ViiV Healthcare Awards Southern Initiative Grants to Reduce HIV Disparities Among African Americans and Latinos

/PRNewswire/ -- ViiV Healthcare today announced the grant awardees of the Positive Action Southern Initiative, focused on supporting African American and Latino populations in Alabama, Georgia, Louisiana, and Mississippi to help high-risk HIV/AIDS individuals and provide linkages to HIV/AIDS care and treatment adherence.

"The Positive Action Southern Initiative awards are being made at a critical time in the national fight against HIV. These funds are nothing short of life-saving. Community organizations are facing tremendous pressure to do more with less in this economic climate and the demands continue to grow, especially among African American and Latino communities in Southern states," stated A. Cornelius Baker, Senior Policy Advisor of the National Black Gay Men's Advocacy Coalition. "I am excited that ViiV is supporting such important initiatives that address disparities in HIV and support the goals of the National HIV/AIDS Strategy."

In the U.S., 1.1 million people are living with HIV/AIDS(i) and African Americans and Latinos account for a disproportionate share of new HIV infections (62 percent). In 2007, the Southern United States accounted for almost half (46 percent) of new AIDS cases and has the greatest number of people estimated to be living with AIDS(i).

The Southern Initiative is part of ViiV Healthcare's Positive Action, a collaborative, community-focused program designed to address gaps in services or programs that support care and treatment adherence among individuals living with HIV/AIDS. ViiV Healthcare has committed $850,000 this year to support Positive Action Community Grants in the U.S. and $500,000 over the next two years to support the Southern Initiative grantees. ViiV Healthcare is hosting the grant recipients at this week's United States Conference on AIDS, where they will enable the development of a Regional HIV Network to share best practices and resources to advance the fight against HIV.

ViiV Healthcare has selected a total of seven organizations to receive grants over the next two years to support their programs specifically focused on reducing disparities in HIV/AIDS linkages to care and treatment among African American and Latinos in Alabama, Georgia, Louisiana, and Mississippi. The following organizations were selected as grant awardees:

-- Aid to Inmate Moms, based in Montgomery, AL, will continue its
collaboration with local AIDS Service Organizations to support
HIV-positive incarcerated women with critical counseling services.
-- Atlanta Harm Reduction Coalition, based in Atlanta, GA, will provide
additional case management services for HIV-positive individuals who
are re-entering the community from the state's jails and prisons.
-- Family Service of Greater Baton Rouge, based in Baton Rouge, LA, will
expand its Corrections Referral and Case Management program to serve
more HIV-positive individuals exiting the corrections system and to
successfully connect them with quality care.
-- Grace House in Jackson, MS, will expand its CLEAR (Choosing Life:
Empowerment, Action, Results) program to serve more HIV-positive
clients and provide services aimed at improving treatment adherence,
cognitive behavior, and prevention activities.
-- Positive Impact, based in Atlanta, GA, will provide additional
intensive case management services for HIV-positive Latino individuals
and HIV-positive African American women.
-- Southwest Louisiana AIDS Council based in Lake Charles, LA, will
expand its medical systems navigation program, FAST (Find, Assess,
Stabilize, and Treat), to serve additional newly-diagnosed persons,
previously incarcerated persons, and those who have not successfully
remained in care.
-- Union Mission's J.C. Lewis Primary Health Care Center, based in
Savannah, GA, will enhance its Healthy Living education and adherence
program for homeless and low-income persons living with HIV/AIDS.



"ViiV Healthcare received a great response from grassroots organizations in the South demonstrating the need is great. The awardees' proposed programs are unique and provide promise towards alleviating HIV in the United States among communities most impacted by the disease. ViiV Healthcare puts the interests of those affected by HIV at the center of everything we do. We are honored to support communities through these grants. It is our hope the initiatives will positively impact those areas in critical need of HIV/AIDS resources," said Bill Collier, Head of North America, ViiV Healthcare.

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FDA Approves Pediatric Use of Chemical Poisoning Treatment

/PRNewswire/ -- The U.S. Food and Drug Administration has approved the pediatric use of Protopam Chloride (pralidoxime chloride), a drug used to treat poisoning by organophosphate pesticides and chemicals (e.g., nerve agents). The drug is approved to be administered either by intravenous (IV) or intramuscular (IM) injections.

"We know this drug has been widely used for many years to treat poisoning in pediatric patients in emergency situations," said Russell Katz, M.D., director of the Division of Neurology Products in the FDA's Center for Drug Evaluation and Research. "Improving the drug's label with new dosing information for children will give health care professionals better guidance on how to use this drug safely and effectively."

"It can be difficult to use IV drugs in children, particularly in emergency situations, so having the new option of IM injection may help health care professionals use this medicine quickly and accurately," said Dianne Murphy, M.D., director of the FDA's Office of Pediatric Therapeutics.

Organophosphate pesticides are typically used in the farm setting and by professional exterminators. A person poisoned with organophosphate pesticides or chemicals (e.g., nerve agents) can have mild symptoms, such as a runny nose, teary eyes, or vomiting, to more serious symptoms such as difficulty breathing, weakness and convulsions. When chemical poisoning is suspected, medical attention should be sought immediately and the local poison control center should be contacted by dialing 800-222-1222, nationwide.

Protopam Chloride was approved by the FDA in 1964 to treat various types of pesticide and chemical poisoning in adults. The drug works as an antidote to pesticides and chemicals of the organophosphate class by slowing the attachment of the chemical to nerve endings.

Adverse reactions that have been reported in pediatric and adult use of the drug include: blurred vision, double vision, dizziness, headache, drowsiness, nausea, difficulty breathing, increased heart rate and increased blood pressure.

Protopam Chloride is made by Baxter Healthcare Corp., Deerfield, Ill.

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Flu Shots Available from University Health Services at Clayton State, Starting Sept. 8

Starting on Wednesday, Sept. 8, from 10 a.m. to 4:15 p.m., Clayton State University’s University Health Services (UHS) will be offering flu shots to students, faculty, staff and the community on a first-come, first-serve basis.

“With more than 300 shots available, there is plenty to go around,” says UHS Director Dr. Julia Spinolo.

The 2010/11 seasonal vaccine includes H1N1 and is being offered to anyone six months and older. Only the inactivated vaccine will be offered. The vaccinations will be given in UHS, room 211 of the Clayton State Student Center, during the following hours: Monday, 10 a.m. to 6:15 p.m.; Tuesday through Thursday, 10 a.m. to 4:15 p.m.; and Friday, 10 a.m. to 1 p.m. Types of payment accepted are cash, debit/credit cards and Laker Cards.

UHS typically serves only the Clayton State campus -- except during flu season when the flu vaccine is available. Costs for vaccinations are $20 for the general public and $15 for Clayton State students, faculty, and staff with a valid Laker Card. Please call University Health Services at (678) 466-4940 to make an appointment for a flu shot, although appointments are not necessary.

UHS will have the 2010 Flu Information Sheets and Consent Forms on the UHS website; http://nursing.clayton.edu/uhs/default.htm, so that individuals wishing to get a flu shot can print them out and fill then out beforehand to reduce their waiting time.

University Health Services, under the direction of Spinolo, offers a wide array of services for the Clayton State community including assessments and treatment for acute primary care health care issues, immunizations, minor illness and injury management, laboratory tests, and health education. UHS also maintains all student health records. Dr. D. Ann Travis Honeycutt, family practice physician, is on site to provide professional medical assessments and services.

A unit of the University System of Georgia, Clayton State University is an outstanding comprehensive metropolitan university located 15 miles southeast of downtown Atlanta.

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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Are HERVs an Answer to AIDS Mysteries?

/PRNewswire/ -- Why is it so hard to isolate and purify human immunodeficiency virus (HIV)? Why has no one been able to see, by electron microscopy, a single HIV particle in the blood of AIDS patients, even those who have a "high viral load"? Why does HIV seem to mutate with startling rapidity? AIDS researchers have not been able to come up with answers to these questions.

HERVs--human endogenous retroviruses--might provide explanations that have been overlooked for 20 years, writes Professor Etienne de Harven, M.D., in the fall 2010 issue of the Journal of American Physicians and Surgeons. HERVs are present in all of us, and fragments of their DNA may be confused with HIV in the polymerase chain reaction (PCR) tests used to estimate viral load.

The beautiful photographs of HIV published in both lay and scientific journals are embellished with special effects from computerized image reconstruction. Since they come from cell cultures, which are likely to be contaminated, the particles may be "elegant artifacts" rather than the exogenous virus--a virus of external origin--believed to cause AIDS, de Harven states.

About 8 percent of the human genome consists of sequences incorporated from retroviruses. When cells break down, DNA fragments are released into the circulation--including these viral sequences. Patients with clinical AIDS carry a large spectrum of infectious diseases, so a high level of circulating DNA is expected.

While "AIDS Rethinkers" may challenge the role of HIV in AIDS, or even its existence, they are obligated to explain the observations of clinicians and researchers. HERVs are, at a minimum, a confounding variable that needs to be investigated, de Harven notes.

Puzzles involving the interpretation of diagnostic tests for HIV, the epidemiology and transmission patterns of AIDS, and strategies for prevention and treatment cannot be solved without broadening AIDS research beyond the narrow confines accepted by the "Orthodoxers," de Harven believes. Alternate hypotheses need to be objectively assessed, and conclusions must be based on scientific evidence rather than consensus.

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Study Links Fluoride to Pre-term Birth and Anemia in Pregnancy

/PRNewswire/ -- Fluoride avoidance reduced anemia in pregnant women, decreased pre-term births and enhanced babies' birth-weight, concludes leading fluoride expert, AK Susheela and colleagues, in a study published in Current Science (May 2010). http://www.fluorideandfluorosis.com/Anemia/Current%20Science%20Reprint.pdf

Susheela's team explains that anemia in pregnancy, which can lead to maternal and infant mortality, continues to plague many countries despite nutritional counseling and maternal iron and folic acid supplementation. This is the first examination of fluoride as an additional risk factor for anemia and low-birth-weight babies.

Anemic pregnant women living in India, whose urine contained 1 mg/L fluoride or more, were separated into two groups. The experimental group avoided fluoride in water, food and other sources and ate a nutritious diet per instruction. The control group received no instructions. Both groups supplemented with iron and folic acid.

Results reveal that anemia was reduced and pre-term and low-birth-weight babies were considerably fewer in the fluoride-avoidance group as compared to the control. Two stillbirths occurred in the control group, none in the experimental group.

Susheela et al. writes, "Maternal and child under-nutrition and anemia is not necessarily due to insufficient food intake but because of the derangement of nutrient absorption due to damage caused to GI (gastrointestinal) mucosa by ingestion of undesired chemical substances, viz. fluoride through food, water and other sources."

Fluoride avoidance regenerated the intestinal lining which enhanced the absorption of nutrients as evidenced by the reduction in urinary fluoride followed by rise in hemoglobin levels, they report.

Could the same thing be happening in the United States? State University of New York researchers found more premature births in fluoridated than non-fluoridated upstate New York communities, according to a presentation made at the 2009 American Public Health Association's annual meeting.

Previous published research shows fluoride can interfere with the reproductive system (http://www.fluoridealert.org/health/repro).

Current Science reports that adverse reactions of fluoride consumption are known to occur including reducing red blood cells, reducing blood folic acid activity, inhibiting vitamin B12 production and the nonabsorption of nutrients for hemoglobin biosynthesis.

"Citizens must demand that water fluoridation be stopped," says attorney Paul Beeber, President, New York State Coalition Opposed to Fluoridation, Inc. "It's disturbing that public-health officials and organized dentistry continue to ignore the overwhelming evidence revealing fluoride to be non-nutritive, unnecessary and unsafe," says Beeber.

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Infant's Gaze May Be an Early, but Subtle, Marker for Autism Risk

/PRNewswire/ -- Kennedy Krieger Institute announced today new study results showing an early marker for later communication and social delays in infants at a higher-risk for autism may be infrequent gazing at other people when unprompted. Published in the September issue of the Journal of Child Psychology and Psychiatry, the study also found that six-month-old high-risk infants demonstrated the same level of cause and effect learning skills when compared to low-risk infants of the same age.

The study observed 25 infant siblings of children with autism (high-risk group) and 25 infants with no family history of autism (low-risk group) at six months of age in order to assess cause and effect learning as well as social engagement. Infant siblings of children with autism are considered at high-risk for the disorder, as they are 25 times more likely to develop autism. Researchers at Kennedy Krieger, in collaboration with colleagues at the University of Delaware, created a novel, multi-stimuli social learning task, where infants were seated in a custom chair with an attached joystick within easy reach, a musical toy located to the right and their caregiver on the left. Researchers evaluated how quickly the infant learned that the joystick activated the toy and the infant's level of social engagement with their caregiver.

Researchers found that, like the low-risk group, the high-risk siblings exhibited typical levels of social gazing when their caregivers actively engaged them, such as pointing at the toy and expressing excitement. However, high-risk sibs spent less time looking to their caregivers and more time fixated on the non-social stimuli (toy or joystick) when the caregiver was not engaging them, which could indicate a disruption in development related to joint attention. Joint attention is often a core deficit for children with autism.

"My colleagues and I wanted to create a task that would involve learning something novel and would give babies an opportunity to pay attention to either an object or their caregiver," said Dr. Rebecca Landa, corresponding study author and director of Kennedy Krieger's Center for Autism and Related Disorders. "This study shows that there is a particular vulnerability in high-risk siblings at six months of age. They are not as socially interactive and engaged on their own as their peers, but still respond typically when engaged by their caregivers, making for a subtle difference that could be easily overlooked by both parents and some professionals."

The study also showed no evidence of impaired associative learning in the high-risk siblings. Both groups demonstrated cause and effect learning abilities; once the infants learned that pulling the joystick activated the toy, they increased how often they pulled on the joystick to activate the toy's music. This finding supports past research demonstrating that associative learning is a relative strength in older individuals with autism and may help to explain why children with autism respond well to teaching approaches that utilize a predictable reward system when children exhibit desired behaviors.

"Babies in both groups of the study learned the multi-stimuli task to the same degree," said Dr. Landa. "While the high-risk siblings are at a higher risk for developing autism later in life, they still have the capacity to learn cause and effect as well as their low-risk peers at this young age."

Implications from the overall study findings reveal that like older children, infants at high risk for autism may benefit from frequent exposure to simple cause and effect learning opportunities to aid in their development. For example, Landa recommends using simple songs paired with easy, predictable gestures to promote language and social learning, rather than using electronic toys that children can enjoy and operate without engaging with their peers or caregivers.

It is expected that about 20 percent of the high-risk infants in this study will receive a diagnosis of autism. While participants in this study have not yet reached their third birthday, the age at which the research diagnoses are confirmed, the study findings help to highlight the vulnerability of developing social initiation skills in high-risk infants. This study is the first of its kind, and a follow-up will soon be published from the Center for Autism and Related Disorders at Kennedy Krieger Institute.

The research study was supported by grants from the National Institutes of Mental Health.

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Explaining “How & Why” Cancer Cells Eat Us Alive

Newswise — Four key studies now propose a new theory about how cancer cells grow and survive, allowing researchers to design better diagnostics and therapies to target high-risk cancer patients. These studies were conducted by a large team of researchers at Thomas Jefferson University’s Kimmel Cancer Center.

This new idea also explains why so many cancer patients say that “their cancer is eating them alive” – an accurate observation that has never been understood, the researchers say.

These four new studies, co-published in the September issue of the journal Cell Cycle, provide evidence that tumor growth and metastasis is directly “fueled” by normal supporting cells.

These supporting cells are called fibroblasts, and they produce the stroma (connective tissue) that surrounds tumor cells. As the cancer progresses, increasing numbers of these stromal cells eat themselves to provide recycled nutrients to tumor cells – leading to dramatic weight loss in patients.

They also found that without recycled nutrients provided by fibroblasts, tumor cells are more fragile and die. Based on this breakthrough, the researchers propose that available drugs (now on the market), which sever the “parasitic” connection between tumor cells and fibroblasts, may be effective therapeutics.

“We think we have finally figured out how cancer really works – and this reverses 85 years of dogma, upon which current cancer research and therapy is based,” says the study’s senior investigator, Michael P. Lisanti, M.D., Ph.D., Chairman of Jefferson’s Department of Stem Cell Biology & Regenerative Medicine.

The prevailing theory, known as the Warburg Effect, developed by German researcher Otto Warburg in 1924 (for which he won a Nobel prize), says that tumor cells change their metabolism in order to fuel their own growth. As evidence, Warburg pointed to a lack of mitochondria, which are tiny “power plants,” in laboratory cancer cells, saying these cells have found another way to produce the energy they need.

Richard Pestell, MB, BS, MD, Ph.D, FRACP, director of the Kimmel Cancer Center and co-author on these studies notes, “These studies suggest that the absence of mitochondria in laboratory cancer cells may reflect in part that cultured cells have had to adjust to life outside of their original environment, without their stromal partner.” Drs. Lisanti, Pestell and colleagues found this out by performing a simple experiment in which they mixed cancer cells and fibroblasts together, and then searched for mitochondria. The found the fibroblasts didn’t have any mitochondria, and that the cancer cells had all the mitochondria.

“The Warburg Effect is happening, but it is happening to fibroblasts, not to cancer cells. Fibroblasts have no mitochondria because they are eating them to provide energy to cancer cells, and cancer cells have a ton of mitochondria because they need these power plants to process all the recycled nutrients given to them by fibroblasts, which then helps them grow and spread,” Dr. Lisanti says.
They have dubbed this finding “The Reverse Warburg Effect.”

“It’s amazing,” Dr. Lisanti says. “Much of what we know about cancer is backwards because cancer researchers used isolated tumor cells for most cancer studies. Now, when we put cancer cells back in their stromal environment, we see how cancer cells critically depend on fibroblasts for their survival.”

Tumor cells do this by employing oxidative stress as a weapon. Then, oxidative stress in fibroblasts “tricks” these stromal cells into eating themselves to feed cancer cells, the researchers say. This process of “self-eating” or “self-cannibalism” is called autophagy.

During periods of starvation, normal cells undergo autophagy. This metabolic re-programming allows cells to recycle nutrients by continually eating themselves, including their mitochondria. This permits starving cells to recycle nutrients and to survive under hostile conditions.

Now, Dr. Lisanti and colleagues have figured out how cancer cells take advantage of this recycling process. To satisfy their large appetite, hungry cancer cells induce oxidative stress in the fibroblasts and this stress forces the stromal cells to eat themselves, which provides recycled nutrients or “food” to fuel survival of nearby cancer cells.

“It’s that simple. Cancer cells are eating us alive by stealing nutrients from normal cells using oxidative stress, and by employing those recycled nutrients to support their own growth. Stem cells are then recruited from the bone marrow to produce fresh fibroblasts, to continually fuel cancer cell growth,” Dr. Lisanti says. “For years, cancer patients have said they felt as though the cancer in their body was eating them alive. These patients were right. Essentially, the cancer knows how to induce oxidative stress and turns a local wasting process into a whole-body phenomenon.”

Co-author Ubaldo Martinez-Outschoorn, M.D., a medical oncologist at Jefferson says “Patients have been telling us that cancer is eating them alive for years: Now we know they were right!” One of his cancer patients recently said, “Doc, I can’t eat enough food to maintain my weight. No matter how much I eat, I feel tired, and I am always losing weight.”

“Now that we understand the mechanism, this reverses our thinking about cancer metabolism and about how to stop this stress and starve the cancer cells,” he says.

In one of the published studies, Dr. Lisanti shows that using anti-oxidants can prevent oxidative stress in the fibroblasts, thus cutting off the fuel supply to cancer cells, starving them. “We are now performing drug screening assays to discover new anti-oxidants and other molecules like this,” he says.

The researchers have additionally identified two key metabolites – ketones and lactate – produced by the co-opted fibroblasts that provide high-energy food to the cancer cells. This finding also explains a mystery and provides a warning.

The mystery concerns why people with diabetes are much more likely to develop cancer than non-diabetics. The reason, Dr. Lisanti says, is that diabetic patients produce elevated levels of ketones, and he now shows that ketones fuel cancer cell growth.

The warning comes from the common use of lactate, a type of sugar, in cancer patients. Surgeons often give their cancer patients an intravenous solution of lactate before, during, and after surgery, Dr. Lisanti says. “But we see that cancer cells are using energy-rich fuels, such as lactate, to increase their numbers of mitochondria to power cancer cell growth, survival, and metastasis, so surgeons may want to re-consider or stop this practice.”

The findings have led the researchers to question the value of research using isolated laboratory cancer cells – the basis of most cancer research – and the anticancer drugs that result from it.

For example, genetic mutations have long been thought to be the root cause of cancer, but Dr. Lisanti’s group observed that these alterations might be the consequence of the tumor cell’s interactions with the normal stroma. Oxidative stress induced by cancer cells in fibroblasts feeds back upon cancer cells, amplifying the production of reactive oxygen species (ROS). They believe that ROS is then used by cancer cells to mutate their own genes to promote survival.

“These ROS molecules cause DNA damage in the cancer cells, resulting in genomic instability - random mutations and DNA breakage, as well as abnormal chromosome numbers. This instability helps cancer cells evolve into a more aggressive form,” Dr. Lisanti says.

“So, we see three consequences resulting from activating oxidative stress in normal stromal cells,” he says. “First, it forces stromal cells to make food for cancer cells. Second, this abundance of food protects the cancer cells against death. Finally, oxidative stress modifies cancer cell DNA, causing mutations and allowing them to evolve into a more aggressive form.”

Additionally, the researchers say their new theory of stromal metabolic re-programming suggests that cancer cells do not need blood vessels to feed them, which explains why some angiogensis inhibitors (drugs that shut down blood vessel growth) have not worked – and, in fact, may be dangerous.

“If an aggressive cancer cell can use oxidative stress to extract nutrients from normal stromal cells, it can go anywhere without the need for a blood supply. This may be how cancer cells spread all over the body,” Dr. Lisanti says. “Furthermore, angiogenesis inhibitors induce hypoxia, which is low oxygen, in the stroma. This is exactly the condition that drives nutrient recycling via autophagy. So angiogenesis inhibitors may help provide food or recycled nutrients to feed cancer cells. This explains why angiogenesis inhibitors have been very disappointing in clinical trials, as they may be having just the opposite effect, promoting cancer cell growth and metastasis.”

These new findings also have clear implications for cancer diagnosis, the researchers say. Many of the molecules that Dr. Lisanti’s group identified could be used as diagnostics to identify high-risk cancer patients or to monitor the success of their anti-cancer therapy.

Among them is caveolin-1 (Cav-1), which is produced by fibroblasts. Dr. Lisanti had shown earlier that loss of Cav-1 predicts poor prognosis in breast cancer patients, and is linked to early tumor recurrence, metastasis, and drug resistance. He now understands why, as breast cancer patients with absent stromal Cav-1 are feeding their cancer cells via recycled nutrients. That explains why a loss of stromal Cav-1 is such a good biomarker for identifying high-risk patients.

“The idea that a cancer cell’s local environment is important for tumor growth is now well-accepted by the cancer research community,” Dr. Lisanti says. “Now we show why this notion is correct.”

These studies were funded in part by grants from the NIH/National Cancer Institute, Susan G. Komen for the Cure, The American Cancer Society, The Breast Cancer Alliance, The Falk Medical Research Trust, The Landenberger Research Foundation and The Pennsylvania Department of Health.

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African-Americans Have Higher Risk for Blood Clots After Receiving Drug-Coated Stent

/PRNewswire/ -- African-American race is a distinct risk factor for developing life-threatening blood clots after receiving a drug-coated stent, according to research reported in Circulation: Journal of the American Heart Association.

African-American race was the strongest predictor of clotting that occurs more than 30 days after implantation, researchers said.

For the study, researchers examined data on 7,236 patients who had stents, coated with clot-prevention drugs, implanted to prop open narrowing arteries. The drug-coated stents, also called drug-eluting stents, were implanted between mid-2003 and the end of 2008.

Even after considering other known risk factors -- such as diabetes, hypertension and kidney problems -- researchers found that African-Americans still experienced a higher rate of thrombosis or clotting.

The bottom line is this is not just because this population is sicker or less compliant, but there is something else there that needs to be explored," said Ron Waksman, M.D., the study's lead author.

In the study, African-American patients were nearly three times as likely to experience clotting as non-African-American patients. African-Americans' clotting rates compared to non-African Americans were:

-- 1.71 percent vs. 0.59 percent after 30 days;
-- 2.25 percent vs. 0.79 percent at one year;
-- 2.78 percent vs. 1.09 percent at two years; and
-- 3.67 percent vs. 1.25 percent at three years.


The rate of death from all causes at three years was also higher among African-Americans, 24.9 percent vs. 13.1 percent in other races.

"Physicians and patients need to know that African-Americans are at a higher risk of developing stent thrombosis, which is associated with heart attack or death," said Waksman, associate director of the Division of Cardiology at Washington Hospital Center and professor of medicine and cardiology at Georgetown University.

In the study, African-Americans had increased rates of stent thrombosis even though they took post-surgery anti-clotting medication as prescribed at a higher rate than other races.

Further studies are needed to determine what should be done to reduce the blood clotting risks in African-Americans, Waksman said. Possible genetic differences in the way African-Americans' bodies react to the anti-clotting medication clopidogrel may have an impact.

Clopidogrel, a common drug prescribed post-stent implantation, carries a black box warning on its label from the Food and Drug Administration because the drug loses its ability to keep blood clots from forming in some patients whose bodies have trouble converting clopidogrel to its active form.

In some studies, researchers found that this genetic difference occurs more often in African-Americans than in white patients. Blood tests or genetic testing determine if someone is a "poor metabolizer" of clopidogrel.

More African-American participants are needed in key clinical trials to determine if the treatment works before a drug is on the market, Waksman said. "We are committed to further exploring these disparities and how African-Americans can benefit from drug-eluting stents without increasing the risk of stent thrombosis."

Co-authors are Sara D. Collins, M.D.; Rebecca Torguson, M.P.H.; Michael A. Gaglia Jr., M.D., M.Sc.; Gilles Lemesle, M.D.; Asmir I. Syed, M.D.; Itsik Ben-Dor, M.D.; Yanlin Li, M.D.; Gabriel Maluenda, M.D.; Kimberly Kaneshige, B.S.; Zhenyi Xue, M.S.; Kenneth M. Kent, M.D., Ph.D.; Augusto D. Pichard, M.D.; William O. Suddath, M.D.; and Lowell F. Satler, M.D.

Author disclosures and funding information are on the manuscript.


Statements and conclusions of study authors published in American Heart Association scientific journals are solely those of the study authors and do not necessarily reflect the association's policy or position. The association makes no representation or guarantee as to their accuracy or reliability. The association receives funding primarily from individuals; foundations and corporations (including pharmaceutical, device manufacturers and other companies) also make donations and fund specific association programs and events. The association has strict policies to prevent these relationships from influencing the science content. Revenues from pharmaceutical and device corporations are available at www.americanheart.org/corporatefunding.

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Study Compares Risk With Two Diabetes Drugs

/PRNewswire/ -- In contrast to previous reports, the risks of the composite endpoint of heart attack, heart failure, both, or death were the same - about 4 percent - for patients taking the diabetes drugs rosiglitazone or pioglitazone, according to a study published in the American Heart Association journal Circulation: Cardiovascular Quality and Outcomes.

"This study provides patients and their doctors with another source of information about rosiglitazone and pioglitazone (sold as Avandia and Actos, respectively) as they determine the best therapy for diabetes patients," said Debra Wertz, Pharm.D., lead author and outcomes research manager at HealthCore, Inc., the research subsidiary of health insurance company WellPoint, Inc.

This study evaluated more than 36,000 diabetes patients. Of the 28,938 patients who were propensity-score matched, a methodology used to provide an estimation of treatment-effects that is as unbiased as possible, 602 patients taking rosiglitazone and 599 taking pioglitazone over a 33-month period suffered either a heart attack, heart failure, both, or died. This translates to about 4 percent of all patients taking either medication. The individual specific adverse events were also not significantly different between the two groups, and were:

-- Heart attack - 96 patients on rosiglitazone and 121 patients on
pioglitazone;
-- Heart failure - 265 patients taking rosiglitazone and 243 taking
pioglitazone;
-- Heart attack and heart failure - 24 patients on rosiglitazone and 18
on pioglitazone; and
-- Death - 217 patients taking rosiglitazone and 217 taking pioglitazone.


The study included 36,628 patients who had submitted insurance claims to WellPoint affiliates for either of the two diabetes medications between 2001 and 2005. Patients' average age was 54, and 58 percent were male. Wertz and her team obtained death records from the National Death Index, a central database administered by the National Center for Health Statistics.

The investigators divided patients into two equal groups, one receiving rosiglitazone and the other, pioglitazone. After adjusting the data for (removing/minimizing the effect of) age, gender, prior heart and blood vessel diseases and diabetes-related complications and severity indicators, they compared the incidence of heart attack, heart failure and death for an average 14 months of treatment and 19 months of post-treatment follow-up.

Diabetes is a disease in which the body cannot adequately produce the hormone insulin or uses it improperly. The disease can cause a potentially dangerous buildup of sugar in the blood and also increases the risk of heart and blood vessel diseases, which are the main causes of death for people with diabetes.

Rosiglitazone, sold under the trade name Avandia by GlaxoSmithKline, and pioglitazone, sold as Actos by Takeda Pharmaceuticals, belong to the same class of drugs, called TZDs or thiazolidinediones. They help the body use insulin more effectively by boosting the body's sensitivity to the hormone and thus help control blood sugar.

This study has results different from earlier ones that found a greater risk of heart attack among rosiglitazone users compared to patients on other treatments or placebo. In 2007, the Food and Drug Administration decided that the benefits of rosiglitazone outweighed the risks, and it remained on the market although its use decreased significantly. In July 2010, an FDA advisory committee again reviewed numerous studies, including this study, and recommended that rosiglitazone remain on the market, although with additional warnings or restrictions. The FDA has not yet ruled on this latest recommendation.

"Besides its findings that rosiglitazone and pioglitazone have comparable risks, what distinguishes this latest study from other claims-based analyses is its analysis of death records, which include out-of-hospital deaths," Wertz said. The study also followed patients for a longer period of time than some of the earlier research, according to the investigators.

"One of the reasons we embarked on this analysis was to see if there were any differences in effect that we could identify between these two agents," said Mark J. Cziraky, Pharm.D., study co-author, and vice president of research development and operations at HealthCore. "We did not find that with the approach and methods we took within this population."

Other co-authors are Chun-Lan Chang, Ph.D.; Chaitanya A Sarawate, M.S.; Vincent J. Willey, Pharm.D.; and Rhonda L. Bohn, M.P.H., Sc.D.

Author disclosures are on the manuscript. WellPoint, Inc. funded this research.


An accompanying editorial, "Improving Surveillance for Drug Safety: Lessons from Rosiglitazone," by Frederick A Masoudi, M.D., M.S.P.H., is available.


Statements and conclusions of study authors published in American
Heart Association scientific journals are solely those of the study
authors and do not necessarily reflect the association's policy or
position. The association makes no representation or guarantee as to
their accuracy or reliability. The association receives funding
primarily from individuals; foundations and corporations (including
pharmaceutical, device manufacturers and other companies) also make
donations and fund specific association programs and events. The
association has strict policies to prevent these relationships from
influencing the science content. Revenues from pharmaceutical and
device corporations are available at http://www.americanheart.org/
corporatefunding.

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Epilepsy Organizations Award Grants for New Gene Therapy to Treat Epilepsy and Novel Surgical Intracranial EEG to Detect Seizures in Uncontrolled Patients

/PRNewswire/ -- The Epilepsy Therapy Project (ETP) and the Epilepsy Foundation (EF) today announced the latest grant recipients of its New Therapy Grants Program, a unique joint venture of the non-profit epilepsy organizations, to advance promising epilepsy research in clinical development. The grant awards, totaling approximately $200,000 in funding, will support an experimental gene therapy that directly targets epileptogenic brain tissue, as well as an electrode system that has the potential to improve the efficacy of surgical therapies for certain epilepsy syndromes.

"Patients need new options to treat and manage epilepsy, and through this grant program we are excited to see such remarkable innovation in the field. The fields of gene therapy and surgical treatment of epilepsy remain cutting-edge with much to be explored in terms of advancing epilepsy treatment outcomes," said Orrin Devinsky, MD, ETP Co-Founder and Vice President for Translational Programs, Professor of Neurology, Neurosurgery, and Psychiatry, and Director, NYU Comprehensive Epilepsy Center, New York University. "By choosing to support these two promising programs, we hope to see important strides made while encouraging researchers and companies to pursue new ideas and approaches in epilepsy and seizure conditions."

The New Therapy Grants program grants are designated to facilitate the advancement of new treatments through critical early-stage clinical development or to bridge the gap from preclinical to clinical development to ensure patients will have the opportunity to benefit from groundbreaking progress in the field of epilepsy. The award committee, which is comprised of clinical, scientific and industry representatives, evaluates applications to support new therapeutic approaches submitted by highly qualified clinical experts and scientists with the greatest potential for near-term patient benefit.

"The need and market opportunity for new therapies in epilepsy is unmistakable," said Warren Lammert, Chairman of the Epilepsy Therapy Project. "One third of the people with epilepsy live with uncontrolled seizures despite all available therapies and perhaps another one third achieve seizure control but at the price of unacceptable side-effects including fatigue and impact to cognition. Yet moving promising ideas out of research labs and on through the process of clinical and commercial development is an enormously expensive process with miniscule odds of success for each individual project. Further, epilepsy therapy development has been neglected by government and private funding sources, and current economic uncertainties have further diminished the availability of risk capital. In this environment, the importance of our New Therapy Grants in moving the most promising new research ideas across the starting line on to a path of clinical development cannot be overstated. My hope is that we can mobilize increased support and expand this vital program so necessary to improving the lives of people living with epilepsy."

"These research projects represent the essence of translational research and the focus of our New Therapy Grants Program," said Joyce Bender, chair of the Epilepsy Foundation board of directors. "We proudly applaud our grant recipients because their studies may provide new treatment options, which could lead to an improved quality of life for the nearly 3 million people in the United States and 50 million people worldwide living with epilepsy."

The Grant Recipients

Galanin Gene Delivery to the Hippocampus for Mesial Temporal Lobe Epilepsy

-- Prospect of one-time gene therapy that produces anti-convulsant and
neuroprotective benefits
-- Experimental therapy may offer less invasive therapeutic option and a
prospective paradigm shift in patient care for certain forms of
epilepsy


Scott McPhee, Ph.D., Vice President of Clinical Development, Asklepios BioPharmaceutical Inc., and Nicholas Boulis, M.D., Assistant Professor, Neurosurgery, Emory University, will be conducting preclinical studies of a Galanin gene delivery for selected patients with uncontrolled Mesial Temporal Lobe Epilepsy (MTLE). Direct delivery of a gene therapy to the temporal lobe offers the significant potential of a less invasive, more effective alternative approach that precludes the trauma and resulting complications of surgical tissue removal, and avoids the side effects of standard pharmacological treatments. The protein galanin has been shown to suppress seizures. Gene delivery of galanin DNA has been shown to have anticonvulsant and neuroprotective effects in models of MTLE. Unlike traditional anti-epileptic medications, galanin gene delivery may be administered in a one-time intervention that provides long-term supplemental galanin in the epileptogenic tissue. The proposed therapeutic approach represents a paradigm shift in the treatment of epilepsy because gene delivery offers to locally regulate activity rather than destroying tissue. In addition, it has the unique and significant potential to one day provide a strategy for the treatment of critical brain tissue in which tissue removal is not currently a therapeutic option. These experiments may not only provide a unique opportunity for the development of novel epilepsy therapies but may also advance the cause of neurological gene therapy in general.

The preclinical research outlined by the grant recipients is expected to support the filing of an

Investigational New Drug (IND) Application for a Phase I clinical trial. Funding of the preclinical protocol is subject to appropriate institutional review and approvals, as well as securing the additional financial support needed to complete the research.

Intracranial EEG Acquisition System with Online Fast Ripple Detection

-- New technology to refine how surgeons will identify and define
epileptogenic regions of the brain
-- Potential to improve surgical outcomes and broaden viability of
treatment for certain epilepsy syndromes


A Columbia University Medical Center research team headed by Catherine Schevon, M.D., Assistant Professor, Neurology, received funding to support the refinement of an intracranial EEG recording system, an online detection system to better define the epileptogenic region of the brain, the area of the brain related to seizure activity, before therapy or surgery.

Surgical excision of the epileptogenic brain region is an important treatment modality for medically refractory partial epilepsy, with greater than 60 percent or more of patients achieving seizure freedom. The success rate is notably worse, however, when a structural lesion cannot be identified, and may be as low as 35 percent in patients with extratemporal non-lesional syndromes. In these cases, the resection choice depends almost entirely on accurate interpretation of the intracranial EEG (iEEG), obtained by recording from electrodes implanted directly onto the brain surface or into the parenchyma. Recognizing these limitations surgical therapy for extratemporal epilepsy syndromes is not currently recommended for widespread clinical use.

High frequency oscillations (HFO) in the brain can identify areas for epilepsy surgery treatments, but are technically difficult to detect, largely limiting their clinical utility. Grant funding will be applied to the development of this new system to bring automatic online HFO detection into clinical practice, making current surgical treatments more effective, and potentially simplifying surgeries for many epilepsy syndromes. By increasing the specificity of the identification of the epileptogenic region, seizure outcomes can be improved while the area of brain that must be removed is minimized.

Upcoming Grant Applicants: Note Deadline for Letter of Intent is September 3, 2010

The New Therapy Grants Program is requesting proposals from scientific and clinical investigators pursuing innovative projects that demonstrate a clear path to commercialization. The program accepts the submission of proposals ranging from $50,000 to $500,000. The deadline to submit a Letter of Intent (LOI) is September 3, 2010. Applicants who have an accepted LOI have until October 15, 2010, to submit their full proposals. To view additional requirements, please visit http://www.epilepsy.com/etp/support_translational.

The New Therapy Grants Program is a unique partnership between two leading epilepsy non-profit organizations, the Epilepsy Therapy Project and the Epilepsy Foundation. The mission of the New Therapy Grants Program is to drive the development of new therapies for epilepsy, accelerating the advancement of research from the laboratory to the patient. Funding is provided for grants supporting the research and development of new therapies in both academic and commercial settings worldwide.

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'Legacy of Katrina' Report Details Impact of Stalled Recovery on Mental Health Status of Children

/PRNewswire/ -- Five years ago Hurricane Katrina and the flooding of New Orleans caused the evacuation of 1.5 million Gulf Coast residents. After a year, 500,000 people remained displaced, many residing in highly transitional shelters, including the notorious FEMA trailer parks. Now at the five-year mark, substantial consequences from this prolonged displacement have resulted in widespread mental health issues in children living in the region, according to a new study by the National Center for Disaster Preparedness (NCDP) at Columbia University's Mailman School of Public Health and a related white paper from the Children's Health Fund (CHF). Together, these documents indicate that although considerable progress has been made in rebuilding the local economy and infrastructure, there is still an alarming level of psychological distress and housing instability. Investigators believe that housing and community instability and the uncertainty of recovery undermine family resilience and the emotional health of children. These factors characterize what researchers are calling a failed recovery for the Gulf region's most vulnerable population: economically disadvantaged children whose families remain displaced.

The CHF report, "Legacy of Katrina: The Impact of a Flawed Recovery on Vulnerable Children of the Gulf Coast," expands upon on a study by NCDP researchers, who have followed a cohort of more than 1,000 families affected by Katrina and the ensuing disruption. According to the Gulf Coast Child & Family Health Study, funded by the Children's Health Fund and published in the current issue of American Medical Association's Journal of Disaster Management and Public Health Preparedness, the widespread mental health problems still experienced by Gulf Coast children serve as a barometer for the failed recovery of their families and their communities. Over one-third of the children in displaced families have been clinically diagnosed with at least one mental health problem since Katrina -- with behavioral and conduct disorders the most common of these problems. Yet fewer than 50% of parents seeking needed mental health counseling for their children were able to access professional services. Furthermore, nearly half of the households in the study were still living in unstable conditions and, five years later, 60% of respondents still report their situation as being unstable or worse than it was before Katrina.

"This study points to a major crisis facing the children of the post-Katrina Gulf Region," says Irwin Redlener, M.D., director of the National Center for Disaster Preparedness at Columbia's Mailman School of Public Health and president of the Children's Health Fund. "From the perspective of the Gulf's most vulnerable children and families, the recovery from Katrina and the flooding of New Orleans has been a dismal failure."

"Previous studies have demonstrated a significant increase in the prevalence of anxiety, depression, and post-traumatic stress disorder, following Hurricane Katrina, as well as a rise in violence and suicide," said Italo Subbarao D.O., MBA, deputy editor of AMA's Disaster Medicine and Public Health Preparedness Journal. "This study adds further credence to widely accepted views that adults and children affected by catastrophic emergencies can experience up to a 40% increase in mental and behavioral illness."

According to David M. Abramson, Ph.D., MPH, director of research at the NCDP and senior author of the study which looked at the roles of parents and communities in children's recovery, "Children are completely dependent upon others in their lives to provide the security and stability that will help them recover. This suggests that the many support systems in children's lives - their parents, their communities, and their schools - are not yet functioning properly. The slow recovery of children's mental health in Gulf Coast populations is a bellwether indicator of how well the region is recovering."

Additional key findings:

-- Even as long as four and a half years after the event, about 45% of
parents report that their children are experiencing emotional or
psychological problems that they hadn't experienced prior to Katrina.

-- Children post-Katrina are 4.5 times more likely to have serious
emotional disturbance than pre-Katrina. For the purposes of this
study, such disturbances were defined as emotional issues,
hyperactivity, conduct and problems relating to peers.

-- Nearly half of people who had been displaced for over a year by
Katrina are still living in unstable conditions.


The study findings are supported by clinical data from the Children's Health Fund, which provides mobile clinics that travel to underserved areas in the Gulf Coast to provide care for families and children. In the period of June 2009 through June 2010, despite improvement in housing conditions in Louisiana, psychiatric, developmental or learning-related disorders in children were diagnosed as frequently as respiratory illness. And in New Orleans alone, approximately 30,000 school children were not able to return to public school. However, data also shows that children who were relocated sooner did better in school than students with longer periods of displacement and those who were enrolled in higher performing schools did the best, thus highlighting the importance of social systems in a child's post-disaster recovery.

Both the study and the clinical reports from the Children's Health Fund's Gulf Coast pediatric programs paint a clear picture of how insufficient government response and recovery efforts continue to take a toll on children's welfare, especially those who are the most underserved. Dr. Redlener, a pediatrician and professor at Columbia University's Mailman School of Public Health, outlined a number of implications for policymakers and others: "Affected families need urgent assistance to return to a state of 'normalcy' characterized by safe communities and stable housing. Nearly two out of three children affected by Katrina continue to experience serious mental and behavioral problems or the stress of unstable housing or both, with children living in poverty over two times as susceptible to serious emotional disorders. We believe that this represents at least 20,000 children affected by Katrina--and perhaps considerably more. Immediate action needs to be taken to increase mental health services in the region."

Dr. Redlener continues, "And it's not just clinical services that are needed by these marginalized families. Every effort must be made to rapidly bring back a 'state of normalcy', that is, stable safe housing for every family in communities with appropriate access to essential services and economic stability."

The Gulf Coast Child & Family Health Study has collected mental health data in the Gulf Coast since January 2006 and covers a random sample of 1,079 households in Louisiana and Mississippi, including 427 children. Face-to-face interviews were conducted by trained interviewers, and the key outcome variable was Serious Emotional Disturbance, based upon the Strengths and Difficulties Questionnaire (SDQ), a widely validated diagnostic screener. The data were collected in four waves over the course of four years with the majority of data for this analysis drawn from the fourth round of data, collected through March 2010.

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Old Drug Holds Promise Against Opportunistic Lung Bug

/PRNewswire/ -- A drug to treat inflammation plays a surprising role reducing the level of infection caused by an opportunistic bug that is deadly for AIDS and cancer patients and others with weakened immune systems.

The drug, sulfasalazine, spurs the body to get rid of the fungal evaders by enhancing the body's ability to chew them up instead of leaving the debris to litter the lungs, where it would continue to provoke an onslaught of harmful inflammation.

Besides opening a new avenue for research on Pneumocystis pneumonia or PCP, caused by the fungus Pneumocystis jirovecii, the work with mice also offers the possibility of manipulating immune cells called macrophages to improve treatment of infections.

The findings by scientists at the University of Rochester Medical Center were published August 19 in the journal PLoS Pathogens.

During a bout with Pneumocystis, the lungs become a battlefield, where the body pits an array of impressive forces against marauding microbes. But even when the body gets the upper hand, the damage is tremendous. Immune cells like neutrophils and macrophages can flood the lungs, literally suffocating the patient. And when the debris from dead microbes fills the lungs, more and more immune cells are called in to clean up the area, making matters worse. It becomes harder and harder to breathe.

"Many people assume that once the microbe is dead, patients usually start to feel better immediately. But with Pneumocystis, patients do not always undergo a rapid clinical improvement following antibiotic treatment. Even though the bug has been killed, the debris that is left in the lungs continues to promote inflammation," said corresponding author Terry Wright, Ph.D., an infectious disease specialist and associate professor of Microbiology and Immunology and of Pediatrics.

Pneumocystis is a common bug that infects nearly everyone at some point; the authors say that more than 80 percent of children have been infected by the age of 2. Most people shake off the infection without consequence, but for people with cancer, AIDS, or other diseases that compromise their immune system, the infection can be deadly. Usually there are few signs that the patient is sick until the infection is well established and the fungus is widespread in the lungs. Among cancer patients, mortality rates as high as 40 percent have been reported.

Since the body's immune response is central to how Pneumocystis kills patients, doctors use two different types of drugs in tandem to treat patients - an antibiotic to kill the bug, and steroids or another type of drug to reduce the consequent inflammation.

Central to the study were mice in which the disease progresses in a manner very similar to AIDS patients. The remarkable strides in AIDS therapy in recent years have come with a down side for many patients, thanks to Pneumocystis: When anti-retroviral therapy kicks in, a patient's immune system often becomes stronger very quickly - and if the fungus is present, the immune system attacks it vigorously, causing a potentially deadly form of pneumonia.

Wright's team looked at the effects in mice of sulfasalazine, an anti-inflammatory drug that has proven useful in treating conditions like Crohn's disease and rheumatoid arthritis. The team found that Pneumocystis-infected mice treated with sulfasalazine developed much less severe disease than untreated mice. The sulfasalazine-treated mice had better lung function, less weight loss, and were generally healthier than untreated animals.

While some of the benefit was due to the drug's anti-inflammatory properties and was expected, the result included a big surprise: The drug also spurs the body to remove the bug more aggressively by boosting the activity of immune cells called macrophages.

"This was unexpected," said first author Jing Wang, Ph.D., research assistant professor in Pediatrics. "Since we reduced the response of the immune system, you would think the mice would get sicker. But instead, the mice treated with sulfasalazine were healthier. At first we thought it was due solely to the anti-inflammatory activity of the compound, but it turns out that sulfasalazine actually results in a reduced fungal burden. The drug helps the body clear the infection.

"We initially thought we had done something wrong, and so we repeated the experiment again and again. Then, when new technology was developed, we were able to document that the body cleared the infection more readily with sulfasalazine," added Wang.

Scientists have long known that the body's immune T cells are central to the body's response to fight off the infection. The Rochester team showed that the body's T cells spur macrophages to attack the fungus - to engulf its particles and chew them up in a process known as phagocytosis.

While scientists have long suspected that role for macrophages, the Rochester team relied on a new technology to gather the first direct evidence of macrophages engulfing fungal particles. The scientists worked closely with Timothy Bushnell, Ph.D., and others at Rochester's Flow Cytometry Resources Core, investigating new ways to use lasers to capture images of molecular events. Bushnell's team ultimately connected the team with scientists at Amnis. Together the group developed a new way to capture macrophage phagocytosis in single cells from mice infected with Pneumocystis. The technology enabled the team to capture more than 40,000 such events, compared to just a handful when using conventional microscopy.

The team showed that as macrophage activity increased, the animals' health improved and levels of fungus decreased. For example, 17 days after infection, mice treated with sulfasalazine had nine times as many macrophages that had engulfed fungal particles compared to mice that had not been treated with the compound.

"This marks a new direction in which to look for new therapies to treat Pneumocystis as well as other inflammatory diseases. Identifying modulators that can increase or decrease the action of our immune system in a precise manner is a growing area of research," said Wright. Recently researchers have come to realize that there are different kinds of macrophages, and Wright noted that the type whose activity is trigged by sulfasalazine does not contribute to inflammation.

In addition to Wang and Wright, other authors include Francis Gigliotti, M.D., professor of Pediatrics and of Microbiology and Immunology, and also chief of Infectious Disease at Golisano Children's Hospital; Samir Bhagwat, Ph.D., research assistant professor of Pediatrics; and Thaddeus George from the Amnis Corp. in Seattle. The work was funded by the National Heart Lung and Blood Institute and the Strong Children's Research Center.

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Gender Bender: Do Gender Knee Implants Provide Better Outcomes?

/PRNewswire/ -- A gender-specific total knee prosthesis was developed to more closely match the anatomy of the female knee, aiming to be a better fit resulting in better outcomes for women. However, a recent study in the Journal of Bone and Joint Surgery (JBJS) found that 85 women who received a gender-specific implant in one knee and a standard prosthesis in the other knee found no clinical benefits of the gender-specific knee.

"We conducted this study to investigate whether women derive less benefit, or perhaps less predictable benefit, from total knee replacement using a standard conventional total knee implant," said Young-Hoo Kim, M.D., orthopaedic surgeon and lead author of the study.

After receiving knee implants - one gender-specific and one standard prosthesis - the women were assessed for at least two years after surgery. The knees with the gender-specific implant and the knees with the standard implant had similar knee scores and similar range of motion while lying down (125 degrees for the knees with standard implants and 126 degrees for the knees with gender-specific implants). All patients except three were able to bend their knees at least 90 degrees.

Additionally, patient satisfaction with the implants was similar (8.3 points for the standard implants and 8.1 points for the gender-specific implants). A rating of 6 to 8 meant "satisfied," and a rating of 9 to 10 meant "fully satisfied."

Important findings included:
-- The majority of women in the study (71 females or 84 percent) had no
preference between the two implants,
-- eight women (9 percent) preferred the standard prosthesis, and
-- six (7 percent) preferred the gender-specific prosthesis.

Implantation prostheses of either design resulted in improved quality of life in terms of pain, walking distance, deformity, and function after surgery.

Although the gender-specific implants were specially designed to fit women, Dr. Kim's study showed that the standard prostheses fit women's knees better than the gender-specific implants. "Our data demonstrated that the standard prosthesis fit the distal part of the femur (where the thigh and knee connect) better than the gender-specific prosthesis did," said Dr. Kim, who is from The Joint Replacement Center of Korea, Ewha Women's University School of Medicine in South Korea. The gender-specific prosthesis was so small that it exposed more bone, which resulted in increased bleeding immediately after surgery.

Dr. Kim and his colleagues were surprised by the study results. "We indeed expected the gender-specific prostheses to outperform the standard prostheses," he said.

Because the women in the study did not have any clinical benefit from the gender-specific knee implants, Dr. Kim now recommends that women receive a properly sized standard total knee prosthesis. "We have learned that gender-specific total knee prostheses fail to show any clinical benefits. So, we feel that proper size standard total knee prostheses are needed for both men and women," he added.

Although patients were only followed for approximately two years, studies have shown that results after two years are similar to those seen five to ten years after total knee replacement. "Because the duration of follow-up was short, we can draw no conclusions about the advantage of the gender-specific prosthesis with regard to long-term function," Dr. Kim concluded.

Disclosure: The authors did not receive any outside funding or grants in support of their research for or preparation of this work. Neither they nor a member of their immediate families received payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity.

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Chronic Health Conditions Common for Stem Cell Transplant Survivors

/PRNewswire/ -- Although hematopoietic cell transplantation (HCT) cures many blood diseases, two-thirds of long-term survivors report at least one chronic health condition after the procedure, according to a recent study published online in Blood, the journal of the American Society of Hematology. Overall, these patients were three and a half times more likely to develop a severe or life-threatening health condition, such as cardiovascular, endocrine, or musculoskeletal problems, as well as new cancers, when compared with their cancer-free siblings.

"Although hematopoietic cell transplants have helped thousands of patients survive cancer, the burden of chronic illnesses borne by these survivors is substantial," said senior study author Smita Bhatia, MD, MPH, professor and Ruth Ziegler Chair in Population Sciences at City of Hope Comprehensive Cancer Center in Duarte, CA. "We hope the results of this study build awareness of the problem to help ensure a continued high quality of life among transplant survivors through life-long follow-up and proactive care."

It is estimated that more than 45,000 patients undergo HCTs each year to combat life-threatening diseases such as leukemia, lymphoma, and aplastic anemia. The procedure restores blood-forming cells in the patient's bone marrow that have been destroyed by anti-cancer treatments, such as chemotherapy. Although previous studies have shown that more than 70 percent of those who survive the first two years after HCT are expected to become long-term survivors, the elimination of the cancer has not always led to a full restoration of health. The high-intensity chemo- and radiotherapies needed prior to transplantation can damage many organs and have a negative impact on the overall health of HCT survivors.

The researchers for this study examined the prevalence and severity of chronic health conditions reported by 1,022 HCT survivors who received their transplants at City of Hope or the University of Minnesota between 1974 and 1998 for a blood cancer or severe aplastic anemia. The results were compared to those of 309 siblings of the participants. Each of the HCT survivors and siblings completed a questionnaire, which included questions regarding physical health conditions, access to and use of medical care, and sociodemographic characteristics.

The results showed that chronic health conditions were widespread in the HCT survivors. Sixty-six percent of these patients reported at least one chronic condition, half reported at least two chronic health conditions, and more than a third (35 percent) reported three or more conditions. In comparison, 39 percent of the siblings reported at least one chronic health condition, but only 15 percent had two or more conditions, and 6 percent had three or more. A severity score of grade 1 (mild) through 4 (life-threatening) was also assigned to each health condition. Mild and moderate conditions include ocular issues, hearing impairment, hypertension, and sensory problems while severe conditions include cardiovascular, gastrointestinal, and muscuskeletal problems, as well as new malignancies. In the HCT cohort, 18 percent reported conditions of the severest level (grade 3 or 4), while only 8 percent of the sibling group had grade 3 or 4 conditions.

Additionally, 53 percent of the HCT survivors who had received grafts from a donor experienced chronic graft-versus-host disease (GVHD), a complication in which the foreign transplanted cells attack the cells in the recipient's body. Although GVHD is treatable, this complication contributed significantly to the increased risk of multiple severe or life-threatening conditions in these patients. Among the survivors with GVHD, nearly one-quarter had severe or life-threatening conditions such as cardiovascular and gastrointestinal disorders, and more than half had two or more health conditions.

The researchers concluded that HCT survivors have a high rate of illness due to chronic health conditions, especially those with chronic GVHD, and recommended that health-care providers conduct systematic and targeted follow-up of these high-risk patients.

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