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September 25, 2003

Research Notes

Grants awarded to researchers
Kevin Crowley of the Learning Research and Development Center has a received a $408,903 grant from the National Science Foundation for research on conceptualizing and assessing World Wide Web-based informal science learning.

The National Institute on Aging has granted $299,378 to Robert Gibbs of pharmacy to study cholinergic lesions in the brain and age-related cognitive impairment.

The chemistry department’s Scott Nelson has been awarded $400,564 by the American Cancer Society for a project, “Synthesis and Evaluation of Small Molecule Microtubule Stabilizing Agents.” Interruption of microtubule dynamics has proven to be an effective target for cancer chemotherapy. The National Science Foundation has granted $628,217 to the education school’s Margaret Smith for a project, “ESP Enhanced Secondary Mathematics Teacher Preparation” to address challenges facing mathematics teacher education.

Thomas Smithgall of the School of Medicine has received a $360,000 American Cancer Society grant for his research project, “BCR Putative Effector of Cytoplasmic Tyrosine Kinases.” Work in Smithgall’s laboratory focuses on molecular mechanisms that control cancer cell growth.

The National Institute on Deafness and Other Communication Disorders has granted $325,822 to Katherine Verdolini-Marston of the School of Health and Rehabilitation Sciences to study “Biophysiological Mechanisms of Heightened Speech and its Efficacy.” The project will examine the biomechanics of “loud” or “heightened” speech and how workers (such as teachers) who need to speak loudly for long periods of time can be trained to do so without hurting their voices.

Diana Wood of the University Center for International Studies has received a $375,000 grant from the Freeman Foundation to fund ongoing seminars for secondary school teachers who teach about East Asia.

IV formula changes can reverse some problems in those in need of intestine transplants Intravenous feedings may do well to provide patients with small bowel failure their required daily nutrition, but its long-term use can cause their liver to fail and Parkinson’s-like neurological symptoms, particularly in those patients who do develop liver problems.

While the components of total parenteral nutrition (TPN) that contribute to liver failure remain a mystery, the tiniest amount of manganese typically added to TPN is responsible for the same kind of toxic effects on patients with liver failure as have been seen in miners with prolonged exposure to ore, in whom manganese poisoning was first described.

Removing manganese from TPN formulas can reverse these neurological deficits, Karen Laughlin of the Thomas E. Thomas E. Starzl Transplantation Institute reported at the VIII International Small Bowel Transplant Symposium this month.

“Every patient being evaluated for intestinal transplantation should have routine tests to determine the level of manganese in their blood. We have found it essential to perform these profiles and we adjust the TPN accordingly,” said Laughlin, assistant professor in the Pitt pharmacy school’s Department of Pharmacy and Therapeutics, and clinical pharmacist with the Starzl Transplantation Institute’s Center for Intestinal Rehabilitation and Transplantation.

“High manganese levels present a bigger problem than one would think,” she added.

Of 59 TPN-dependent patients who were evaluated for intestine, liver/intestine or multivisceral transplantation at Pitt, 46 patients (78 percent) had elevated levels of manganese.

Most of these patients — 34 of the 46 — had significant complications involving their liver. In contrast, only two of 13 patients with normal manganese levels had any liver problems, which also were milder in comparison.

Manganese is an essential trace element necessary for good nutrition and contained in unrefined cereals and green leafy vegetables. As such, it is a staple ingredient in most TPN formulas.

“I would surmise that most pharmacists and providers of TPN are not aware of the possible development of manganese toxicity in patients with short gut syndrome who require long-term TPN therapy,” Laughlin said.

Symptoms of manganese poisoning include delayed thinking, difficulty concentrating, tremors and rigid or stiff movements of the arms and legs.
About 25 percent of adult patients and 45 percent of pediatric patients on long-term TPN develop liver failure. Most often, the TPN will cause blockages within the bile duct system of the liver which, as a result, make it difficult for manganese and other toxins to be adequately excreted. With successful intestinal transplantation and resumption of normal function of the intestine, the risk of manganese toxicity and other associated TPN problems are reversed or totally eliminated.

Experience with intestine transplants discussed
An approach pioneered by the University of Pittsburgh Medical Center’s Thomas E. Starzl Transplantation Institute has resulted in less rejection, infection and lowered immunosuppression in its recent patients compared to those transplanted five and 10 years ago. The center’s trend toward higher patient survival rates is continuing, according to clinical results presented by a member of the Pittsburgh team at the VIII International Small Bowel Transplant Symposium this month.

Since May 1990, 240 patients have received 259 transplants involving the small intestine at Pitt, representing the largest clinical experience of any center in the world, reported Geoffrey Bond, assistant professor of surgery at the Starzl Transplantation Institute and Pitt’s School of Medicine.

While overall, the one-year patient survival for the entire experience is 80 percent, one-year survival for patients transplanted within the last five years improved to 90 percent, compared to 72 percent in both 1990 and 1995.

The overall five-year patient survival is 60 percent and 10-year patient survival is 39 percent. An adult and child who were transplanted more than 13 years ago at the University are the world’s longest surviving recipients of a liver-intestine transplant.

“The improvements we have seen in survival rates are clearly related to changes we’ve made with respect to immunosuppression,” Bond said. “As we have better come to understand the rejection process and the unique characteristics of the small intestine, we have been able to make important refinements to therapy. This evolution of care has had a real impact on our patients, and the entire field has benefited as well.”

While in 1990 the availability of the drug tacrolimus made successful transplants of the intestine feasible for the first time, infection and rejection problems still plagued the field. Over the years, additional advancements have been made and improved survival rates have been achieved. One approach that has had an impact on results at Pitt is its unique clinical protocol that involves far fewer drugs and much lower doses of immunosuppressive agents than conventional therapies.

“We’re seeing less infection and fewer adverse side effects and complications that are usually associated with high doses of anti-rejection drugs,” said Bond.

The approach has many of the patients transplanted in the last year or so taking a single anti-rejection drug as few as one to three times a week.

In 1990, the rate of opportunistic infection was between 45 and 55 percent. Now infection occurs in about 9 percent of cases. Rates of rejection also have improved. In 1990, the rate was 88 percent. Today it is 40 percent, a remarkable improvement for an organ that is particularly prone to immune system attack.

Of the 259 transplants performed at Pitt, 102 (44 percent) were of the small intestine alone, performed in 74 adults and 41 children. While combined liver and intestine transplants accounted for 36 percent of the transplants, more were performed in children — 67 compared to 27 in adults.

Multivisceral transplants, which include the small intestine, liver, stomach, pancreas and duodenum, were performed in 25 adults and 12 children, and modified multivisceral transplants without the liver were performed in nine adults and four children.

“The shortage of organs remains a limiting factor to successful intestine transplantation, particularly for very young children, for whom size-matched organs are in short supply. To overcome this problem, we have been utilizing larger donors and subsequently reducing the graft size prior to transplantation,” said Bond.

In a separate presentation, the Pittsburgh team reported the use of a combination of techniques they have developed that have allowed organs from larger donors to be used.

Sixteen children underwent transplants of the intestine alone or in combination with the liver using organs donated by larger individuals that were reduced in size to fit the recipients. The novel surgical approaches have permitted proper healing of the abdominal wall and all patients remain alive, well and free from total parenteral nutrition (TPN).

Patients with intestinal failure require intravenous nutrition with TPN, which can cause life-threatening complications such as liver failure and line infections. As such, intestinal transplantation is considered a life-saving procedure that also can have a profound effect on quality of life. More than 80 percent of the patients transplanted at Pitt no longer require TPN and are able to return to a completely normal diet.

Intestinal transplants are not experimental. Since April 2001, Medicare has approved transplants of the small intestine.

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