A new study finds that exposure to a chemical component of diesel exhaust particles can compromise the ability of resistance arteries to regulate blood flow to bone marrow. Post-menopausal females, the elderly and males are most likely to be impacted, according to a new vascular biology study — using an animal model — presented at the 120th Annual Meeting of The American Physiological Society (APS; the-aps/) in Washington, DC.

The study, Effects of Age, Gender, and Estrogen on Endothelium-Dependent Vasodilation Subsequent to Phenanthraquinone Exposure, was conducted by Rhonda D. Prisby, Judy Muller-Delp and Timothy R. Nurkiewicz, all of the Center for Interdisciplinary Research in Cardiovascular Sciences at the West Virginia University School of Medicine in Morgantown, WV, USA. Dr. Nurkiewicz is presenting the findings on behalf of the University’s interdisciplinary cardiovascular research team. The research was funded by the Health Effects Institute and the National Institutes of Health.

Background

Diesel exhaust contributes significantly to the U.S. ambient air pollution burden. This form of air pollution is the product of diesel fuel combustion, commonly generated by buses, trucks, trains and ferries. The particles can remain airborne for extended time periods, and travel long distances prior to being inhaled. When inhaled, chemical components such as polyaromatic hydrocarbons (PAH) attached to the particles can interact with the body. Quinones are PAHs and are among the more toxic components of diesel exhaust. In the current study, the investigators used phenanthraquinone (PQ) because previous research found PQ to compromise the ability of larger blood vessels to relax. They have also noted that in certain populations, exposure to particle pollution may exacerbate various cardiovascular diseases.

The principal nutrient artery (PNA) is the major resistance vessel that regulates blood blow to the femoral bone marrow. The ability of arteries to dilate (widen) declines with age and this corresponds with reduced blood flow in an artery’s target organ. Impaired blood flow regulation in the bone marrow can have wide- and long-reaching health consequences. It is unclear what PQ does to the ability of this artery to dilate, and how age or gender alters any such effect.

Summary of Methodology

Against this backdrop the research team sought to determine whether PQ impairs vasodilation in the PNA and identify whether age, gender or estrogen alters the presumed effects of PQ. The researchers isolated and cannulated femoral PNAs from intact and ovariectomized (OVX) female rats (6, 14 and 24 months) and male rats (6 and 24 months). To evaluate the ability of the PNA to dilate when it was incubated with PQ, researchers used the chemical acetylcholine (ACh). A series of ACh doses were administered over time, starting with low doses and graduating to higher doses to produce maximum dilation of the artery

Results

The researchers found that:

* exposure to PQ had greatly compromised — by approximately 65 percent — the ability of the blood vessels to effectively dilate in six month old male rats, but had no effect in female rats;

* at 14 months (female rats) and 24 months (female and male rats), PQ had impaired and abolished vasodilatation, respectively;

* in all OVX rats (i.e., the young females who had lost estrogen due to menopausal status), PQ abolished vasodilatation;

* following the loss of estrogen, particularly at six months where a cardioprotective effect was previously observed, PQ exposure had obliterated vasodilation.

Conclusion

This study demonstrates that exposure to the diesel particle component PQ, can compromise the ability of the PNA to regulate bone marrow blood flow in males, the elderly and post-menopausal females in an animal model. These findings may provide an important link to other discoveries involving the protective effects of estrogen to environmental pollutants.

Physiology is the study of how molecules, cells, tissues and organs function to create health or disease. The American Physiological Society (APS) has been an integral part of the scientific discovery process since it was established in 1887.

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The APS annual meeting was part of the Experimental Biology 2007 (EB ’07) gathering.

Contact: Donna Krupa

American Physiological Society

Diet sodas may have fewer calories for your waistline, but they don’t reduce your risk of heart problems and even stroke in actuality. In a new Manhattan Study (NOMAS) presented at this week’s American Stroke Association’s International Stroke Conference, states that people who drank diet soda every day had a 61% higher risk of vascular events than those who reported no soda drinking.

Hannah Gardener, Sc.D., lead author and epidemiologist at the University Of Miami Miller School Of Medicine in Miami comments:

“If our results are confirmed with future studies, then it would suggest that diet soda may not be the optimal substitute for sugar-sweetened beverages for protection against vascular outcomes. The take-home message is that high sodium intake is a risk factor for ischemic stroke among people with hypertension as well as among those without hypertension, underscoring the importance of limiting consumption of high sodium foods for stroke prevention.”

People who consumed more than 4,000 milligrams (mg) per day of sodium had more than double the risk of stroke compared to those consuming less than 1,500 mg per day.

In the study started in 1993, researchers asked subjects of 63% women and 21% male, 24% African American and 53% Hispanic to report how much and what kind of soda they drank. Seven categories emerged: no soda (meaning less than one soda of any kind per month); moderate regular soda only (between one per month and six per week), daily regular soda (at least one per day); moderate diet soda only; daily diet soda only; and two groups of people who drink both types: moderate diet and any regular, and daily diet with any regular.

In almost 10 full years of follow up, 187 ischemic strokes were reported. Researchers calculated that stroke risk, independent of hypertension, increased 16% for every 500 mg of sodium consumed per day.

Five hundred and fifty nine vascular events were reported in 9.3 years of observation. Researchers accounted for participants’ age, sex, race or ethnicity, smoking status, exercise, alcohol consumption and daily caloric intake.

Only a third of participants met the current U.S. Dietary Guidelines for Americans that recommend daily sodium intake fall below 2,300 mg, or about a teaspoon of salt. Average intake among all soda drinkers was 3,031 milligrams.

Agriculture Secretary Tom Vilsack states:

“The 2010 Dietary Guidelines are being released at a time when the majority of adults and one in three children are overweight or obese and this is a crisis we can no longer ignore. These new and improved dietary recommendations give individuals the information to make thoughtful choices of healthier foods in the right portions and to complement those choices with physical activity. The bottom line is that most Americans need to trim our waistlines to reduce the risk of development diet-related chronic disease. Improving our eating habits is not only good for every individual and family, but also for our country.”

Source: American Heart Association

Sy Kraft, B.A.

The potential for stem cells derived from menstrual blood to benefit stroke sufferers will be jointly investigated by researchers at the University of South Florida, Cryo-Cell International, Inc., a global stem cell company based in Oldsmar, FL, and Saneron CCEL Therapeutics, Inc. a Tampa-based biotechnology company. The research team is supported by a $100,000 grant from the Florida-based Technology Transfer/ Commercialization Partnership Grant through the James and Esther King Biomedical Research Program, and a Florida Hi-Tech Corridor Industry Seed Matching Grant from USF Connect for another $52,000.

“Recent laboratory studies using animal models have shown transplanted menstrual blood-derived stem cells produced therapeutic effects following stroke,” said Dr. Cesar Borlongan, co-principal investigator and a USF neuroscientist. “We will be testing the possibility that these cells promote the growth of blood vessels and neurons that can aid in brain repair following stroke.”

In previous animals studies using transplanted stem cells from menstrual blood, Dr. Borlongan and his research team found that the cells were safe and, unlike embryonic stem cells, did not run the risk of creating tumors. In their next stage of study under the new grant, the researchers will transplant menstrual blood-derived stem cells (alone as well as conditioned and treated in a variety of ways) to determine the molecular and cellular components involved in repairing damage following stroke induced chemically in laboratory mice.

“Our long-term goal is to advance the clinical application of self-donor (autologous) cell therapy for stroke,” said Dr. Borlongan, who serves as a consultant to Saneron-CCEL.

Menstrual blood is a novel and plentiful source of stem cells with great potential for differentiation into a variety of cell types, according to the researchers.

“Menstrual blood offers an adult stem cell alternative that circumvents the ethical and logistical limitations of embryonic stem cells and their retrieval offers greater ease, and with a wider window of opportunity for harvest than other adult stem cells,” concluded Dr. Borlongan.

“This project is a natural extension of ongoing collaborative research efforts between Saneron, USF, and Cryo-Cell over the last 10 years. The menstrual blood-derived stem cells provide a renewable source of adult stem cells that is easily obtainable,” said Nicole Kuzmin-Nichols, co-principal investigator and Saneron president and chief operating officer. “This study was designed as a proof of concept study, that when combined with other ongoing studies may lay the foundation for a future clinical trial using these cells as a potential therapy for stroke patients.”

“Menstrual blood-derived stem cells have already demonstrated significant promise in preclinical studies to treat a variety of conditions,” said Dr. Julie Allickson, Cryo-Cell’s vice president of laboratory operations and research and development. “We look forward to gaining further insights from this exciting research investigation that may possibly lead to future potential therapeutic applications for the treatment of stroke.”

Source:
Randolph Fillmore
University of South Florida (USF Health)

DiscoveryBioMed, Inc. (DBM) announced that it has been awarded a $750,000 Small Business Innovations Research (SBIR) Phase 2 grant by the National Institutes of Health (NIH) to continue the research into the discovery and development of small molecules to alleviate multiple chronic human diseases including cystic fibrosis (CF), hypertension and chronic kidney diseases with hypertension.

“We are proud to have been awarded this grant and to have our technology again recognized and validated by the NIH,” said Dr. Erik Schwiebert, Chief Executive Officer of DiscoveryBioMed. “With our academic partners at the University of Alabama at Birmingham and at Johns Hopkins University School of Medicine, we stand ready to test lead compounds for safety and efficacy in both CF and hypertensive animal models.”

DBM has adapted a known electrical bioassay method to be high-throughput screening friendly, a necessary solution to bring the bioassay to the molecular target endogenous to the apical cell membrane of polarized renal and respiratory epithelia. The molecular target in play for this drug discovery program is an epithelial ion channel that is the rate-limiting step for the handling of salt in the distal portions of the kidney and in the respiratory tract. When over-active, this sodium channel can cause dehydration of the airways and too much salt in the blood, leading to high blood pressure.

“To successfully study this ion channel target, we had to bring the bioassay to the target where it is most comfortable, the apical membrane of a polarized epithelium simulated in in vitro 3D culture,” continued Dr. Schwiebert. “Researchers refer to this target as ‘twitchy’ since it does not behave the same in other experimental systems. It also depends upon factors produced by the epithelium itself to maintain proper activity. DBM brought the assay to the target and remains true to the principle that the target should be endogenous to a human or mammalian epithelial cell system to empower the most biologically-relevant drug discovery program. We believe screening on life-like human cell platforms is essential in development of drugs that ultimately will be provided to human patients.”

Additionally, DiscoveryBioMed has a pair of closely related lead compounds in hand that it will use as a medicinal chemistry platform. Additional hit-to-lead compounds are emerging. At the end of Phase 2, DBM anticipates having pre-clinical animal data and, possibly, proof-of-concept efficacy data in animals and in humans to show to potential out-license partners.

Source
DiscoveryBioMed, Inc.

American HHS Secretary Tommy G Thompson today announced a new Medicare demonstration program that will save seniors and persons with disabilities substantial money — up to 90 percent in some cases — on the life-enhancing medicines they take for serious diseases, including cancer, multiple sclerosis and rheumatoid arthritis.

The demonstration program, created as part of the Medicare Modernization Act, will extend Medicare coverage to prescription medicines that can be self-administered rather than administered by a health care provider. The demonstration will help up to 50,000 beneficiaries with serious illnesses who do not have comprehensive prescription drug coverage today.

“This demonstration will provide access and affordability to life-saving medicines for people fighting serious diseases,” Secretary Thompson said. “Through this coverage, seniors will save thousands of dollars on essential medicines that they can take at home. It will relieve some of the burden of battling a debilitating disease.”

The initiative, known as the Medicare Replacement Drug Demonstration, was mandated under Section 641 of the Medicare Prescription Drug, Improvement, and Modernization Act of 2003 (MMA). As set by Congress, enrollment in the demonstration will be open to 50,000 people and total spending on the covered drugs will be up to $500 million.

Under this initiative, Medicare will pay for certain drugs and biologicals that can be taken by the patient at home and that replace drugs which are currently covered under Medicare Part B when given in a doctor’s office. In addition, newer, more effective medications that replace some currently covered oral anti-cancer drugs will also be covered.

“Covering drugs that you can administer yourself improves access to high-quality care,” said Mark B. McClellan, M.D., Ph.D., administrator of the Centers for Medicare & Medicaid Services (CMS). “In some cases, by avoiding the need for doctor visits and intravenous injections, costs and medical complications may be reduced and access and ease of treatment will increase. And many beneficiaries will get literally tens of thousands of dollars worth of help in purchasing these critical medicines right away, ahead of the Medicare drug benefit in 2006.”

Drugs for treatment of such diseases as rheumatoid arthritis, multiple sclerosis, pulmonary hypertension and a variety of cancers will be included in the demonstration. The drugs were selected based on criteria developed after extensive input from physicians and other experts. The drugs and the diseases that are covered are listed below.

Beneficiary cost sharing for these drugs will mirror the “standard” Medicare Part D prescription drug benefit when it is implemented in 2006 (participants will not pay the monthly premium in the demonstration, however). Beneficiaries with limited resources and incomes of less than 150 percent of the federal poverty level (FPL) will have even lower cost sharing requirements.

The demonstration will give Medicare beneficiaries a glimpse of the significant savings coming their way when the Part D prescription drug benefit is fully implemented in 2006.

Examples of estimated savings over a year include:

– Patients with Chronic Myelogenous Lymphoma (a cancer) using Gleevec could save nearly 90 percent or $40,654 annually. Gleevec has an estimated annual cost of $45,952, but patients in the demo would only pay $5,298.

– Patients with Multiple sclerosis could save 75 percent or $12,260 annually off medicines that cost an estimated $16,298 annually. They would pay only $4,038.

– Patients with rheumatoid arthritis could save 75 percent or $11,975 annually off medicines that cost an estimated $16,000. They would pay only $4,025.

– And patients with pulmonary hypertension using Tracleer could save 86 percent or $31,255 off of a cost that otherwise could reach $36,136. They would pay only $4,881.

Low-income beneficiaries in the demonstration would save significantly more. Using the above examples, for those between 135 and 150 percent of the FPL estimated savings would be: for Gleevec they would pay $638, for MS and rheumatoid arthritis patients they would pay $628, and for someone taking Tracleer their annual cost would be $638. For those between 100 and 135 percent of the FPL, they would pay at most $60 per year for any of the drugs covered in the demonstration program, and seniors below 100 percent of FPL could pay less.

“Seniors are going to save substantial money on their prescription medicines thanks to the new drug benefit under Medicare, and this demonstration will give them a sense of the savings that are on the way,” Secretary Thompson said. “For seniors currently without drug coverage, this new benefit will help strengthen their health and their pocketbook. It provides substantial savings on the out-of-pocket costs they currently pay for medicines.”

As directed by Congress in creation of the demonstration, approximately 40 percent of the funding will be allocated for oral anti-cancer medications. If more beneficiaries apply than Medicare is able to serve, CMS will select participants among the cancer and non-cancer groups randomly from the applications received, on an alternating basis between the two groups.

To be eligible for the demonstration, a beneficiary must be enrolled in Medicare Part A and Part B, Medicare must be their primary payer, and the beneficiary may not have comprehensive drug coverage through other sources (such as TriCare, Medicaid, or an employer or union sponsored plan). A beneficiary must also have a signed certification from a doctor that he or she requires one of the drugs covered under the demonstration for the indicated disease.

“We intend to work with our state and local partners, and with patient organizations and others, to help beneficiaries with these serious diseases find out about how to take advantage of this program — and about the additional help now available to assist with drug costs,” Dr. McClellan said.

CMS is conducting an Open Door Forum on June 29 with patient advocacy groups, physician specialty groups, physicians and drug manufacturers so they can help beneficiaries in applying for the program.

To enroll in the demonstration program, beneficiaries should complete an application, get their physician to complete the required form certifying their need for the covered drug, and submit both forms to CMS’ demonstration contractor, TrailBlazer Health Enterprises.

Participants in the demonstration will be able to get their drugs at a local retail pharmacy or by home delivery through Caremark, Trailblazer’s subcontractor for administering the drug benefit.

The demonstration will run through Dec. 31, 2005, at which time all beneficiaries will be able to enroll in the new Medicare Part D drug benefit.

Starting immediately, applications may be downloaded from the CMS Web site at cms.hhs/researchers/demos/drugcoveragedemo.asp. Starting July 6, customer service representatives will be available at 1-866-563-5386, TTY Number: 1-866-536-5387 to answer questions about the demonstration and assist beneficiaries in obtaining and completing the application forms. Between now and July 6, beneficiaries who have questions can call 1-800 MEDICARE. Applications will be accepted for consideration beginning July 6 through Sept. 30.

Those beneficiaries who are able to get their applications in by Aug. 16 will be in an “early selection” process that will give them coverage by Sept. 1.

Applications will be accepted through Sept.30, at which time another selection process will be held. As long as the application is received by Sept.30, all applicants will have an equal chance to get into the demonstration. If enrollment slots are still available, applications will continue to be accepted after that date.

MEDICARE REPLACEMENT DRUG DEMONSTRATION – ANNUAL BENEFICIARY COSTS

Contact: CMS Public Affairs
(202) 690-6145

View drug information on Gleevec; Tracleer.

Catastrophic injuries are a sad reality of war and our brave men and women of the military are aware of these risks and still elect to carry out their duties in defending our country. The US Government allocates billions of dollars in outfitting our soldiers with the latest in protective gear and life saving equipment. Ironically, some of this gear may be contributing to the debilitating injuries many soldiers are suffering. Due to this increase, Dr. Richard A Kaul of New Jersey Spine and Rehabilitation, in tandem with US Army One Source, has begun Project Backbone. This is an initiative that will provide no cost back and spine care for veterans of the conflicts in Iraq and Afghanistan.

Thankfully, due to the increased safety protocols, the fatality rate in these conflicts have been significantly decreased from those of prior wars. Unfortunately, the injury to fatality ratio is at an all time high, 16:1 (rates were 2:1 in Korea and Vietnam) and the majority of these injuries have been musculoskeletal and spinal injuries. According to a Military study, 56% of all fractures suffered during combat were spine related. These injuries were results of gunshot trauma, blast trauma and injuries incurred throughout deployment. Furthermore, according to a study at Johns Hopkins University, one third of all medical evacuations were due to these types of injuries and were the leading cause for discharge before enlistment was completed. In addition, only 1% of those who suffered these injuries returned to active duty.

Back and spine conditions may begin as early as the training phase of an enlistee’s service. The arduous and grueling training process has been well documented and soldiers are put through amazing amounts of physical and mental stresses to adequately prepare them for deployment. One of the most common and also useful practices is runs, walks and hikes over miles of terrain, sometimes up to 25 miles. This increases stamina and endurance which is essential for the soldier. However, this is all done while carrying from 97 lbs to 127 lbs of gear on their backs. All of this gear is necessary and most soldiers would not survive without it. However, An Army Science Board study from 2001 noted that the weight soldiers carry could decrease mobility and increase fatigue and injury. The report recommended the soldiers carry no more than 50 lbs for any length of time. Yet, these soldiers are carrying twice that for up to 25 miles. Doctors have found that over time the increased weight on the spine can lead to spondylolisthesis, herniated discs and sciatica. This study also led to the introduction of what is known as backpack palsy. A condition caused by carrying the increased amounts of weight causing compressing of the nerves in the arms and shoulders leading to nerve damage, chronic pain and RSD due to impinged nerves.

The Armed Forces also face a much greater risk of injury during battle especially from gunshots, bomb blasts or IED’s (Improvised Explosive Devices). This was especially apparent during our occupation of Afghanistan when roadside bombs became an epidemic and were causing a high rate of fatalities. The US Military responded by unveiling the MRAP. These vehicles were made to be capable of driving over explosives without sustaining any damage to either the vehicle or soldiers inside. However, months later the Afghan insurgents began to build much more powerful IED’s in an effort to thwart these vehicles. Still, the vehicles withstood this increased power of these explosions. However, the sheer force of these explosions were lifting these 15 ton vehicles off the ground. The result was passengers suddenly being thrust upward and their heads to strike the steel inner roof of the vehicle and then quickly slamming back into the seat. This caused both cervical and lumbar spinal compressions and due to the speed at which both compressions occurred in succession, several instantaneous spinal injuries occurred and 14 soldiers were completely paralyzed from these attacks.

Spinal injuries have not been solely limited to our forces on the ground. A similar military study linked those in the Air Force to be at a very high risk of degenerative spinal conditions as well. A study examined 109 former military parachutists. 46 of these parachutists had a radiological examination of the lumbar spine, the results were:

– 21.7% had vertebral body fractures

– 84.7% had lumbar disc degeneration of varying grades

– 10.8 % degenerations were considered “severe”

This seems to be a realistic concern considering the speed the body is traveling when landing a parachute jump. Even with the canopy fully open and all conditions properly factored the jumper can be hitting the ground at over 20mph. This force is absorbed by the lower extremities, which in turn is absorbed by the spine. This impact often causes the disc degeneration and vertebral fracture that were cited in the study.

Sadly, it does not seem that the US Governments Medical Guidelines have kept in step with advances in medicine, especially those regarding back, neck and spine care. According to the Department of Defense’s Clinical Practice Guideline, there is no protocol past conservative modalities (chiropractic care, physical therapy and pain reduction through the use of pharmacological drugs). These modalities offer nothing in the way of curing the condition and may often worsen the condition due to improper diagnosis and care. Also, this has led to a startling rate of opiate addiction. One government study found as high as 14% of returning veterans had an addiction to opiates. If a veteran elects to have a surgical intervention, most VA Hospitals are still employing the traditional approach to spine surgery. These surgeries include a very large incision, dissection of muscles, bones and nerves, prolonged hospital stays, months of recovery time and an astounding rate of post-operative infection. The US Government has not kept its policies up to date with the latest advancement is medical technology, especially in the area of spine and more specifically Minimally Invasive Spinal Treatments.

These astounding facts have prompted Dr. Richard A Kaul to begin Project Backbone in an effort to see that these veterans can receive the most complete and accurate care possible. Dr Kaul is a pioneer in Minimally Invasive Spine Procedures as well as Interventional Pain Management. “I have had veterans come to see me before and the main hurdle seemed to be their insurance carriers not acknowledging the need for further treatment beyond conservative care.”

Through this initiative veterans will receive no cost consultations and no out of pocket expenses for surgical or pain management treatments. “These brave men and women put their lives on the line on a daily basis. The least we can do to show our gratitude is ensure that they have access to the most effective care possible”, says Dr. Richard A Kaul .

“They have spent months or even years away from their families. The last thing we would want to do is have them lose more time with ineffective treatments and unnecessary hospital stays. Their goal is to spend as much time with their families as they can. We share that goal.”

Source:

New Jersey Spine and Rehabilitation

The Los Angeles Times on Friday examined the weekly serialized radio drama “Body Love,” which depicts black characters “wrestl[ing] with a slew of health problems while trying to navigate prickly relationships and cope with financial strains.” The 15-minute episodes focus on two extended families who “make progress through modest lifestyle changes.” The soap opera-style show features characters who “give in to cravings for burgers, … resist taking insulin, … quit smoking, then backslide; lose weight, then regain it,” the Times reports. After the shows, local hosts take calls from listeners and discuss practical steps for improving their health.

University of Alabama public health professor Connie Kohler created the show, and students and faculty at the university write the episodes. The project launched in 2003 with funding from a three-year, $250,000 grant from the Robert Wood Johnson Foundation. The first 80 episodes ran between 2003 and 2007 on about six radio stations in Atlanta, Jackson, Miss., and across Alabama. The show also recently launched in Port St. Lucie, Fla., and organizers are negotiating a deal in Tacoma, Wash. Funding also comes from local entities, such as the Alabama Eye Bank, procured through fundraising efforts. Most of the stations that air BodyLove are small, locally owned stations that do not subscribe to listeners’ tracking services, but station managers report that the show has a strong audience base.

According to the Times, using “soap opera as a vehicle for social change has been around for decades.” China, Kenya, Mexico, Pakistan and other nations have used the concept to address issues such as HIV/AIDS, adult literacy and sexual assault. Pauline Seitz, who directs a matching grant program under RWJF, said, “This is a model that’s been so successful in other countries, I wonder why we aren’t seeing more of it here.” She added, “We all learn through stories. We’re captivated by them, moved by them, motivated by them.”

Kohler and her partners are working on new episodes of BodyLove, as well as a
new three-minute show focusing on obesity that will air on radio stations in urban areas with large black populations, such as Los Angeles, Miami and Washington, D.C. The project will be funded in part by NIH. Two other projects, including one in Spanish, will air in Iowa and focus on teen pregnancy (Simon, Los Angeles Times, 4/11).

Reprinted with kind permission from kaisernetwork. You can view the entire Kaiser Daily Health Policy Report, search the archives, or sign up for email delivery at kaisernetwork/dailyreports/healthpolicy. The Kaiser Daily Health Policy Report is published for kaisernetwork, a free service of The Henry J. Kaiser Family Foundation© 2005 Advisory Board Company and Kaiser Family Foundation. All rights reserved.

Researchers at Children’s Hospital Boston report finding a new way to increase stem cells in blood, suggesting a possible treatment to help patients who undergo chemotherapy or bone marrow transplant for leukemia and other cancers recover their immune function more quickly. In the June 21 issue of Nature, they demonstrate that a stable analog of prostaglandin can enhance the blood-forming system, both during embryonic development and after it’s been damaged.

The discovery, made possible through high-volume drug screening in zebrafish, marks the first time stem-cell production has been induced by a small-molecule drug, says the study’s senior author, Leonard Zon, MD, of the Children’s Hospital Boston Stem Cell Program and Division of Hematology/Oncology. Other studies, including one from Zon’s own lab*, have identified ways of increasing formation of blood stem cells, which give rise to each of the body’s various blood cell types. However, the methods are technically complex and haven’t lent themselves to broad medical use.

The hospital now hopes to conduct a clinical trial of the drug, a long-active derivative of prostaglandin E2 known as dmPGE2. This compound was originally tested more than 20 years ago for patients with gastritis, but was never marketed as a drug.

Currently, patients undergoing bone marrow transplant must wait for marrow from a matched donor to replenish their stem cells and reproduce the full array of blood cell types, including all the cells of the immune system. When there’s no suitable donor for a marrow match, patients can receive umbilical cord blood, which also contains blood stem cells. But the number of stem cells in one cord of blood is often not adequate for older children and adults, leaving them with diminished immune function and high risk for infections.

Zon and colleagues Trista North, PhD, and Wolfram Goessling, MD, PhD, both also of Children’s Stem Cell Program, zeroed in on dmPGE2 by screening more than 2,500 chemicals in zebrafish. Knowing that two genes, runx1 and cmyb, are required for blood stem cells to develop in vertebrate embryos, they looked for compounds that altered the expression (activation) of these genes. North spent six months placing 15,000+ tiny embryos in wells, each containing a different chemical five embryos to a well, 48 wells to a plate then checking each embryo 24 hours later to monitor its development and count its blood stem cells.

The screen identified 82 chemicals that markedly increased or decreased gene activity. Of these, 10 turned out to affect the prostaglandin pathway: five increased the formation of blood stem cells, and five decreased it. “We weren’t specifically looking for prostaglandins,” says Zon, a Howard Hughes Medical Institute investigator who is also a member of the Harvard Stem Cell Institute. “This was a surprise finding.”

A variety of experiments confirmed that prostaglandins, particularly dmPGE2, promote blood stem cell formation, while chemicals that block prostaglandin synthesis (such as aspirin or ibuprofen), suppress blood stem cell formation. Finally, in zebrafish whose marrow was depleted by irradiation, those given dmPGE2 recovered blood cell populations more quickly.

Prostaglandins are known to be released by the body when inflammation is present such as after an injury – and may be among the compounds that aid recovery. “So it makes some sense that prostaglandins would have the ability to enhance regrowth of cells,” Zon says.

“The zebrafish is ideal for investigating blood formation,” says North. “It reproduces quickly and in large number and has a blood-forming system that shares many similarities with that of mammals.” Zebrafish embryos develop outside the mother’s body and can take up chemicals through their skin, making it easy to test the developmental effects of large numbers of compounds very rapidly, while their transparent skin makes it possible to visualize the blood stem cells in live fish.

The researchers also confirmed their observations in mammalian models. When dmPGE2 was added to mouse embryonic stem cells in the lab, production of blood stem cells increased. In mice that underwent bone marrow transplant, treatment with dmPGE2 led to enhanced blood-stem-cell formation, and the stem cells remained present in the marrow more than six months after transplantation, indicating long-term engraftment. “The fact that we confirmed the zebrafish discovery in a mammalian system suggests it may also be applicable in humans,” says Goessling.

The clinical trial, projected to begin in 2008 at Children’s Hospital Boston in conjunction with the Dana-Farber/Harvard Cancer Center, will recruit patients undergoing cord blood transplant for leukemia. Patients will receive cord blood to replenish their blood systems, some of it treated with dmPGE2 to enhance blood-stem-cell formation. “Having more stem cells should help the blood system to regrow faster and minimize complications, such as infections,” says North.

The research was funded by the National Institutes of Health and the American Cancer Society.

Children’s Hospital Boston
21 Autumn St., 2nd Fl.
Boston, MA 02115
United States
childrenshospital

The economic value of family caregiving in the U.S. reached $375 billion in
2007, according to a new report by AARP’s Public Policy Institute. The report, which updates
a groundbreaking study by AARP last year, finds that the value of family caregiving was $375
billion, 7 percent higher than the estimated value of $350 billion in 2006.

The estimated value exceeds the $311 billion spent nationally in 2007 for Medicaid. The
value of family caregiving also exceeds Medicaid’s long-term care spending in every state.
The new estimate reflects an increase in the U.S. population, the aging of the population,
and a higher estimate of the average value for one hour of care.

The report, “Valuing the Invaluable, The Economic Value of Family Caregiving, 2008 Update,”
estimates that 34 million Americans provide more than 20 hours of care per week to another
adult, making informal caregiving a cornerstone of U.S. health and long-term care.

“Family caregivers are a vital and largely unrecognized part of America’s health and long-
term care system,” said AARP Policy Director John Rother, noting that family caregiving has
been shown to reduce hospital readmissions and delay entry into nursing homes. “We often
overlook how much family and friends contribute-whether it’s picking up groceries each week
or providing daily health care for their loved ones.”

The AARP report notes that informal caregivers of people 50-plus spend an average of $5,531
out-of-pocket in 2007 to care for their loved ones. That spending is often coupled with lost
workdays, wages, health insurance and retirement savings. More than one-third of informal
caregivers are forced to quit their jobs or reduce their working hours, with women more likely
to leave the labor force entirely. Caregivers also frequently struggle with health care bills
and medical debt-and experience chronic stress. Even less noticed is the physical, financial
and emotional toll caregiving can take, Rother added.

The AARP report makes several recommendations to assist caregivers, including adopting “family
friendly” workplace policies; assessing caregivers’ needs and providing them with needed supports;
expanding funding for the National Family Caregiver Support Program and the Lifespan Respite Care
Act; and supporting family caregivers in chronic care coordination programs and care transitions.

Rother concluded: “Family caregivers are likely to be stretched even further in today’s tumultuous
economy. Now is the time to ensure caregivers have the support they need. Everyone – business,
government and individuals – can do more to give back to those who give so much.”

The full report, “Valuing the Invaluable: The Economic Value of Family Caregiving 2008 Update,” is
available here.

AARP is a nonprofit, nonpartisan membership organization that helps people 50+ have independence,
choice and control in ways that are beneficial and affordable to them and society as a whole. AARP
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UroToday – In the September 22, 2009 issue of the Proceedings of the National Academy of Sciences, Dr. Robert Schlaberg and colleagues verify that the DNA and protein from the xenotropic murine leukemia virus-related virus (XMRV) exists in prostate cancer (CaP) tissue.

The initial report in 2006 linked the gammaretrovirus XMRV in CaP patients with reduced activity against the RNASEL gene. A strong correlation between the R462Q variant and XMRV was present; XMRV 89% of XMRV positive cases and only 16% of XMRV negative cases were homozygous (QQ) for this variant. While only CaP specimens were evaluated in the initial report, the present study also assessed benign prostate tissue.

The investigators developed a molecular clone of XMRV, called pXMRV1 and demonstrated that it could replicate in LNCaP cells. The particles released from XMRV-infected cells showed morphology consistent with type-C retroviral cores. To determine the presence of XMRV in clinical samples, 233 CaP and 101 benign prostate samples were studied. Quantitative PCR amplified XMRV proviral DNA from tissue. XMRV DNA was detected in 14 cases (6.2%) of CaP and in 2 cases (2.0%) of benign cases. Calculations determined that each 10-Ојm section from a CaP sample contained the same amount of proviral DNA as 6-7 XMRV-infected cultured cells. Immunohistochemistry using XMRV-specific antisera was performed on prostate samples from XMRV PCR positive cases and in cell cultures to validate the assay. In the CaP cases, 54 (23%) had XMRV protein expression compared with 4 (4%) of controls. XMRV protein was in the epithelial cells in 46 tumors (85%), in both epithelial and stromal cells in 4 tumors (7.5%), and only in stromal cells in another 4 tumors (4%). XMRV positivity was 5-fold higher in CaP than in benign controls, and was positive in 18% of Gleason score 6 tumors, 27% of Gleason score 7 tumors, 29% of Gleason score 8 tumors, and 29% of Gleason score 9 tumors. There were no significant differences between cases and controls regarding the RNASEL R462Q variant. This means the at risk population for XMRV infection increases from only men with the RNASEL variant to all men.

Schlaberg R, Choe DJ, Brown KR, Thaker HM, Singh IR

Proc Natl Acad Sci U S A. 2009 Sep 22;106(38):16351-6.
doi:10.1073/pnas.0906922106

UroToday
Contributing Editor Christopher P. Evans, MD, FACS

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