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July 21, 2011

Research Notes

Better blood storage needed

Transfused blood may need to be stored in a different way to prevent the breakdown of red blood cells that can lead to complications, say researchers from Pitt’s School of Medicine and Wake Forest University.

In the online version of Circulation, the team reported the latest findings from its exploration of the interaction between red blood cell breakdown products and nitric oxide (NO), revealing new biological mechanisms that can reduce blood flow and possibly damage vital tissues after administration of blood that has been stored for longer than 39 days.

Transfusion of many units of blood or of blood stored for a long time may be associated with a greater frequency of complications, such as increased infection risk, kidney, lung or multi-organ failure and death, particularly among medically vulnerable patients, said senior investigator Mark T. Gladwin, chief of the Division of Pulmonary, Allergy and Critical Care Medicine and director of Pitt’s Vascular Medicine Institute.

“When blood sits for a while, some of the cells break down and release their contents, which include molecules of hemoglobin and red blood cell microparticles,” he said. “These accumulate in the stored bag of blood and are transfused into the patient with the blood. In the bloodstream, the hemoglobin and microparticles bind to and destroy NO, a very important molecule that is used by the body to keep blood vessels dilated for normal blood flow.”

The scavenging of NO causes blood vessel constriction that can prevent tissues and organs from getting adequate oxygen and activate the platelets and the coagulation system, as well as cause inflammation, Gladwin said.

Researchers found that human blood stored under standard conditions accumulated “free” hemoglobin that no longer was contained in a cell and microparticles of damaged cells. Those breakdown products reacted with NO about 1,000 times more quickly than did intact red blood cells. Also, transfusion of even very low concentrations of hemoglobin caused blood vessel constriction and hypertension in a rat model.

Senior author Daniel B. Kim-Shapiro of Wake Forest said, “Avoiding the storage lesion, as it is referred to in our field, could require a new approach to how donor blood is stored prior to transfusion.

“By understanding the mechanism of the storage lesion, we can design methods to make blood transfusion safer. For example, perhaps we can restore nitric oxide activity that is lost upon transfusion, use preservation solutions that better limit the degradation of blood cells, or develop agents that scavenge free hemoglobin.”

Research projects are underway to find approaches to correct the problem, and to assess the safety of blood that has been stored for longer than 14 days. Currently, federal guidelines allow transfusion of blood that has been stored for up to 42 days.

Pitt co-authors included Chenell Donadee and Nicholaas J.H. Raat of pulmonary, allergy and critical care medicine; Albert D. Donnenberg of medicine, and Darrell Triulzi of pathology.

The study was funded by the National Institutes of Health, the Institute for Transfusion Medicine and the Hemophilia Center of Western Pennsylvania.

Cardiac outcomes predicted

A new method for scoring the severity of illness for patients after cardiac arrest may help to predict their outcomes, according to health sciences researchers. Their findings, published online in Resuscitation, also show that none of the severity categories rules out the potential for a patient’s recovery.

“Traditionally, we have used historical or event-related information, such as initial cardiac rhythm or whether someone witnessed the collapse, to categorize these patients upon arrival at the hospital,” said lead author Jon C. Rittenberger, a faculty member in emergency medicine. “Unfortunately, more than 10 percent of the time, such information is unavailable, which limits our ability to tailor therapies, counsel families about prognosis or select patients for clinical trials.”

The researchers looked at retrospective data for more than 450 post-cardiac arrest patients treated at UPMC Presbyterian, 2005-09.

Four distinct categories of illness severity were identified based on a combination of neurological and cardiopulmonary dysfunction during the first few hours after restoration of a patient’s spontaneous circulation. The researchers looked at rates of survival, neurologic outcomes and development of multiple organ failure for patients in each category, and found wide variations among the groups.

“Now, objective data available to the clinician at the bedside during initial evaluation may provide a better way of predicting outcomes and guiding the decisions of families and clinicians. We found that the category of illness severity had a stronger association with survival and good outcomes than did such historically used factors as initial rhythm of arrest or where it happened,” said Rittenberger.  “Our results indicate that illness severity should be carefully measured and accounted for in future studies of therapies for these patients.”

Pitt co-authors included Samuel A. Tisherman of critical care medicine, Margo B. Holm of occupational therapy and Francis X. Guyette and Clifton W. Callaway of emergency medicine.

The research was supported by a grant from the National Center for Research Resources.

Abuse higher against sexual minority youth

Young people who identify themselves as gay, lesbian or bisexual, experience same-sex attractions or engage in same-sex sexual behaviors are more likely to experience sexual abuse, parental physical abuse and bullying from peers than other youth, according to a Graduate School of Public Health (GSPH) study.

In addition, these adolescents — identified as “sexual minority youth” in the study — are more likely to miss school due to fear.

The American Public Health Association recently published the findings online; the study will appear in the August issue of the American Journal of Public Health.

Study author Mark S. Friedman, a faculty member in behavioral and community health sciences, said: “The higher rates of abuse experienced by sexual minority youths are clearly one of the driving mechanisms underlying higher rates of mental health problems, substance use, risky sexual behavior and HIV by sexual minority adolescents and adults. These youth experience sexual and physical abuse and bullying because they identify as gay, lesbian or bisexual or experience same-sex attraction; abuse does not ‘cause’ sexual orientation or identification.”

Friedman and his co-authors conducted a meta-analysis of 37 studies in 18 geographic areas that compared the likelihood of self-reported childhood sexual abuse; physical abuse perpetrated by a parent or guardian, or peer victimization between high-school aged sexual minority and non-minority youth.

They found that sexual minority youth are:

Nearly three times more likely to report childhood sexual abuse, compared with other adolescents;

1.3 times more likely to report parental physical abuse than other adolescents;

1.7 times more likely to report being threatened or injured with a weapon, or otherwise assaulted as compared to their peers, and

Nearly three times more likely to report missing school because they were afraid.

Studies revealed a high rate of prior sexual abuse among bisexual female (40 percent), lesbian (32 percent), bisexual male (24 percent), gay male (21 percent) and heterosexual female (17 percent) youth, compared to heterosexual male adolescents (5 percent).

According to the report, children and adolescents who experience sexual and parental physical abuse are more likely to suffer from psychological, substance abuse, behavioral and criminal problems.

Those who are abused and assaulted by peers are more likely to experience poor school performance, delinquency, social isolation, psychological and substance abuse problems and other issues, the study said.

In addition, the U.S. Centers for Disease Control and Prevention recently released a study that found adolescents who identify as gay, lesbian or bisexual are more likely than their heterosexual peers to take unhealthy risks.

The GSPH study was funded by the National Institute of Mental Health.

Pitt co-authors included Michael P. Marshal, Thomas E. Guadamuz, Chongyi Wei and Ron Stall, all of the Department of Behavioral and Community Health Sciences and the Center for Research on Health and Sexual Orientation.

Docs colorblind in mock ICU care

Simulations typically used for medical training could provide a way to examine interactions between physicians and patients to reveal, for example, how race and other factors influence decision-making, said Pitt School of Medicine researchers. In a study published in Critical Care Medicine, they found that hospital-based physicians did not treat black and white mock patients differently in an intensive care scenario, but they overestimated the preference for life-sustaining intervention in both groups and among blacks in particular.

Previous research has shown that compared to white patients, black patients with late-stage cancer are more likely to be admitted to an intensive care unit and to receive life-sustaining interventions such as dialysis or breathing support by a ventilator, said lead investigator Amber E. Barnato, a faculty member in the Department of Medicine. Also, research suggests that black patients are more likely to prefer aggressive life-sustaining treatment.

“For our study, we examined whether physician decision-making was influenced by patient race to play a role in creating these differences,” she explained. “Unlike previous research efforts in which physicians sat in a booth and asked questions that prompt videotaped patient responses, we used extensively trained actors to portray patients in a mock triage setting, which we believe is more likely to capture what happens in the real world.”

Conducted at Pitt’s Peter M. Winter Institute for Simulation Education and Research, the scenario mimicked the triage environment and time pressure in which decisions about ICU admission and intubation typically are made.

The researchers simulated a scenario in which a black or white patient with either end-stage gastric or pancreatic cancer experienced dangerously low blood pressure or oxygen levels. Then they assessed how doctors dealt with it medically and surveyed them about their perceptions of patient preferences.

Of the 33 physicians who participated, 12 were emergency room doctors, eight were hospitalists and 13 were intensivists. Each participated in an encounter with one black and one white patient, and did not know the study was examining the influence of race on decision-making.

Four black and four white actors playing patients and family caregivers were trained to give certain answers in response to anticipated physician questions about the medical problem: If asked, they would reveal that they knew the tumor to be widespread; the treating oncologist said they were too weak to receive chemotherapy and that death could occur within six months, and they didn’t want to be admitted into an ICU, be on a ventilator or be resuscitated. The patient’s chart provided neither prognostic or treatment information, nor an advance care plan.

The researchers found no treatment decision differences regarding administration of opiate pain killers, a trial of noninvasive mechanical ventilation, elicitation of intubation preferences, chart documentation of preferences, ICU admission, intubation, comfort measures only and palliative care consultation.

Surveys showed that the physician participants believed that a black patient with late-stage pancreatic cancer was more likely than a similar white patient to prefer potentially life-prolonging chemotherapy over palliative care and to want breathing support via a ventilator to extend life by one week, and less likely to want a “do not resuscitate” order if hospitalized.

“These findings could mean that in this setting, physician beliefs about patient preferences did not change their treatment decisions,” Barnato said. “It’s also possible that there were no differences because this scenario isolated race from other social and cultural variables, such as socioeconomic status, religiosity, trust and level of advanced care planning, that may influence physician behavior.”

Future research will explore the interaction of race and those variables in end-of-life decision-making.

“The challenge is to find a way to use simulation with larger numbers of participants,” Barnato noted. “If we can do that, we could gain invaluable insight into the dynamic between doctors and patients.”

Pitt co-authors included Derek C. Angus and Deepika Mohan of critical care medicine, Robert M. Arnold of medicine and Cindy L. Bryce of the Graduate School of Public Health’s Department of Health Policy and Management.

The study was funded by the National Cancer Institute and the American Cancer Society.

Morphing muons may show why matter dominates

Pitt researchers were part of an international team of physicists that recorded activity in a particle beam that could help explain the composition of the universe.

The Japan-based T2K collaboration, which includes approximately 500 scientists from 59 institutions worldwide, recently reported that a beam of neutrally charged particles known as neutrinos transformed from one type of neutrino into another as it was fired 185 miles through the Earth, from one side of Japan to the other.

The morphing of muon neutrinos into electron neutrinos was the first observed conversion, or oscillation, involving these “flavors” of neutrino, as the particle’s three varieties are known.

Pitt physics and astronomy faculty members Vittorio Paolone, Steven Dytman and Donna Naples oversaw the electronics that detected the type and concentration of neutrinos in the particle beam as it left the Japan Proton Accelerator Research Complex (J-PARC) in Tokai. Those readings were compared against the content of the particle beam when it reached the Super-Kamiokande detector in Kamioka to determine the level of neutrino oscillation, Paolone said.

The crossover of the muon neutrinos to electron neutrinos presents a new avenue for exploring the universe’s structure, Paolone explained. It will allow scientists to study charge-polarity violation in neutrinos, the phenomenon thought to be the reason why the universe contains far more matter than antimatter.

When the universe was created, matter and antimatter existed in equal amounts, Paolone said. But unknown disruptions as the universe was developing gave one state an advantage over the other.

The T2K experiment suggests that neutrinos might have had some part in causing the unbalance, he said.

The T2K results unexpectedly reopened the possibility of explaining how matter trumped antimatter, Paolone said. Previous research had determined that particles known as quarks also undergo charge-polarity violation, but further study found it occurred on too small of a scale to change the balance of the universe.

“Charge-polarity violation may have occurred early on in the development of the universe, changing matter so that it became the dominant state,” Paolone explained. “The question is, what tipped the balance toward matter?”

The T2K experiment is funded primarily by Japan’s Ministry of Education, Culture, Sports, Science and Technology.

Support for the American collaborators also comes from the U.S. Department of Energy, Office of Science.

The J-PARC facility was damaged during the March 2011 earthquake in Japan. The complex is expected to begin operating again by late 2011.

GERD, cancer risk studied

A study published in the current issue of Archives of Surgery has found that medically treated patients with mild or no symptoms of gastroesophageal reflux disease (GERD) are at higher risk for developing esophageal cancer than those with severe GERD symptoms.

Principal investigator Blair A. Jobe, director of esophageal research and esophageal diagnostics and therapeutic endoscopy and a faculty member in the School of Medicine’s Department of Cardiothoracic Surgery, said: “Typically, patients with severe GERD symptoms are screened for Barrett’s esophagus, but those with mild or absent symptoms are not. Unfortunately, many patients who develop adenocarcinoma don’t know that they have Barrett’s esophagus until it has transformed into cancer and become advanced, leading to obstruction.”

Barrett’s esophagus is a change in the cells lining the esophagus, often due to repeated stomach acid exposure, which can develop into esophageal cancer.

The study divided into three groups 769 GERD patients who were having their first upper endoscopy (in which a flexible endoscopic camera is guided through the esophagus and stomach to look for tissue changes): patients who were referred for upper endoscopy for any clinical indication regardless of symptoms; patients with typical GERD symptoms, such as heartburn, regurgitation and difficulty swallowing, and patients with atypical GERD symptoms, such as hoarseness, throat-clearing, mucus, coughing and a lump sensation in the throat.

Endoscopy revealed that 122 of these patients, or 15.9 percent, had Barrett’s esophagus or adenocarcinoma.

Patients who were managing their GERD symptoms adequately with proton pump inhibitors (PPIs) were 61 percent more likely to have Barrett’s esophagus or adenocarcinoma if they reported no severe GERD symptoms, compared to patients taking PPIs who reported severe symptoms. Patients with severe GERD symptoms often experienced irritation or swelling of the esophagus, but that was associated with decreased odds of having esophageal cancer.

“Our research indicates that even patients without severe symptoms may benefit from Barrett’s esophagus screening,” Jobe noted. “If GERD patients are screened early enough, there is a better chance that Barrett’s esophagus can be identified before it becomes cancerous. We are learning that the chronic and long-term use of PPIs may not be entirely without consequences and may lead to more insidious problems such as calcium malabsorption or cause one to be asymptomatic in the face of continued esophageal injury from GERD.”

Pitt co-authors included Omar Awais, James D. Luketich, Katie S. Nason and Matthew J. Schuchert of cardiothoracic surgery.

The study was funded by the Robert Anthony McHugh Research Fund for the Prevention and Early Detection of Esophageal Cancer, the David Gold and Irene Blumenkrantz Esophageal Cancer Research Fund, the Sampson Family Endowed Chair, the UPMC Heart, Lung and Esophageal Surgery Institute, the American Surgical Association Foundation Fellowship Award and grants from the National Institutes of Health (NIH).

Jobe and his Pitt colleagues have established the Barrett’s Esophagus Risk Consortium, in which primary care patients are being screened with in-office, small-caliber, unsedated endoscopy in an attempt to better understand risk factors for the condition as well as to lower the threshold for screening. The multicenter effort is funded by NIH.


The University Times Research Notes column reports on funding awarded to Pitt researchers as well as findings arising from University research.

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