February 26, 1999
Volume XXXII No. 8

Pain researcher Hargreaves
receives NIH's MERIT Award

Studies in tooth pulp target mechanisms of pain,
may shed light on opportunities for therapeutic intervention

Dr. Hargreaves

Dr. Kenneth Hargreaves, a ground-breaking pain researcher who is professor and chair of the Department of Endodontics, received the prestigious MERIT Award this month from the National Institutes of Health (NIH). He joins a select group of Health Science Center researchers who hold active MERIT Awards or were MERIT designees in the past.

MERIT stands for "Method to Extend Research In Time." This designation enables the researcher to continue his work without competitive renewal at the start of his next award period. Dr. Hargreaves' award extends support for his "Sympathetic Fiber Modulation of Neurogenic Inflammation" program of research without renewal through at least 2009.

Dr. Hargreaves studies the pain process in tooth pulp models. The pulp is the soft innermost part of the tooth. It is made up of blood vessels and nerves and nourishes the tooth. Though it is well protected by the enamel and the dentin, the nerve may become irritated or infected by decay, trauma or a crack in the tooth.

Endodontics is a dental discipline that includes study of therapy of inflamed or infected tooth pulp. The most commonly known therapy is the root canal treatment. When dentists perform root canal treatment, they are removing the infected pulp, cleaning and disinfecting the space where the pulp was removed, and filling the space.

Dr. Hargreaves has studied tooth pulp injury as a pain model for nine years. His goal is to shed light on pain-producing and pain-relieving mechanisms throughout the body. Among his contributions, he developed the "gold standard" test for measuring thermal hyperalgesia in animals--a method that has been used extensively in pain studies nationwide. The Science Citation Index indicates that in 1997, this method was cited in a new publication every 5.8 days. Statistics completed for part of 1998 show an increase in citations to every 4.5 days.

Dr. Hargreaves' studies have received more than $3.5 million in federal support and more than $670,000 in non-federal research funding since 1991. Currently he holds two major federal grants--a five-year, $947,804 award from the National Institute on Drug Abuse (NIDA) and a five-year, $847,481 award from the National Institute of Dental and Craniofacial Research (NIDCR, known as the NIDR until recently). The latter is the project receiving MERIT status.

Dr. Hargreaves' NIDCR project involves studying tooth pulp for interaction between two classes of neurons. His laboratory is examining signals sent between sympathetic nerves and "pain fibers." The sympathetic nerves are part of the sympathetic nervous system--the portion of the body's nerve network that controls the "fight or flight" response in animals, resulting in higher blood pressure, increased heart rate and slowed digestion.

"We're trying to better understand how the body senses it has an injury," Dr. Hargreaves said. "We also want to know why, after some forms of injury, patients tend to develop long term or chronic pain that in many cases is poorly treatable. Regulation of pain fibers by sympathetic nerves could contain the answers."

Dr. Hargreaves' team also is studying how nerves change function after injury. "In cases of chronic pain, it's been shown that certain genes are turned on or off, that new proteins are expressed in nerve fibers, and that new synaptic connections grow in the brain or its periphery," he said. "We are interested in 'molecular remodeling,' which involves changing the altered neurosensory state to its original or normal state."

Dr. Hargreaves' NIDA grant, meanwhile, enables his lab to study the pain-relieving effects of cannabinoids, a group of substances produced in the brain. Dr. Hargreaves was the first to publish analgesic findings on the peripheral CB1 receptor, a site of pain-relieving action for the cannabinoid group. He also was the first to report that diminished activity of the body's endogenous cannabinoids may be a cause of chronic pain.

"This is an example of a potential way to interrupt the pain process, not only in the brain but in peripheral tissues such as tooth pulp, joints and muscle," Dr. Hargreaves said.

The NIDA is interested in the findings in part because they may help explain why some individuals report pain relief after using marijuana, which is extracted from the namesake "cannabis" plant and holds many of the same pain-dulling properties as cannabinoids.

Dr. Hargreaves has published 60 original papers, 26 reviews or chapters, and 145 abstracts. He serves as associate editor for the Journal of Pharmacology and Experimental Therapeutics, and the Journal of Orofacial Pain, and on three other editorial boards.

The last Health Science Center MERIT winner was Dr. Arun Roy, cellular and structural biology, in 1997. He holds two MERIT designations, an extreme rarity in federal scientific funding.

Health Science Center specializes
in pain research

Dr. Kenneth Hargreaves has studied pain in tooth models since the early 1980s at the National Institutes of Health (NIH) and at the University of Minnesota. Recruited to the Dental School as endodontics chair in 1997, one of the factors that most attracted him was the "cross-fertilization" potential of pain management and research projects throughout the Health Science Center's schools.

"Pain research is certainly a common denominator across our schools," he said. "This is one of the themes being developed at a grass-roots level and we are close to achieving a critical mass of researchers bringing considerable expertise to bear on this complex subject."

All NIH institutes fund research of pain because it cuts across all disciplines, Dr. Hargreaves said. "A number of complementary, multidisciplinary ways to examine pain questions are being used. The Health Science Center's continuing opportunity is to leverage faculty members' multidisciplinary expertise onto an important and fundamental question in health care."

Opportunities are plentiful, he said, for pain research collaboration among dentists, neurologists, nurse anesthetists, anesthesiologists, rheumatologists, basic scientists, molecular medicine faculty, psychiatrists and health economists.

Snake venom derivative benefits
stroke patients, national trial finds

Dr. Solomon Dr. Sherman

A new drug derived from the venom of the Malay pit viper provides substantial benefit to stroke patients, especially when administered within three hours of the attack.

That's the finding of a nationwide clinical trial that included the Health Science Center. Dr. David Sherman from the Department of Medicine, Division of Neurology at the Health Science Center, announced the findings to a national audience Feb. 4 in Nashville, Tenn.

The multicenter, 500-patient study of ViprinexTM, also known as ancrod, was sponsored by the drug's developer, Knoll Pharmaceuticals. The company selected Dr. Sherman to present the results on behalf of all the investigators and centers in the study. Dr. Diane Solomon, medicine/neurology, was the principal investigator for the Health Science Center's clinical site.

In the Stroke Treatment with Ancrod Trial (STAT), 500 patients with acute, ischemic strokes were randomized to receive either ancrod or a placebo beginning within three hours of stroke onset. The mean age of patients enrolled in the study was 73. Acute, ischemic strokes are those that cut off blood supply to the brain either permanently or for a few minutes. The duration and severity of the blockage determine the severity of symptoms.

"We found that patients receiving ancrod were more likely to have a good outcome than patients who did not get ancrod," Dr. Sherman said. "More stroke patients in the ancrod group were able to regain a state of independence. Improvement usually was evident within a few days, and continued through the final 90-day study limit."

The large, 500-patient study built on a previous study of 132 stroke patients treated within six hours of acute, ischemic stroke. That study found that 50 percent of ancrod patients were essentially unimpaired at 90 days after their strokes, compared with 34 percent of placebo patients. After that preliminary trial, coordinators decided to administer ancrod to patients in the next trial sooner after the stroke onset.

Ancrod works by down-regulating "fibrinogen"--the substance in the blood that is converted into clots. "This drug lowers fibrinogen levels, reducing the blood's capacity to form new clots and improving its ability to flow through the small arteries," Dr. Sherman said.

Dental research finding treatments
for temporomandibular joint pain

Dr. Solomon For 15 years, a San Antonio woman who suffers severe pain because of arthritis has been unable to eat regular food. She can neither chew nor even open her mouth without enduring agonizing pain.

While the rest of us take eating for granted, she has had to subsist on whatever she can put in a blender. Arthritis or an injury to the face can cause pain in the temporomandibular joint (the TMJ connects the upper and lower jaws).

This destructive disease often strikes in the late teens and early 20s. Of the 50,000 Texans who suffer from it each year, approximately 90 percent are women. TMJ deterioration can lead to physical deformity and debilitating pain, making gainful employment impossible. Diet becomes restricted, leading to weight loss.

Gustavo Zardeneta, Ph.D., interim director of research in the Department of Oral & Maxillofacial Surgery, and his colleagues are working on developing treatments that can be used in the disease's early stages to prevent its devastating effects.

To find treatments, the research team is studying the composition of outflow (secretions from the affected joint) in patients who suffer from TMJ pain. Stephen B. Milam, D.D.S., Ph.D., interim chairman of the Department of Oral & Maxillofacial Surgery, and John P. Schmitz, D.D.S., Ph.D., assistant professor, perform surgery to irrigate the joint and relieve the pain. The outflow from this surgery is then taken to the laboratory for extensive research.

"We are studying the substance that comes out of the patients' TMJs to determine what is causing the deterioration. If we learn what causes the problem, then we can decide what can be used to fight it," said Dr. Zardeneta, assistant professor. "Soon, we hope to be able to inject novel biochemicals into the TMJ to reverse the deterioration process and alleviate the pain. In addition, we are working to create TMJ disks for those whose joints are severely deteriorated."

Paper's advisory board visits

Burkett, Salazar, Fernandez
E-N Advisory Board
San Antonio Express-News staff members Lynnell Burkett, editorial page editor (left, top photo), and Veronica Salazar, vice president for community relations (center), share a laugh with Dr. Sylvia Fernandez, director of the Health Science Center's Office of Special Programs. Dr. Fernandez serves on the Express-News' 1999 Community Advisory Board, which met Feb. 11 in the Briscoe Library's History of Medicine Room. In the bottom photo, Express-News staff members (left to right) Terry Scott Bertling, assistant managing editor, features; Robert Rivard, editor and senior vice president; Dr. Fernandez; and Craig Thomason, metro editor, visit before the meeting. The Community Advisory Board brings together individuals who have distinguished themselves in their respective fields, who share a history of public service and who hold a strong commitment to the community. Members include a pastor, a university professor, a high school history teacher, a staff member of the San Antonio Housing Authority and an employee of Kelly Air Force Base. The board's feedback and suggestions help strengthen the newspaper's commitment to fairness, balance and accuracy in its reporting. The feedback also helps the Express-News remain accessible to diverse publics in San Antonio. "Everyone has his or her perspective on what the newspaper should or should not print," Dr. Fernandez said. "The board members represent diverse groups to ensure that their views are made known." Advisory board meetings are held monthly at locations around the city.

Oak Hills Lions Club honoree

honoree Steve Kustelski, president of the Oak Hills Lions Club, awards the club's 1999 occupational therapy (OT) scholarship to Emilie Kahlich of the Health Science Center. Kahlich, a senior OT student who is interested in working with pediatric patients, was selected for her academic achievement and for her entry in the OT department's scholarship essay competition. Her paper, titled "The Importance of Children's Independence in Daily Activities," discussed ways to help young patients overcome developmental dysfunction. Several Oak Hills Lions Club officers and members, President John P. Howe, III, Dean Marilyn Harrington of the School of Allied Health Sciences, and OT faculty and students were on hand for the scholarship presentation. The Lions Club generously raised the scholarship to the $1,000 level this year.

Mac Users to focus on operating systems

The Health Science Center's Macintosh Computer Users Group will meet at noon Wednesday, March 3, in library room 2C. The topic is "Emulation on the Macintosh," a method of using certain hardware or software programs for running Windows OS and Windows operating systems on a Mac.

Andrew McIntosh and Ron Gerling from Apple Computer will demonstrate how Macintosh computers can run a variety of programs. Mac Users Group meetings are open to all interested individuals.

San Antonio native changing lives one tiny face at a time

Genesis Dr. Garza and Genesis
While little Genesis Martinez' first years of life have been anything but easy, Jaime R. Garza, M.D., D.D.S., and his colleagues are giving the toddler the opportunity to enjoy a happy childhood free of hateful taunts and hurtful stares.

Three-year-old Genesis was born with a cleft lip and palate. The cause of this common birth defect is unknown; it occurs once in every 700 births. Between the sixth and 11th week of development in the womb, parts of the lip and/or palate in these infants did not come together properly.

In San Antonio and the South Texas/Border Region, children like Genesis receive comprehensive treatment from birth through early adulthood from a team of medical experts at the Health Science Center. Patients are seen annually or more frequently if necessary by the team, and on an as-needed basis by individual team members.

The Cleft Palate/Craniofacial Unit, a section of the Division of Plastic and Reconstructive Surgery at the Health Science Center, is led by Joel E. Pessa, M.D., assistant professor. The team consists of plastic surgeons, a pediatric hand surgeon, orthodontists, prosthodontists, pediatric dentists, otolaryngologists, speech pathologists, audiologists, geneticists and a social worker.

For Genesis, her treatment began at age 3 months when Dr. Garza, head of the Division of Plastic and Reconstructive Surgery, performed surgery to correct the cleft lip. When she was about 11 months old, she underwent surgery to have the cleft palate repaired.

"We will now wait to see how her speech develops. She will undergo intensive speech therapy. If she still has difficulty speaking, Genesis will need to have surgery on the back of her throat. This helps to partially seal the space between the nasal cavity and the oral cavity so air doesn't escape through her nose during speech," he said.

When Genesis is about 15 years old, she will have the final surgery, rhinoplasty on her nose. However, if a child experiences psychological problems because of teasing before that age, the nose surgery may be done earlier, Dr. Garza explained.

"The real trauma to these children occurs in early childhood through adolescence. They endure ridicule from their peers," he said. "Everything we do with these patients is aimed at getting them through their early school years looking as normal as possible.

"We are interested in their mental development as much as their physical development. We try to intervene as early as possible before irreparable mental damage is done," Dr. Garza added. "Our team strives to give these children what they deserve--a healthy childhood and the self-confidence needed to be happy throughout life."


Making the Rounds


Secrets of long life explored

Dr. Franceschi Dr. Claudio Franceschi (right), professor of immunology at the University of Bologna, visits with Dr. Walter Ward, Department of Physiology, after the Italian researcher's Feb. 1 lecture at the Health Science Center. Dr. Franceschi, who spoke on the "Immunology and Genetics of Human Longevity: The Model of Centenarians," discussed potential hypotheses for why a few people live to be 100 or more. Possible explanations, he said, include well-preserved immune systems inherited from long-lived ancestors, and genetic factors associated with longevity. Of Italy's 57 million people, about 5,000 are centenarians, he said. One-third of them are relatively healthy, showing no major age-related diseases such as cancer, dementia or cardiovascular disease. Women are far more likely than men to reach 100, he said. Dr. Franceschi spoke at the Department of Physiology Seminar.

Next American Cancer Society grant deadline is April 1

Researchers, make a note: April 1 and Oct. 15 are the deadlines for 1999 American Cancer Society (ACS) grants.

Instructions, policies and computer-interactive application forms for Research Project Grants, Postdoctoral Fellowships and Clinical Research Training Grants for Junior Faculty are available on the World Wide Web. Researchers may contact Liz Buel, Office of Grants Management, ext. 2330, to get a paper copy of the forms.

Proposals must focus on poor or underserved populations, but may address a variety of behavioral, epidemiological, policy, health delivery, clinical and basic science issues.

Interdisciplinary collaborations are encouraged, according to ACS guidelines. The novelty and uniqueness of the proposed projects will be an important aspect in the evaluation process.

In general, grants awarded will be for three years and up to $250,000 per year, including 25 percent indirect costs, according to the guidelines. Grant applications for behavioral or epidemiological studies that could require more than three years and a higher budget will be considered and must be well documented and justified.

An estimated five Research Project Grants or Clinical Research Training Grants--and three Postdoctoral Fellowships--can be awarded each funding cycle.


nursing students

Finnish exchange students Mikko Matilainen (left in photo inset) and Sami Räsänen review community assessment materials--the same activity occupying Portuguese exchange students Humberto Domingues (left in larger photo) and Amancio Carvalho. The four nursing students, assisted by Dr. Adrianne Linton, associate professor in the Department of Chronic Nursing Care (pictured), are participating in a program that promotes international understanding with a focus on community health nursing.

Dr. Linton is the Health Science Center's site coordinator for the program, supported by a grant from the Fund for the Improvement of Postsecondary Education through the U.S. Department of Education.

Dr. Linton and Lois Cole, instructor in the Department of Chronic Nursing Care, are coordinating the student exchange, which began in January and continues through the first week of April. The Health Science Center is one of eight participating universities in this country and in Europe. The principal investigator is Dr. Mary Duffy, University of Utah School of Nursing.

"The word 'exchange' really does apply well here, because I'm hoping the students will take away understanding of us and our health care system, its strengths and its deficiencies, and share with us some of the ways their systems differ from ours," Dr. Linton said.

Two students from the Health Science Center, Misty Gabel and Todd Siebert, currently are studying in Finland, and a third, Wren Wetzel, was on a planning committee that met in Portugal.

Index of issues

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