Click for Philadelphia, Pennsylvania Forecast




Neural Stem Cells Improve Motor Function in Brain Injuries  

Neural stem cells, transplanted into injured brains, survive, proliferate, and improve brain function in laboratory models according to research based at the School of Medicine. The findings, published in the October edition of the journal Neurosurgery, suggest that stem cells could provide the first clinical therapy to treat traumatic brain injuries. Traumatic brain injuries occur in two million Americans each year and are the leading cause of long-term neurological disability in children and young adults.

"Transplantation of neural stem cells in mice three days after brain injury promotes the improvement of specific components of motor function," said Dr. Tracy K. McIntosh, professor of neurosurgery, Director of Penn's Head Injury Center, and senior author of the study. "More importantly, these stem cells respond to signals and create replacement cells: both neurons, which transmit nerve signals, and glial cells, which serve many essential supportive roles in the nervous system."

If stem cells are blank slates, able to become any type of body cells, then neural stem cells (NSCs) are slates with the basics of neurology already written on them, waiting for signals in the nervous system to fill in the blanks. The NSCs used by Dr. McIntosh and his colleagues were cloned from mouse progenitor cells and grown in culture. The advantage of NSCs exists in their ability to easily incorporate themselves into their new environment in ways other types of transplants could not.

In humans, traumatic brain injury is associated with disabilities affecting mobility, motor function and coordination. Following NSC transplantation in mice, the researchers used simple tests to determine motor skills. They found that mice with transplanted NSCs recovered much of their physical ability. The transplanted NSCs, however, seemed to have little effect in aiding recovery of lost cognitive abilities.

"The ultimate goal, of course, is to translate what we have learned into a therapy for humans," said Dr. McIntosh. Neural transplantation has been suggested to be potentially useful as a therapeutic intervention in several central nervous system diseases including Parkinson's disease, Huntington's disease, ischemic brain injury, and spinal cord injury. While Dr. McIntosh is impressed with the results of NSC transplants in mice, similar trials for humans are not expected in the near future.

The lead author on this study is Dr. Peter Reiss, a visiting fellow from the University of Cologne working in Dr. McIntosh's laboratory. Much of the work was performed in collaboration with the laboratory of Dr. Evan Y. Snyder, Harvard Medical School.

Other contributing researchers from the department of neurosurgery at Penn include, Dr. Chen Zhang, Dr. Kathryn E. Saatman, Dr. Helmut L. Laurer, Dr. Luca G. Longhi, Dr. Ramesh Raghupathi, Dr. Philipp Lenzlinger, Dr. Jonathan Lifshitz, Dr. John Boockvar, Dr. Grant Sinson, and Dr. M. Sean Grady. Other contributing researchers include Dr. Edmund Neugebauer, University of Cologne, Germany and Dr. Yang D. Teng, Harvard Medical School.

back to top

More Patients Die in Hospitals with Lower Nurse Staffing

In the first study of its kind, Penn researchers have determined that patients who have common surgeries in hospitals with the worst nurse staffing levels have up to a 31% increased chance of dying. More nurses at the bedside could save thousands of patient lives each year, as reported last week in The Journal of the American Medical Association (JAMA).

Penn researchers found that every additional patient in an average hospital nurse's workload increased the risk of death in surgical patients by 7%. Patients with life-threatening complications were also less likely to be rescued in hospitals where nurses' patient loads were heavier. The findings impact the national legislative agenda.

"Nurses report greater job dissatisfaction and emotional exhaustion when they're responsible for more patients than they can safely care for. Failure to retain nurses contributes to avoidable patient deaths," said Dr. Linda Aiken, director of the Center for Health Outcomes and Policy Research at the School of Nursing. "Patients facing planned hospitalization should inquire about nurse-to-patient ratios and choose their hospitals accordingly." Hospital nurse staffing levels vary widely, usually from four patients per nurse on most unit types to up to ten or more.

Specifically, the Penn nursing researchers found that:

• If all hospitals in the nation staffed at eight patients per nurse rather than four, the risk of hospital deaths would increase by 31 percent, roughly translating to as many as 20,000 avoidable deaths in the U.S. annually. Some 4 million surgeries like the ones studied are performed each year.

• Having too few nurses may actually cost more because of the high costs of replacing burnt-out nurses and higher costs of caring for patients with poor outcomes.

• Adding two patients to a nurse already caring for four, increases the risk of death by 14 percent, adding four increases the risk by 31 percent.

• "It is clear that nurses are saving lives," said Dr. Aiken. "Nurses are the front line of surveillance and early detection of potentially life-threatening problems."

The report, "Hospital Nurse Staffing and Patient Mortality, Nurse Burnout, and Job Dissatisfaction," concluded in the October 23/30 issue of JAMA: "when taken together, the impacts of staffing on patient and nurse outcomes suggest that by investing in registered nurse staffing, hospitals may avert both preventable mortality and…problems with low nurse retention in hospital practice."

The study, funded by the National Institute of Nursing Research of the National Institutes of Health, examined data collected from 168 hospitals, 232,342 surgical patients, and 10,184 nurses in Pennsylvania from 1998 to 1999. The researchers examined data on relatively common general surgeries (e.g. gall bladder), orthopedic surgeries (e.g. knee or hip replacement), and vascular surgeries, excluding cardiac surgery such as coronary bypass. Some routine but emergency surgeries were included, such as appendectomies.

back to top

Gene that Regulates Development of Heart Cells Identified

Scientists at the School of Medicine have identified and described a small gene that regulates the delicate balance involved in the healthy growth and replication of heart muscle cells.

"This finding is likely to be important for our understanding of the causes of congenital heart disease. It is also relevant to our attempts to regrow damaged heart muscle," said the corresponding author of the study, Dr. Jonathan A. Epstein, of the departments of medicine and cell & developmental biology. The study appeared in the September 20 issue of the journal Cell.

The newly identified heart gene, Hop (an acronym for homeodomain only protein), is a small protein that lacks certain residues required for DNA binding, but is activated early in fetal development and continues modulating the expression of cardiac-specific genes throughout life. Hop appears to bind directly to another important regulator of development, serum response factor (SRF), and block SRF from binding to DNA. By inhibiting the expression of SRF, Hop protects cardiac muscle cells from over-development, and from developing fatal abnormalities.

"There has been a lot of effort to try to determine how SRF is regulated in different tissues," Dr. Epstein said. "Now we see that Hop plays a vital part."

The study was funded by the National Institutes of Health, the American Heart Association, and the W.W. Smith Foundation.

Others who participated in the research are:  Dr. Fabian Chen, Dr. Hyun Kook, Dr. Rita Milewski, Dr. Aaron D. Gitler, Dr. Min Min Lu, Dr. Jun Li, Dr. Ronniel Nazarian, Dr. Robert Schnepp, Dr. Kuangyu Jen, Dr. Greg Runke, and Dr. Mary C. Mullins, all of Penn; Dr. Christine Biben, Dr. Joel P. Mackay, Dr. Jiri Novotny, all of the Victor Chang Cardiac Research Institute, Carlinghurst, Australia;  Dr. Robert Schwartz, of Baylor College of Medicine, Houston, TX, and Dr Richard P. Harvey, of the Chang Institute and the University of New South Wales, Australia.

back to top

Foxd3 Gene Allows Stem Cells to Remain Stem Cells

In the search to understand the nature of stem cells, researchers at the the School of Medicine have identified a regulatory gene that is crucial in maintaining a stem cell's ability to self-renew. According to their findings, the Foxd3 gene is a required factor for pluripotency--the ability of stem cells to turn into different types of tissue--in the mammalian embryo. Their research was presented in the October 15 issue of the journal Genes and Development.

"Stem cells represent a unique tissue type with great potential for disease therapy, but if we are to use stem cells then we ought to know the basis of their abilities," said Dr. Patricia Labosky, assistant professor in the department of cell and developmental biology. "Among the stem cell regulatory genes, it appears that Foxd3 gene expression keeps stem cells from quickly differentiating--that is, developing into different types of tissue--holding back the process so that an embryo will have enough stem cells to continue developing normally." 

"Our findings implicate Foxd3 as one of the few genes serving as a ‘master switch' of the developing embryo," said Dr. Labosky. "These genes determine the fate of cells by turning on or off other genes in response to signals in the embryo." Foxd3 joins previously identified genes, such as Oct4, Fgf4, and Sox2, which control the pluripotency of embryonic stem cells in the early stages of embryogenesis. In their experiments, Dr. Labosky and her colleagues found that these genes are still expressed despite the lack of Foxd3. This suggests Foxd3 functions either downstream of Oct4, Fgf4 and Sox2, or along a parallel pathway.

The researchers determined that normal embryonic development can be restored by adding non-mutant embryonic stem cells to the Foxd3-mutant embryos, indicating that Foxd3 acts in the inner cell mass and its derivatives. According to Dr. Labosky, Foxd3 is a key regulator of mammalian stem cells, with a clear counterpart in humans. Foxd3 gene expression is a diagnostic characteristic of human embryonic stem cells, suggesting that the gene may function in a similar fashion in mouse and human cells.


  Almanac, Vol. 49, No. 10, October 29, 2002