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September 1, 2005


Researchers focus on mercury emissions from coal-fired power plants

Pennsylvania’s total mercury emissions are the second highest in the United States. Controlling those emissions is the goal of Pitt research funded by the U.S. Department of Energy to study the reactions of mercury and associated trace metals in coal-fired power plants.

Under a three-year, $400,000 grant, environmental engineering professor Radisav Vidic and his colleagues will study chemical reactions and transformation of mercury in flue gases of coal-fired power plants. They will then develop and validate a mathematical model to predict mercury emissions.

“If we can understand fundamentals of the catalytic reactions that are promoted by solid surfaces present in coal combustion systems, we will be able to describe key phenomena responsible for the fate of mercury in coal-combustion systems,” said Vidic. “Subsequently, we can develop more effective and efficient technologies for controlling mercury emissions from coal-fired power plants.”


Treatment shows promise for clinical vascular applications

Imagine a chemical compound — similar to one used to restore flow in the Alaskan oil pipeline — that could dramatically increase blood flow to the heart. Pitt researchers are working on such a concept by using a purified form of a polyethylene oxide-derived drag reducing polymer (DRP) to see if the same theory can be applied to the human vascular system.

John J. Pacella, a sixth-year fellow at the Cardiovascular Institute, received the Young Investigator Award for his entry titled, “Drag Reduction Polymer Infusion: A Novel Approach for the Treatment of Coronary Artery Disease,” at the recent meeting of the American Society of Echocardiography.

Pacella’s research focuses on the use of this particular DRP in combination with echocardiography technology to treat and diagnose microvascular disease. The researchers hope that this translational research may some day be used successfully to treat patients with unstable coronary artery disease to help return adequate blood flow to the heart.

Coronary artery disease is a condition in which there is narrowing of the coronary arteries causing a decreased blood supply to the heart. According to the Department of Health and Human Services, coronary artery disease also is one of the leading causes of mortality in the United State, accounting for more than 1 million deaths per year.

“The study findings are significant because when we injected these DRPs into animal models with compromised blood flow reserve, we found that blood flow had dramatically increased within the capillaries,” said Pacella.

“Additionally, we found that it didn’t take very much DRP to restore adequate blood flow; as little as two parts per million of DRP in the subjects,” added Flordaliza Villanueva, associate professor of medicine and director of noninvasive research at the Cardiovascular Institute and Pacella’s mentor.

Blood flow reserve refers to the ability of the heart to augment blood flow during stress such as exercise. In normal patients, this event occurs seamlessly. However, in patients with coronary artery disease, this event becomes difficult for the heart to manage during times of stress, which could be as simple as going up a flight of stairs.

Echocardiography is a noninvasive cardiac imaging procedure that enables physicians to diagnose heart disease and valve disorders as well as gain new insight into coronary physiology.

In the current study, the researchers looked at two groups of animals and discovered that DRPs restored blood flow to the heart muscle despite the presence of severe coronary blockage.

Collaborating with Pacella and Villanueva was Marina Kameneva, research associate professor of surgery and bioengineering.

The research was supported by a post-doctoral research fellowship award from the Pennsylvania-Delaware affiliate of the American Heart Association.


Role reversal discovered for viral protein associated with lymphoma development

A protein previously thought to merely hinder the activity of a key cellular protein linked to cancer cell death now appears to mimic the cellular signaling of that protein, potentially leading to the development of lymphoma. The findings, published in the Aug. 22 on-line edition of Proceedings of the National Academy of Sciences, demonstrate that a viral protein associated with human herpesvirus 8, or HHV8, may help to cause lymphoma by activating a key pathway involved in the production of lymphocytes, a common cell type found in lymphoid tissue that divide over and over and eventually develop into lymphoma.

The protein, called vFLIP K13, had been thought to protect virally infected cells from attack from the body’s own immune system by inhibiting the activity of a cellular protein called caspase 8 that is associated with apoptosis, or programmed cell death. However, when Preet M. Chaudhary, senior author of the study and professor of medicine at the School of Medicine, and his colleagues analyzed transgenic mice expressing vFLIP K13, they found that vFLIP K13 failed to block cell death pathways and instead mimicked a recently discovered signaling function of caspase 8, which led to the proliferation of lymphocytes.

Chaudhary and his colleagues observed tumor formation in 59 mice over the course of 30 months. They found that the vFLIP-expressing transgenic mice had more lymphomas than the control group mice: 11.8 percent compared 1.8 percent, respectively.

Further analysis also revealed that instead of inhibiting caspase 8, vFLIP K13 copied its signaling activity, resulting in the activation of a distinct cellular pathway called NF-8B that is involved in the development of lymphoma. “In effect, vFLIP K13 actively promoted the growth of cancer cells through this pathway. Based on these findings, we believe the NF-8B pathway may be a promising target for novel therapies directed against HHV8-associated tumors,” said Chaudhary. He added that there is a dire need for new therapies that target this disease since most patients with HHV8-associated lymphomas are highly immune suppressed and are difficult to treat, given the toxicity associated with conventional therapies.

HHV8, originally linked to Kaposi’s sarcoma — the most common cancer among AIDS patients — also is associated with lymphoid diseases such as primary effusion lymphoma and multicentric Castleman’s disease, a noncancerous but severe disorder characterized by enlargement of the lymph nodes. Recent studies have also linked HHV8 infection to HIV-related solid immunoblastic/plasmablastic lymphomas.

Other Pitt authors of the study were Hittu Matta and Sandra Schamus, Hillman Cancer Center, University of Pittsburgh Cancer Institute.

The study was supported by the National Institutes of Health and the Mario Lemieux Foundation.


Gene could prevent leading age-related cause of blindness

Pitt researchers have discovered a gene linked to age-related maculopathy (ARM), the leading cause of untreatable blindness in the elderly. The discovery suggests a simple test might be able to identify those at risk for what is commonly known as macular degeneration and may lead to the development of more effective preventive strategies.

Researchers report that variations of a gene called PLEKHA1 are strongly associated with a person’s risk of developing ARM. The results, a culmination of 15 years of research, will be published in the September issue of the American Journal of Human Genetics and currently are available on line.

The discovery of the gene came about through the team’s efforts to map the genes of 612 families affected by ARM and an additional 323 individuals without a history of macular degeneration. Pooling data from a number of gene mapping studies, researchers were able to identify multiple locations on the chromosomes where there are common gene variants among people with ARM. Specifically, researchers found that a region on chromosome 10 was the one most likely to contain a major gene that influences the risk of ARM. Further analysis of chromosome 10 found that a variation in PLEKHA1 to be strongly associated with a person’s risk of developing ARM.

Earlier this year, researchers from The National Eye Institute and several universities used similar methods to identify the first gene variant thought to be a major contributor to ARM, complement factor H (CFH) on chromosome 1. The Pittsburgh study confirms involvement of this gene and, for the first time, shows that the association results also accounted for findings from previous genetic studies of macular degeneration families. The new study found that having both CFH and PLEKHA1 indicate a greater risk for macular degeneration.

“CFH was the first piece of the puzzle,” said Michael Gorin, professor of ophthalmology in the School of Medicine and professor of human genetics in the Graduate School of Public Health (GSPH). “To fully understand the pathology of macular degeneration, we knew we needed to expand our investigation to find all of the genes that play a part in this condition. PLEKHA1 is an important second piece, and we’ll keep searching for the rest of the pieces until we get this solved.”

By identifying a number of genetic variants for ARM, researchers hope to develop a simple set of DNA tests to identify individuals who are at increased risk of this sight-robbing condition. Additionally, they hope to develop new preventive strategies and a better understanding of how ARM occurs.

An important clue to understanding the cause and mechanism of ARM was revealed through this discovery. PLEKHA1, like CFH, is involved in the cellular processes related to inflammation, which supports the hypothesis that damage caused by ARM is, in part, due to inflammation.

An estimated 200,000 Americans develop a severe form of macular degeneration each year, making it the leading cause of blindness in people aged 65 and older. As many as 30 percent of individuals over the age of 75 have evidence of macular degenerative changes.

In addition to Gorin, contributing authors to this study are Johanna Jakobsdottir, graduate student in biostatistics, GSPH; Tammy Mah, ophthalmology, School of Medicine; Daniel Weeks, professor of human genetics and biostatistics, GSPH; Robert Ferrell, professor of human genetics, GSPH, and Yvette Conley, assistant professor of health promotion and development, School of Nursing, and assistant professor of human genetics, GSPH.

The research was supported by the National Eye Institute of the National Institutes of Health, as well as by Research to Prevent Blindness, The Eye & Ear Foundation of Pittsburgh and the Ruth and Milton Steinbach Foundation.


Stem cell trial of heart bypass patients begins

The University of Pittsburgh Medical Center (UPMC) has been granted approval by the U.S. Food and Drug Administration (FDA) to conduct a clinical trial to determine the safety and feasibility of injecting a patient’s own bone marrow-derived stem cells directly into the heart during conventional heart bypass surgery.

The trial will involve patients with ischemic heart disease who are scheduled for off-pump (beating heart) coronary artery bypass grafting surgery. In addition to assessing the safety and feasibility of using a patient’s own stem cells as a potential therapy for heart disease, researchers also will be trying to determine just how many stem cells are needed to produce the best results.

Patients who give their consent to participate will be randomized to one of four treatment groups and neither they nor the researchers will know into which group they are assigned until the conclusion of the study. Researchers hope to enroll a total of 24 patients — six in each group — whom they will follow over the course of one year.

In May, UPMC was given clearance by the FDA to conduct a similar trial in patients needing heart assist devices as a bridge to organ transplantation. Both studies are being directed by Amit Patel, director of the Center for Cardiac Cell Therapy at UPMC and Pitt’s McGowan Institute for Regenerative Medicine. Patel also is assistant professor of surgery in the Division of Cardiothoracic Surgery, School of Medicine.

“Stem cell therapy as an adjuvant to traditional bypass surgery is the next step to help determine the best way to help very sick heart failure patients. This is the first randomized study in the U.S. to evaluate the combination of cell therapy with traditional surgical revascularization and may help answer a number of key questions,” explained Patel.

“Standard surgical and catheter-based treatments are reasonably effective for treating chest pain, reducing the risk of heart attack and improving heart function,” added Joon S. Lee, clinical director of UPMC’s Cardiovascular Institute and assistant professor of medicine and associate chief, division of cardiology, School of Medicine.

“But none has the ability to actually restore or repair damaged heart tissue. The aim of stem cell therapy is to repopulate the ailing heart muscle with cells that may help restore blood supply and help the heart regain its ability to contract more effectively and efficiently.”

According to the American Heart Association, nearly 13 million Americans have coronary artery disease. Despite medical advances, coronary heart disease results in about 500,000 deaths each year.


Study shows high number of ICU patients develop acute renal failure

In the first multinational study of acute renal failure (ARF) in ICU patients, an international group of researchers has found that a surprisingly high number of intensive care patients — one in 20 — develop a severe form of ARF, and an alarmingly high number of those patients will die in the hospital. The study was published last month in the Journal of the American Medical Association.

Researchers analyzed data from 29,269 critical care patients from 54 medical centers in 23 countries over the span of 15 months. They found that universally almost 6 percent of these patients developed ARF while in the hospital and, of those patients, 60 percent died while hospitalized.

“It’s interesting that a person in any hospital, in any country has such a high risk of having kidney failure. An estimated five million Americans will go to the ICU this year and, if this number holds true, 250,000 will go into acute renal failure. Compare this with the 100,000 Americans who will develop chronic renal failure this year and the numbers are staggering,” said John Kellum, corresponding author of the paper and professor of critical care medicine at Pitt’s School of Medicine. “And this is something we simply did not know, nor could we have predicted.”

The study was undertaken by the Beginning and Ending Supportive Therapy for the Kidney (BEST Kidney) investigators, an international group of critical care and nephrology experts, to gather baseline information on ARF.

Additionally, researchers reported that of the surviving patients, 86 percent were not dependent on dialysis after discharge. The BEST Kidney investigators say that this could be an important clue in treating ARF.

The BEST Kidney investigators include 98 researchers from 23 countries, including Ramesh Venkataraman, assistant professor of critical care medicine, who supervised the portion of the study conducted at the University of Pittsburgh Medical Center.


Gene therapy for congenital MD termed a success

Pitt researchers report the first study to achieve success with gene therapy for the treatment of congenital muscular dystrophy (CMD) in mice, demonstrating that the formidable scientific challenges that have cast doubt on gene therapy ever being feasible for children with muscular dystrophy can be overcome. Moreover, their results, published in the on-line edition of the proceedings of the National Academy of Sciences, indicate that a single treatment can have expansive reach to muscles throughout the body and significantly increase survival.

CMD is a group of some 20 inherited muscular dystrophies characterized by progressive and severe muscle wasting and weakness noticed soon after birth. No effective treatments exist and children usually die quite young.

Despite gene therapy being among the most vigorously studied approaches for muscular dystrophy, it has been beset with uniquely difficult hurdles. The genes to replace those that are defective in CMD are larger than most, so it has not been possible to apply the same methods successfully used for delivering other types of genes. And because CMD affects all muscles, an organ that accounts for 40 percent of body weight, gene therapy can only have real therapeutic benefit if it is able to reverse genetic defects in every cell of the body’s 600 muscle groups.

By using a miniature gene, similar in function to the defective one in CMD, and applying a newly developed method for “systemic” gene delivery, the Pitt researchers have shown that gene therapy for muscular dystrophy is both feasible and effective in a mouse model of especially profound disease. Using this approach, the team, led by Xiao Xiao, associate professor of orthopaedic surgery and molecular genetics and biochemistry at the School of Medicine, reports that treated mice had physiological improvements in the muscles of the heart, diaphragm, abdomen and legs. They grew faster, were physically more active and lived four times as long as untreated animals.

The most common form of CMD, and also one of the most severe, is due to a genetic mutation of laminin alpha-2, a protein that is essential for maintaining the structures that surround muscle cells and is an integral link in the chain of proteins that regulate the cell’s normal contraction and relaxation. If the protein is defective, or is lacking, this outside scaffold, called the extra-cellular matrix, disintegrates, and the muscle cells become vulnerable to damage.

Simply replacing the defective gene with a good laminin alpha-2 gene is not possible because its size makes it impossible for researchers to get it to squeeze inside viral vectors — disarmed viruses that are used to shuttle genes into cells. But the team found a good stand-in in a similar protein called agrin that when miniaturized could be inserted inside an adeno-associated virus (AAV) vector. Xiao’s laboratory is known for its work developing this vector, which they previously have shown is the most efficient means for delivering genes to muscle cells.

In the current study, the authors show that two strains of AAV, AAV-1 and AAV-2, were effective in transferring the mini-agrin gene to cells in two mouse models. The AAV-1 vector was given by systemic delivery — a single infusion into the abdominal cavity — a method the authors only recently described and which they used for the first time in this study to transfer a therapeutic gene. The AAV-2 vector was delivered locally, given by intramuscular injection to different muscles of the leg. With both approaches, muscle cells were able to assimilate and copy the genetic instructions for making mini-agrin. Once produced, the mini-agrin protein functionally took the place of the laminin alpha-2 protein by binding to the key proteins on either end, thus restoring the cell’s outside scaffolding and re-establishing the missing link to key structures inside the cell.

While the authors are excited about the results achieved in their experiments using systemic gene delivery, they say their results are far from ideal and more work lies ahead.

“It’s probably not realistic to expect that we can achieve complete success using the mini-agrin gene, which, while somewhat similar, is structurally unrelated to laminin alpha-2. Unless we address the underlying cause of congenital muscular dystrophy we’re not likely to be able to completely arrest or cure CMD,” said Chungping Qiao, the study’s first author and a research associate fellow in Xiao’s lab.

Future directions for research include finding a way to engineer the laminin alpha-2 gene. For this study, the authors chose to use the mini-agrin gene because researchers from the University of Basel, Switzerland, already had demonstrated it could improve the symptoms of muscular dystrophy in a transgenic mouse model, which has little clinical relevance. The Pitt researchers also might explore approaches that combine genes that promote both muscle and nerve growth, as well as focus on improving the AAV vectors.

Other authors on the study are Jianbin Li, Tong Zhu, Xiaojung Ye, Chunlian Chen and Juan Li, all from the Department of Orthopaedic Surgery, as well as Romesh Draviam and Simon Watkins, Department of Cell Biology and Physiology.

The research was supported by the National Institutes of Health Paul Wellstone Muscular Dystrophy Cooperative Research Center and the National Institute of Arthritis and Musculoskeletal and Skin Diseases and through a fellowship awarded to Qiao by the Muscular Dystrophy Association.


Roundup lethal at even lower concentration, research shows

As amphibians continue to disappear mysteriously worldwide, a Pitt researcher may have found more pieces of the puzzle. Elaborating on his previous research, assistant professor of biological sciences Rick Relyea has discovered that Roundup, the most commonly used herbicide in the world, is deadly to tadpoles at lower concentrations than previously tested; that the presence of soil does not mitigate the chemical’s effects, and that the product kills frogs in addition to tadpoles.

In two articles published recently in the journal Ecological Applications, Relyea and doctoral students Nancy Schoeppner and Jason Hoverman found that even when applied at concentrations that are one-third of the maximum concentrations expected in nature, Roundup still killed up to 71 percent of tadpoles raised in outdoor tanks.

Adding soil made no difference: After exposure to the maximum concentration expected in nature, nearly all of the tadpoles from three species died.

This research was funded by the National Science Foundation, Pitt’s McKinley Fund and the Pennsylvania Academy of Science.


Placentas provide cells similar to embryonic stem cells

Routinely discarded as medical waste, placental tissue could feasibly provide an abundant source of cells with the same potential to treat diseases and regenerate tissues as their more controversial counterparts, embryonic stem cells, suggests a Pitt study to be published in the journal Stem Cells and available in the on-line publication Stem Cells Express.

A part of the placenta called the amnion, or the outer membrane of the amniotic sac, is composed of cells that have strikingly similar characteristics to embryonic stem cells, including the ability to express two key genes that give embryonic stem cells their unique capability for developing into any kind of specialized cell, the researchers report. According to the results of their studies, these so-called amniotic epithelial cells could in fact be directed to form liver, pancreas, heart and nerve cells under the right laboratory conditions.

“If we could develop efficient methods that would allow amnion-derived cells to differentiate into specific cell types, then placentas would no longer be relegated to the trashcan. Instead, we’d have a useful source of cells for transplantation and regenerative medicine,” said senior author Stephen C. Strom, associate professor of pathology at the School of Medicine and a researcher at the McGowan Institute for Regenerative Medicine.

According to U.S. census figures, there are more than 4 million live births each year. For each discarded placenta, the researchers calculate there are about 300 million amniotic epithelial cells that potentially could be expanded to as many as 60 billion cells.

The amnion is derived from the embryo and forms as early as eight days after fertilization, when the fate of cells has yet to be determined, and serves to protect the developing fetus. According to the researchers’ studies using placentas from full-term pregnancies, amniotic epithelial cells have many of the telltale surface markers that define embryonic stem cells, and also express the Oct-4 and nanog genes that are known to be required for self-renewal and pluripotency — the ability to develop into any type of cell.

The authors point out that despite their remarkable similarities to embryonic stem cells, amniotic epithelial cells are not stem cells per se, because they can’t grow indefinitely. This may be due to the fact that these amnion-derived cells do not express a certain enzyme, called telomerase, that is important for normal DNA and chromosome replication and, by extension, ultimately cell division.

“Perhaps it’s to their advantage that the amnion epithelial cells lack telomerase expression, because telomerase is associated with many cancers and one of the main concerns about stem cell therapies is that transplanted stem cells would replicate in the recipient to form tumors,” noted Toshio Miki, first author of the paper and an instructor in pathology at the School of Medicine.

To help determine if amnion-derived cells that are delivered directly to tissues would cause tumors, the researchers conducted studies in immune system-deficient mice and found no evidence that tumors had developed seven months after the cells were injected into multiple sites.

While amniotic epithelial cells do not share the same capacity for unlimited replication as do embryonic stem cells, they still can double in population size about 20 times over without needing another cell type serving as a feeder cell layer. This is significant, because to replicate, the currently available embryonic stem cell lines require a bed of mouse cells, traces of which can end up in each new generation of stem cells. Amniotic epithelial cells, on the other hand, create their own feeder layer, with some cells choosing to spread out at the bottom of the culture dish thereby giving those cells just above them the best environment for replicating and for retaining their stem cell characteristics.

With the addition of various growth factors, the authors report the amnion-derived cells could differentiate to become liver cells, heart cells, the glial and neuronal cells that make up the nervous system, and pancreatic cells with genetic markers for insulin and glycogen production.

The research was supported by the Alpha-1 Foundation and the National Institute of Diabetes and Digestive and Kidney Diseases. Other authors are Thomas Lehmann and Hongbo Cai, both from pathology, and Donna Stolz, from cell biology and physiology.


Pitt to teach green building in tropics

Starting this fall, Pitt students will be able to travel to the University at Campinas (UNICAMP) in São Paulo, Brazil, to conduct research in green construction and sustainable water use technology under a new Pitt program funded by a $3.2 million Integrative Graduate Education and Research Traineeship (IGERT) grant from the National Science Foundation.

The program, spearheaded by the Mascaro Sustainability Initiative (MSI) in Pitt’s School of Engineering and a joint effort of the school and the Center for Latin American Studies within Pitt’s University Center for International Studies, will allow engineering doctoral students to journey to São Paulo for eight-month international research rotations at UNICAMP, one of the top engineering schools in South America.

“Sustainability is a global issue, and an appropriate technology for the U.S. may not be appropriate for another region,” noted principal investigator Eric Beckman, who is Bayer Professor of Chemical Engineering at Pitt and co-director of MSI. “At UNICAMP, students will gain an international perspective on technology and design, with an eye to learning about novel approaches to sustainability developed by our Brazilian colleagues.

“We believe that by learning to adapt to the Brazilian culture and to study, research and live in Brazil for an extended period, the IGERT fellows will then have the confidence and ability to adjust to other cultures throughout the world,” Beckman added.

In an effort to increase the number of Hispanic students in the field of engineering, the program also includes partnerships with the University of Texas at El Paso and the University of Puerto Rico at Mayagüez. Students from those institutions will be able to complete a Master of Science degree at their home institutions, transitioning into the IGERT program during their final semester and pursuing a doctoral degree at Pitt.

The program, which is the first IGERT grant led by Pitt, involves faculty from all seven engineering departments at the University. Co-principal investigators are associate professors of industrial engineering Kim LaScola Needy and Mary Besterfield-Sacre; Robert Ries, assistant professor of civil engineering and director of Pitt’s Green Construction Program, and Laura Schaefer, assistant professor of mechanical engineering.


Researchers find clue to cocaine addicts’ behavior

Pitt researchers, working with rats, have zeroed in on the brain circuitry mechanism whose disruption contributes to the impulsive behavior seen in users of cocaine as well as other psychostimulant drugs. The same circuitry has been implicated in such disorders as schizophrenia, depression and post-traumatic stress disorder, wrote the researchers.

Neuroscience research associate Yukiori Goto and professor Anthony A. Grace described their findings in the journal Neuron. In their studies, they sought to understand the effects of cocaine sensitization on the connections between two higher brain regions — the prefrontal cortex and the hippocampus — and the nucleus accumbens, the region involved in processing reward behavior. The prefrontal cortex is involved in processing information, and the hippocampus is involved in learning and memory.

The connections to the nucleus accumbens seem to be bidirectional, said the researchers, and the interactions with the prefrontal cortex and hippocampus could affect the “plasticity” of connections in the neurons of the nucleus accumbens. This means that disruptions to the normal connections could affect behavior.

Goto, the corresponding author, and Grace’s electrophysiological studies of the effects of cocaine on this circuitry demonstrated that the drug did disrupt this normal plasticity.

The researchers found that the cocaine induced abnormal enhancement of neuronal connections — a phenomenon called long-term potentiation (LTP).

The researchers also performed behavioral studies on the cocaine-sensitized rats, to explore the behavioral effects of this disruption. They placed the rats in a plus-shaped maze. The rats were taught that in response to a visual cue they should turn left or right toward one arm or the other of the maze to obtain a piece of cereal.

Goto and Grace found that, while the cocaine-sensitized rats learned the correct response strategy faster than normal rats, they were significantly less able to change strategies when they were required to ignore the cue in order to receive the reward.

Thus, although abnormally induced LTP by psychostimulants at limbic inputs might not interfere with learning a response strategy, it may reduce the capacity of these animals to consider alternate response strategies, concluded Goto and Grace. “In this way, the disruption of synaptic plasticity by cocaine sensitization may contribute to the affective- and context-inappropriate impulsive behaviors that are characteristic of drug addiction.”


To fetus, second-hand smoke could be as bad as maternal smoking

A re-examination of data from earlier studies suggests that exposure to second-hand smoke during pregnancy can be just as detrimental to a developing fetus as primary exposure through maternal smoking, according to a recent paper from the Graduate School of Public Health.

In a study published in the online journal BMC Pediatrics, Stephen G. Grant, associate professor of environmental and occupational health, reports that both active maternal smoking and secondary maternal exposure result in similarly increased rates of genetic mutation that are basically indistinguishable.

“This analysis shows not only that smoking during pregnancy causes genetic damage in the developing fetus that can be detected at birth, but also that passive — or secondary — exposure causes just as much damage as active smoking, and it is the same kind of damage,” said Grant.

Grant’s primary area of study is genotoxicity and the mechanisms of DNA repair. “These kinds of mutations are likely to have lifelong repercussions for the exposed fetus, affecting survival, birth weight and susceptibility to disease, including cancer.”

This is a startlingly different conclusion than that reached by three previous studies looking at the potential effects of tobacco smoke exposure to babies in the womb, one of which Grant co-authored.

The primary papers largely discounted the effects of secondary — and sometimes even direct exposure through maternal smoking — or produced contradictory results.

The original studies looked at mutation rates at the HPRT gene located on the X chromosome in cord blood samples from newborns.

Grant’s analysis pooled the studies’ data, looking for frequency of induced mutation as well as the resulting molecular spectrum of mutations.

In particular, the new analysis redefines the “non-smokers” used as controls to consider their second-hand exposure to tobacco smoke through other family members at home, at work or in social situations at restaurants or even outdoors.

“Moreover, we found similarly increased induced mutation in women who had quit smoking during pregnancy, usually when they found out they were pregnant,” said Grant, who also is an assistant investigator at the Magee-Womens Research Institute.

“Perhaps, like certain pharmaceutical warnings, it would be appropriate to caution women to quit smoking if they are pregnant or likely to become pregnant. It is equally imperative that workplace protection be offered to reduce passive exposure.”

This study was supported by funding from the National Institute of Child Health and Human Development and the University of Pittsburgh Competitive Medical Research Fund.


THC shown to help bladder disorders

IP 751, a potent synthetic analog of a metabolite of THC — the principal active ingredient of marijuana — effectively suppresses pain and bladder overactivity in hypersensitive bladder disorders such as interstitial cystitis (IC), according to animal model study results presented at the annual meeting of the International Continence Society.

IP 751 is a potent anti-inflammatory and a powerful analgesic, although the mechanisms by which it works are unknown.

Researchers at the School of Medicine injected IP 751 into rat models of acute and subacute bladder inflammation. IP 751 significantly suppressed bladder overactivity in both animal models without affecting bladder contractility. By doing this, IP 751 can ease bladder pain. By stopping the underlying cause of irritation — overactivity of the bladder — IP 751 is able to eliminate the associated pain.

“Interstitial cystitis is a difficult disease to treat, and not all treatments work well on all patients,” said Michael Chancellor, professor of urology. “Any new option we can give our patients to alleviate their painful symptoms is very exciting.”

According to the National Institute of Diabetes and Digestive and Kidney Diseases, 700,000 Americans have IC; 90 percent are women. IC is one of the chronic pelvic pain disorders, defined by recurring pain in the bladder and surrounding pelvic region.


Human muscle-derived stem cells could stop stress incontinence

Human muscle-derived cells, pluripotent stem cells found in muscle, have been used to cure stress urinary incontinence in animal models, a finding which signals that these cells are prime candidates to treat the condition in adults. The research is being presented by Pitt researchers at this week’s meeting of the International Continence Society.

Pittsburgh researchers led by Michael Chancellor, professor of urlogy, injected the human muscle-derived stem cells into the periurethral muscle of a well-established animal model for stress urinary incontinence. After four weeks, the models’ leak-point pressure, the pressure at which urine would leak from the bladder, had been restored to levels that would be seen normally.

Researchers believe that the human muscle-derived cells were able to restore leak-point pressure to normal levels by differentiating into new muscle fibers, which prevented periurethral muscle atrophy.

Clinical trials using muscle-derived cell therapy for incontinence have begun in Toronto.


Paramedics need more experience inserting breathing tubes

Across the United States, many patients require insertion of emergency breathing tubes before arriving at a hospital, but emergency medicine researchers at the Pitt School of Medicine have found that many paramedics — the highest level of pre-hospital providers — do not get enough clinical experience in this life-saving skill. These findings are reported in the August issue of the journal Critical Care Medicine. The journal’s findings are available on line at

Endotracheal intubation (ETI) is an emergency medical procedure whereby trained medical personnel place a clear, flexible plastic tube into a patient’s windpipe to deliver oxygen to the lungs.

Paramedics collectively perform approximately 12,000 intubations every year in Pennsylvania.

Pitt researchers found that two-thirds of Pennsylvania paramedics performed intubation fewer than three times per year, and 40 percent performed no intubations at all.

“We need to find better ways to train paramedics to perform this very difficult procedure or find better and simpler ways to manage the airway,” said Henry E. Wang, assistant professor of emergency medicine and lead author of the study. Previous studies of complex medical procedures have shown that the occurrence of errors, adverse events and poor outcomes is associated with the volume of procedural experience.

Paramedic students in the United States are required to perform only five intubation procedures before graduation, compared to emergency medicine residents who are required to perform 35, or anesthesiology residents who must complete 50, before graduation.

“The entire health care delivery system is going through an evolutionary process, and everyone, from paramedics to trauma surgeons, is re-examining many medical procedures to assess their usefulness,” added Donald M. Yealy, professor and vice chairman of emergency medicine and one of the study authors.

Wang said, “It is unrealistic to expect every paramedic in every pocket of the United States to master this incredibly difficult skill. Further studies need to be done to determine if the procedure needs to be modified, or if we need to do a better job as health care educators to train and maintain paramedics’ rapid airway management skills.”

Other Pitt collaborators include David Hostler, emergency medicine, and Judith R. Lave, health policy and management, Graduate School of Public Health.

This study was funded in part by the Agency for Healthcare Research and Quality.

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