for a short period of time to condition it,” said Hess. “What it does is elicit these protective pathways so when potentially lethal ischemia comes, you can survive it.” What it also appears to do is help permanently improve blood flow to these deep regions of the brain.

Age and being a female are two of the major risk factors for dementia. With nearly 15 percent of the U.S. population age 65 and older and half being female, Hess calls dementia a major health concern. “This is a big epidemic coming. This is a big killer and disabler, and everybody is concerned about this.”

A two-year, $750,000 translational grant from the National Institute of Neurological Disorders and Stroke should help Hess and his research team do the additional animal studies needed to move this safe and inexpensive technique for dementia to human studies.

“We think reduced cerebral blood flow, particularly in the deep white matter, is a major trigger of dementia,” Hess said. The white matter is primarily composed of axons, which connect neurons and different areas of the brain to each other and enable the brain to communicate with the body. The white protective coating on the axon is why this deep brain area is called white matter.

Hess, who is also a stroke specialist, says this area is particularly vulnerable to ischemia because the blood vessels that feed it are small and have long, tortuous routes. Strokes and/or impaired blood flow can lead to classic dementia symptoms such as forgetfulness and an unsteady gait.

By age 70, essentially everyone has some white matter disease, but in some it can be devastating. “You cannot go out in a car and find where you are going. You may not even be able to find your car. You can’t cook meals without setting the house on fire,” Hess said.

“What we want to do long term is find people who are at risk for dementia – they already have some white matter damage you can see on an MRI – then we condition them chronically with this device in their home,” Hess said. Chronically is a key word because, as with exercise, when this conditioning stops, so do its benefits. In fact, this passive therapy provides blood vessels many of the same benefits as exercise. “If you can exercise, you probably don’t need this,” Hess adds.

Previous studies in their animal model of vascular dementia have shown that just two weeks of daily, short bouts of ischemia to an appendage can improve the health of the important white matter. The new grant is allowing them to use a similar approach for periods of one and four months in older mice of both genders to better understand the mechanisms of action and how long and how often therapy is needed. While they don’t make as much as human, mice do make more amyloid, a protein that deposits in the brains of patients with Alzheimer’s, when brain blood flow is impaired. Mice make less with the conditioning, so the researchers also are looking further at that result.

A small intramural grant is enabling similar studies with a pig model in collaboration with University of Georgia colleagues Dr. Simon R. Platt, professor of neurology and neurosurgery in the College of Veterinary Medicine, and Dr. Franklin D. West, assistant professor in the College of Agricultural and Environmental Sciences.

While he notes that multiple natural mechanisms are activated, Hess and his team are focusing on how the temporary bouts of increased blood flow prompt endothelial cells to make the precursor for the blood vessel dilator nitric oxide.

“The enzyme that makes nitric oxide is upregulated and stimulated quickly,” Hess said. Nitric oxide gas has a short life, but when a lot is dumped in the blood, it’s oxidized into nitrite – the same stuff put in hot dogs – which circulates throughout the bloodstream so it goes wherever blood goes. Although just how this happens is unclear, when the nitrite gets to an area of low blood flow, it is converted back to nitric oxide, which helps improve flow, Hess said.

The MCG researchers are applying for federal funding to do trials in humans who are at high risk for stroke because of small vessel disease deep in the brain. In 2012, they published results of a small study in the journal Stroke indicating that successive, vigorous bouts of leg compressions following a stroke trigger natural protective mechanisms that reduce damage and double the effectiveness of the clot buster tPA. Similar studies have been done by others in patients with heart disease.

Vascular dementia is considered the second most common cause of dementia after Alzheimer’s disease, according to the Alzheimer’s Association. There are currently no drugs approved by the U.S. Food and Drug Administration specifically for vascular dementia.

Collaborators at MCG and GRU include Dr. Mohammad B. Khan, postdoctoral fellow in Dr. Hess’ lab; Dr. Nasrul Hoda, College of Allied Health Sciences; Dr. Philip Wang, Department of Psychiatry and Health Behavior; Dr. Ali Syed Arbab, Department of Biochemistry and Molecular Biology; Dr. Nathan Eugene Yanasak, Department of Radiology and Imaging;  and Dr. Jennifer Waller, Department of Biostatistics and Epidemiology.

GRU among 15 centers awarded federal funding to train physician-scientists in ob-gyn

Georgia Regents University is among 15 institutions in the nation to receive federal funding to help train the next generation of physician-scientists in obstetrics and gynecology.

GRU will receive $1.7 million over the next five years from the National Institutes of Health’s Eunice Kennedy Shriver National Institute of Child Health and Human Development to train obstetrician-gynecologists to also become independent investigators in diverse women’s health fields such as infertility and high-risk pregnancy.

“We want individuals with fire in their belly to be able to get involved in research,” said Dr. Michael P. Diamond, chairman of the Department of Obstetrics and Gynecology at the Medical College of Georgia at GRU, the university’s senior vice president for research and principal investigator for the new program in Augusta. “It’s a great opportunity to train clinicians to be clinical investigators.”

Diamond had been a research director on the Women’s Reproductive Health Research Career Development Program since its inception in 1998. When he came to MCG and GRU in 2013 from Wayne State University, Diamond’s goals included starting a program here.

The program is available for junior faculty as well as residents or fellows who have just completed training at locations across the nation or at MCG. National recruitment efforts start in September. The program funds two positions at a time for a maximum of five years in Augusta. Federal dollars will help support the salaries and the research of the program scholars.

Having committed time for research is difficult for physicians, particularly more junior physicians trying to juggle building a practice and a solid research program, Diamond said. The federal grant enables the physicians to focus on research at least 30 hours weekly.

The program will not only be important to individuals, but also to the medical school and university as it strives to reach the next level of academic achievement nationally, Diamond said. More minds focused on finding new knowledge will also help drive treatment forward for a variety of conditions affecting women, he said.

Dr. Nita J. Maihle, a breast cancer researcher who is associate director of education for the GRU Cancer Center and professor in the MCG Department of Biochemistry and Molecular Biology, is the program director. Dr. Ayman Al-Hendy, an obstetrician-gynecologist who directs his department’s Division of Translational Research, is recruitment director; and Dr. Lara M. Stepleman, psychologist and co-director of the GRU Educational Innovation Institute, is assisting the evaluation of the scholars.

Scholars can select mentors from a sizeable group of faculty who want to help more junior colleagues with their research career development, Diamond said. Examples include Dr. Larry B. Layman, chief of the Section of Reproductive Endocrinology, Infertility and Genetics, and an NIH-funded investigator pursuing better understanding of clinical problems such as delayed puberty.

Other institutions receiving federal funding this year for the program are the University of Alabama at Birmingham; Northwestern University at Chicago; Oregon Health & Science University; University of Pennsylvania; Magee-Women’s Research Institute and Foundation; University of Washington; University of California, San Francisco; University of Michigan; University of California, San Diego; University of Utah; Women and Infants Hospital-Rhode Island; Wayne State University; University of Colorado, Denver; and Yale University.

According to the 2014 Physician-Scientist Workforce Working Group Report from the NIH, issues such as years of reductions in federal funding to support research, increasing clinical demands and the increased cost of medical education translate to a shortage of both physician-scientists and mentors across many specialties. The career development grant strives to reverse this national trend and train the next generation of physician-scientists in obstetrics and gynecology, Diamond said.

For more information, contact Diamond at michael.diamond@gru.edu or 706-721-3591, Maihle at nmaihle@gru.edu or 706-421-5991 and Al-Hendy at aalhendy@gru.edu or 706-721-3591.

Hypertension in professional football players likely results from trauma on the field

The regular physical trauma that appears to put professional football players at risk for degenerative brain disease may also increase their risk for hypertension and cardiovascular disease, researchers say.

The frequent hits football players experience, particularly frontline defenders such as linemen, likely continually activate the body’s natural defense system, producing chronic inflammation that is known to drive blood pressure up, according to a study in The FASEB Journal.

While strenuous physical activity clearly has its benefits, it also produces skeletal muscle damage, which literally tears some cells apart, said Dr. R. Clinton Webb, cardiovascular researcher who chairs the Department of Physiology at the Medical College of Georgia at Georgia Regents University.

As an example, long-term, muscle cell tears actually help build muscle, but short term they spill cell contents, including damage-associated molecular patterns, or DAMPs, which capture the attention of the immune system, said Cam McCarthy, a fifth-year graduate student working in Webb’s lab and the study’s corresponding author.

DAMPs activate what should be a short bout of inflammation to deal with the danger, but in football players, this likely happens over and over again in just a single game. “We think that this increase in blood pressure we see in football players is due to the repeated trauma and immune system activation,” McCarthy said.

The trauma can be significant. The sheer size and strength of linemen today mean that those on the offensive and defensive line repeatedly smash into each other at a force equivalent to about a 30-mph car crash, the researchers write. Resistance training done off the field to improve lean muscle mass, likely results in more torn cells and additional activation of the immune response.

Higher blood pressure has been associated with professional and even college football, but exactly why remains unclear, Webb said. He noted that the cause is likely multifactorial and not simply the obesity found in the preponderance of players. While players’ blood pressure tends to drop toward normal after each season, a long-term impact is likely, the researchers said. Professional football players, for example, have a higher incidence of cardiovascular disease than the general population and live, on average, 10 years less.

The researchers hope that by fully understanding the cause, preventive strategies, maybe even something as simple as taking a daily baby aspirin to reduce inflammation, can reduce the short- and long-term impact of higher blood pressure.

Webb and his team have evidence that – at least in rats – circulating levels of DAMPs are increased in hypertension and increasing evidence of their direct role in hypertension. DAMPs appear to raise blood pressure by activating toll-like receptors on endothelial cells, which comprise the single-cell-thick lining of blood vessels. Toll-like receptors are located in all tissue and cell types and these pattern-recognition receptors are always on the lookout for danger and invaders, such as bacteria, McCarthy said.

The researchers theorize that toll-like receptors are activated a lot in football players, particularly linemen, who may be involved in literally a 100 hits per game. Results include arteries that are stiffer, less able to dilate, and higher blood pressure.

The researchers suspect that release and downstream effects of DAMPs likely play a role as well in the damage to the brain, called chronic traumatic encephalopathy, which can occur in these athletes from years of blows to the head.

While increased hypertension in professional athletes may seem like a paradox, the researchers note that hypertension is the most common cardiovascular complication seen in competitive athletes, even ultramarathon runners.

In fact, reports in the lay literature of elevated blood pressure in football players prompted McCarthy and Webb to do a scientific literature search where they found more evidence of the problem, but not the complete cause behind it. That led to their published hypothesis and to their current pursuit of funding to measure DAMPs levels before, during and after season in college football players.

A 2009 study in the Journal of the American Medical Association looking at the prevalence of cardiovascular disease risk factors among NFL players compared with their peers in the general population showed significantly higher blood pressures. However, other cardiovascular risk factors, such as lipid and cholesterol levels, were mostly similar despite the fact that the players were generally taller and heavier. The study also noted an increase in the past three decades in body mass index for linemen.

Fat, particularly in the abdominal area, is a known risk factor for hypertension and other cardiovascular diseases. A 2005 JAMA study showed that the percentage of NFL players with a body mass index of 30 or greater, which is considered obese, was double that of their non-football-playing peers. Offensive and defensive linemen had the highest BMIs. However, despite the pervasiveness of overweight, particularly among linemen, labeling body weight as the only culprit, is premature and doesn’t take into account the complexity of hypertension, the MCG researchers write.

Related studies looking at cardiovascular risk factors among NFL players in different positions showed linemen tend to have higher total cholesterol and triglyceride levels than other players in addition to higher blood pressures. A 2013 study in the journal Circulation showed that even college football players had elevated blood pressures that categorized them as pre-hypertensive and that, particularly linemen, were showing signs of unhealthy increases in the size of their heart related to pumping against increased blood pressure.

Webb and McCarthy’s FASEB study was supported by the American Heart Association and the National Institutes of Health.

National Disaster Life Support Foundation signs agreement to make courses available in China

The National Disaster Life Support Foundation, based at the Medical College of Georgia at Georgia Regents University, has signed an agreement with the Jiao Tong University School of Medicine in Shanghai and Xingcheng Medical Consulting & Services Company to teach standardized courses on disaster support throughout China.

The courses are part of a program designed to help a wide array of providers – from police to paramedics to hospital administrators and firefighters – best work together in the aftermath of natural and man-made disasters. It was developed as an outgrowth of the 1996 Atlanta Olympics bombing, when it became apparent that responding agencies are often trained differently.

The program includes a Core Disaster Life Support Course® that gives hospital-based and frontline medical providers the essentials of natural and man-made disaster management. Basic and advanced courses offer progressively more hands-on training and knowledge. The overarching goal is to give all types of responders a common knowledge base and jargon and to eliminate ambiguity, said Dr. Richard Schwartz, chairman of the MCG Department of Emergency Medicine and Hospitalists Services, who had the original idea for the program.

The courses, first introduced in 1999, were developed by the Medical College of Georgia, University of Georgia, University of Texas Southwestern Medical Center in Dallas and the University of Texas at Houston’s School of Public Health. The nonprofit National Disaster Life Support Foundation was established in 2004 to oversee the program, and they began a partnership with the American Medical Association to widely disseminate the program in 2006.

Today, there are about 90 domestic training sites, and courses have been taught in 49 states and in more than 20 foreign countries. There are training sites in 11 countries, including places like Mexico, Japan, India and Saudi Arabia, and now China, the world’s most populous country.

“The courses are unique and valuable because they are standardized across all disciplines of first responders; they deal with all types of hazards, and they are competency based,” said Jack Horner, executive director of the NDLSF. “To date, more than 120,000 students have been trained, and a growing number of health professional schools have added the program to their curriculum. Disasters know no borders and they know no language barrier either.”

Two proteins work together to help cells eliminate trash and Parkinson’s may result when they don’t

Two proteins that share the ability to help cells deal with their trash appear to need each other to do their jobs and when they don’t connect, it appears to contribute to development of Parkinson’s disease, scientists report.

Much like a community’s network for garbage handling, cells also have garbage sites called lysosomes, where proteins, which are functioning badly because of age or other reasons, go for degradation and potential recycling, said Dr. Wen-Cheng Xiong, developmental neurobiologist and Weiss Research Professor at the Medical College of Georgia at Georgia Regents University.

Inside lysosomes, other proteins, called proteases, help cut up proteins that can no longer do their job and enable salvaging of things like precious amino acids. It’s a normal cell degradation process called autophagy that actually helps cells survive and is particularly important in cells such as neurons, which regenerate extremely slowly, said Xiong, corresponding author of the study in The Journal of Neuroscience.

Key to the process – and as scientists have shown, to each other – are two more proteins, VPS35 and Lamp2a. VPS35 is essential for retrieving membrane proteins vital to cell function. Levels naturally decrease with age, and mutations in the VPS35 gene have been found in patients with a rare form of Parkinson’s. VPS35 also is a critical part of a protein complex called a retromer, which has a major role in recycling inside cells. Lamp2a enables unfit proteins to be chewed up and degraded inside lysosomes.

If the two sound like a natural couple, scientists now have more evidence that they are. They have shown that without VPS35 to retrieve Lamp2a from the trash site for reuse, Lamp2a, or lysosomal-associated membrane protein 2, will be degraded and its vital function lost.

When the scientists generated VPS35-deficient mice, the mice exhibited Parkinson’s-like deficits, including impaired motor control. When they looked further, they found the lysosomes inside dopamine neurons, which are targets in Parkinson’s, didn’t function properly in the mice. In fact, without VPS35, the degradation of Lamp2a itself is accelerated. Consequently, yet another protein, alpha-synuclein, which is normally destroyed by Lamp2a, is increased. Alpha-synuclein is a major component of abnormal protein clumps, called Lewy bodies, found in the brains of patients with Parkinson’s.

“If alpha-synuclein is not degraded, it just accumulates. If VPS35 function is normal, we won’t see its accumulation,” Xiong said.

Conversely, when MCG scientists increased expression of Lamp2a in the dopamine neurons of the VPS35-deficient mice, alpha-synuclein levels were reduced, a finding that further supports the linkage of the three proteins in the essential ability of the neurons to deal with undesirables in their lysosomes.

Without lamp2a, dopamine neurons essentially start producing more garbage rather than eliminating it. Recycling of valuables such as amino acids basically stops, and alpha-synuclein is free to roam to other places in the cell or other brain regions where it can damage still viable proteins.

The bottom line is dopamine neurons are lost instead of preserved. Brain scans document the empty spaces where neurons used to be in patients with neurodegenerative diseases such as Parkinson’s and Alzheimer’s. One of the many problems with treatment of these diseases is that by the time the empty spaces and sometimes the associated symptoms are apparent, much damage has occurred, Xiong said.

Putting these pieces together provides several new, early targets for disease intervention. “Everything is linked,” Xiong said.

Dopamine is a brain chemical with many roles, including motor control, and patients with Parkinson’s have a loss of the neurons that secrete this neurotransmitter. At least in mice, VPS35 is naturally expressed in dopamine neurons in areas of the brain affected by Parkinson’s.

Xiong and her colleagues reported in 2011 that reduced expression of VPS35 enables activity of the dormant-in-healthy-adults protein BACE1 to increase along with accumulation of the brain plaque that is a hallmark of Alzheimer’s. Xiong said then that impaired VPS35 function likely also was a factor in Parkinson’s.

In a definite vicious circle, trash starts overwhelming the brain cell’s natural garbage disposal system. Proteins start getting misfolded and dysfunctional, potentially destructive proteins such as BACE1 and Lamp2a end up in the wrong place and get activated/inactivated, while good proteins get chopped up and/or bad proteins accumulate.

Parkinson’s disease is characterized by uncontrolled shaking, an unstable gait and cognitive loss. The research was funded by the National Institutes of Health and the Department of Veterans Affairs. Postdoctoral Fellow Dr. Fulei Tang is the study’s first author.

Fat mice bred to have more muscle give insight, new targets for battling obesity’s cardiovascular risk

Even without losing fat, more muscle appears to go a long way in fighting off the bad cardiovascular effects of obesity.

That emerging evidence has scientists looking hard for new targets to uncouple the unhealthy relationship between fat and cardiovascular disease.

“If you look at the exercise literature, we understand very well that if you exercise, things get better. What we don’t really understand is what about exercise is good; what does it tell us about physiology and how disease starts, and how can you customize it to different populations?” said Dr. David Stepp, vascular biologist in the Vascular Biology Center at the Medical College of Georgia at Georgia Regents University.

Stepp and his colleagues have evidence that an increase in muscle mass – a huge consumer of glucose, a natural energy source that is often elevated in obesity – could mean a healthier ticket for some.

While fat has the unhealthy habit of storing fuel, “muscle is a much more metabolically active tissue, even when it’s just sitting there,” Stepp said. “It burns more oxygen at rest; it burns more energy at rest; so it burns more calories at rest.” Some of things scientists don’t know is if muscles secrete something that improves glucose metabolism or if just having more glucose-consuming muscle is the apparent magic.

A new $2.2 million grant from the National Heart, Lung, and Blood Institute is helping fill in those important blanks as it illuminates new points for intervening in one of the worst consequences of obesity.

“We are trying to establish links between the health of skeletal muscles and the circulatory system,” said Dr. David Fulton, Director of the MCG Vascular Biology Center and Co-Principal Investigator with Stepp on the grant. “When you eat, most of the glucose ends up in your skeletal muscle. When you are young, most of your body mass is skeletal muscle, so that glucose is efficiently distributed in the places where it should go to get used for energy and work.”

Stepp and Fulton were authors on a 2014 study in the Journal of the American Heart Association that showed the benefits of adding muscle when fat is monopolizing the body. They looked at normal mice and mice genetically altered to be obese – mice with voracious appetites that soon doubled their normal weight – as examples of a healthy and unhealthy human. When they deleted myostatin, a natural, negative regulator of muscle growth, from both, both groups developed bigger muscles. The normal mice also had less fat tissue.

But it was the obese-with-muscles mice that truly benefited in the cardiovascular sense: glucose tolerance and blood vessel dilation went up and insulin resistance and superoxide production went down. More muscle didn’t result in these additional changes in the leaner mice.

“If the insulin burner gets bigger and the storage (fat) gets smaller, that’s good,” Stepp said. “What we have demonstrated is that if the burner gets bigger, no matter what the storage does, it’s still good.”

When they looked further at the obese mice, minus the muscles, they also found the superoxide- producing gene Nox1 is a major culprit in obesity-related vascular disease. In fact, the gene is overexpressed in the blood vessels of the fat mice, apparently driven by high glucose levels in the blood.

Obese mice with no muscle added but Nox1 removed also experience cardiovascular improvement, an observation that Postdoctoral Fellow Dr. Jennifer Thompson is pursuing further with a new American Heart Association grant.

Meanwhile, Stepp and Fulton are exploring how elevated blood glucose elevates Nox1, acknowledging that while it makes intuitive sense, the science needs to be clear. Because while the search is on for Nox1 inhibitors, there aren’t any at this moment. Fulton and Stepp hope their studies will further inspire the search and identify additional points of intervention as well.

“We know that high glucose goes to Nox1 goes to superoxide, and superoxide goes to cardiovascular disease. What we don’t know is what is in between glucose and Nox1,” Stepp said. A possibility is galectin-3, a receptor for proteins that get coated with glucose when circulating levels of the sugar get too high. At least in culture, when glucose is added to cells, they produce more Nox1. But when the scientists block galectin-3 and add glucose, Nox1 doesn’t increase.

While it’s known that sugar-coating messes up protein function, the scientists aren’t certain what galectin-3 is doing. Is it clearing the dysfunctional proteins, telling them to die, and/or driving up Nox1? So they are looking at the signaling between all of the above. They are also developing additional mice models, where Nox1 and galectin-3 are removed from already genetically fat mice, to further explore their role in vascular dysfunction. They will also explore the cardiovascular impact, such as blood pressure and how well blood vessels dilate in response to stress, in their fat mice models with added muscle as well as the two new knockouts.

The bottom line: they want to know if they can break “the metabolic connection” between fat and cardiovascular disease. “Where is the key event that causes all these bad things to happen?” Stepp said, and, of course, where and how best to intervene.

Myostatin is part of the yin and yang of muscle growth that enables us, with some effort, to have good, but not excessive, muscle mass. High myostatin levels can produce muscular dystrophy; low ones can mean incredible bulk. Myostatin levels tend to decrease with exercise and increase with aging.

Injectable or infusible myostatin inhibitors are under study for muscular dystrophy and frailty syndrome, where older individuals lose so much muscle mass that they fall frequently. But the drugs are not generally available, even to scientists. While experience with the inhibitors is limited, life with less myostatin appears to be a good thing: Stepp said mice short one copy of the myostatin gene live longer, and humans with documented myostatin deficiency tend to be Olympic athletes.

12 new Harrison Scholars named at MCG

Twelve members of the Class of 2019 at the Medical College of Georgia at Georgia Regents University are the newest Harrison Scholars and the recipients of scholarships made possible by the largest gift in the medical school’s history.

The unprecedented $66 million gift by Dr. J. Harold Harrison, the renowned vascular surgeon from Kite, Georgia, and 1948 MCG graduate, and his wife, Sue, enables MCG to offer 12 scholarships – six full and six partial – to each freshman class. Six scholarships – three full and three partial – were given to students in the Class of 2018.

“What a remarkable gift to our medical school,” said Dr. Peter F. Buckley, MCG dean. “The Harrison’s generosity continues to ensure that we are able to continue to recruit the best and brightest students – diverse in their backgrounds and experiences – to Georgia’s public medical school.”

The full scholarships, the first MCG has ever offered, cover the entire $28,358 annual, instate tuition cost, said Dr. James B. Osborne, president and CEO of the MCG Foundation, which has oversight of the Harrison gift. Six Harrison Scholars received partial scholarships of $15,000 annually.

“Every year we are privileged to choose a brilliant group of the next great physicians to attend this medical school,” said Dr. Paul Wallach, MCG vice dean for academic affairs. “These scholarships help us ensure that the most outstanding among them also choose us.”

The merit-based scholarships, which emphasize intellect and outstanding leadership potential, are effective for four years but will be reviewed annually to ensure that recipients continue to meet eligibility standards.

Osborne, a longtime friend of Harrison’s said of the most recent scholarship recipients, “I know Dr. Harrison would be pleased at the caliber of students who will carry on his legacy as a scholar, innovator and physician.”

“We are grateful to our MCG Foundation leadership and to Dr. Wallach for another stellar group of scholars this year,” Buckley added. “We are proud of them, and of course, we are proud of all our medical students.”

In addition to the student scholarships, 10 University Distinguished Chairs, funded at $2 million each, will be established over the next five years thanks to the Harrison gift.

Harrison died June 2, 2012, and a few months later, GRU announced that Harrison and his wife, Sue, had given his name and $10 million toward construction of a new academic home for the medical school. The J. Harold Harrison, M.D. Education Commons opened this fall. The MCG Foundation announced the $66 million gift for student scholarship and endowed chairs for faculty in April 2013.

This year’s recipients are:

  • John Ahn, of Calhoun, Georgia, studied biology at Andrews University in Berrien Springs, Michigan. While in college, he spent six months working and living in two hospitals in Chad, one of Africa’s poorest countries. Ahn survived four bouts with malaria while there performing an array of jobs with other volunteers, from feeding malnourished babies to changing dressings. “Through that experience, I developed a meaningful attraction to the heart of medicine: the patients,” he writes.
  • Katharine Armstrong, of Atlanta, wants to pursue a career as a pediatric oncologist. While studying music and biochemistry at Washington and Lee University in Lexington, Virginia, watching her best friend’s father lose his battle with cancer solidified her future goal. Spending two months after her sophomore year living with a family in Argentina and teaching at a secondary school only confirmed her desire to work with children.
  • Leah Brown of Oconee County, Georgia, graduated from the University of Georgia with a degree in microbiology and is considering a career in infectious diseases. “Maybe I won’t physically touch every patient … but my footprints will be made regardless, for the one who makes the pivotal step in a journey is not always so clearly remembered. But every step can make a lasting impression,” she writes.
  • Mariah Burch, of Atlanta, is a graduate of Boston University with a degree in neuroscience, who also shadowed MCG alum Dr. Thomas Calk, whom she says taught her an invaluable lesson while treating a patient with a genetic abnormality that left him with severe mental and physical disabilities. “During the appointment, Dr. Calk and the patient seemed like old friends. When the patient left, his smile was genuine. I observed that even if it’s not possible to heal a patient, it is possible to improve his or her life,” she writes.
  • Christine Gross, of North Augusta, is a graduate of the University of South Carolina with a degree in biology, who also received her doctorate from Georgia Regents University. Gross aspires to be a physician-scientist. “I believe the best scientists have an eye for the needs of patients, and the finest physicians understand the science behind the medicine they prescribe,” she writes.
  • Vishwajeeth Pasham, of Alpharetta, Georgia, is a graduate of the University of South Florida who studied biomedical sciences. Before deciding to go to medical school, Pasham spent time shadowing physicians and scientists, including an M.D./Ph.D., who practiced plastic surgery and researched wound healing.
  • Alexandra Sawyer, of Atlanta, is a graduate of the University of Georgia, where she studied epidemiology and health promotions. Through her work with the Farm Worker Family Health Program, she gained valuable perspectives on public health, but she “valued most the times I sat down with patients to discuss their individual questions and gained a deepened desire for the clinical skills to assist them further,” she writes.
  • Ryan Schwertner, of Saint Simons Island, Georgia, graduated from the University of Georgia with a degree in biology. “I want to be the doctor that people trust to act in their best interest, no matter what, and after completing medical school, this is the doctor that I believe I can become,” he writes.
  • William “Cole” Skinner, of Savannah, a graduate of the University of Georgia with a degree in biology, spent his childhood learning life lessons while gardening with his grandfather, also a physician. “Through gardening together, Pop taught me an invaluable lesson about being a physician. Though I was too young to observe him at work, I will always recall his selfless attitude. Whether it was responding to patient calls during the night or happily helping those who he knew could not pay their bill, he always put his patients first,” he writes.
  • Andrew Warren, of Atlanta, is a graduate of the Georgia Institute of Technology, where he studied biology. As a Georgia Tech President’s Scholar, he was able to travel to Yugoslavia as an expedition leader. On the trip, the group explored the causes of and gained appreciation for the 1990’s ethnic conflict and subsequent breakup of Yugoslavia.
  • Erena Weathers, of Atlanta, is a graduate of the University of Georgia with a degree in microbiology and bacteriology. As a hobby and a way to relieve the stress of school and work, she runs a blog about how to maintain weight while eating well.
  • Wells Yang, of Johns Creek, Georgia, is a graduate of the Georgia Institute of Technology, where he studied biomedical engineering. “Both medicine and engineering revolve around solving problems, and although their objectives may be different sometimes, the same passion and dedication are necessary to succeed in both professions,” he writes.