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November 24, 2004

Research Notes

Patients who get breathing tube prior to hospital arrival fare worse

Emergency medicine researchers at the University have found that patients with similar traumatic brain injuries who receive an emergency breathing tube at the scene of an accident fare worse than those intubated after arriving at the hospital.

The researchers also found that these patients’ neurologic and functional outcome was nearly twice as bad. These findings are reported in the November issue of Annals of Emergency Medicine.

Endotracheal intubation is an emergency medical procedure whereby trained medical personnel place a flexible, clear, plastic breathing tube down into the trachea to help air pass freely to and from the lungs. Often patients with traumatic brain injury need help to breathe to prevent further injury.

While out-of-hospital intubation is a valuable interventional tool in helping to save patients’ lives, earlier studies had suggested that this rapid intervention might be more harmful than helpful.

The Pitt researchers conducted a retrospective analysis using data obtained from the Pennsylvania Trauma Outcome Study between 2000 and 2002 and studied adult patients with severe head injuries.

The primary outcome for most of these patients was death, with secondary outcomes being various types of neurologic and functional impairment. Among the 4,098 patients who were intubated, odds of death were about four times greater if they were intubated out of the hospital. Neurologic and overall functional impairment also was greater.

“These findings present important challenges to the emergency medicine profession and EMS communities,” stated Donald M. Yealy, professor and vice chairman of the Department of Emergency Medicine at the School of Medicine and one of the study authors. “Paramedics, while very well trained, don’t often have opportunity to perform this procedure, and must attempt it in a difficult environment and without many of the aids available in the hospital. Perhaps these findings indicate that we need to reassess how we manage these cases,” he added.

Collaborating with Yealy were lead author Henry Wang, Andrew B. Peitzman, P. David Adelson and Laura D. Cassidy, all from Pitt.


Researchers receive grants for breast cancer research

The Department of Defense (DOD) breast cancer research program has announced that Pitt researchers will receive more than $1 million in grants for breast cancer research.

The awards, given to only 14 percent of grant applicants, will allow Pitt researchers to initiate six original projects on breast cancer prevention, detection and treatment.

Pitt projects funded by the DOD grants include:

• “Differential MDR Activity in Breast Cancer Stem Cells,”  Albert Donnenberg, University of Pittsburgh Cancer Institute;

• “Design, Synthesis and Biological Evaluation of Focused Combinatorial Libraries of Antiestrogens,” Jelena M. Janjic, graduate student, School of Pharmacy;

• “Statistical Modeling on Life Expectancy of Breast Cancer Patients,” Jong-Hyeon Jeong, Department of Biostatistics, Graduate School of Public Health;

• “Genetic Analysis of DNA Repair Deficiency in Novel Non-Tumor Adjacent and Tumor Cell Lines Suggests a New Paradigm of Breast Cancer Etiology,” Jean J. Latimer, Magee-Womens Research Institute;

• “Identification of Stem Cells in a Novel Human Mammary Epithelial Culture HMEC System That Reproducibly Demonstrates Ductal Organotypic Architecture in 3 Weeks,” Jean J. Latimer, Magee-Womens Research Institute, and

• “An Organotypic Liver System for Tumor Progression,” Alan Wells, Department of Pathology, School of Medicine.

The DOD breast cancer research program was established in 1992 to provide funds for novel concepts in breast cancer research.


Laparoscopic gastric bypass effective for recurrent GERD

Laparoscopic gastric bypass surgery can effectively control gastroesophageal reflux disease (GERD) symptoms in morbidly obese patients who had previous antireflux surgery, with the additional benefit of weight loss and improvement of co-morbidities, according to a study published in the November issue of the journal Obesity Surgery.

The School of Medicine study found that gastric bypass is feasible and effective in controlling GERD in patients who had previous antireflux surgery and who have subsequently gained significant weight, and in obese patients who have had previous antireflux procedures and continued to have problems with GERD.

“Despite a morbidity rate of 42.8 percent, this study showed that all patients did well with zero mortality and were satisfied with their condition during the follow-up period, suggesting that the long-term outcome of laparoscopic gastric bypass in obese patients who had previous antireflux surgery is promising,” said Ioannis Raftopoulos, assistant professor of surgery in the Division of Thoracic and Foregut Surgery at the School of Medicine, and principal author of the study. “There also was a significant improvement of GERD symptoms following the laparoscopic gastric bypass, which was maintained during follow-up.”

In addition, 70 percent of associated co-morbid medical conditions were either resolved or improved significantly.

“Although a direct cause-effect relationship between obesity and GERD has not been clearly established, obesity is often associated with GERD. Up to 55 percent of morbidly obese patients presenting for laparoscopic Roux-en-Y gastric bypass have symptoms of chronic GERD,” said James D. Luketich, professor of surgery, chief of the Division of Thoracic and Foregut Surgery, co-director of the Mark Ravitch/Leon C. Hirsch Center for Minimally Invasive Surgery and senior author of the study.

GERD is a significant public health problem affecting up to 40 percent of the American adult population.

Laparoscopic gastric bypass after antireflux surgery is a technically more difficult procedure, which is reflected in the prolonged operative time (mean 372 min.) and length of hospital stay (mean 4.8 days).

“It is important to emphasize that success rates for first time redo antireflux surgery, which would be the alternative to laparoscopic gastric bypass, range between 60 percent and 80 percent and fall to 50 percent for second time redo antireflux surgery,” Raftopoulos said.

“This degree of weight loss is equal to that experienced by patients who undergo gastric bypass surgery primarily for obesity, and is enough to impact dramatic improvements in obesity-related co-morbid medical conditions.” said Anita P. Courcoulas, assistant professor of surgery, and director of bariatric surgery at UPMC Shadyside and a co-author of the study.


Natural alternatives to NSAIDs relieve disc, arthritic pain

Omega-3 fatty acids for neck and low-back pain from disc and arthritic causes may be an alternative to non-steroidal anti-inflammatory drugs (NSAIDs), according to a study presented at a recent annual meeting of the American College of Nutrition Symposium on Advances in Clinical Nutrition.

Joseph C. Maroon, professor and vice chairman of the Department of Neurological Surgery in the School of Medicine and a member of the American College of Nutrition, presented the prospective study called “Natural Alternatives to Non-steroidal Anti-inflammatories.”

Annually, more than 100,000 people in the United States are hospitalized and nearly 20,000 patients die of complications related to the use of NSAIDs for the treatment of pain and inflammation. Recently, Vioxx, one of the most widely used NSAIDs, was pulled from the U.S. market due to heart complications.

Maroon and colleague Jeffrey Bost, physician assistant, surveyed 120 patients they had placed on omega-3 essential fatty acids (EFA), found in fish oil, for treatment of their neck and low back pain, which resulted from disc disease and arthritis. Of those patients, 59 percent experienced decreased joint pain and 68 percent were able to discontinue NSAIDs including Vioxx, Motrin, Celebrex  and Bextra. The study also found that most patients had no side effects and that 86 percent planned to continue the use of omega-3 EFAs.

Discogenic disease is one of the greatest causes of pain and disability in the United States, affecting approximately 1 out of 4 people at some time in their lives. Many studies have shown a marked inflammatory reaction at the site of the herniated lumbar discs, according to Maroon.

“It is important for patients to understand that less toxic alternatives to anti-inflammatories are available,” he said.

“Previous studies have shown that omega-3 EFAs prevent blood clots, reduce pain, enhance the immune system and cause dilation of the blood vessels. In fact, as of September of this year, the FDA now recognizes that omega-3 EFAs can prevent coronary artery disease. Two clinical trials also have shown that arthritis patients who take fish oils could eliminate or sharply reduce their use of NSAIDs.”


Tiny exosomes may be ‘magic bullet’ for drug-free organ transplants

Bubble-like nanoscale particles that are shed by dendritic cells may hold the key to achieving transplant tolerance — the long-term acceptance of transplanted organs without the need for drugs, according to a study by Pitt researchers published in the Nov. 15 issue of the journal Blood. The results provide some of the first information about what these structures called exosomes actually do.

Exosomes are no larger than 65-100 nanometers — 1,000 times smaller than the diameter of a human hair — yet each contains a potent reserve of major histocompatibility complex (MHC) molecules. MHC molecules are gene products that cells use to determine self from nonself. Millions of exosomes scurry about within the bloodstream, and while their function has been somewhat of a mystery, researchers are beginning to surmise that they play an important role in immune regulation and response.

Adrian Morelli of the Thomas E. Starzl Transplantation Institute became intrigued by the tiny exosomes while researching ways to harness dendritic cells, specialized white blood cells that present antigens to other immune system cells, as a means to donor-specific immune tolerance.

Considered the “Holy Grail” of transplantation, tolerance means a recipient’s immune system fully accepts a donor graft without immunosuppressive drugs and without compromising its ability to respond appropriately to infections.

Because certain dendritic cells have tolerance-enhancing qualities, several approaches under study involve giving recipients donor dendritic cells that have been modified in some way. The idea is that the modified donor cells would convince recipient cells that a transplanted organ from the same donor is not foreign.

“What may be a more effective approach is to make use of these tiny, MHC-rich vesicles that we can siphon from donor dendritic cells and that we have found are captured by recipient dendritic cells and processed in a manner important for cell-surface recognition,” explained Morelli, assistant professor of surgery at the School of Medicine. “What this means is that we can efficiently deliver donor antigen using the exosomes as our magic bullet. Further research will determine if we can actually influence transplant tolerance.”

The function and mechanisms for dendritic cell-derived exosomes had never before been elucidated, so Morelli and colleagues sought to do so by following the fate of exosomes that they extracted from dendritic cells of one mouse strain and injected into the bloodstream of mice of a different strain.

The exosomes were labeled with a dye, and methods such as flow cytometry, confocal microscopy and immuno-electron microscopy helped the researchers track their every movement and activity within the mouse.

Very quickly and efficiently, the donor exosomes were captured by one of three recipient immune system cell types: antigen-presenting dendritic cells and macrophages, both originating in the spleen, and Kupffer cells of the liver.

Of particular interest to the researchers were those exosomes that were caught by the dendritic cells of the spleen, the site where dendritic cells typically present antigens as bounty to T cells that do their part to destroy the foreign invaders. Yet, what the researchers discovered was that these dendritic cells internalized the exosomes instead of displaying them to T cells, this despite the exosomes’ rich endowment of donor MHC molecules.

Once internalized, the exosomes were ushered inside larger vesicles, special endosomes called MHC-II enriched compartments, where they were processed with the dendritic cell’s own MHC molecules.

This hybrid MHC-II molecule, now loaded with a peptide of donor MHC, was then expressed on the cell’s surface. As one family of MHC molecules, MHC-II serves as a beacon for a specific population of T cells called CD4+ T cells. Such cells are activated during chronic rejection in a process associated with the indirect pathway of immune recognition.

“This finding is significant because current immunosuppression therapies used in the clinical setting are not able to efficiently prevent T cell activation via the indirect pathway. Perhaps the CD4+ T cells normally involved in this pathway would retreat from attack if they encountered a cell surface marker that is of both donor and recipient origin, such as that which we observed following the dendritic cell’s internalization of the donor-derived exosomes,” said Morelli.

Also significant, the researchers report, is that the process of internalizing the donor exosomes does not affect maturation of the dendritic cell. Only immature dendritic cells can capture antigens efficiently and are believed to participate in the induction of transplant tolerance. By contrast, once mature, dendritic cells are capable of triggering the T cell activation that leads to transplant rejection.

Additional research will be required to determine whether donor-derived exosomes will enhance the likelihood that an organ transplant from the same donor will be accepted. Under a recently awarded National Institutes of Health grant, Morelli plans to address this question with studies involving mice that receive heart transplants following infusion with exosomes from the same donor.

In addition, animal studies conducted at Pitt by Paul Robbins, professor of molecular genetics and biochemistry, provide evidence that exosomes can reverse arthritis. Morelli and Robbins plan to collaborate on future research.

“This is an exciting new area of investigation, which appears to hold great promise in the area of transplant tolerance,” commented senior author Angus W. Thomson, professor of surgery and immunology at the Starzl Transplantation Institute and the School of Medicine.

“So much more remains to be understood, but this current study, whereby we have offered the first details about the mechanism of dendritic cell-derived exosomes, is a significant start.”

According to the Pitt authors, few research groups are engaged in active study of exosomes with most of the research taking place in Europe.

In addition to Morelli and Thomson, other authors of the study published in Blood include Adriana T. Larregina, William J. Shufesky, Mara G. Sullivan, Donna Beer Stolz, Glenn D. Papworth, Alan F. Zahorchak, Alison J. Logar, Zhiliang Wang, Simon C. Watkins and Louis D. Falo Jr.


Student finds new genus, species of  amphibian

While on a geology class trip, a Pitt undergraduate student came across a previously unknown genus and species of a 300-million-year-old amphibian.

Adam Striegel, a Pitt senior liberal studies major, found a fossilized skull of an ancient meat-eating amphibian with a vicious set of teeth.

The fossil is only the third 300-million-year-old amphibian skull ever found in the world, according to David Berman, curator of vertebrate paleontology at Pittsburgh’s Carnegie Museum of Natural History.

Charles Jones, lecturer and undergraduate adviser in the Department of Geology and Planetary Science, last March led his class on a field trip to a newly cut road near the Pittsburgh International Airport.  During the outing, Striegel picked up a grapefruit-sized rock on which he thought he saw the imprint of a fern and showed it to Jones.

Jones immediately knew that what Striegel had thought were fern fronds was actually a double row of jagged teeth — and the rock was actually a skull. “I knew at that moment that this would be the nicest vertebrate fossil that I would probably ever touch,” said Jones.

Striegel  will donate the fossil to the museum. After the museum’s scientists finish preparing it and publish their findings, either the genus or the species will likely be named “Striegeli.”

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