RxPG News : Transplantation

Increased drop out rates among HIV infected patients on the liver transplantation wait list

Tue, 25 Jan 2011 19:32:02 PST

( from http://www.rxpgnews.com ) French researchers determined that infection with human immunodeficiency virus (HIV) impaired results of transplant surgery for liver cancer, with more HIV infected patients dropping off the transplantation wait list. The team found that overall survival and recurrence-free survival was not impacted following liver transplantation in patients with controlled HIV disease. Details of this single center study—the largest to date—are published in the February issue of Hepatology, a peer-reviewed journal of the American Association for the Study of Liver Diseases (AASLD).

More than 40 million individuals are infected with HIV; of these roughly two to four million and four to five million are also carriers of chronic hepatitis B virus (HBV) and hepatitis C virus (HCV), respectively. With the introduction of highly active antiretroviral therapy (HAART) in 1996 the survival of patients with HIV infection has improved dramatically and now end-stage liver disease has become the principal cause of death among HIV- positive patients co-infected HBV or HCV. Prior studies have shown that 25% of liver-related mortality in HIV-positive patients is attributable to hepatocellular carcinoma (HCC), or liver cancer.

"Liver transplantation is the optimum treatment for HCC and can also be considered for controlled HIV-positive patients with liver cancer," said René Adam, MD, PhD, from Hospital Paul Brousse in France and lead author of the current study. "Our study showed that HIV infection impaired the results of liver transplantation on an intent-to-treat basis but exerted no significant impact on overall survival and recurrence-free survival following transplantation."

The research team analyzed data from 21 HIV-infected and 65 HIV-negative patients with HCC who were listed for liver transplantation between 2003 and 2008. All HIV-positive patients were treated with HAART and had not experience any AIDS event or opportunistic infections prior to being place on the wait list.

Researchers observed a trend towards a higher drop-out among HIV-positive wait listed patients (23%) compared to patients without HIV (10%). Patients with HIV who dropped out had significantly higher alpha-fetoprotein (AFP) levels at the time of listing than those who received a transplant—98 μg/L versus 12 μg/L, respectively. A similar difference in AFP levels was not found in HIV-negative patients—18 μg/L in those who dropped out versus 13 μg/L for those who underwent liver transplantation. Only one HIV-positive patient who did not have increased AFP levels while on the wait list dropped out due to progression from controlled HIV to AIDS.

Medical evidence indicates a major predictive factor for HCC recurrence post-transplantation is an increase in patient's AFP level of more than 15 μg/L per month while on the waiting list. "Our study confirmed the importance of this preoperative factor (AFP levels), as all HIV-positive patients who dropped out displayed a rise in AFP levels," Dr. Adam concluded. "There is clearly a critical need for more effective neoadjuvant therapy in HIV-positive patients with HCC, however there are no objective arguments to contraindicate liver transplantation in this group if strict criteria are used for selection and patients are closely monitored until surgery."

Increased mortality risk in later years in obese children following Liver transplantation

Thu, 28 Oct 2010 18:27:35 PST

( from http://www.rxpgnews.com ) A new study from the University of Washington reported obese children are at increased mortality risk in later years following primary liver transplantation (LT). Pediatric patients who are thin or severely thin, experience an early mortality risk—within the first year post-LT. Details of the ten-year survival analysis are published in the November issue of Liver Transplantation, a peer-reviewed journal of the American Association for the Study of Liver Diseases (AASLD).

Childhood obesity is a serious public health concern worldwide. According to the World Health Organization (WHO), the prevalence of obesity has been increasing at an alarming rate, with 22 million children under the age of five worldwide who are overweight. In the U.S., the National Center for Health Statistics estimates that 17% of children between the ages of 2 and 19 years old are overweight or obese.

"Controversies exist regarding the mortality of patients undergoing liver transplantation at the extremes of body mass index (BMI), and in pediatric patients weight is typically the only factor considered in survival analysis," explained lead study author André Dick, M.D., from Seattle Children's Hospital and the University of Washington. "Our study is the largest thus far to report on the impact of pre-transplant BMI on post liver transplant survival in the pediatric population." Prior studies in adult populations have shown there to be a negative impact on post transplantation survival for LT patients with extreme BMIs.

For the present study, researchers reviewed data from the Organ Procurement and Transplantation Network (OPTN) and found that 7,942 patients less than 18 years of age (who had full BMI data) underwent primary liver transplantation between 1987 and 2007. Using the WHO BMI criteria, the authors categorized patients as severely thin, thin, normal weight, overweight, or obese. During the study period 61% of patients were at normal weight.

Results indicate that children who were thin or severely thin had a significantly lower survival (84%) at one year compared to the survival (89%) of children in the normal and overweight groups. Researchers found no significant difference in survival during the first year after transplantation for obese pediatric patients. However, by the twelfth year following LT, those in the obese group had significantly lower survival (72%) than the survival (77%) of normal weight or overweight pediatric patients.

The authors observed that obesity had a significantly negative impact on pediatric patient survival more than five years after LT. They speculate post metabolic syndrome (PTMS) could contribute to the late morbidity and mortality due to the time it takes to develop long-term obesity-related conditions such as diabetes, hypertension, and hyperlipidemia. Moreover, long-term use of immunosuppressive therapy following transplantation, which while improving patient survival, can exacerbate the effects of PTMS. "Further research is needed to determine the optimal immunosuppressive regimen that will lessen the effects of PTMS," concluded Dr. Dick. "Pre- and post-transplant identification of malnourished or obese pediatric patients, along with optimization of their modifiable risk factors will help to best use scarce donor organs and maximize patient survival."

Researchers find faster, less-intrusive way to identify transplant recipients' organ rejection

Thu, 23 Sep 2010 04:00:00 PST

( from http://www.rxpgnews.com ) STANFORD, Calif. - A simple, inexpensive blood test could soon help doctors halt organ rejection before it impairs transplanted hearts and kidneys.

In the past, we couldn't spot rejection episodes until they harmed the organ, said Atul Butte, MD, PhD, who is co-senior author of the new research and an associate professor of medical informatics and of pediatrics at the Stanford University School of Medicine, in addition to director of the Center for Pediatric Bioinformatics at Lucile Packard Children's Hospital. Our goal is to develop blood tests that will keep transplanted organs functioning so that patients can avoid a second transplant.

Butte and his collaborators have made a big step toward that goal. The Stanford team found three easily measured proteins that rise in the blood during acute rejection, in which a patient's immune system attacks his or her transplanted organ. The research, which will be published online Sept. 23 in PLoS-Computational Biology, is the first-ever report of an immune-rejection signal that is shared by two kinds of transplanted organs. The protein signals are now being validated in liver- and lung-transplant recipients as well.

The new blood test circumvents the invasive, expensive, slow system now used to keep tabs on transplants. Currently, all organ recipients receive functional monitoring of their new body parts. Heart transplant patients get regular echocardiograms, for instance. If organ function drops, doctors cut a tiny sample from the transplanted tissue to check for rejection, and then adjust patients' immune-suppressing drugs accordingly. About 25 percent of kidney recipients and 40 percent of heart recipients experience an episode of acute rejection in the first year after transplant.

The new blood test will let doctors skip directly to drug dosing before a transplant is damaged. As well as treating rejection early, doctors could use the test to reduce doses of immune-suppressing drugs for patients whose bodies are handling their transplanted organs well, thus reducing unnecessary drug side effects. Butte predicts the test will be commercially available in three to five years.

The new technique makes use of an existing method to detect proteins in blood, called enzyme-linked immunosorbent assay, or ELISA, that is already used to diagnose diseases such as strep throat. The Stanford team found new proteins for diagnostic ELISA kits to target.

To identify the new protein markers, the researchers started from publicly available data documenting changes during transplant rejection in levels of messenger RNA, the molecule that tells cells to make new proteins from the instructions in the genetic code. These changes gave the team clues about which proteins might appear in the blood during rejection.

From 45 protein candidates identified via mRNA data, the team zeroed in on 10 for which ELISA-based laboratory test kits were already available. Using blood samples from 39 kidney and 63 heart transplant recipients, the kits found three proteins that reliably increased in the blood during acute rejection.

Because ELISA-based diagnostics are already used in clinical settings, it won't be hard to modify the technology for transplant patients, Butte said. Stanford University has filed patent applications for the new test.

The researchers also independently validated their method of using public RNA data to identify marker proteins by confirming that the computational method detected known biomarkers for several other diseases. The new discovery method is exciting, Butte said, because it could be applied to many diseases that lack good diagnostic tools.

For a disease like pancreatic cancer, where we find it late and patients die quickly, we have a huge medical need for identifying good diagnostic markers, he said. Why don't we use public data to help us with this process?

Northwestern first site open for spinal cord stem cell trial

Wed, 22 Sep 2010 04:00:00 PST

( from http://www.rxpgnews.com ) CHICAGO --- Northwestern Medicine is the first site open for enrollment in a national clinical research trial of a human embryonic stem cell-based therapy for participants with a subacute thoracic spinal cord injury. Following the procedure, participants will receive rehabilitation treatment at The Rehabilitation Institute of Chicago (RIC).

Northwestern also is the lead site of the trial, sponsored by Geron Corporation (Nasdaq: GERN). The trial eventually will include up to six other sites and enroll up to 10 participants nationally.

We are very pleased to be the first participating center in the world's first human embryonic stem cell clinical trial for spinal cord injury, said lead national investigator Richard Fessler, M.D., professor of neurological surgery at Northwestern University Feinberg School of Medicine and a surgeon at Northwestern Memorial Hospital.

Injection of oligodendrocyte progenitor cells directly into the spinal cord lesion is a rational way to attempt to arrest or reverse the structural damage in the spinal cord caused by severe trauma, Fessler said. We are eager to begin evaluating the effects of these cells in subjects with severe spinal cord injuries.

RIC is a vital member of the research team for this novel stem cell clinical trial, said David Chen, M.D., medical director of the RIC Spinal Cord Injury Rehabilitation Program. RIC's team of spinal cord injury rehabilitation specialists is responsible for customizing the rehabilitation care plan and therapeutic intervention for each participant, which may include robotic walking therapy and other procedures to facilitate the participant's neurologic repair and recovery. At RIC, restoring the participant's ability is our objective and the scientific application of embryonic stem cells offers new hope for recovery.

The primary objective of the phase I trial is to assess the safety and tolerability of special cells called human embryonic stem cell-derived oligodendrocyte progenitor cells when they are injected into the spinal cord injury of paralyzed subjects. The injuries have to have occurred within two weeks for someone to be eligible for the procedure.

In addition to evaluating safety, the secondary aim of the trial is to see if the stem cells improve neuromuscular control or sensation in the trunk or lower extremities.

In previous animal studies, these stem cells have demonstrated the ability to remyelinate or recoat damaged nerve cells that have lost their ability to conduct electrical impulses down the axon. The stem cells also have shown nerve-growth stimulating properties leading to restoration of function in animal models of acute spinal cord injury.

The trial is supported by positive animal research, Fessler said. He noted the trial is using the lowest dose possible for a human based on the animal studies.

Subjects eligible for the Phase I trial will have documented evidence of functionally complete (ASIA Impairment Scale grade A) spinal cord injury with a neurological level of T3 to T10 spinal segments and agree to have GRNOPC1 injected into the lesion sites between 7 and 14 days after injury.

Improving clinical use of stem cells to repair heart damage

Tue, 13 Jul 2010 04:00:00 PST

( from http://www.rxpgnews.com ) Presenting at the UK National Stem Cell Network annual science conference today(13 July), Professor Michael Schneider describes a new approach to treating heart attack and cardiomyopathy using stem cells.

Professor Schneider, British Heart Foundation Professor at Imperial College London, said Recent clinical trials using stem cells to treat heart damage have been successful in terms of safety but unfortunately the bone marrow stem cells used tend to give only a small improvement in how well the heart is pumping.

We really want to use stem cells from the patients themselves that we know can give rise to beating heart cells and these are not found in bone marrow. The good news is that we're now finding ways to identify and purify such cells.

Around 1000 patients have been treated in approximately 20 trials worldwide, mostly using bone marrow stem cells or derivatives of bone marrow cells to repair damage caused by heart attack. There has also been a significant body of work looking at ways of producing beating heart cells from stem cells. The best proven approaches to creating new beating heart cells are using embryonic stem cells, induced pluripotent cells and heart-derived stem cells.

Professor Schneider continued: Using heart-derived stem cells to treat heart attack and cardiomyopathy has some advantages over embryonic and induced pluripotent cells as they are potentially safer. It's also notable that of these three cell types, it's only heart-derived cells that are in current human clinical trials for this sort of treatment.

The biggest challenge is to make an ideal product for transplant, which would be either a mixture of heart muscle- and blood vessel-forming cells or a pure population of some sort of precursor that could give rise to both muscle and blood vessel cells.

Professor Schneider's team have discovered a way to identify heart stem cells so as to purify them for transplant. They first developed the method in mice and although the identifying markers are quite different in human cells, they have been able to successfully map their knowledge from mice onto humans. This research is funded by the British Heart Foundation, the European Research Council, the European Union (through the EU FP7 CardioCell consortium), the Leducq Foundation and the Medical Research Council.

Professor Schneider said We've developed a method to identify cells that have three important characteristics: They are definitely stem cells; they have the right molecular machinery turned on in order to become heart muscle or blood vessel; and they don't yet have any of the full characteristics of heart muscle or blood vessel cells such as producing cardiac myosin - an important protein in heart muscle cells.

The next stage of the research is to develop this technique into a method for extracting, purifying and multiplying heart stem cells in the clinic to be used to repair heart damage arising from heart attack or cardiomyopathy. Professor Schneider's laboratory uses advanced robotics, automated microscopy and other high-throughput methods to screen many thousands of experimental conditions in order to devise the best ways to grow the cells and instruct them to go down the route of becoming heart muscle.

Some patients with hepatitis B faring better after liver transplant

Tue, 04 May 2010 04:00:00 PST

( from http://www.rxpgnews.com ) ROCHESTER, Minn. -- Treatment to reduce recurrence of hepatitis B appears to improve liver transplant outcomes for some patients, according to a Mayo Clinic study presented at the American Transplant Congress under way May 1-5 in San Diego.

We found that in patients with hepatitis B, the number of patients who were listed for a second transplant within three years decreased by 50 percent between 1996 and 2005, says Ray Kim, M.D., the senior investigator of the research team.

Hepatitis B infection is a major cause of liver damage that can eventually lead to end-stage liver disease and the need for a liver transplant. In the past, hepatitis B recurred in some transplant patients, causing liver damage and the need for a second transplant.

In the past 10 years, new medications have improved our ability to control hepatitis B, says Dr. Kim. Today, transplant recipients routinely are treated with antiviral therapy and hepatitis B immune globulin to reduce the risk of recurrence. We wanted to know if the medication protocols were making a difference in patient outcomes, he says.

Researchers reviewed data provided by the Organ Procurement and Transplantation Network of 31,242 liver transplants in the United States. The underlying reasons for transplantation were categorized as hepatitis B, hepatitis C or other.

From 1996 to 1998, 6.5 percent of liver transplant patients with hepatitis B were listed for a second transplant. For 2003 to 2005, the number of liver transplant patients with hepatitis B listed for a second transplant was 3.3 percent -- roughly a 50 percent reduction.

For patients with hepatitis C or other underlying liver disease, there were smaller declines in relisting numbers. Preventing recurrence of hepatitis C has proved to be more challenging than preventing recurrence of hepatitis B, says Dr. Kim.

Over the same periods, mortality rates increased for all three groups. For patients with hepatitis B, the death rate was 10.8 percent from 1996 to 1998. The rate increased to 12.8 percent for 2003 to 2005.

Our results show that transplant outcome is consistently improving for patients with hepatitis B with a significant decrease in need for second transplants, says Dr. Kim. The increases in mortality rates are concerning. The incidence of liver cancer has increased and it may explain some of the mortality. However, more work needs to be done to understand the reasons.

Dr. Kim says the study results are significant because an estimated 800,000 Americans have hepatitis B. That number is likely an under-representation, he says. In some U.S. immigrant communities, which often are excluded in disease tracking national surveys, the hepatitis B infection rate is 5 to 15 percent.

Those high numbers portend a continued high demand for liver transplants. In the United States, nearly 16,000 people are waiting for liver transplants.

Study shows liver transplant center impacts patient outcomes

Sun, 02 May 2010 04:00:00 PST

( from http://www.rxpgnews.com ) ROCHESTER, Minn. -- For patients in need of a liver transplant, their choice of a transplant center can make a noteworthy difference in their outcomes, according to a Mayo Clinic study presented at the American Transplant Congress under way May 1-5 in San Diego.

We did find significant variation between centers in patient outcomes in the first year after transplant, says Ray Kim, M.D., one of the lead investigators on the study. Previous studies have looked at outcomes based on factors about the recipients and donors involved, but no known previous study has focused on what effect the transplant center could have on patient outcomes.

Researchers documented an average 30 percent difference in risk for failed transplant between centers. Between centers with the best and worst outcomes, there may be as much as a fourfold difference in risk. Failed transplant was defined as either patient death or the need for a subsequent liver transplant within a year. Though one intuitively expects a certain amount of difference between centers, this effect seems larger than previously thought. The bottom line for patients: do your homework before selecting a transplant center, he says.

But transplant center size alone, measured in patient volume, didn't account for the difference in outcomes. Results showed that the number of transplants performed didn't materially affect outcomes, says Dr. Kim. This implies the largest center won't necessarily have the best results. Similarly, a smaller center may deliver similar outcomes.

Using data from the Organ Procurement and Transplantation Network, Mayo Clinic researchers reviewed data from 12,233 patients who received liver transplants to treat chronic liver disease. The data included transplants performed at more than 100 U.S. hospitals that performed at least one liver transplantation surgery from 2005 to 2008.

Of those transplants, 15 percent failed within a year. The outcome differences between transplant centers were greatest during the first three months post-transplant.

Data used in the study was combined and analyzed without naming the transplant centers. The goal of the research is not to point fingers, says Dr. Kim. The study was undertaken with the hope of finding ways for the transplant community to make the best use of a very limited resource, namely the donated organs. The data clearly showed that where the transplantation is done makes a difference whether the outcome of a transplant will be successful. In the United States, nearly 16,000 people are waiting for liver transplants.

Dr. Kim notes that there may be several ways transplant center factors can affect transplant outcomes. The most immediate factor is quality of care provided at the center, including surgical, medical and nursing expertise. In addition, how patients and donor organs are selected for transplantation also contributes to the outcome. And last, where the center is located geographically has a substantial impact on availability and quality of donated organs.

Your own stem cells can treat heart disease

Tue, 17 Nov 2009 05:00:00 PST

( from http://www.rxpgnews.com ) CHICAGO --- The largest national stem cell study for heart disease showed the first evidence that transplanting a potent form of adult stem cells into the heart muscle of subjects with severe angina results in less pain and an improved ability to walk. The transplant subjects also experienced fewer deaths than those who didn't receive stem cells.

In the 12-month Phase II, double-blind trial, subjects' own purified stem cells, called CD34+ cells, were injected into their hearts in an effort to spur the growth of small blood vessels that make up the microcirculation of the heart muscle. Researchers believe the loss of these blood vessels contributes to the pain of chronic, severe angina.

This is the first study to show significant benefit in pain reduction and improved exercise capacity in this population with very advanced heart disease, said principal investigator Douglas Losordo, M.D., the Eileen M. Foell Professor of Heart Research at the Northwestern University Feinberg School of Medicine and a cardiologist and director of the program in cardiovascular regenerative medicine at Northwestern Memorial Hospital, the lead site of the study.

Losordo, also director of the Feinberg Cardiovascular Research Institute, said this study provides the first evidence that a person's own stem cells can be used as a treatment for their heart disease. He cautioned, however, that the findings of the 25-site trial with 167 subjects, require verification in a larger, Phase III study.

He presented his findings Nov. 17 at the American Heart Association Scientific Sessions 2009.

Out of the estimated 1 million people in the U.S. who suffer from chronic, severe angina -- chest pain due to blocked arteries -- about 300,000 cannot be helped by any traditional medical treatment such as angioplasty, bypass surgery or stents. This is called intractable or severe angina, the severity of which is designated by classes. The subjects in Losordo's study were class 3 or 4, meaning they had chest pain from normal to minimal activities, such as from brushing their teeth or even resting.

The stem cell transplant is the first therapy to produce an improvement in severe angina subjects' ability to walk on a treadmill. Twelve months after the procedure, the transplant subjects were able to double their improvement on a treadmill compared to the placebo group. It also took twice as long until they experienced angina pain on a treadmill compared to the placebo group, and, when they felt pain, it went away faster with rest. In addition, they had fewer overall episodes of chest pain in their daily lives.

In the trial, the CD34+ cells were injected into 10 locations in the heart muscle. A sophisticated electromechanical mapping technology identifies where the heart muscle is alive but not functioning, because it is not receiving enough blood supply.

Study finds transplant patients have worse outcomes from cancer

Sun, 17 May 2009 11:12:13 PST

( from http://www.rxpgnews.com ) After comparing two patient cancer registries—one featuring transplant patients and the other the general population—researchers at the University of Cincinnati (UC) have found that transplant patients experience worse outcomes from cancer.

These results will be published in the May 15, 2009, edition of the journal Transplantation, which is currently in press.

Yun Miao, MD, PhD, Jason Everly, PharmD, Steve Woodle, MD, and colleagues at UC compared lung, colon, breast, prostate, bladder, kidney and skin cancer data in 635 adult transplant recipients from the Israel Penn International Transplant Tumor Registry with that of about 1.2 million adults from the general population in the Surveillance, Epidemiology and End Results (SEER) database.

"It has been known for some time that transplant recipients are at an increased risk of developing cancer, but the outcomes of cancers that arise in organ transplant recipients have not been defined," says Woodle, professor and chief of transplant surgery and co-author of the study.

"In this study, we wanted to examine the influence of transplantation on the outcomes of individual types of cancers arising in organ transplant recipients," adds Miao, co-author and research fellow in the division.

The Israel Penn International Transplant Tumor Registry is the largest and most comprehensive transplant tumor registry in the world and was created by doctors at the UC College of Medicine.

The SEER registry collects information on cancer incidence, survival and prevalence for roughly 26 percent of the United States population and compiles reports and statistics based on this information along with cancer mortality rates for the entire nation.

A comparison of results in transplant recipients to the general population also demonstrated that transplant patients were more likely to have early stage renal cell (kidney) cancer and more advanced colon, breast, bladder and skin cancer at the time of diagnosis.

Disease-specific survival was worse in the transplant population for each of these seven cancers analyzed and was a negative risk factor for survival.

Now, researchers want to conduct further studies to find out why this may be the case.

"Transplant patients receive immunosuppressive therapies to prevent them from rejecting transplanted organs," says Woodle. "We want to see if immunosuppressive therapies contribute to the poorer outcomes in transplant recipients."

He says the worse outcomes in transplant recipients may have occurred because this population is not as healthy as the general population or because their cancers may be more aggressive as a result of their immunosuppression treatments.

"Some of our data supports this premise, as the extent of the cancers at diagnosis were greater in the transplant recipients," Woodle continues. "This was surprising since transplant recipients are generally followed more closely than the general population."

Everly, co-author and board-certified oncology pharmacist in the division, says that this data may change the way physicians screen transplant patients for cancer.

"We found that most cancers developed within five years following transplantation," he says, noting that more frequent and detailed checks should be made in order to catch the cancer in its earliest stages. "This may alter the way doctors should screen these patients for cancer."

Scientists trick immune system into accepting organ transplant

Tue, 07 Apr 2009 10:49:02 PST

( from http://www.rxpgnews.com ) Sydney, April 7 - In a significant breakthrough, scientists have tricked the immune system into accepting a new organ transplant as its own, eliminating dependence on toxic immunosuppressive drugs for a lifetime.

Jonathan Sprent and Kylie Webster from Sydney's Garvan Institute of Medical Research, with colleagues Shane Grey and Stacey Walters, have successfully tested the method on mice.

'Under normal circumstances, the body would attack a transplanted organ unless immunosuppressive drugs such as cyclosporin were given,' said Sprent.

'In this project, mice were given a substance, or 'complex', that altered their immune systems, so that they accepted transplanted cells as their own.'

Sprent developed the 'complex' with Charles Surh from California's Scripps Research Institute and Onur Boyman, physician, who heads the Basic Immunology Unit at the University Hospital of Lausanne in Switzerland, said a Garvan release.

The results are now online in the current edition of the Journal of Experimental Medicine.

Lung transplantation a viable option in patients under 70

Tue, 10 Mar 2009 22:55:53 PST

( from http://www.rxpgnews.com ) New research published in the March issue of the Journal of the American College of Surgeons suggests that lung transplantation should be used with caution in patients older than 60 years and that the procedure is associated with high rates of mortality after one year in patients 70 and older.

Lung transplantation has been the gold-standard treatment for a variety of end-stage lung diseases, but candidate selection varies greatly among transplantation centers. The International Society for Heart and Lung Transplantation (ISHLT) reports that since 1985 the percentage of older patients receiving lung transplantation has increased steadily, with 24 percent of recipients in 2006 being older than age 60. This trend has raised concerns among transplant centers, since there is no consensus on potential age limits for the operation.

"These data underscore the importance of carefully considering age among potential lung transplantation recipients," said Eric S. Weiss, MD, division of cardiac surgery, The John Hopkins Hospital, Baltimore, MD. "Although age is only one of many important criteria, advanced age appears to have a major impact on post-surgical mortality. Our findings suggest that lung transplantation remains a viable option for appropriate candidates younger than age 70."

This new research study in JACS expands on previous findings reported by Dr. Weiss and colleagues. In October 2007 (93rd annual Clinical Congress Congress of the American College of Surgeons), Dr. Weiss reported that lung transplants improved survival rates in patients over 60 years of age. In this previous study the Johns Hopkins researchers looked at factors that create positive results in a 60-plus patient population, which has typically been regarded as not being the best candidates for lung transplantation. Upon analyzing patient outcomes, the researchers found that the survival rates between older and young patients were not all that different, especially at the 30-day survival period, and they concluded that this elderly patient population should not be categorically excluded from being offered the procedure as a treatment option. In the study just released in JACS, the researchers are able to make more specific recommendations for patients in the 60 to 70-years of age range, and beyond.

This new retrospective study examined 8,363 adult patients who underwent lung transplantation between 1999 and 2006. The United Network for Organ Sharing (UNOS) database provided the data, which was stratified into four quartiles (Q) of age: Q1, 18 to 45 years; Q2, 46 to 55 years; Q3, 56 to 60 years; Q4, 61 to 79 years. Patients in Q4 were further examined in smaller increments of age to assess differences in outcomes among the oldest groups of transplant recipients.

Patients in all four age quartiles had similar 30-day and 90-day mortality rates, but patients in Q4 experienced the highest mortality rates at 1-year post-transplant (21.4 percent, p=0.002). Of the 57 patients identified as 70 or older, 34 percent of the patients died during the study period. Additionally, both the 90-day and the 1-year mortality rates of the 70 years or older cohort was significantly higher than those patients under 70 (27 percent versus 9 percent for 90 day; and 42 percent versus 18 percent for 1 year; p< 0.001 for both comparisons).

Lung transplants: Doing more is better and safer, a Johns Hopkins study suggests

Tue, 27 Jan 2009 05:00:00 PST

( from http://www.rxpgnews.com ) Transplant surgeons at Johns Hopkins have evidence that hospitals performing at least 20 lung transplant procedures a year, on average, have the best overall patient survival rates and lowest number of deaths from the complex surgery.

Researchers say their latest findings, to be presented Jan. 27 at the 45th annual meeting of the Society of Thoracic Surgeons in San Francisco, could serve as a patient safety benchmark or national standard for all hospitals to meet. The study is believed to be the first overall assessment since the procedure was perfected and widely adopted in the 1990s of how each of the 79 U.S. and Canadian medical centers licensed to perform lung transplantation measure up.

Institutions performing 20 more lung transplants annually, the researchers say, see the chances of an organ recipient surviving the critical first month of recovery plateau, at over 95 percent. Chances of recipients surviving the first year post-surgery are practically the same, at 83 percent. The contrast is sharp for the three-quarters of hospitals performing significantly fewer lung transplants. Then, an organ recipient's chances of dying within the first month after surgery nearly doubles, dropping survival rates to 90 percent if the hospital performs two or less per year, and to 73 percent after one year.

This, researchers say, occurred despite lower-volume centers having less severely ill patients than higher-volume centers.

Lung transplantation is an incredibly complex procedure, and our results show that the so-called '-center-effect-' is a very real phenomenon: Hospitals that do more, do them better, says study senior investigator and transplant surgeon Ashish Shah, M.D., who has performed over 100 lung transplants in the past decade For best patient outcomes, you need the right staff operating at peak skill level, with patient support systems ingrained in both their clinical operations and their organization's culture.

More than 1,400 lung transplants occurred in the United States in 2007, the last full year for which statistics are available. Thirty-nine percent of patients have survived for at least a year; 6 percent died within a month of surgery. Another 2,000 Americans remain on lung waiting lists, while 90 more are waiting for both a heart and lung.

Shah, an associate professor at the Johns Hopkins University School of Medicine and its Heart and Vascular Institute, says lung transplantation is unlike other kinds of transplant surgery. The lungs are at increased risk of infection during the procedure because the organ is exposed to the outside air and potential bacteria. Recuperation also takes longer than with other types of organ transplant, such as kidney, with patients often spending up to a week in post-surgical intensive care, plus many more months of specialized physical therapy.

The actual surgery, he points out, can cost $150,000 to $300,000 and involves a team of roughly 20 specially trained personnel, such as surgeons, an anesthesiologist, critical care specialists, many specially trained nurses, physical, respiratory and speech therapists, and dietitians.

As part of the latest analysis, researchers reviewed 10,494 patient records for all single-lung and double-lung transplants performed in the United States and Canada from 1998 to 2007. The data came from the United Network for Organ Sharing (UNOS), a national network that allocates donated organs across the country.

Our findings do not mean that only high-volume centers should perform lung transplantation, says lead study investigator Eric Weiss, M.D., a postdoctoral research fellow in cardiac surgery at Hopkins

But it does mean that patients should consider consistently high volumes when evaluating their choices of where to have their transplant done, and it does mean that lower-volume centers really do need to learn from the higher-volume hospitals, taking a careful look at what they are doing right to raise their survival rates and lower a recipient's chances of dying or suffering complications from surgery, says Weiss.

Weiss also performed a similar analysis of the center-volume effect in heart transplants, presented at the same meeting held last year.

Our hope is that this evidence will be useful in establishing budgets and staffing objectives so that low-volume centers, too, can steadily improve their patient outcomes in lung transplantations, says Shah.

Roughly 20 institutions perform 20 or more lung transplants annually, on average. They include The Johns Hopkins Hospital, with 25 in 2006, 21 in 2007 and 15 in 2008. On average, one-year survival rates at The Johns Hopkins Hospital, Shah says, have risen consistently with volume increases, from 70 percent in the early 1990s to 95 percent in 2007.

Discovery to help trick body into accepting transplants

Sat, 24 Jan 2009 14:50:17 PST

( from http://www.rxpgnews.com ) Sydney, Jan 24 - A discovery can trick the body into accepting tissues or transplants as its own, eliminating the necessity for immunity suppressing medicines.

Stacey Walters, a researcher in immunology at Garvan Institute of Medical Research, has found that mice genetically engineered to produce large amounts of B cell activating factor - do not reject transplants.

She has shown that increased numbers of B cells - in turn stimulate the production of T regulatory cells, which then control T cells, the body's killer cells.

The surprising thing about the results is that B cells, which make antibodies, were not known to have any role in the production of T regulatory cells. Nor would it have been thought possible for them to influence the body's response to a transplant, which has been considered a function of T cells only.

'In normal situations, something has to turn the immune system off once your body's fought an invader, such as a virus. It's the T regulatory cells that come in and say 'enough's enough',' Walters explained.

Just to make sure it was the B cells that were provoking the changes, she repeated her experiments on a mouse in which B cells were genetically knocked out, but high BAFF levels preserved. She found that when there are no B cells, normal allograft rejection occurs, said a Garvan release.

Walter's results provide an insight into previously unknown interrelationships between various classes of immune cells. Manipulating these relationships may offer a way of preserving organ grafts in the future without the need for toxic immunosuppressive drugs.

The findings have been published in the Journal of Immunology.

Single adult stem cell can self renew, repair tissue damage in live mammal

Sun, 14 Dec 2008 05:00:00 PST

( from http://www.rxpgnews.com ) The first demonstration that a single adult stem cell can self-renew in a mammal was reported at the American Society for Cell Biology (ASCB) 48th Annual Meeting, Dec. 13-17, 2008 in San Francisco.

The transplanted adult stem cell and its differentiated descendants restored lost function to mice with hind limb muscle tissue damage.

The adult stem cells used in the study, conducted at Stanford University, were isolated from a mixed population of satellite cells in the skeletal muscle of mice.

The skeletal adult muscle stem cells (MusSC), which live just under the membrane that surrounds muscle fibers, normally respond to tissue damage by giving rise to progenitor cells that become myoblasts, fusing into myofibers to repair the tissue damage.

The scientists transplanted the MusSC into special immune-suppressed nude mice whose muscle satellite cells had been wiped out in a hind limb by irradiation.

The mice would only be able to repair injury if the transplanted MuSC took. The scientists, Alessandra Sacco and Helen Blau, had genetically engineered the transplanted MusSC to express Pax7 and luciferase proteins. As a result, every transplanted cell glowed under ultraviolet light and was easy to trace.

To be able to detect the presence of the cells by bioluminescence was really a breakthrough, says Blau. It taught us so much more. We could see how the cells were responding, and really monitor their dynamics.

Through luminescent imaging as well as quantitative and kinetic analyses, Sacco and Blau tracked each transplanted stem cell as it rapidly proliferated and engrafted its progeny into the irradiated muscle tissue.

The scientists then injured the regenerated tissue, setting off massive waves of muscle cell growth and repair, and subsequently showed that the MuSC and descendents rescued the second animal's lost muscle healing function.

After isolating the luciferase-glowing muscle stem cells from the transplanted animal, the scientists duplicated, or cloned, the cells in the lab. Like the original MuSC, the cloned copies were intact and capable of self-renewal.

We are thrilled with the results, says Sacco. It's been known that these satellite cells are crucial for the regeneration of muscle tissue, but this is the first demonstration of self-renewal of a single cell.

The ability to isolate and then transplant skeletal adult muscle stems cells could have a wide impact in treating not only a variety of muscle wasting diseases such as muscular dystrophy but also severe muscle injuries or loss of function from aging and disuse.

In other experiments, the researchers transplanted between 10 and 500 luciferase-tagged MuSC into the leg muscles of mice.

These cells also proliferated and engrafted, forming new myofibers and fusing with injured fibers.

Unlike tumor cells, the transplanted stem cells achieved homeostasis, growing to a stable, constant level and ceasing replication.

After demonstrating that the transplanted stem cells proliferated and fully restored the animal's lost function, Sacco and Blau recovered new stem cells from the transplant with full stem cell potency, meeting the final gold standard test for adult multipotent stem cells.

Spanish surgeons achieve tracheal transplant breakthrough

Thu, 20 Nov 2008 17:37:23 PST

( from http://www.rxpgnews.com ) London, Nov 19 - In a surgical first, Spanish surgeons have achieved the world's first whole organ transplant using a windpipe made with the patient's own stem cells.

The tissue-engineered transplant resolves the danger of the body's rejection of foreign organs, making anti-rejection drugs redundant.

The transplant was carried out on Claudia Castillo, a 30-year old mother of two, at the Hospital Clinic of Spain's Barcelona in July when her windpipe narrowed after she contracted tuberculosis and needed a replacement to save her lung from being infected, BBC said.

To make the new airway, the doctors took a donor windpipe, or trachea, from a patient who had recently died.

They washed the tissues of the donor trachea with chemicals and relocated the organ with Castillo's own cells in a special chemical process.

The re-populated windpipe, when transplanted, convinced the body that it was a part of it, thereby avoiding the danger of rejection.

Five months on, Castillo is in perfect health, The Lancet reports.

Scientists from Bristol helped to grow the cells for the transplant and the European team believes such tailor-made organs could become the norm.

'Before this, we had been doing this work only on pigs,' Surgeon Professor Paolo Macchiarini of the Hospital Clinic of Barcelona, Spain, who led the operation, said. 'I was scared, but it went well.'

It went so well that four days after the transplant the organ merged with the body indistinguishably.

Castillo is living an active, normal life, and is able to look after her children Johan, 15, and Isabella, four. She can walk up two flights of stairs without getting breathless, medical reports said.

Martin Birchall, professor of surgery at the University of Bristol who helped grow the cells for the transplant, said: 'This will represent a huge step in surgery. Surgeons can now see and understand the potential for adult stem cells and tissue engineering to radically improve their ability to treat patients with serious diseases.'

He said that in 20 years time, virtually any transplant organ could be made in this way.

US scientists have already successfully implanted bladder patches grown in the laboratory from patients' own cells into people with bladder disease.

The European research team, which also includes experts from the University of Padua and the Polytechnic of Milan in Italy, is applying for funding to do windpipe and voice box transplants in cancer patients.

New technique eliminates toxic drugs in islet transplant in diabetic mice

Thu, 20 Nov 2008 05:00:00 PST

( from http://www.rxpgnews.com ) CHICAGO -- The body's immune system hates strangers. When its security patrol spots a foreign cell, it annihilates it.

This is the problem when people with type 1 diabetes undergo human islet cell transplantation. The islet cells from a donor pancreas produce robust amounts of insulin for the recipient -- often permitting independence from insulin therapy. However, the immune system tries to kill the new hard-working islets.

A person who has the transplant procedure must take powerful immunosuppressive drugs to prevent their bodies from rejecting the cells. The drugs, however, are toxic to the new islet cells and put patients at risk for infections and cancer.

Now researchers at Northwestern University's Feinberg School of Medicine have found a way to trick the immune system of mice into believing those transplanted islets are its own cells. This new technique eliminated the need for the immunosuppressive drugs in mice with chemically-induced diabetes after they had islet transplantation.

We made the recipient feel that the donor cells are their own, explained Stephen Miller, co-principal investigator and the Judy Gugenheim Research Professor of Microbiology-Immunology at the Feinberg School. This technique is a highly attractive potential therapy for human islet cell transplantation. The findings were reported in the journal Proceedings of the National Academy of Science in the fall.

As many as 3 million people in the U.S. may have type 1 diabetes, a disease that develops in children and adolescents. There are about 50 to 70 islet transplants, an experimental procedure, annually in North America.

Miller said he was happily surprised to see that such a high percentage of recipients of the transplanted islet cells -- greater than 70 percent -- maintained transplants long-term. His research showed the host's tolerance to these transplanted cells seemed to be permanent, lasting for at least 150 days. Xunrong Luo, assistant professor of medicine in nephrology at the Feinberg School, was co-principal investigator for the study.

In the study, researchers took a type of white blood cell from the islet donor's spleen, called splenocytes, and treated them with a chemical that masked the cells' identity. They then injected these chemically treated cells into diabetic mice before and after the mice underwent islet cell transplantation. As a result, the immune system of the mice didn't try to reject the cells, because it didn't perceive them as foreign and dangerous.

When the same test was done without pre-treated cells, the immune system rejected the transplanted islets within 15 days.

In an upcoming study, Miller and Luo will work with mice that have autoimmune disease that destroys their islet cells, as occurs in type 1 diabetes. Researchers will use therapies that prevent the autoimmune system's response against its own beta cells (which are part of the islets) as well as prevent the recipient's immune responses against the transplanted islet cells.

We have ways we can do both, Miller said. Hopefully this next study will show we can take combined therapies for underlying autoimmune disease and transplanted islets. If we do that together, we hopefully can cure an animal who became diabetic from autoimmune disease. If successful, the next step would be testing the technique on human subjects.

Miller said this technique also has applications for treating other autoimmune diseases such as multiple sclerosis.

Pure insulin-producing cells produced in mouse

Thu, 20 Nov 2008 05:00:00 PST

( from http://www.rxpgnews.com ) Singapore researchers have developed an unlimited number of pure insulin-producing cells from mouse embryonic stem cells (ESCs).

These pure insulin-producing cells, which according to electron microscopy studies, have the same sub-cellular structures as the insulin-producing cells naturally found in the pancreas, were highly effective in treating diabetes in the mouse model.

The transplants of pure insulin-producing cells reduced the blood glucose levels of diabetic mice with high blood glucose levels.

The experiments also showed that the subsequent removal of the transplanted cells from the diabetic mice restored the blood glucose to its original high level.

None of the diabetic mice involved in the transplant experiments developed teratoma, which are a type of tumour often associated with ESCs and which could complicate their use in human therapeutic treatment.

Furthermore, the pure insulin-producing cells managed to retain their insulin-production and glucose-sensing capacity over time.

The Singapore researchers' achievement provides proof of principle that this strategy could be applied to human ESCs to obtain similar pure insulin-producing cells.

These research findings were published in two separate papers in the July and August 2008 online versions of the journal Stem Cell Research.

Conducting the research were scientists at the Institute of Medical Biology (IMB), which is under Singapore's Agency for Science, Technology and Research (A*STAR), and the Yong Loo Lin School of Medicine (YLLSoM ) at the National University of Singapore (NUS).

The team of researchers was co-led by Dr. Lim Sai Kiang, an IMB principal investigator and a research associate professor at the YLLSoM Department of Surgery, and Dr. Li Guodong, a research associate professor at National University Medical Institutes, YLLSoM, NUS.

Commenting about these findings, Dr. Gordon Weir, Director of the Clinical Islet Transplantation Program at Harvard Medical School, who also holds appointments at the Harvard Stem Cell Institute and Joslin Diabetes Centre, said, The amount of careful work done by this group of researchers is impressive. We need something to put into diabetic patients to treat their condition, and these findings tell us interesting things about the development of beta cells.

The strategic approach by the group offers avenues for further research in the treatment for diabetes. Said Dr. Lim, Our ability to isolate and then multiply insulin-producing cells from differentiating ESCs provides an unlimited supply of pure insulin-producing cells to study in unprecedented detail many aspects of these cells.

Added Dr Li, Besides providing a tool to facilitate basic research in test tubes and animals, these insulin-producing cells may be also used to replace the isolated native pancreatic cells that are hard to obtain in a large amount, for pharmacological tests.

First trial of gene therapy for advanced heart failure shows promising results

Mon, 10 Nov 2008 05:00:00 PST

( from http://www.rxpgnews.com ) NEW YORK (Nov. 10, 2008) -- Phase I results of the first clinical trial of gene therapy for patients with advanced heart failure show the approach to be promising, with improvements in several measures of the condition's severity.

In Phase I clinical trials, researchers test a new treatment in a small group of people for the first time to evaluate its safety, determine a safe dosage range, and identify side effects.

Patients enrolled in the multicenter CUPID trial (Calcium Up-Regulation by Percutaneous Administration of Gene Therapy in Cardiac Disease) undergo a minimally invasive cardiac catheterization procedure which introduces a specially engineered gene that stimulates production of an enzyme necessary for the heart to pump more efficiently.

NewYork-Presbyterian Hospital/Columbia University Medical Center was the first to offer the therapy in the New York City area. The Hospital is now recruiting patients for the Phase II CUPID trial to further assess safety and effectiveness in patients with advanced heart failure.

Data from the Phase I trial, which was initiated in May of 2007, were presented at the American Heart Association (AHA) Scientific Sessions 2008 in New Orleans yesterday. Seven of nine patients who were given the drug showed improvements over six months in several areas: symptomatic (five patients), functional (four patients), biomarker (two patients) and left ventricular function/remodeling (six patients). Two patients with pre-existing antibodies to the viral vector delivery system did not show improvements. Importantly, the approach was shown to have an acceptable safety profile, as determined by an independent safety committee and by the study investigators.

We are encouraged by these initial findings, which indicate that this therapy has the potential to help patients with advanced heart failure, says Dr. Donna Mancini, the study's principal investigator at NewYork-Presbyterian Hospital/Columbia University Medical Center, where she is medical director of cardiac transplantation and is professor of medicine at Columbia University College of Physicians and Surgeons.

The Phase II randomized, double-blind, placebo-controlled clinical trial will compare the therapy at two- or three-dose levels with placebo. CUPID is expected to enroll 46 patients with advanced heart failure at 13 U.S. hospitals.

Gene therapy is a technique for correcting defective genes responsible for disease development by inserting genes into a patient's cells and tissues. In most gene therapy studies, a normal gene is inserted into the genome to replace an abnormal disease-causing gene. A carrier molecule called a vector must be used to deliver the therapeutic gene to the patient's target cells. Currently, one of the most common vectors is a non-pathogenic virus most people have been exposed to in adolescence that has been genetically altered to carry normal human DNA.

More than 5 million people in the U.S. have heart failure. Patients with severe form of the disease have trouble breathing because the heart muscle is not strong enough to pump fluid out of their lungs. Approximately 70 percent die of the disease within 10 years, and the five-year survival rate is less than 50 percent. Heart failure is the only cardiovascular disease whose incidence has been increasing rather than decreasing in recent years.

Experts discuss effects of chronic kidney disease on women's sexual health

Fri, 07 Nov 2008 05:00:00 PST

( from http://www.rxpgnews.com ) Chronic kidney disease (CKD) exacts a significant toll on a woman's sexuality and gynecologic health. The various effects of kidney failure and its treatments on women's sexual health from adolescence through menopause will be the topic of an in-depth series of presentations at the American Society of Nephrology's 41st Annual Meeting and Scientific Exposition in Philadelphia, Pennsylvania.

Women whose kidneys are failing experience hormonal changes that can have numerous adverse effects on the body. In a program moderated by Margaret J. Bia, MD, of the Yale University School of Medicine in New Haven, Connecticut, and Denyse Thornley-Brown, MD, of the University of Alabama at Birmingham, experts will explore the sexual life cycle of women with CKD and discuss the medical impacts that kidney disease has on their sexuality from childhood through advanced age.

Lynne P. Yao, MD, of the Inova Fairfax Hospital for Children in Fairfax, Virginia, will highlight the latest information on issues of adolescence, revealing the abnormalities that can develop in girls with CKD. These children are particularly vulnerable and can experience impaired growth and abnormal menstrual cycles due to altered metabolism and hormone deficits. Physicians face a number of challenges that are unique to treating these patients.

Next, Tracy Breen, MD, of the Mount Sinai School of Medicine in New York City will discuss how CKD can contribute to ovarian failure and premature menopause. Because kidney disease disrupts the balance of hormones produced by the body, women with the condition can experience symptoms of menopause at a young age.

Susan H. Hou, MD, of the Loyola University Health System in River Forest, Illinois, will then provide an overview of issues related to pregnancy and fertility in female kidney disease patients. Fertility is decreased in these women, and when they do conceive, the likelihood of a healthy and successful pregnancy is less than that seen in women without kidney disease. Females with kidney disease who become pregnant also risk developing hypertension and kidney function loss. Dr. Hou will highlight the many strides that have been made in improving the health of pregnant women with kidney disease as well as the serious issues that must still be addressed to make it safe for these women to become pregnant and give birth.

Finally, Manjula Kurella-Tamura, MD, of Stanford University in Palo Alto, California, will present information on menopause and hormone replacement therapy in women with CKD. Because estrogen may have a protective effect against developing kidney disease, many women are not diagnosed with kidney disease until they reach menopause. Between 40 and 70% of women with CKD are menopausal and therefore are likely to consider taking hormone replacement therapy to relieve their symptoms. Dr. Kurella-Tamura will discuss the controversies regarding the use of hormone replacement therapy in these women and whether recommendations should be any different than those for women with normally functioning kidneys.

ERSD, heart disease and African-Americans with hypertensive nephrosclerosis

Thu, 06 Nov 2008 05:00:00 PST

( from http://www.rxpgnews.com ) For most patients with chronic kidney disease (CKD), the risk of experiencing a cardiovascular related death is greater than the risk of progressing to end-stage renal disease (ESRD). According to research being presented at the American Society of Nephrology's 41st Annual Meeting and Scientific Exposition in Philadelphia, Pennsylvania, African Americans with CKD caused by high blood pressure (hypertensive nephrosclerosis) demonstrated a higher risk of progressing to ESRD than dying from heart disease related events.

Tahira Alves, MD, of Vanderbilt University in Nashville, Tennessee, will present the cardiovascular and renal results from the AASK (African American Study of Kidney Disease) Cohort Study (2002-2007), which followed the original AASK Trial (1996-2001). Of 1,094 eligible patients from the original AASK Trial, 691 were enrolled in the subsequent AASK Cohort study. The patients received intensive follow-up to keep their blood pressure at a target level of less than 130/80 mm Hg (millimeters of mercury). The average age at the start of the study was 55 years.

During 11 years' follow-up, the patients were at higher risk of progressing to ESRD than of experiencing cardiovascular disease events such as myocardial infarction (heart attack). For each 100 patient-years of follow-up, there were four cases of ESRD (permanent loss of kidney function requiring dialysis or transplantation). By comparison, the rate of cardiovascular disease events was 3.2 per 100 patient-years.

The risk of death from cardiovascular disease was 0.8 per 100 patient-years. Of 74 deaths that occurred during the Cohort period of the AASK Study, more than 60 percent were from causes other than cardiovascular disease.

The finding that ESRD risk is higher than cardiovascular risk for African Americans with hypertensive nephrosclerosis is in direct contrast to what has been previously reported in other CKD populations. The AASK trial and the subsequent cohort study allow the medical community to gain a broader understanding of incident cardiovascular disease and mortality during long-term follow-up in an entirely African-American population with nondiabetic hypertensive nephrosclerosis, comments Dr. Alves.

The findings are limited by the fact that the primary goal of the AASK trial was to detect changes in kidney function, ESRD, and/or risk of death. Cardiovascular events were measured as a secondary outcome.

The results may provide additional insight into the relationship between high blood pressure and kidney disease in African Americans, as well as some of the reported racial differences in the rates and outcomes of ESRD. The study is timely given the increased recognition of medical health disparities observed among African American patients, Dr. Alves adds. This type of information is needed if solutions are to be sought at the clinical and policy levels.

Breakthrough to nip transplant rejection in the bud

Fri, 31 Oct 2008 12:25:11 PST

( from http://www.rxpgnews.com ) London, Oct 31 - A chance discovery by biologists will help trick the immune system into believing that a transplanted organ is the body's own, not a foreign element, nipping its rejection in the bud.

The scientists confirmed the two-way transfer of a molecule called MHC that instructs the immune system to tell 'self' from 'non-self'. By disrupting this, transplanted organs should become 'invisible' to the host's immune system, hence out of the pale of attacks.

Such an advance would be a major medical breakthrough because current methods of preventing organ rejection involve weakening the host's immune system, which can lead to life-threatening infections.

The researchers made this discovery when they transplanted kidneys or hearts from one set of mice into another, with each set of mice having a different version of the molecule being studied.

They then conducted tests to see if the molecules were transferred. In the recipient mice, the donated kidneys or hearts and the host tissue expressed both types of molecules. This is the first time that this transfer has been shown to happen in a living system.

Wilson Wong, senior researcher from King's College London, said that 'that this study will lead to a better understanding of the immune system to benefit the development of new therapies in areas related to transplantation.'

'The medical potential of this finding is enormous,' says Gerald Weissmann, a doctor and editor-in-chief of The FASEB Journal, which carried the report.

'Understanding molecular miscegenation - should not only make transplantation more widespread and effective, but also shed light on how microbes disrupt our body's immune apparatus for distinguishing self from non-self,' he added.

The FASEB Journal - is published by the Federation of American Societies for Experimental Biology - and is the most cited biology journal worldwide, according to the Institute for Scientific Information.

Anti-seizure drug could be fatal

Tue, 28 Oct 2008 04:00:00 PST

( from http://www.rxpgnews.com ) Patients treated for their prolonged seizures with the sedative propofol may be at high risk for complications and even death. New research presented at CHEST 2008, the 74th annual international scientific assembly of the American College of Chest Physicians (ACCP), shows that the use of propofol as an antiepileptic agent in patients with refractory status epilepticus (RSE), prolonged seizures that do not respond to initial treatment, was associated with significant mortality and morbidity.

RSE is a difficult clinical problem seen in patients with primary epilepsy and in those with other conditions such as trauma, tumors, and infections affecting the brain. Although propofol is used to treat patients with RSE, it is more commonly used for sedation during surgeries or other patient procedures but at a much lower dose and shorter duration than that used for the control of seizures.

Patients with RSE treated with propofol are at high risk for propofol-related side effects because of the high propofol infusion rates and prolonged treatment duration necessary in these patients, said Vivek Iyer, MD, Mayo Clinic, Rochester, MN. However, it is well described that propofol toxicity can occur even with brief exposure to the drug.

Dr. Iyer and his colleagues from Mayo Clinic reviewed 39 consecutive patients (median age of 54 years) from 1997 to 2007, who were admitted to the ICU with RSE, in order to examine the link between propofol use and related side effects, including propofol infusion syndrome (PRIS). PRIS is a usually fatal complication of propofol use that has been reported especially at high infusion rates for prolonged periods. For this study, PRIS was defined by the unexplained presence of at least one or more of the following: metabolic acidosis, rhabdomyolysis, bradycardia, and/or cardiac arrest.

Propofol was used in 32 (82 percent) of the patients (group A) for a median of 63 hours and a median peak infusion rate of 67 mcg/kg/min. Other agents, such as midazolam and pentobarbital, were used in the other seven (18 percent) patients (group B). Within group A, three patients had sudden unexplained cardiac arrest while on propofol infusions, resulting in two deaths, while no deaths occurred in group B. Median hospital stay (12 days) and ICU length of stay (9 days) did not differ between the two groups. The overall occurrence of PRIS was 30 percent of patients in group A (seven patients with bradycardia, three patients with sudden unexplained cardiac arrest) compared with less than 3 percent (one patient with bradycardia) in group B.

In light of the new data, Dr. Iyer advises that caution should be taken with the use of propofol to treat patients with RSE. There are several other medications we can turn to in the case of uncontrolled seizures, he said. Alternative agents should first be tried for patients with RSE, and propofol should only be used after exhausting all other options.

With increasing awareness of the risks of propofol, physicians may become more cautious about using propofol for prolonged periods and at high doses, James A. L. Mathers, Jr., MD, FCCP, President of the American College of Chest Physicians.

Study points to 1 cause of higher rates of transplanted kidney rejection in blacks

Fri, 29 Aug 2008 04:00:00 PST

( from http://www.rxpgnews.com ) A Johns Hopkins research team reports it may have an explanation for at least some of the higher organ rejection rates seen among black - as compared to white - kidney transplant recipients.

In a study of 50 healthy adult men, 25 black and 25 white, significantly different amounts of certain immune system cells were found between the races.

These cells, known as human leukocyte antigen-specific, or HLA-specific B cells, when sensitized produce antibodies linked to transplanted kidney rejection, says Andrea Zachary, professor of medicine at Johns Hopkins and lead researcher of the study.

It's been long known that HLA-reactive antibodies produced by B cells are one of the ways that transplanted organs are rejected. Zachary developed a novel method for counting HLA-specific B cells more accurately, leading to the hypothesis that B cell numbers make a difference in transplant retention and rejection.

Now that we have an accurate way to count these cells, we are able to confirm what we long suspected, that blacks might have a bigger army of HLA-specific B cells, says Zachary who presented her findings at the Congress of the International Transplant Society in Sydney, Australia on Aug. 12.

Zachary says that patients become sensitized when exposed to HLA in blood or tissue that is not their own. Sensitized HLA-specific B cells then produce antibodies that attack transplanted organs containing foreign HLA. Patients can become sensitized from a blood transfusion, transplantation or pregnancy.

If the recipient is not sensitized, B cells represent only a patient's potential for making antibodies, says Zachary. However about a third of patients in need of a kidney are sensitized since they're often on their second or third transplantation and may have undergone transfusions. In the study, Zachary and her team gathered blood samples from 25 adult black males and 25 adult white males. They were all healthy and all non-sensitized. They also gathered blood samples from 10 sensitized adult black males and 25 sensitized white males.

Results showed that the black non-sensitized males tested had an average of 17.2 percent more HLA-sensitive B cells than the white non-sensitized males tested. Among the sensitized group, black males had an average of 22.9 percent more HLA-sensitive B cells than white males.

HLA antigens are proteins that sit on the surface of blood and tissue cells. Each person has a specific set, similar to a fingerprint. Rejection of a transplant occurs when the recipient's immune system sees the donor's HLA antigens as foreign and attacks those antigens with cells or antibodies. The amount of antibody made depends on the number of B cells a recipient has.

Knowing that blacks have an increased number of HLA-specific B cells - which increases their opportunity for antibody-mediated rejection - we may be able to customize treatments for black recipients to account for these differences and lessen the likelihood that the organ will be rejected, says Zachary.

Cartilage regeneration '20,000 Leagues Under the Sea'

Wed, 04 Jun 2008 04:00:00 PST

( from http://www.rxpgnews.com ) HOUSTON, June 4, 2008 -- Bioengineers at Rice University have discovered that intense pressure -- similar to what someone would experience more than a half-mile beneath the ocean's surface -- stimulates cartilage cells to grow new tissue with nearly all of the properties of natural cartilage. The new method, which requires no stem cells, may eventually provide relief for thousands of arthritis sufferers.

This tissue-engineering method holds promise not only for cartilage but also for tissues to repair bladders, blood vessels, kidneys, heart valves, bones and more, said lead researcher Kyriacos Athanasiou, Rice's Karl F. Hasselmann Professor of Bioengineering.

The findings appear this week in the journal PLoS ONE. They are the latest from the emerging field of tissue engineering, a new discipline that aims to capitalize on the body's innate healing abilities to develop new ways of growing tissues that can be used to surgically repair wounds without risk of rejection.

Cartilage, a tissue in the human body that cannot heal itself, has long been a target of tissue engineers. Cartilage is the skeleton's shock absorber, and its stiffness, strength and other mechanical properties derive not from living cartilage cells but from the densely woven matrix of collagen and proteoglycan that surrounds them. This extracellular matrix, or ECM, is produced during cartilage development in children, but cannot be repaired following injury in adulthood.

Injured cartilage often serves as the focal point for arthritis formation, so tissue engineers have long sought a means of growing new cartilage that can be transplanted into adults to repair damaged joints before arthritis can develop. Unfortunately, cartilage is difficult to engineer, in part because there are no natural healing processes to mimic.

Athanasiou's Musculoskeletal Bioengineering Laboratory has focused on cartilage for more than 10 years, and he said the new process is the first he has studied that produces cartilage that's almost identical to the body's own tissue.

The combination of hydrostatic pressure and growth factors used in this process result in an engineered cartilage ECM with properties nearly identical to that of native cartilage, he said. This research appears very promising for treating arthritis, as cartilage can now be produced in our lab that is almost identical in composition to native tissue.

So far, the process has been tried only with cells from cows and has yet to be tested in live animals. Athanasiou cautions that it will be several years before the process will be ready for clinical testing in humans.

The new findings are based on three years of data collected by graduate student Benjamin Elder, who is simultaneously earning a doctorate in bioengineering at Rice and a medical degree at Baylor College of Medicine under Rice and Baylor's Medical Scientist Training Program.

In the study, Elder took small samples of cartilage from calves' knees, dissolved the ECM and isolated the living cartilage cells, or chondrocytes. The calf chondrocytes were used to create tissue-engineered cartilage. The engineered cartilage was placed into a chemical bath of growth factors and sealed inside soft plastic containers that were placed inside a chamber connected to a hydraulic press. For one hour per day, the bags were squeezed at intense pressures.

Our knees are filled with fluid, and when we walk or run the hydrostatic pressure on the cartilage cells in the knee approaches the pressures we used in our experiments, Elder said. But in daily activities, these pressures are fleeting, just a second or so at a time.

Most of the prevailing strategies in tissue engineering attempt to reproduce the conditions that cells experience in the body. Athanasiou said the unconventional approach of using unnaturally high-pressure stemmed from insights gained during years of previous experiments.

Elder said, By combining high pressure and growth factors, we were able to more than triple the biomechanical properties of the cartilage. We're not sure why they reinforce one another, but we do not get the same results when we apply them independently.

Elder, who earned both a bachelor's and master's degree from Yale in four years, has a 4.2 grade point average at Rice and is on track to earn his bioengineering doctorate in just three years. He's already finished two years of medical school and will resume his medical studies in the fall.

Ben's an exceptional student and he embodies the future of this field, Athanasiou said. He plans to pursue a career in neurosurgery, where he will be able to conduct future work in tissue engineering and translate it from the laboratory bench to the patient's bedside.

U of M sets course for cure of fatal childhood skin disease

Tue, 03 Jun 2008 04:00:00 PST

( from http://www.rxpgnews.com ) Physicians at the University of Minnesota and University of Minnesota Children's Hospital, Fairview have set the path to a cure for a young boy's fatal genetic skin disease, recessive dystrophic epidermolysis bullosa (RDEB), by using a cord blood and bone marrow transplant. Nate Liao, a 25-month-old from Clarksburg, N.J., underwent the experimental therapy in October 2007.

We have established a new standard of care for these EB patients, beginning with Nate, said John Wagner, M.D., the lead University of Minnesota Medical School physician who developed the clinical trial. Nate's quality of life is forever changed.

Because they lack collagen type VII, children with RDEB have skin that is exquisitely delicate. The skin and lining of their gastrointestinal (GI) tract is fragile; tearing and blistering occur with minimal friction. Coughing and vomiting often result in tears in the lining of the esophagus and stomach. Those affected must have their entire body continuously wrapped in bandages. Those who do not succumb from malnutrition and infection in childhood will acquire a uniformly fatal, aggressive cancer of the skin in young adulthood.

In collaboration with Angela M. Christiano, Ph.D., professor of dermatology and genetics and development at Columbia University Medical Center (New York, N.Y.), and investigators at Asahikawa Medical College (Asahikawa, Japan), and Jefferson Medical College (Philadelphia, Penn.), University of Minnesota researchers, Jakub Tolar, M.D., Ph.D., and Bruce Blazar, M.D., discovered that certain stem cells found in bone marrow could correct the biochemical defect in RDEB in a mouse model of the disease. Marrow-derived stem cells greatly lengthened the life expectancy of the mice and healed existing blisters. Further testing by Columbia demonstrated that for the first time, these mice were producing collagen type VII and anchoring fibrils, the structures needed to bind skin to the body.

This is the first time physicians have approached the treatment of RDEB from a systemic perspective, using marrow-derived stem cells as a means to replace the missing protein, collagen type VII, throughout the body. Through the infusion of cells obtained from a healthy donor, the stem cells produce collagen type VII and correct the underlying genetic defect.

In October 2007, Nate Liao received marrow- and umbilical cord blood-derived stem cells and progenitor cells from his healthy, tissue-matched brother. Over the next six months, the skin and lining of his GI tract slowly improved, and skin biopsies on days 60, 130, and 200 documented increasing amounts of collagen type VII. By day 130, Nate's skin and the lining of his GI tract were beginning to show clinical signs that his skin was anchoring to his body.

Wagner and his team sought an external review of the skin biopsies. Photographs of the biopsies have been sent to dermatopathologists in London, England, and Portland, Ore., for independent analysis. Based on the success seen in Nate, Wagner will enroll additional RDEB patients into the clinical trial. Jacob Liao, Nate's brother who also has RDEB, received an unrelated donor cord blood transplant on May 30.

Study finds good outcomes for older lung transplant patients

Tue, 05 Feb 2008 06:40:00 PST

( from http://www.rxpgnews.com ) In the world of organ donation, it has been common practice to exclude older patients from receiving transplants because of limited donor supply and lower survival rates.

However, patients such as Lois Tumanello, who received a successful lung transplant at 65, are proving that perhaps age does not always matter.

A new UCLA Medical Center study shows that select patients age 65 and older can safely undergo lung transplantation and have acceptable outcomes. The findings are reported in the February issue of the peer-reviewed Journal of Thoracic and Cardiovascular Surgery.

Since 1999, UCLA has been one of the few transplant centers in the country to offer lung transplants to patients 65 and older who were otherwise healthy candidates for the procedure.

Over the past decade, various reports have shown that older recipients undergoing all types of solid-organ transplantation can have good outcomes, said study co-author Dr. Abbas Ardehali, associate professor of cardiothoracic surgery and director of the UCLA Lung Transplant Program. We wanted to define the short- and medium-term outcomes of lung transplantation in these older patients to determine whether the outcomes were acceptable.

The study reviewed records of UCLA patients who received lung transplants between March 2000 and September 2006. During this period, 50 transplant surgeries were performed on 48 patients between the ages of 65 and 72. A group of 50 patients younger than 65 were matched to the older cohort for comparison purposes.

Survival rates for both groups were similar. The early survival rate of the older patients was 95.7 percent, compared with 95.9 percent for the younger cohort. The one-year survival rate was 79.7 percent for the older group and 91.2 percent for the younger, and the three-year survival rate was 73.6 for the older group and 74.2 percent for the younger.

Researchers found that older patients were more likely to receive single-lung transplants (76 percent, compared with 16 percent for the younger group) and to receive nonstandard lungs (46 percent, compared with 28 percent). Nonstandard lungs are those considered less than perfect but still acceptable for transplantation.

Stanford study finds transplant patient thrives 2 years after stopping immunosuppressive drugs

Wed, 23 Jan 2008 05:00:00 PST

( from http://www.rxpgnews.com ) STANFORD, Calif. - Luck smiled on Larry Kowalski when his brother agreed to donate a kidney Kowalski needed to live. He was even luckier that his brother's kidney was such a good match.

That last stroke of luck led Kowalski to connect with a team of researchers at the Stanford University School Medicine, whose efforts have enabled him for two years to live free of the heavy-duty drugs that transplant patients normally have to take for the rest of their lives.

The researchers describe Kowalski's case in a brief report to be published in the Jan. 24 issue of The New England Journal of Medicine on the technique they developed, based on 25 years of research by Samuel Strober, MD, professor of immunology and rheumatology. The journal issue also includes two reports from other research groups, describing their efforts to achieve organ transplantation without long-term immunosuppressive drugs.

Kowalski, now 50, was 3 years old when doctors discovered he had been born with only one kidney. His single kidney held out until he was 47. Then a blood test indicated that it was beginning to fail.

Kowalski's 49-year-old brother agreed to help, and that turned out to be crucial. His brother was a perfect fit of the six proteins most important in matching the immune systems of transplant donors with recipients.

Transplant recipients are matched as closely as possible with the donor organs to minimize the body's normal response to reject the organs. The biggest danger with organ transplantation lies not in the surgery, but in the recipient's own body rejecting the organ as a foreign invader. Without drugs to suppress that reaction, usually the recipient's immune system encounters unfamiliar proteins on the transplanted organ, attacks the organ and eventually destroys its function.

But unless the recipient has an identical twin, there will always be some minor differences between the organs, so even close matches require a lifetime of immunosuppressive drugs. Long-term use of these drugs can cause cancer, bothersome side effects and, most ironic for kidney transplant recipients, kidney damage.

The ultimate goal for transplant patients is to get their bodies to tolerate their donor organs without drugs. Transplant doctors have been trying to develop ways to do this for years, with little success.

The fact that Kowalski had such a good match with his brother's kidney made him an ideal candidate for the Stanford clinical study. The researchers were investigating whether a procedure that involved adjusting Kowalski's immune system, plus infusing blood cells from the brother who donated the kidney, could allow Kowalski's body to tolerate his brother's kidney.

The therapy was first developed in mice by Strober, the senior author of the study. In the last few years, Strober worked with Robert Lowsky, MD, associate professor of blood and marrow transplantation, to adapt this strategy from mice for human lymphoma and leukemia patients. The procedure combines localized blasts of irradiation and antibody treatments to tweak the recipient's immune cells. Then the recipient gets an infusion of blood cells from the donor. The procedure boosts levels of a type of immune cell called regulatory T cells. These cells function as the immune system's peacekeepers and can avert the attack that causes rejection.

When the Stanford transplant team approached Kowalski with the offer, he jumped at the chance that might allow him to forego a lifetime of immunosuppressive drugs.

In February 2005, Kowalski received his brother's kidney at Stanford Hospital. He was started on an immunosuppressive drug with the intention that it would be temporary. His only notable complication came about a month after his transplant, when Kowalski had to be hospitalized briefly for a fever. He returned to work as a restaurant owner three months after the transplant.

Doctors began to taper the use of the immunosuppressive drug and, after six months, Kowalski was drug-free.

Essentially, my immune system contains half my brother's immune cells and half of my own, said Kowalski. It's enough that my body thinks my brother's kidney is mine.

After all the mouse studies leading up to testing in patients, Kowalski's case is rewarding for Strober. It's been a long, long road that ends up with clinical trials that could lead to somebody's benefit, he said. Tolerance has been the goal for decades, and we are just now beginning to see the fruits of all that labor.

Kowalski could be called the poster child of the procedure so far, but others in the same research study haven't fared as well. Six other patients treated before him haven't been able to go off of their drugs, but their kidneys came from donors not as perfectly matched as Kowalski's was.

He was the first patient in a new iteration of the technique that is being tried only in perfectly matched donors and recipients. So far, one patient that followed Kowalski is showing promising results but is not yet off the drugs, said lead author John Scandling, MD, professor of nephrology and Kowalski's kidney transplant specialist.

The research team found Kowalski remains in good health 34 months after he stopped taking the immunosuppressive drugs. An interview with Kowalski shows this to be an understatement. Not only does he run four restaurants in California, but he bikes, snowboards, scuba dives, goes to the gym regularly and, most taxing of all, is the father of a 3-year-old. By anyone's definition, he is in great health.

The idea of getting off drugs holds tremendous appeal for patients, said Scandling. So far, there is hope, but we still have a long way to go.

Researcher transplants stem cells to try to save patients' legs

Mon, 21 Jan 2008 05:00:00 PST

( from http://www.rxpgnews.com ) CHICAGO -- A Northwestern University Feinberg School of Medicine researcher has launched the first U.S. trial in which a purified form of subjects' own adult stem cells was transplanted into their leg muscles with severely blocked arteries to try to grow new small blood vessels and restore circulation in their legs.

The first two subjects in the 20-site national trial recently underwent the stem cell transplant process at Northwestern Memorial Hospital.

Severely blocked arteries in the leg and sharply diminished blood flow can result in wounds that don't heal, the breakdown of tissue and gangrene. This painful condition is called critical limb ischemia (CLI) and results in the amputation of more than 100,000 limbs every year in the United States. It's a serious, emerging health problem that affects 1.4 million people. An estimated 15 percent of the population will have this disease by the time they reach age 70.

The Northwestern-led phase I/IIa study -- which will include 75 people with CLI around the country -- targets patients who have exhausted all other medical options including angioplasty, stents and bypass surgery to repair blocked circulation in their legs.

They're at the end of the therapeutic road and they're ultimately facing potential amputation, said Douglas Losordo, M.D., the Eileen M. Foell Professor of Heart Research and principal national investigator for the study. This is hopefully a way to help them avoid that.

Losordo is director of the university's Feinberg Cardiovascular Research Institute and director of cardiovascular regenerative medicine at Northwestern Memorial Hospital.

The stem cells themselves can assemble into blood vessels, Losordo said. They can also secrete growth factors that stimulate and recruit other stem cells to come into the tissue and help with the repair. It's an amazing biology we're trying to leverage in these folks.

He said preclinical studies transplanting stem cells into the limbs have shown this approach to be effective in mice and rats. Based on that, we think it has a good chance of helping humans, Losordo noted.

This is a dreadful disease in which the profession has failed to offer much in the way of relief for these patients, Losordo said. We're hoping this will have some impact.

Critical limb ischemia is the result of advanced peripheral artery disease, which affects about 10 million people in the United States. In peripheral artery disease, people develop blockages in their arteries and vessels that slow or stop the blood flow to their legs. When they have pain at rest in their lower legs and wounds on their legs or feet that will not heal, the condition is called CLI. If left untreated, CLI can result in a patient having toes, a foot or even a leg amputated.

As CLI progresses, people begin to experience pain when they walk, then when just sitting. The worst pain is at night because blood flow is decreased when people lie down. Some have to sleep in chairs to aid the blood flow and lessen the pain.

Peripheral artery disease is a big health problem, Losordo said. There is an emerging awareness of this disease on public health.

High blood pressure, high cholesterol, smoking and diabetes all raise the risk of having the condition. But some people don't smoke, have diabetes or high blood pressure and can still have blocked arteries in their legs, Losordo said.

For the randomized, double blind, placebo-controlled trial, Losordo uses the subject's own purified stem cells. The subject first takes a drug for five days to stimulate the release of his or her stem cells, called CD34+ cells, from bone marrow. An intravenous line is then inserted into a subject's vein to collect blood through a machine that removes a population of blood cells that contains the CD34+ stem cells. Losordo further selects and enriches the cells to select only CD34+ cells.

Implanting embryonic cardiac cells prevents arrhythmias

Wed, 05 Dec 2007 05:00:00 PST

( from http://www.rxpgnews.com ) When researchers at Cornell, the University of Bonn and the University of Pittsburgh transplanted living embryonic heart cells into cardiac tissue of mice that had suffered heart attacks, the mice became resistant to cardiac arrhythmias, thereby avoiding one of the most dangerous and fatal consequences of heart attacks.

The discovery, reported in this week's issue of Nature, has profound implications for using cell-transplant therapies to restore damaged heart tissue.

The researchers, including Michael Kotlikoff, the Austin O. Hooey Dean of Cornell's College of Veterinary Medicine, one of the paper's senior authors, discovered that a protein called connexin43, expressed by the transplanted embryonic heart cells, improved electrical connections to other heart cells. The researchers showed that the improved connections helped activate the transplanted cells deep within the damaged section of the heart tissue. The technique reversed the risk of developing ventricular arrhythmias after a heart attack, the number one cause of sudden death in the Western world.

In the past, scientists have transplanted a variety of cell types into failing hearts with modest improvement of function, although transplanting skeletal muscle cells made things worse and led to more arrhythmias. Surprisingly, when co-author Bernd Fleischmann at the University of Bonn and colleagues transplanted embryonic cardiac cells, the hearts' electrical stability and function returned to normal.

Scientists recognize the untapped potential of using cell-based therapies to counter many debilitating diseases, but they have not had tools to assess the function of the cells once transferred. In Kotlikoff's laboratory, the researchers determined that the transplanted embryonic cells were making electrical connections with normal heart cells. Using genetically modified heart cells that express a fluorescent sensor, they established that transplanted heart cells were activated during normal heart contractions.

For the first time we were able to see how cells used in therapy are working with other cells in a complex organ within a living animal, establishing the mechanism of the therapeutic effect, Kotlikoff said.

Professor Guy Salama at the University of Pittsburgh School of Medicine was also able to map voltage signals across the surface of the hearts, establishing that the implanted cells improve conduction of electrical signals within the damaged heart tissue.

While doctors could never use cells from a human embryonic heart for transplantation, researchers at the University of Bonn engineered skeletal muscle to express connexin43 and achieved the same restorative results as they did with the embryonic heart cells.

These results have important implications for therapy, although they must be verified in the context of naturally occurring heart damage, Kotlikoff said. One can envision using a patient's own cells by deriving heart cells from stem cells to improve heart function and decrease arrhythmia risk.

Cross-species transplant in rhesus macaques is step toward diabetes cure for humans

Thu, 18 Oct 2007 04:00:00 PST

( from http://www.rxpgnews.com ) St. Louis, Oct. 18, 2007 � With an eye on curing diabetes, scientists at Washington University School of Medicine in St. Louis have successfully transplanted embryonic pig pancreatic cells destined to produce insulin into diabetic macaque monkeys � all without the need for risky immune suppression drugs that prevent rejection.

The transplanted cells, known as primordia, are in the earliest stages of developing into pancreatic tissues. Within several weeks of the transplants, the cells became engrafted, or established, within the three rhesus macaque monkeys that received them. The cells also released pig insulin in response to rising blood glucose levels, as would be expected in healthy animals and humans.

The approach reduced the animals' need for insulin injections and has promise for curing diabetes in humans, says senior investigator Marc Hammerman, M.D., the Chromalloy Professor of Renal Diseases in Medicine. The transplants worked without a need for immune suppression and that is a major obstacle we have overcome.

The researchers' results appear online and will be published in the journal Xenotransplantation in November.

Although the transplants fell short of producing sufficient insulin to cure the macaques' diabetes, Hammerman predicts that with additional research, including the transplantation of additional embryonic pig cells into the animals, he will be able to reduce their need for insulin injections entirely.

The new research follows on the heels of reports by Hammerman and his colleagues demonstrating that transplanted pig pancreatic primordia can cure both type 1 and type 2 diabetes in rats, without using immune suppression drugs. Other scientists have tried different types of pancreatic cell transplants � in animals and humans � as a stepping stone to curing diabetes, but they all require anti-rejection drugs. These drugs must be taken daily to stave off rejection and have adverse effects of their own that limit the success of the transplants.

As a treatment for diabetes in people, pig insulin typically works as well as the human form. Before recombinant DNA technology enabled pharmaceutical companies to manufacture human insulin in the 1980s, pig and cow insulin were routinely given to diabetic patients.

The primates in the current study had type 1 diabetes, the form that occurs when islet cells in the pancreas stop producing insulin all together. The Washington University researchers transplanted 19 embryonic pig pancreatic primordia into each diabetic monkey. Each primordium is smaller than the diameter of a period that ends a sentence and is transplanted into a membrane that envelops the intestines and other digestive organs.

The transplanted cells were retrieved from the pig embryos early in their development, which is believed to render them invisible to the primates' immune system or induce a state of tolerance, either of which eliminates the need for immune suppression.

The researchers determined by multiple methods that the transplanted cells became established within the primates. And as the cells matured, they began to release pig insulin. We found using every method that the cells engraft long-term and, thus, are not rejected by the animals' immune systems, Hammerman says. It's been more than two years since our first transplant was carried out. That particular primate doesn't produce any primate insulin, but has pig insulin circulating in its bloodstream that has reduced by more than 50 percent the amount of injected insulin the animal needs, compared to levels before the transplant. The animals have never received immune suppression drugs.

Two of the macaques remain healthy. One, however, became anemic about six weeks post-transplant and was euthanized a month later after developing acute respiratory distress. The researchers could not find a link between this animal's illness and the pancreatic cell transplants.

The two remaining macaques have each received two transplants of embryonic pancreatic cells. One of the animals has been followed for 23 months after his first transplant, and the amount of insulin he needs to have injected has declined by some 55 percent over baseline levels. The other macaque has been followed for 10 months after his initial transplant, and his need for injected insulin continues to decline over time.

Hammerman and his colleague Sharon Rogers, research instructor in medicine, are leaders in the emerging field of organogenesis, which focuses on growing organs from transplanted embryonic organ precursors known as primordia. Unlike embryonic stem cells, which can become virtually any cell type, primordia are locked into becoming cells of a particular organ.

We are encouraged by these results, Rogers says. The absence of a need for immune suppression in diabetic rats gave us hope that we were on the right track. But many findings in rats do not hold true for species that are more closely related to humans, such as non-human primates. This one did.

The team will now determine how best to eliminate the need for injected insulin in the diabetic macaques that receive transplants, thus demonstrating long-term effectiveness of the technique, and establish the absolute safety of pancreatic primordia transplants. If these experiments succeed, the researchers plan to conduct clinical trials in humans with diabetes.

We hope to find out how to apply our findings to human type 1 and type 2 diabetics because the embryonic pig primordia would represent an unlimited source of tissue for transplantation, Hammerman says.

Reunion with patient inspires follow-up study on treatment for DiGeorge syndrome

Tue, 16 Oct 2007 04:00:00 PST

( from http://www.rxpgnews.com ) More than 20 years ago, doctors at Mattel Children's Hospital UCLA performed a successful bone marrow transplant on a baby girl who was born without a thymus gland and was suffering from severe immune deficiency. It marked the first time a bone marrow transplant, rather than a thymic transplant, had been used to treat the genetic condition known as DiGeorge Syndrome (DGS).

The doctors lost track of the young girl when her family moved away but were reunited with her when she returned to UCLA for heart treatment in 2005. Upon rechecking the young woman's immune system, they were pleased to learn that she continued to do well.

Inspired by her positive long-term outcome � along with a handful of other DGS bone marrow transplant patients worldwide � UCLA researchers embarked on a study to follow up on the benefits of bone marrow transplant treatment. Their findings are published in the October 2007 issue of the peer-reviewed Journal of Allergy and Clinical Immunology.

Overall, the researchers found that survival with bone marrow transplant was greater than 75 percent, similar to thymic transplantation.

We believe that this long-term follow-up study indicates that bone marrow transplant is a good procedure � and more readily available than thymic transplantation � for complete DiGeorge syndrome, said co-author Dr. E. Richard Stiehm, professor of pediatrics in the division of immunology, allergy and rheumatology at Mattel Children's Hospital UCLA. This also suggests that the thymus may not be necessary for immune development after birth, or that other tissues, such as the skin, may serve as a thymus equivalent.

DiGeorge syndrome is a common genetic immunodeficiency that occurs in one out of every 2,000 people. The syndrome includes thymic and parathyroid deficiency, chromosome abnormalities, low calcium levels and decreased immunity. Patients often have heart problems and developmental delay, which bone marrow or thymic transplants do not correct. Only a few patients have the severely deficient immune systems characteristic of complete DGS, which is similar to severe combined immunodeficiency (also known as bubble boy syndrome) and is fatal if untreated.

In this first report of extended survival in patients with complete DGS who were treated with bone marrow transplant with long-lasting immune reconstitution, researchers described the medical history and current immune function of two DGS patients who received transplants more than two decades ago. Now in their 20s, both patients lead normal lives free of serious infections and have preserved immune function.

The study also reviewed nine additional cases from other centers internationally and assessed the current status of all patients but one.

The thymus produces hormones that stimulate the production of certain infection-fighting cells. It is also of central importance in the maturation of T-cells (thymic cells), which help build immunity.

According to Stiehm, the thymus gland is the university of the immune system.

Stem cells must go there to be educated before entering the circulation to fight organisms, he said. The thymus continues to put out T-cells for a lifetime. It puts out naive T-cells that are then exposed to microbes to become memory T-cells. It was previously thought that the body needs a continuous supply of new naive cells to keep the immune system functioning, but now we think that maybe it's not necessary, since the memory cells from the donor may serve for a lifetime.

The significance is that adult memory cells from bone marrow, or peripheral blood, can persist in the circulation for several decades and keep the patient well, even though new naive T-cells from the thymus are not produced.

A bone marrow transplant works by replacing the patient's marrow with healthy marrow from a matched donor. Ultimately, the new marrow helps the patient produce normal blood cells.

A thymic transplant is an effective but complicated procedure that involves transferring the thymus tissue of another infant undergoing heart surgery, culturing it, and then surgically implanting it in the patient. It then takes several months for the thymus gland to grow and allow the patient to develop a functioning immune system.

Thymus transplantation is available in the U.S. only at Duke University's medical center. By contrast, bone marrow transplant is a standard procedure available at many large medical centers across the country and internationally.

Kidney research points to ways to more effectively use organs

Mon, 01 Oct 2007 04:00:00 PST

( from http://www.rxpgnews.com ) WINSTON-SALEM, N.C. � Several new studies suggest how transplant surgeons can make more effective use of kidneys from deceased donors � even those that are at the outer limits of acceptance criteria � according to researchers from Wake Forest University Baptist Medical Center.

At the 13th Congress of the European Society for Organ Transplantation held in Prague,Czech Republic, Rajinder Singh, M.D., a fellow in transplantation surgery, presented the results of three studies suggesting not only the potential to expand acceptance criteria, but specific ways to achieve optimum results.

�Our experience suggests that the limits of donor acceptability may continue to expand as we are able to achieve acceptable short-term results with kidneys that once would have been discarded,� said Robert Stratta, M.D., senior researcher. �Our findings point to the importance of matching donor and recipient ages, reducing waiting times for transplantation, and taking steps to reduce delayed graft function and acute rejection.�

The research involved kidneys from deceased donors that met standard criteria for donation (SCD) as well as those from �expanded criteria� donors (ECDs). The ECD category was created by the United Network for Organ Sharing in 2002 so that higher risk donor organs, once considered unsuitable, could be transplanted safely.

The ECD category includes kidneys from deceased donors over age 60 or those over age 50 with health conditions such as high blood pressure, stroke or elevated levels of a protein called creatinine. Levels of creatinine, which is produced by muscle, are used to determine kidney function.

Extreme Donors: In one study, the researchers compared results using ECD organs with what they term �extreme� ECD organs, which included either donors over age 70; donation after cardiac death, which used to be taboo because of the risk of the organ being deprived of oxygen; organs stored more than 30 hours before transplant, or kidneys in which the filtering units were scarred at least 30 percent.

With a mean follow up of 30 months, outcomes with 80 extreme ECD kidneys were comparable to 71 conventional ECD kidneys. Both patient survival and survival of the transplanted organs were similar between the two groups.

Age-Matching: In a second study, the group looked at whether there is an advantage to matching the ages of donors and recipients. The study, involving 243 recipients, compared results when ECD kidneys (from donors age 60 and older) were transplanted in older recipients and SCD kidneys from younger donors (under 60) were transplanted into younger recipients to results in donor/recipient combinations in which age-matching did not occur.

Mortality was higher (9.5 percent) in the age-mismatched group than in the age-matched group (3.3 percent). The difference occurred regardless of whether the donors and recipients were older or younger than 60.

�Donor and recipient age-matching in deceased donor kidney transplants may confer a survival benefit independent of recipient age,� said Stratta, director of abdominal transplantation.

Identifying Risk Factors: In another analysis, the researchers sought to identify risk factors for kidney graft failure, which is when a transplanted organ ceases to function. They reviewed 56 cases of graft failure in 390 patients who received kidneys from deceased donors. Twenty-nine of the failed organs were from SCDs and 27 from ECDs. Risk factors for graft loss in both groups included diabetes in the recipient, recipients being over age 60, episodes of acute rejection, or delayed graft function.

Acute rejection is when the body shows early signs of rejecting the transplanted kidney. Delayed graft function is when the recipient requires temporary dialysis to support the transplanted kidney before it begins functioning on its own. Other risk factors for kidney graft failure that approached statistical significance were waiting times greater than 26 months and undergoing dialysis for more than 42 months before a transplant.

Stratta said understanding more about risk factors allows physicians to take preventive measures.

�Delayed graft function was the most important risk factor affecting ECD kidneys, and it can be markedly reduced by using a pump to force fluid through the kidneys before transplant,� said Stratta. �With SCD kidneys, acute rejection was the major risk of organ failure, which suggests the importance of sophisticated compatibility testing and strong anti-rejection medication in an attempt to improve outcomes.�

Immune system modulation can halt liver failure in animals

Tue, 25 Sep 2007 04:00:00 PST

( from http://www.rxpgnews.com ) Massachusetts General Hospital (MGH) researchers have a developed a totally new approach to treating liver failure � manipulating the immune response. If the results of the animal study can be applied in human patients, the approach may be able to keep patients alive until donor organs become available or to support liver function until the organ can regenerate itself, eliminating the need for a transplant. The findings are being reported in the journal PLOS One.

�We have identified a non-hepatic source of cells that can easily be expanded to the scale required for clinical application,� says Martin Yarmush, MD, PhD, director of the Center for Engineering in Medicine at MGH, the paper�s senior author. He also is the Helen Andrus Benedict Professor of Surgery and Bioengineering in the Harvard-MIT Division of Health Science and Technology (HST) and a senior scientific staff member at the Boston Shriners Burns Hospital.

The liver is one of the few major organs that is able to regenerate itself. But when the organ is damaged by diseases like chronic hepatitis, long-term alcohol consumption, or other causes, ongoing inflammation can increase cell death and suppress the natural regenerative process. The only current treatment for end-stage liver failure is transplantation, which is limited by the organ supply and requires long-term immunosuppressive treatment. While external liver assist devices have successfully supported some patients, such machines require a supply of preferably human liver cells, which have been difficult to acquire and expand.

For their investigation, the MGH research team used mesenchymal stem cells (MSCs) � cells from the bone marrow that develop into tissues supporting blood cell development in the marrow cavity. Previous research has shown that MSCs are able to inhibit several immune system activities. A supply of MSCs can be extracted from a patient�s own marrow and expanded to levels that could be therapeutically useful. To evaluate the ability of human MSCs to treat organ failure involving inflammatory activity, the investigators tested several ways of using the cells to treat rats in which liver failure had been induced.

Several approaches to administering MSCs reduced the biological signs of liver failure and improved the animals� survival. Although simply transplanting MSCs was not effective, two methods of delivering molecules secreted by the cells lessened inflammation within the liver and halted cell death. Cycling the blood of rats with liver failure through an external bioreactor containing MSCs also greatly reduced the metabolic signs of liver failure in the animals. Even more significantly, 71 percent of the rats treated with the MSC-seeded bioreactor survived, while only 14 percent of those in a control group were alive one week later.

�One essential function of MSCs in the bone marrow is to secrete molecules that promote the growth and maturation of blood cells,� say co-lead author Biju Parekkadan, an HST graduate student working in Yarmush�s lab. �We are now finding that these same molecules can be used as potent immunotherapeutics and envision a multi-tiered treatment of liver failure based on this work. A patient presenting with liver failure could first be treated with an intravenous injection of an �off-the-shelf� drug containing MSC-produced factors in an effort to halt cell damage and allow the organ to regenerate. If that is not effective, an MSC-based support device could be used as a bridge to transplantation or even as a long-term treatment.�

The researchers note that exactly how MSC-produced molecules inhibit the movement of immune cells into a damaged organ is not yet known and is currently under investigation. They also hope to examine the possibility of combining both MSCs and liver cells in a potential support device and to test the potential of MSCs to treat other immunological diseases.

Brown scientists take the petri dish to new dimensions

Wed, 19 Sep 2007 04:00:00 PST

( from http://www.rxpgnews.com ) PROVIDENCE, R.I. [Brown University] � A team of Brown University biomedical engineers has invented a 3-D Petri dish that can grow cells in three dimensions, a method that promises to quickly and cheaply produce more realistic cells for drug development and tissue transplantation.

The technique employs a new dish � cleverly crafted from a sugary substance long used in science laboratories � that allows cells to self-assemble naturally and form �microtissues.� A description of how the 3-D dish works appears in the journal Tissue Engineering.

�It�s a new technology with a lot of promise to improve biomedical research,� said Jeffrey Morgan, a Brown professor of medical science and engineering.

Morgan conceived and created the 3-D Petri dish with a team of Brown students led by Anthony Napolitano, a Ph.D. candidate in the biomedical engineering program. Napolitano spent two years perfecting the new dish and recently won a $15,000 award from the National Collegiate Inventors and Innovators Alliance to develop the patent-pending technology into a commercially viable product.

�This technology is an inexpensive and easy-to-use alternative to current 3-D cell culture methods,� Napolitano said. �It�s the next generation.�

The technology tackles a topic of increasing interest to scientists: creating hothouse cells that look and behave more like cells grown in the human body. Since 1877, scientists have relied on the Petri dish to grow, or culture, cells. The cells stick to the bottom of the dishes and spread out as they multiply. In the body, however, cells don�t grow that way. They are surrounded by other cells in three dimensions, forming tissues such as skin, muscle, and bone. This is what happens in Morgan�s 3-D dish.

The clear, rubbery dish is the size of a silver dollar. It is made from a water-based gel made of agarose, a complex carbohydrate long used in molecular biology. This gel has a few benefits. It is porous, allowing nutrients and waste to circulate. And it is non-adhesive, so cells won�t stick to it. At the bottom of the dish sit 820 tiny recesses or wells. When cells are added to the dish �about 1 million at a time � roughly 1,000 sink to the bottom of each well and form a pile. These close quarters allow cells to self-assemble, or form natural cell-to-cell connections, a process not possible in traditional Petri dishes.

The result: microtissues consisting of hundreds of cells, even of different types. In Tissue Engineering, the Brown team describes how they combined human fibroblasts, which make connective tissue, and endothelial cells, which line the heart and blood vessels. The cells came together to form spheres and doughnut-shaped clusters. The process was quick � self-assembly took place in less than 24 hours.

�These microtissues have several potential uses,� Morgan said. �They can be used to test new cancer compounds and other drugs. And they can be transplanted into the body to regenerate tissue, such as pancreatic cells for diabetics. While there are other methods out there for making microtissues, our 3-D technology is fast, easy and inexpensive. It can make hundreds of thousands of microtissues in a single step.�

Differences in culture techniques matter in biomedicine, according to a growing body of research. Studies show sometimes dramatic differences in the shape, function and growth patterns of cells cultured in 2-D compared with cells cultured in 3-D. For example, a recent Brown study found that nerve cells grown in 3-D environments grew faster, had a more realistic shape and deployed hundreds of different genes compared to cells grown in 2-D environments.

That�s why several laboratories are pursuing 3-D cell culture methods. Brown Technology Partnerships has filed a patent application based on the technology developed in the Morgan lab and is actively pursuing licensing partners.

Sexual function affected by stem cell transplant according to long-term study

Tue, 18 Sep 2007 04:00:00 PST

( from http://www.rxpgnews.com ) WASHINGTON, Sept. 18, 2007 -- A long-term study found that a type of stem cell transplant used for patients with life-threatening diseases, such as leukemia and lymphoma, results in decreased sexual function and activity for recipients. Further, males are likely to recover from these changes over time, while the sexuality of female patients remains compromised. In addition, neither male nor female long-term cancer survivors regained levels of sexual activity and function equal to those of their peers who have not had cancer, according to a Blood First Edition Paper prepublished online today. Blood is the official journal of the American Society of Hematology.

�Survival without a sex life should not be what cancer survivors settle for or what health-care professionals consider a successful outcome of cancer treatment,� stated lead study author, Karen Syrjala, PhD, co-director of the Survivorship Program at the Fred Hutchinson Cancer Research Center. �Sexual dysfunction in survivors of cancer needs to become a priority for research funding and a routine topic of discussion between doctors and their patients after cancer treatment.�

In an allogeneic hematopoeitic stem cell transplantation, patients with diseases of the blood, bone marrow, or certain types of cancers receive an infusion of new stem cells from a sibling or tissue-matched unrelated donor to replace the damaged or destroyed cells in their bone marrow needed for the production of blood cells. Before the transplant, high-dose chemotherapy is administered to kill residual cancer cells and to suppress the immune system so that the patient�s body will not reject the new tissue.

The results of questionnaires on sexual function were reported for 161 patients scheduled to receive this procedure at the Fred Hutchinson Cancer Research Center in Seattle. The patients ranged in age from 22-64 years with an average age of 41 and a nearly even split by gender.

Before the transplant, study participants completed an assessment of their sexual health at the clinic, and, after the procedure, surveys were mailed to the patients to complete at the six-month interval and after one, two, three, and five years. The response rate to the questionnaire averaged 84 percent with all participants completing one or more surveys during the five-year period.

The surveys included 37 questions in the areas of interest, desire, arousal, orgasm, satisfaction, activity, relationship, masturbation, and sexual problems. The male and female versions had the same content except for variations in the problems section according to sex. In addition, those who were not sexually active were provided with a list of possible reasons and asked to mark as many as applied.

At five years, the assessments were compared against a control group consisting of siblings or friends of the study patients that were within five years of the participant�s age and who were of the same gender, ethnicity, race, and educational background. If a local match was not available, the researchers recruited volunteers from the community that fit the criteria.

At the six-month mark, both genders had decreased sexual activity, but, by one year, sexual activity for the majority of the men (74 percent) had recovered to the levels seen at the beginning of the study. For women, recovery of sexual activity took longer, with just over half (55 percent) returning to sexual activity after two years. Though sexual activity was restored for these patients, for those who were sexually active at the five-year mark, 46 percent of the men and 80 percent of the women reported problems that disrupted sexual function.

According to the researchers, sexual dysfunction in transplant patients is likely caused by systemic therapies, such as total body irradiation and chemotherapy drugs known as alkylating agents, which are known to permanently damage endocrine glands that play a critical role in the development and regulation of the reproductive system.

In addition, chronic graft-versus-host disease (GVHD), a common complication of transplantation experienced by 65 percent of the patients in this study, may cause shrinkage of the vaginal tissues and changes to the vaginal lining that can contribute to sexual dysfunction in women. For males, testosterone levels and the cavernosal arteries of the penis are affected, eroding libido and erectile function.

Lack of interest or libido explained sexual inactivity in part for nearly 20 percent of female survivors at both six months and five years, suggesting that this problem did not improve over time. In contrast, for males, lack of interest or libido as a reason for inactivity declined from 14 percent to 6 percent between six months and five years.

At the five-year mark, the rates of sexual activity and sexual function for both male and female patients were below those of the control group, suggesting that they did not fully recover from the effects of the cancer itself or cancer treatments. Further studies are needed to determine if hormone treatments for both sexes or other therapies will help these patients achieve the same sexual function and activity as their peers.

The researchers also recommend that patients undergoing stem cell transplantation be made aware of potential changes in their sexuality and given resources to address these needs to help improve long-term quality of life. Men may benefit from reassurance that erectile function and sexual desire should improve by one to two years after treatment, but that methods such as testosterone replacement, erectile-function medications, and other adaptive strategies can be considered if problems continue. For women, methods that focus on communication with their partners about changes in sensation, strategies for enhancing libido, and use of vaginal lubricants, dilators, or vibrators to assist with adapting to genital changes may help to maintain sexual responsiveness.

Embryonic stem cells used to grow cartilage

Thu, 06 Sep 2007 04:00:00 PST

( from http://www.rxpgnews.com ) HOUSTON, Sept. 6, 2007 � Rice University biomedical engineers have developed a new technique for growing cartilage from human embryonic stem cells, a method that could be used to grow replacement cartilage for the surgical repair of knee, jaw, hip, and other joints.

Because native cartilage is unable to heal itself, researchers have long looked for ways to grow replacement cartilage in the lab that could be used to surgically repair injuries, said lead researcher Kyriacos A. Athanasiou, the Karl F. Hasselmann Professor of Bioengineering. This research offers a novel approach for producing cartilage-like cells from embryonic stem cells, and it also presents the first method to use such cells to engineer cartilage tissue with significant functional properties.

The results are available online and slated to appear in the September issue of the journal Stem Cells. The study involved cells from an NIH-sanctioned stem cell line.

Using a series of stimuli, the researchers developed a method of converting the stem cells into cartilage cells. Building upon this work, the researchers then developed a process for using the cartilage cells to make cartilage tissue. The results show that cartilages can be generated that mimic the different types of cartilage found in the human body, such as hyaline articular cartilage -- the type of cartilage found in all joints -- and fibrocartilage -- a type found in the knee meniscus and the jaw joint. Athanasiou said the results are exciting, as they suggest that similar methods may be used to convert the stem cell-derived cartilage cells into robust cartilage sections that can be of clinical usefulness.

Tissue engineers, like those in Athanasiou's research group, are attempting to unlock the secrets of the human body's regenerative system to find new ways of growing replacement tissues like muscle, skin, bone and cartilage. Athanasiou's Musculoskeletal Bioengineering Laboratory at Rice University specializes in growing cartilage tissues.

The idea behind using stem cells for tissue engineering is that these primordial cells have the ability to become more than one type of cell. In all people, there are many types of adult stem cells at work. Adult stem cells can replace the blood, bone, skin and other tissues in the body. Stem cells become specific cells based upon a complex series of chemical and biomechanical cues, signals that scientists are just now starting to understand.

Unlike adult stem cells, which can become only a limited number of cell types, embryonic stem cells can theoretically become any type of cell in the human body.

Athanasiou's group has been one of the most successful in the world at studying cartilage cells and, especially, engineering cartilage tissues. He said that for his research the primary advantage that embryonic stem cells have over adult stem cells is their ability to remain malleable.

Identifying a readily available cell source has been a major obstacle in cartilage engineering, Athanasiou said. We know how to convert adult stem cells into cartilage-like cells. The more problematic issue comes in trying to maintain a ready stock of adult stem cells to work with. These cells have a strong tendency to convert from stem cells into a more specific type of cell, so the clock is always ticking when we work with them.

By contrast, Athanasiou said his research group has found it easier to grow and maintain a stock of embryonic stem cells. Nonetheless, he is quick to point out that there is no clear choice about which type of stem cell works best for cartilage engineering.

We don't know the answer to that, Athanasiou said. It's extremely important that we study all potential cell candidates, and then compare and contrast those studies to find out which works best and under what conditions. Keep in mind that these processes are very complicated, so it may well be that different types of cells work best in different situations.

Athanasiou began studying embryonic stem cells in 2005. Since funding for the program was limited, he asked two new graduate students in his group if they were interested in pursuing the work as a secondary project to their primary research. Those students, Eugene Koay and Gwen Hoben, are co-authors of the newly published study. Both are enrolled in the Baylor College of Medicine Medical Scientist Training Program, a joint program that allows students to concurrently earn their medical degree from Baylor while undertaking Ph.D. studies at Rice.

Eugene and Gwen are both outstanding students, Athanasiou said. Each earned their undergraduate degree from Rice and each worked in my laboratory as undergraduate students. They have chosen to do this research because they think this may represent the future of regenerative medicine.

U of M begins nation's first clinical trial using T-reg cells from cord blood in leukemia treatment

Wed, 05 Sep 2007 04:00:00 PST

( from http://www.rxpgnews.com ) University of Minnesota researchers have initiated a ground breaking clinical trial to determine the optimal dose and safety of T regulatory cells (T-regs) to decrease the risk of immune reactions common in patients undergoing blood and marrow transplantation.

Ultimately, the researchers hope the experimental cellular therapy will improve overall survival rates for blood cancer patients as well as offer a potential new paradigm for treating autoimmune diseases.

�Toward our quest of making transplants even safer for adults and children with leukemia, lymphoma, multiple myeloma, and other blood and marrow disorders, we are exploring the possibility of using T-regs to enhance the rate of blood and marrow recovery and reduce the risks of graft-versus-host disease, a complication that affects more than 60 percent of patients,� said Claudio Brunstein, M.D., principal investigator of the study.

T-regs are a type of lymphocyte, or white blood cell that normally regulates the body�s immune responses. In the case of transplant, donor T-regs may suppress the recipient�s immune system so that the healthy donor�s blood-forming stem cells and immune cells can grow, helping ward off life-threatening graft-versus-host-disease (GVHD). GVHD occurs when the immune cells within the donated cells attack the body of the transplant recipient. GVHD causes one-third of deaths after transplant.

Researchers have proven in animal models that infusing T-regs after transplant increases the chance of blood and marrow recovery and decreases the risk of GVHD.

�Once we identified that T-regs were highly effective in mouse models, we then spent three years finding ways to make this therapy valuable for transplant patients and potentially useful for patients with autoimmune diseases,� said Bruce Blazar, M.D., director of the Center for Translational Medicine at the University.

The T-regs in this study are isolated from umbilical cord blood (blood collected from the placenta or afterbirth after the birth of a child) because they occur in higher frequency than what is typically found in most adults and are easier to expand in culture prior to treatment. This is the first human clinical trial in the world that uses T-regs derived from umbilical cord blood.

This trial is designed to find the highest possible safe dose of T-regs in immune suppressed patients undergoing a double umbilical cord blood transplant for leukemia, other blood cancer, or bone marrow failure. From data in animal models, University researchers believe there will be no acute side effects with the T-regs.

If the data in humans mimics animal models, T-regs will be a powerful therapy to prevent GVHD and enhance engraftment in transplant patients. Once safety and efficacy data are known, researchers hope to test T-regs for treatment of various autoimmune diseases, such as type I diabetes and multiple sclerosis. University researchers hypothesize that if T-regs are transplanted early in the life of the disease, the cells may help prevent disease progression.

�This is an exciting time. In the near future, I anticipate being able to combine immune cell populations, like T-regs, that stop immune reactions responsible for autoimmune diseases like diabetes, and immune responses to stem cell infusion given to repair already damaged tissues. This brings great hope not only for adults and children with cancer but many other diseases as well. At the close of this clinical trial, we hope to go right to our first clinical trial with T-regulatory cells in the treatment of newly diagnosed diabetes,� said John E. Wagner, M.D., director of the pediatric hematology-oncology and blood and marrow transplantation program at the University of Minnesota.

Inhaling nitric oxide helps transplant success

Wed, 29 Aug 2007 04:00:00 PST

( from http://www.rxpgnews.com ) BIRMINGHAM, Ala. � Administering inhaled nitric oxide (NO) during surgery helps protect liver transplant patients from organ failure, according to a new study from researchers at the University of Alabama at Birmingham (UAB).

The colorless gas improves post-surgical liver function by minimizing reperfusion injury, an unwanted side effect of restoring blood flow swiftly to a donor organ moments after transplantation into the recipient, the study authors said.

The findings on inhaled NO were published in the most recent issue of the Journal of Clinical Investigation. Results from this small study are preliminary and must be confirmed through larger clinical trials, said Rakesh Patel, Ph.D., an associate professor in the UAB Department of Pathology and a co-lead author on the study.

Exactly how the inhaled NO improves organ function at the cellular and molecular level is still unknown, Patel said. What is clear from post-surgical data are the benefits of inhaled NO for transplant patients: decreased hospital length-of-stays, and improved blood-clotting and liver-enzyme activity in post-transplant tests.Inhaled NO was administered to study subjects through an anesthesia mask by UAB anesthesiologists during transplant surgery.

The trial was designed to be �blinded� and placebo-controlled, which means some patients got inhaled NO and others did not, and neither patients nor their surgeons knew who was getting the gas.

�We were pleasantly surprised at how good the inhaled NO patients performed after the results were gathered,� Patel said. He said the results also showed inhaled NO protects transplanted livers from a rise in hepatic cell death.NO can be toxic to humans if breathed at high doses without medical supervision. Doses administered to the Journal of Clinical Investigation study participants were about 80 ppm, which did not cause toxicity and even proved beneficial, Patel said.

A larger clinical trial of inhaled NO involving more patients is about to start up at UAB in conjunction with Seattle-based University of Washington and the U.S. Department of Veterans Affairs Puget Sound Health Care System.Since reperfusion injury is possible in a wide range donated organs, the hope is that inhaled NO holds promise for improving �results to other solid organ transplants, such as heart, lung, kidney and pancreas,� said Devon Eckhoff, M.D., chief of UAB�s liver transplant program and a professor in the Department of Surgery.

Clearly if more donor organs end up healthier after transplantation, then donor-organ shortages may see some relief. �The more organs that are made suitable for transplantation will decrease the wait time for organ transplant recipients and subsequently save lives,� Eckhoff said.

Facial transplantation may be a safer option, study shows

Tue, 28 Aug 2007 04:00:00 PST

( from http://www.rxpgnews.com ) CINCINNATI/LOUISVILLE�Researchers in Cincinnati and Louisville report that immunosuppressive risks associated with facial transplantation may be lower than thought, possibly making the procedure a safer option for people who have suffered severe facial injuries.

Previous data on the immunosuppression risks involved in facial transplantation were misleading, according to Rita Alloway, PharmD, and Steve Woodle, MD, of the University of Cincinnati (UC), and a University of Louisville team led by John Barker, MD, PhD. Their findings appear in the September edition of the journal Plastic and Reconstructive Surgery.

The first recorded facial transplant was performed in France in 2005 on a 38-year-old woman whose nose, lips and chin had been bitten off by a dog. Tissues, muscles, arteries and veins were taken from a brain-dead donor and successfully transplanted to the patient�s lower face.

There have been only two similar attempts since.

In 2004, the British Royal College of Surgeons published a controversial report predicting a high incidence of immunological complications for facial transplants. This data became a benchmark for facial transplant teams and review boards and greatly influenced the facial transplantation debate.

According to Woodle, however, the report did not provide the best risk assessment.

�In estimating the risks of immunosuppression for face transplant recipients, the biggest problem is comparing apples to oranges,� Woodle says. �What we have tried to do is to address the apples and oranges problem by a comprehensive and up-to-date consideration of the issue.�

Both the health status of solid organ transplant recipients and the tissue composition of the solid organs reported in the earlier studies are very different from that of face transplant recipients and their facial tissues, he says.

In the current study, the Cincinnati and Louisville researchers compared the 2004 data with that taken from clinical studies describing kidney and hand transplants using the latest immunosuppression techniques.

They found the outcomes to be very different from those in the 2004 study.

Based on kidney and hand transplantation cases, in which the same drug regimen was used, researchers found that acute, or immediate, rejection may occur in 10 to 70 percent of patients. In of all these cases, however, rejection was reversible by adjusting the immunosuppression medications.

They also found that fewer than 10 percent of patients would experience chronic rejection over five years.

�In considering the most recent and relevant data, we came to the conclusion that the expectations for face transplant recipients should be significantly better than those previously published,� Woodle says.

Coauthor Barker says that the lack of comparable �apples-to-apples� risk data in the field has led to debate over the ethics of face transplantation, which was the inspiration for the Cincinnati-Louisville study.

�This risk-benefit equation is at the center of controversy over facial transplantation,� he says. �Physicians and scientists question whether the risks of life-long immunosuppression for patients justify the benefits of this new treatment.�

Cincinnati coauthor Alloway says that physicians often don�t realize how much patients will endure to gain relief.

�Surveys from transplant professionals have shown that doctors underestimate what people will do for a cure,� Alloway says. �Often, living disfigured is worse than risk associated with this sort of operation and the immunosuppressive risks that accompany it.�

Researchers hope this study will provide a solid foundation for future work with facial transplantation.

�We�re trying to meld the fields of transplantation and immunosuppression to produce maximum expertise on the subject,� Alloway continued. �We�re hoping to decrease toxicity and create a more manageable risk spectrum for surgeons and patients.�

Better life support for artificial liver cells

Thu, 23 Aug 2007 04:00:00 PST

( from http://www.rxpgnews.com ) COLUMBUS , Ohio -- Researchers at Ohio State University are developing technology for keeping liver cells alive and functioning normally inside bioartificial liver-assist devices (BLADs).

Such devices enable people who are suffering from acute liver failure to survive while their own liver cells regenerate, or until they receive a liver transplant. The person's blood or plasma circulates through the device. Inside, living cells -- usually pig or human liver cells -- perform normal liver functions.

For those liver cells to keep working, they need oxygen. Andre Palmer, an associate professor of chemical and biomolecular engineering at Ohio State, and his team are developing innovative ways to chemically modify and package hemoglobin -- the blood molecule in red blood cells that transports oxygen -- to deliver oxygen to liver cells in just the right way.

Palmer presented the project's preliminary results on August 23, 2007, at the American Chemical Society meeting in Boston .

In the body, liver cells are naturally exposed to a range of oxygen concentrations, called an oxygen gradient. But reproducing that natural gradient inside a BLAD is difficult.

If you don't recreate that oxygen gradient and the total amount of oxygen normally delivered, the liver cells in the BLAD won't function as well as they do in the body, Palmer said.

His solution has been to create different kinds of hemoglobin. One he seals inside microscopic polymer capsules; oxygen bound to the hemoglobin diffuses through the polymer over time to reach liver cells. Another is a type of hemoglobin-based oxygen carrier, which consists of long chains of hemoglobin molecules wound into balls that can then transport oxygen to liver cells.

The use of this technology with patients would require clinical trials, which Palmer admits are years away. For now, he is working to prove that he can adjust the oxygen gradient and the amount of oxygen his hemoglobins can transport to liver cells housed in a BLAD.

We've found that by using different types of hemoglobin-based oxygen carriers with different oxygen affinities and tuning the oxygen concentration, we can recreate natural oxygen gradients, Palmer said.

He began developing this technology while at the University of Notre Dame, and since 2006 has been continuing the work at Ohio State.

Though computer simulations had shown Palmer and his team that they could reproduce a natural oxygen gradient in principle, they have now conducted experiments on actual liver cells in the laboratory, and shown that they can do it in reality.

New treatment for glaucoma shows promise in laboratory, say Iowa State researchers

Wed, 01 Aug 2007 04:00:00 PST

( from http://www.rxpgnews.com ) AMES, Iowa Iowa State University researchers have developed a new technique that successfully treated rats for blindness caused by glaucoma. Their experimental treatment will be used on canine patients in the next year. If successful, it is expected to move to human trials.

An estimated 3 million people in the U. S. are affected by glaucoma, the second leading cause of blindness in the developed world and the number one cause of vision loss among blacks. People with elevated intraocular pressure are at greatest risk for developing glaucoma.

Iowa State researchers leading the six-year project are Dr. Sinisa Grozdanic, a veterinary ophthalmologist and assistant professor of veterinary clinical sciences; Donald Sakaguchi, neuroscientist and associate professor of genetics, development and cell biology; and Matt Harper, doctoral student in neuroscience. The team also included researchers from the University of Iowa, Yale University, Tulane University and the University of Miami. The work was presented at a recent meeting of the Association for Research in Vision and Ophthalmology Conference.

The researchers previously determined that animals with glaucoma increase production of proteins with neuron-protective capabilities (neurotrophins) in an attempt to shield against blindness. So, they imitated that process in the laboratory, modifying bone marrow-derived stem cells. Then they transplanted the cells into the eyes.

Once we realized the nature of these self-protective mechanisms, we just tried to mimic the same thing exactly, Grozdanic said. We used bone-derived stem cells from the patient, modified them to produce the neurotrophin and injected these cells into glaucomatous eyes.

A sophisticated computerized analysis of noninvasive measurements of optic nerve function and the retinas electrical activity showed dramatic improvement in the rats visual functions after the procedure.

Four years earlier, the researchers had conducted experiments in which biodegradable polymers coated with neuroprotective substances were inserted into the eyes of rats. As the polymer degrades, the neuroprotective substance is released into the eye. The approach worked well, and the same procedure was successful in dogs with optic nerve damage. However, because polymer-based drug delivery generally lasts for only months and glaucoma destroys vision in humans over a period of decades, the scientists shifted their strategy to a longer-lasting approach. They genetically modified the bone marrow stem cells for transplantation so the delivery of the neuroprotective protein can be achieved for years.

One of the really unique aspects of this approach is that we can isolate these stem cells from the same individual being treated, Sakaguchi said. It eliminates the ethical issues associated with embryonic stem cells, and the immunological problems of graft rejection.

Grozdanic said the results were phenomenal. So, the Iowa State team intends to use the technique on dogs as soon as possible.

Dogs suffer many of the same diseases people do and theres a lot of physiological similarity in their eyes and ours, Grozdanic said.

Four years ago, I was very skeptical that this would work, he said. Now I see positive results. Hopefully in a few years, well be able to say its working in humans.

The cell biology work and the genetic modification were conducted by Sakaguchi and Harper, while Grozdanic developed techniques for evaluating the molecular changes in the animals. Researchers at the University of Miami provided genetic material for the modification while collaborators at Tulane assisted with culturing the bone marrow stem cells. A biodegradable polymer engineered with neuroprotective substances used in preliminary testing was developed by Erin Lavik at Yale University. Three faculty from the University of Iowas Department of Ophthalmology and Visual Sciences Dr. Randy Kardon, Dr. Young Kwon and Dr. Markus Kuehn helped develop models of elevated eye pressure and assessing visual function. They also compared data from tissue from the rats and dogs to data from human donor tissue to help the team better understand molecular changes caused by glaucoma.

First case of successful ovarian tissue transplantation between two, nonidentical sisters

Wed, 01 Aug 2007 04:00:00 PST

( from http://www.rxpgnews.com ) A woman, whose ovaries had failed due to damage caused by chemotherapy and radiotherapy, has received a successful ovarian transplant from her genetically non-identical sister. The transplant restored her ovarian function, she started to menstruate and, after a year, doctors were able to recover two mature oocytes from her ovaries and fertilise them to produce two embryos.

This first case of a successful transplantation of ovarian tissue between two non-identical sisters is reported in the journal Human Reproduction today (Thursday 2 August) [1]. Professor Jacques Donnez, head of the department of gynaecology and professor and chairman at the Catholic University of Louvain in Brussels, Belgium, led the team that carried out the work [2].

In 1990, when she was 20, doctors treated Teresa Alvaro for beta-thalassemia an inherited blood disorder characterised by reduced or absent haemoglobin, which is the oxygen-carrying protein in red blood cells. She received chemotherapy and radiotherapy before having a bone marrow transplant from her 17-year-old sister, Sandra Alvaro, who had an identically matched tissue type (human leukocyte antigen (HLA) type), which meant that Teresas immune system would not recognise her sisters bone marrow as foreign and reject it.

The treatment was successful and Teresa was cured. However, in 1990 there were no procedures available for preserving her fertility before commencement of the treatment by, for instance, removing and freezing her eggs or ovarian tissue. The treatment caused complete ovarian failure, and her ovaries never recovered.

In July 2005, now aged 35, Teresa consulted Prof Donnez and his colleagues about the possibility of ovarian tissue transplantation from her sister to give her a chance of becoming pregnant.

Prof Donnez said: Having already provided bone marrow in 1990, her sister, who was now aged 32 and had never become pregnant, badly wanted to help her sister by donating some of her own ovarian tissue.

Although the option of oocyte donation from the sister to the patient was discussed, the patient refused this option. She preferred a transplant because she wanted to be responsible for the follicular maturation and considered that it was more natural than egg donation, for which her sister would have to undergo ovarian stimulation with follicle stimulating hormones and then oocyte retrieval. In addition, her sister had asked expressly to be the tissue donor and had refused to undergo ovarian stimulation for oocyte donation.

Analysis of the sisters HLA type showed that their genetically different cells coexisted successfully together (chimaerism) and that, therefore, no immuno-suppressive treatment would be required to prevent the ovarian graft being rejected. The earlier bone marrow transplant and resulting mixing of the sisters cells meant that Teresas immune system would recognise Sandras ovarian tissue as self rather than foreign.

In February 2006, Teresa and Sandra were anaesthetised together and three small sections of ovarian tissue were removed from Sandra via laparoscopy and within less than a minute were being sewn on to one of Teresas atrophied ovaries, also via laparoscopy. The sisters were discharged from hospital the day after surgery.

After six months Teresa started menstrual bleeding and this, together with differences in hormone levels, confirmed that ovarian function had been restored. Her menstrual cycles have continued ever since. A year after the transplant, the doctors retrieved two mature oocytes from her ovary and fertilised them with her husbands sperm via ICSI (intracytoplasmic sperm injection) they decided to use ICSI rather than attempting natural conception because the husband had a low sperm count. One of the resulting embryos developed to the two-cell stage and the other to the three-cell stage, but then both ceased to develop further, and so the embryos were not transferred to her uterus.

Prof Donnez said: We do not know why the embryos ceased to develop, but this also happens during normal cycles of IVF. The patient is planning more IVF attempts in the future.

He said that it was too early to say whether this procedure would ever be successful enough to enable a woman to become pregnant successfully and give birth to a live baby. However, the work did give hope to women who had not had an opportunity to freeze either their eggs or their ovarian tissue, and it emphasised the importance of leaving at least one ovary in place during any treatment because the ovary offered an excellent site for a subsequent transplant of ovarian tissue.

This method is an option for women who have not had their ovarian tissue cryopreserved, either because chemotherapy was given before 1996, or because cryopreservation was not proposed or not available in the hospital where the patient was treated, he said.

In theory, the procedure could also be used between two, unrelated women, as long as the two women were HLA compatible and if the donor had previously given bone marrow to the recipient, as in the case we are reporting here, he concluded.

Teresa Alvaro said: Early in 2005 my gynaecologist told me that the chemotherapy that I had to go through in 1990 in preparation for my bone marrow transplant had severely affected my fertility. A few months later I happened to read an article on an American woman who got pregnant after she had ovarian tissue transplanted from her twin sister. I didnt hesitate for a second and went to see Prof Donnez together with my sister. Our antigens appeared to be identical, and therefore the chances of rejection were minimal. The operation was a success. I can get pregnant the natural way. Thats something I could never have hoped for a couple of years ago.

UF to lead research on life-threatening fungus

Tue, 31 Jul 2007 04:00:00 PST

( from http://www.rxpgnews.com ) GAINESVILLE, Fla. - Hear the word fungus, and mushrooms and mold might leap to mind. But the University of Florida is about to house the nation's first research repository for one species that has nothing to do with pizza toppings or marbling blue cheese: Aspergillus, which increasingly poses a major health threat to cancer patients andtransplant recipients.

The National Institutes of Health has awarded $9 million over the nextseven years to the effort. UF researchers are collaborating withcolleagues at Duke University, Brigham and Women's Hospital in Boston and the Dana-Farber Cancer Institute, who will funnel patients'respiratory, urine and blood samples to UF. The repository will supportresearch aimed at learning more about the fungus and efforts to develop more accurate tests to detect it in patients.

Aspergillus is everywhere, particularly in the air we breathe; all of us breathe it in all the time, said principal investigator John Wingard, M.D., director of UF's blood and marrow transplant program anddeputy director of the UF Shands Cancer Center. On a windy day,especially in a dusty environment or every time some dirt gets movedaround, lots of these organisms get aerosolized.

The number of people contracting Aspergillus infections jumpedenormously in the 1990s, Wingard said, and those with weakened immune systems are particularly susceptible. Aspergillosis is the leading cause of death from infection in bone marrow transplant and leukemia patients, as well as among those who receive certain other solid organ transplants, he said. About 15 percent of all bone marrow transplantpatients, for example, will develop an infection from Aspergillus; of those, about two-thirds die.

We haven't had good treatments, we haven't had good prevention methods and, most importantly, we haven't had good diagnostic methods to identify which patients have these infections, Wingard said. Since we often don't recognize that patients have aspergillosis until very late in the course of the infection, by the time we try to treat the infection it is often so advanced we have very poor prospects ofbringing it under control.

A number of hospitals undergoing renovations have experienced outbreaks, in many cases after the organism contaminated ventilation systems or fireproofing materials. Despite hospitals' infection control measures aimed at minimizing risks, including special air filtration systemsdesigned to filter out Aspergillus and other infectious agents, facilities can still have problems and sometimes have even had to temporarily close their patient-care units.

You and I have a good healthy defense, so while we may be colonized by the organisms, we rarely get serious infections, Wingard said. But if we become immunocompromised, those organisms can be deposited on themucosal surface of nasal passages, the sinuses and the bronchi, and theycan start invading and can cause very serious, deadly infections.

Complicating the picture is that aspergillosis is frequently mistakenfor bacterial pneumonia, and tests for the infection often are initiallynegative.

Historically, our only means of diagnosing these infections has been by growing the organism from patient's specimens in the laboratory and then having it identified by an experienced mycologist, said Barbara D. Alexander, M.D., the project's co-principal investigator and director of transplant infectious diseases services and the clinical mycology laboratory at Duke University Medical Center. These conventional methods for diagnosing fungal disease are slow and lack sensitivity. Furthermore, many times the patients are too sick to tolerate the invasive procedures, such as lung biopsy, in order to obtain the samples for laboratory testing.

Wingard said two-thirds of the time tests are negative even thoughpatients have the infection.

That's the biggest challenge - we may suspect patients have theinfection but we can't really know with certainty from currentlyavailable tests whether they truly are infected or not, he said. Weend up making clinical decisions about using drugs that may be toxic or using the wrong drugs in patients when we are not sure whether they have this deadly infection.

Officials are hoping to collect samples from about 200 patients a yearfor the next seven years to better characterize the fungus and improvethe diagnostic accuracy and speed of tests used to detect aspergillosis.The repository will include samples from patients with confirmedinfections that will be compared with samples from patients whosediagnosis is less clear and with samples from patients who are athigh-risk but not infected.

Researchers also will work with Emory University, Indianapolis-basedMiraVista Diagnostics, and the University of Manchester in England to evaluate existing tests and develop new, more accurate and less invasive ones.

While more potent treatment regimens are improving prospects forpatients, so-called emerging pathogens -- viruses, bacteria and fungi -- are a growing medical problem, Wingard said.

With advancing medical technology and more powerful antibiotics,patients are living longer, he said. We have a growing population of patients who are susceptible to very serious infections by viruses,bacteria and fungi that in years past were not medical problems.

New technique to 'see' and protect transplants successful in diabetic animal model

Sun, 29 Jul 2007 04:00:00 PST

( from http://www.rxpgnews.com ) Researchers at Johns Hopkins have found a way to overcome a major stumbling block to developing successful insulin-cell transplants for people with type I diabetes.

Traditional transplant of the cells, accompanied by necessary immune-suppressing drugs, has had highly variable results, from well- to poorly tolerated. Part of the problem, the Hopkins researchers say, is an inability to track the cellsso-called pancreatic beta cellsonce theyre inside the body.

Now a new technique encapsulates the insulin-producing cells in magnetic capsules, using an FDA-approved iron compound with an off-label use, which can be tracked by magnetic resonance imaging (MRI). The product, tested in swine and diabetic mice, also simultaneously avoids rejection by the immune system, likely a major reason for transplant failure. The work will be published online next week in Nature Medicine.

Were really excited because we can track where we put the cells and make sure their protective housing stays intact and that the cells dont move. This could solve the mystery of why current transplantation techniques work only for so long, says one of the studys authors, Aravind Arepally, M.D., assistant professor of radiology and surgery at Hopkins.

Type I diabetesthe most common childhood sortcauses a persons immune system to destroy the pancreatic beta cells that make insulin. Without insulin, blood sugar levels can become dangerously high and lead to complications that include blindness or kidney failure. Careful monitoring of blood sugar levels paired with insulin injections can manage the condition, but transplanting healthy beta cells holds more promise for the moment-to-moment fine-tuning of insulin levels, says Arepally.

Current experimental cell transplantation techniques are done naked and blind, only lasting a short period of time, according to co-author Jeff Bulte, Ph.D., a professor of radiology and chemical and biomolecular engineering at Hopkins. The unprotected transplanted cells are vulnerable to attack by the recipients immune system, and researchers cannot see the cells to figure out why they stop making insulin after a while.

To address both of these challenges, the research team captured beta cells in tiny porous capsules made from a mixture of alginate, a gooey material made from seaweed, and Feridex, a magnetic iron-containing material visible under MRI. They then used a machine that oozes droplets of this mixture to surround and encapsulate individual islet clusters each containing about 500 to 1,000 insulin-producing beta cells. Once the cells are encapsulated, the shell hardens, creating a magnetocapsule that measures less than 1/128 of an inch across.

Theyre tiny spheres with nano-scale pores just big enough too let the good stuff out but keep the bad from getting in, says lead author Brad Barnett, medical student and Howard Hughes fellow at Hopkins. The openings in the magnetocapsule are so small that the bodys immune system sentinels cannot reach and attack the transplanted cells.

The team first transplanted magnetocapsules into the abdomens of mice engineered to develop diabetes. Blood sugar levels in the animals returned to normal within a week and stayed that way for more than two months. In contrast, more than half of untransplanted diabetic mice died, and the rest had very high blood sugar levels.

To mimic human transplantation, the researchers then implanted magnetocapsules into the livers of swine with the help of MRI fluoroscopy, special reflective screens and a computer monitor that provide real-time imaging. The liver was chosen, rather than the usual pancreatic home of beta cells, because it contains many blood vessels that can deliver insulin quickly to the rest of the body.

Getting the magnetocapsules into the right place requires hand-eye coordination normally required when playing video games, says Arepally. The team threaded a long needle-like tube into a large vein near the upper thigh and guided the tube upward, across and into a neighboring blood vessel, ending in the body of the liver.

The pigs underwent MRI and blood tests three weeks after magnetocapsule transplantation. MRI showed that the magnetocapsules remained intact in the liver, and blood tests revealed that the cells were still secreting insulin at levels considered functional in people.

We hope that our magnetocapsules will make tissue-type matching and immunosuppressive drugs problems of the past when it comes to cell-based therapies for type 1 diabetes, says Bulte.

First mouse lung transplants lay groundwork for new ways to prevent transplant rejection in humans

Wed, 11 Jul 2007 04:00:00 PST

( from http://www.rxpgnews.com ) St. Louis, July 11, 2006 Lung transplants have been performed successfully for more than 20 years in humans but never before in mice until now. Surgeons at Washington University School of Medicine in St. Louis have developed the first mouse model of lung transplantation, and theyre hoping it will help explain why the success of the procedure in humans lags far behind other solid organ transplants.

Ultimately, the mouse model could pave the way for developing new therapies to prevent lung transplant rejection a major problem that limits the long-term success of the procedure. The mouse model is described in the June issue of the American Journal of Transplantation.

Five years after lung transplant surgery, only about 45 percent of patients are still alive, according to the U.S. Organ and Procurement and Transplantation Network. This compares with five-year survival rates of about 70 percent for heart and liver transplants and about 80 percent for kidney transplants. About 1,000 lung transplants are performed each year in the United States.

The high failure rate of lung transplants is a huge problem, says lung transplant surgeon Daniel Kreisel, M.D., Ph.D., an assistant professor of surgery and a lead investigator of the research. Unlike other organs, lungs are constantly exposed to bacteria and viruses in the environment, and we think this exposure increases the risk of chronic rejection and the eventual failure of the organ. This is why the mouse model is so critical. It will allow us to understand the molecular mechanisms that control lung transplant rejection.

Lung transplants are the only treatment option for end-stage lung disease, including chronic obstructive pulmonary disease (COPD), cystic fibrosis, pulmonary fibrosis and certain congenital lung defects. Following a transplant, patients must take drugs for the rest of their lives that suppress the immune system and prevent it from attacking the new lung. This leaves them vulnerable to upper respiratory infections, which can quickly develop into pneumonia.

Kreisel and others suspect that these illnesses alter the immune response and increase inflammation, which eventually lead to chronic rejection. They note that mainstay immunosuppressive drugs simply are not effective at preventing chronic rejection for lung transplants, and they hope the mouse model will reveal why.

The current hypothesis is that lung transplant rejection is linked to chronic inflammation from transient viral or bacterial infections, and this can be aggravated by the fact that transplant recipients are taking immunosuppressive drugs, Kreisel says.

Mouse models for heart, liver and kidney transplants have existed for years, but developing a similar model for lung transplantation has proved to be a real technical challenge. Mouse lungs measure less than an inch in length and the pulmonary vein and artery, which carry blood to and from the heart, are as thin as human hair.

Mikio Okazaki, M.D., a postdoctoral fellow, adapted the lung transplantation technique used in rats to the mice. He uses synthetic cuffs to join the donor vessels with those of the recipient. Okazaki has successfully performed several hundred lung transplants in the mice, and the teams analysis indicates the model simulates the same immune response that occurs in humans following lung transplantation.

Before Okazaki and his Washington University colleagues developed the mouse model, researchers had been studying lung transplantation using a nonphysiological mouse model in which a small section of trachea from one mouse was transplanted under the skin of another. Although it was simple to create, the model did not accurately mimic lung transplantation. It was a very artificial model that had little to do with reality, Okazaki says. We think the new model will be far better for studying the underlying immune mechanisms that lead to rejection.

The new mouse lung transplant model has an advantage over those in rats and larger animals because the genetics of mice are well documented and their genes are easier to manipulate. With the mice, we can selectively delete genes to study their function in the transplanted lung or in the recipient, which weve not been able to do effectively in other animal models, says Andrew Gelman, Ph.D., an assistant professor of surgery, who is a lead investigator of this research. By understanding the genes that control lung graft survival, researchers will be able to better guide the development of therapies to counteract chronic rejection.

The mouse model also will allow the researchers to investigate how other transplant-related complications affect the long-term success of the procedure. Many lung transplant patients experience gastric reflux, and doctors suspect this acid exposure damages the lining of the lung and further exposes the organ to pathogens. The mouse model will let researchers evaluate whether gastric reflux increases the risk of lung rejection.

Additionally, the time between surgery to harvest a donor lung and transplant it into a patient is widely suspected to affect its overall function after transplant surgery. The mouse model will help pinpoint the inflammation that underlies damage to the organ when it cant be transplanted quickly and may lead to ways to prevent such injury.

Based on mouse models of other solid organ transplants, researchers have learned that different groups of immune cells contribute to rejection in different organs. Rejection of the lung differs from rejection of the heart in terms of the cells that participate in that rejection, says Alexander Sasha Krupnick, M.D., assistant professor of surgery. Every organ is different. What weve learned about rejection of the heart in mice does not apply to lungs. So we are thrilled to finally have an acceptable mouse model of lung transplantation to help us discover ways to increase the success of these transplants in humans.

Neuroscientist comments on stem cell study's success in helping primates with Parkinson's

Tue, 10 Jul 2007 04:00:00 PST

( from http://www.rxpgnews.com ) Tampa, FL (July 10, 2007) -- A University of South Florida neuroscientist reports that the cutting-edge research study of human stem cells in primates with Parkinsons disease is compelling on several fronts particularly how the transplanted cells did their job of easing disease symptoms.

Paul R. Sanberg, DSc, PhD, Distinguished Professor of Neurosurgery and Director of the Center for Aging and Brain Repair at USF Health, wrote the commentary Neural Stem Cells for Parkinsons Disease: To Protect and Repair published July 9 in the Early Edition online version of journal Proceedings of the National Academy of Sciences of the United States of America (PNAS). The expert commentary is a companion piece to the study conducted by Gene Redmond and colleagues at Yale and Harvard Universities and the Burnham Institute.

That NIH-funded study showed that only a small number of stem cells turned into dopamine-producing cells not enough to improve the primates function by replacing missing neurons. Instead, some stem cells turned into astrocytes, a supportive brain cell that produces neuron-nourishing chemicals. The researchers also identified in the brains of the primate recipients a significant amount of dopamine-producing neurons that were not derived from stem cells. The results suggest that stem cells may actually trigger the brains own self-repair mechanisms by pumping out molecules that boost nerve survival and blood vessel development and decrease neural degeneration.

We at the Center for Aging and Brain Repair at USF Health have been arguing, for some time now, that stem cells are important for brain repair because they provide growth factors and because they send signals to the brain to help it repair itself, Dr. Sanberg said. This study in primates showed the same effects -- that the stem cells are there to act as facilators of repair versus the original hypothesis that stem cells are transplanted to merely replace an injured cell.

Dr. Sanberg said the study has relevance to all audiences. This was one of the first studies to look at stem cells in primates with Parkinsons disease. Its the first step in translating that research, he said. We hear about new sources of stem cells monthly, but how we take those cells and treat disease is going to be a significant amount of translational work. This is one of the first studies that starts that process - looking at primates before going into people with Parkinsons disease.

While the transplanted cells appeared not to form tumors following transplant, Dr. Sanberg said the translational research in primates raises questions that need to be addressed before moving to human trials, including determining the most effective cell dosing and brain sites to target.

Pending further preclinical studies, he concludes in the commentary, the results so far from the current study are supportive for developing a safe and effective stem cell treatment for Parkinsons disease.

Dr. Sanbergs commentary and the study it highlights will also be published in the magazine edition of PNAS. The global journal has been a resource for multidisciplinary research since 1914. Its online edition, where Dr. Sanbergs commentary appears this week, receives nearly 6 million e-visitor hits per month. Content includes research reports, commentaries, reviews, perspectives, colloquium papers, and actions of the Academy. Coverage in PNAS spans the biological, physical, and social sciences.

A gene that protects from kidney disease

Sun, 08 Jul 2007 04:00:00 PST

( from http://www.rxpgnews.com ) Researchers from the European Molecular Biology Laboratory (EMBL) and the University of Michigan have discovered a gene that protects us against a serious kidney disease. In the current online issue of Nature Genetics they report that mutations in the gene cause nephronopthisis (NPHP) in humans and mice. NPHP is a disease marked by kidney degeneration during childhood that leads to kidney failure requiring organ transplantation. The insights might help develop effective, noninvasive therapies.

The kidneys are the organs that help our body dispose of potentially harmful waste. Diseases that affect this fundamental function are very serious but so far only poorly understood. NPHP is such a disease; it causes the kidneys to degenerate and shrink starting early on in childhood often leading to renal failure before the age of 30. So far, kidney transplantation in early age has been the only way to save patients suffering from NPHP. With a new mouse model Mathias Treier and his group at EMBL have shed new light on the molecular mechanisms underlying NPHP opening up novel ways to treat the disease.

Our mice show striking similarities with NPHP patients, says Mathias Treier, group leader at EMBL. Very early on in their lives their kidney cells start to die and the mice develop all the characteristic disease symptoms. It is the first time that a mouse model reveals increased cell death as the mechanism underpinning kidney degeneration in NPHP. The genetic cause is a mutation in a gene called GLIS2.

GLIS2 normally prevents cell death in the adult kidney. It does so by shutting down genes that initiate cell death and that are only required during the development of the organ. A mutation interfering with GLIS2 function reactivates these harmful genes the result being that large numbers of kidney cells die. The organ shrinks and changes in its architecture occur which affect normal kidney function.

To find out if GLIS2 has the same effect in humans Friedhelm Hildebrandt and his team at the University of Michigan carried out a genetic screen of patients suffering from NPHP. They found that like the mouse model some patients carried mutations in the same GLIS2 gene, confirming that GLIS2 is a crucial player in NPHP also in humans.

This is an excellent example of how combining basic research with clinical studies can help uncovering mechanisms of human disease, says Henriette Uhlenhaut who carried out the research in Treiers lab. The next step will be to translate the insights gained into new therapeutic approaches to develop alternatives to kidney transplantations. With GLIS2 we have already identified one promising candidate drug target and our mouse model will help us find many others.

Tough tubes -- Carbon nanotubes endure heavy wear and tear

Mon, 02 Jul 2007 04:00:00 PST

( from http://www.rxpgnews.com ) Troy, N.Y. -- The ability of carbon nanotubes to withstand repeated stress yet retain their structural and mechanical integrity is similar to the behavior of soft tissue, according to a new study from Rensselaer Polytechnic Institute.

When paired with the strong electrical conductivity of carbon nanotubes, this ability to endure wear and tear, or fatigue, suggests the materials could be used to create structures that mimic artificial muscles or interesting electro-mechanical systems, researchers said.

The report, Fatigue resistance of aligned carbon nanotube arrays under cyclic compression, appears in the July issue of Nature Nanotechnology. Despite extensive research over the past decade into the mechanical properties of carbon nanotube structures, this study is the first to explore and document their fatigue behavior, said co-author Victor Pushparaj, a senior research specialist in Rensselaers department of materials science and engineering.

The idea was to show how fatigue affects nanotube structures over the lifetime of a device that incorporates carbon nanotubes, Pushparaj said. Even when exposed to high levels of stress, the nanotubes held up extremely well. The behavior is reminiscent of the mechanics of soft tissues, such as a shoulder muscle or stomach wall, which expand and contract millions of times over a human lifetime.

Pushparaj and his team created a free-standing, macroscopic, two-millimeter square block of carbon nanotubes, made up of millions of individual, vertically aligned, multiwalled nanotubes. The researchers then compressed the block between two steels plates in a vice-like machine.

The team repeated this process more than 500,000 times, recording precisely how much force was required to compress the nanotube block down to about 25 percent of its original height.

Even after 500,000 compressions, the nanotube block retained its original shape and mechanical properties. Similarly, the nanotube block also retained its original electrical conductance.

In the initial stages of the experiment, the force needed to compress the nanotube block decreased slightly, but soon stabilized to a constant value, said Jonghwan Suhr, an assistant professor of mechanical engineering at the University of Nevada in Reno, who received his doctorate from Rensselaer in 2005, and with Pushparaj contributed equally to this report.

As the researchers continued to compress the block, the individual nanotube arrays collectively and gradually adjusted to getting squeezed, showing very little fatigue. This shape memory, or viscoelastic-like behavior (although the individual nanotubes are not themselves viscoelastic), is often observed in soft-tissue materials.

While more promising than polymers and other engineered materials that exhibit shape memory, carbon nanotubes by themselves do not perform well enough to be used as a synthetic biomaterial. But Pushparaj and his fellow researchers are combining carbon nanotubes with different polymers to create a material they anticipate will perform as well as soft tissue. The team is also using results from this study to develop mechanically compliant electrical probes and interconnects.

Scientists identify a mouse embryonic stem cell more like our own

Wed, 27 Jun 2007 04:00:00 PST

( from http://www.rxpgnews.com ) Scientists have discovered a new type of mouse embryonic stem cell that is the closest counterpart yet to human embryonic stem (ES) cells, the National Institutes of Health (NIH) announced today. The cells are expected to serve as an improved model for human ES cells in studies of regeneration, disease pathology and basic stem cell biology.

The findings, reported on-line today in Nature, are the result of a collaborative effort among scientists at the National Institute of Neurological Disorders and Stroke (NINDS), the National Cancer Institute (NCI) both part of NIH and the University of Oxford, U.K.

These mouse cells will teach us about how human embryonic stem cells generate the hundreds of cell types that make up the human body knowledge that will help us realize the promise of stem cell therapy, said NIH Director Elias A. Zerhouni, M.D.

Compared to traditionally studied mouse ES cells, the new cells called epiblast stem cells are not only a closer match to human ES cells, they are one step farther down the developmental path toward the cell types of the adult mouse. They appear at a later stage of development when the embryo and supportive tissues have become more defined.

You can view this cell as the beginning of the organism, said lead scientist Ronald McKay, Ph.D., a senior investigator at NINDS. Dr. McKay also directs the NIH Stem Cell Unit, responsible for storing and characterizing human ES cells approved for use in federally funded research.

Mouse ES cells are typically used as a proxy for human ES cells, even though they differ in several ways, from their appearance under a microscope to chemical modifications in their DNA. By these measures and others, the epiblast stem cells isolated by Dr. McKay and his team are a closer match to human ES cells. Moreover, because theyre farther along the developmental timeline than the traditionally studied cells, they could offer scientists a unique glimpse at a critical point in the life of an ES cell a time when it is poised to start producing mature cell types, including neurons, muscle and bone.

One key to isolating the epiblast stem cells was to work with slightly older mouse embryos. Traditionally studied mouse ES cells come from embryos that haven't yet implanted themselves in the uterine wall. The epiblast is a cluster of cells that forms after implantation. In mammals, it will give rise to all the cells that make up the adult animal, while surrounding tissues will become supportive structures like the placenta.

Another key was to grow the mouse cells using methods developed for growing human ES cells, an innovation made by Paul Tesar, a graduate student in the NIH-Oxford Biomedical Research Scholars program. The program has allowed Mr. Tesar to split his time between the two institutions; it also provided a link between Dr. McKay and Professor Sir Richard Gardner, an expert on mouse embryonic development at Oxford.

Mr. Tesar and Josh Chenoweth, Ph.D., a postdoctoral fellow at NINDS, did the bulk of the work comparing the epiblast stem cells to established mouse and human ES cell lines.

First, they tested whether the epiblast stem cells are capable of becoming diverse cell types a defining feature of ES cells. The epiblast stem cells passed two such tests. When grown in test tubes, the cells also morphed or differentiated into neuron-like cells, muscle cells, and cells found in the body's inner organs, depending on the growth medium. When injected into immunodeficient mice, they formed teratomas large tumors containing bits of cartilage, muscle, fat, skin and other tissues. David Mack, Ph.D., a postdoctoral fellow at NCI, assisted with the teratoma experiments.

Other experiments revealed how similar the epiblast stem cells are to human ES cells, and how different those two cell types are from the classic mouse ES cell. For instance, human ES cells and mouse epiblast stem cells possess nearly the same set of active transcription factors proteins that turn genes on and off. They also have similar chemical tags on their DNA, making it more or less receptive to transcription factors. And in the process of deciding whether they will become gametes (sperm and egg cells) or somatic cells (everything else), epiblast stem cells seem farther along than the classic mouse ES cells. In mouse ES cells, some genes associated with the gamete lineage are turned on. In human ES and mouse epiblast stem cells, those genes are off, but can be switched on through exposure to growth factors.

The similarities between the two cell types, along with the discovery that the same methods can be used to rear them, show that their growth and differentiation are regulated in the same way, Dr. McKay said.

Understanding what stem cells are and how they grow in a dish are still central problems in medical research, he said. If we know how to control their growth and differentiation, we can regenerate cells lost to injury or disease.

With such knowledge, for example, adult human cells could be reprogrammed to act more like human ES cells. One lab recently coaxed mouse skin cells to behave like classic mouse ES cells; the new mouse epiblast cell could be the key to extending this same trick to human tissue.

Dr. McKay emphasized that despite their importance, the new cells won't render the classic mouse ES cells obsolete. The classic cells are easier to grow and are the primary tool that researchers use to create mouse models of human genetic diseases.

First study transplanting angina patients' purified stem cells shows safety and symptom relief

Tue, 26 Jun 2007 04:00:00 PST

( from http://www.rxpgnews.com ) CHICAGO --- The first U.S. study to transplant a potent form of purified adult stem cells into the heart muscle of patients with severe angina provided evidence that the procedure is safe and produced a reduction in angina pain as well as improved functioning in patients' daily lives, reports the lead researcher at Northwestern University's Feinberg School of Medicine.

Within three to six weeks after the severe angina patients were injected with their own stem cells, many who used to experience pain just from walking to the refrigerator, now only had pain when they climbed two flights of stairs.

This is the first human trial in which patients' own purified stem cells, called CD-34 cells, were injected into their hearts in an effort to spur regrowth of small blood vessels that constitute the microcirculation of the heart muscle. Researchers believe the loss of these blood vessels contributes to the pain of chronic, severe angina.

While lead researcher, Douglas Losordo, M.D., cautioned this was a small pilot study, he said the results are encouraging. That's a very meaningful change in lifestyle or functional capacity, he noted.

Losordo is director of the Feinberg Cardiovascular Research Institute and the Eileen M. Foell Professor of Heart Research at the Feinberg School. He also is a cardiologist at Northwestern Memorial Hospital. He conducted the research while he was a professor of medicine at Tufts University School of Medicine.

The primary aim of the study was to test the safety of the technique, but researchers also discovered preliminary indications of the therapy's benefits. The new study is published June 26 in Circulation.

Our goal is to reconstitute the microcirculation, get the blood back into the tissue and alleviate the symptoms, Losordo said.

Evidence in the lab shows the cell therapy appears to work in at least two ways: the CD-34 cells help to form new micro-blood vessels as well as encourage existing cells in the tissue to grow vessels, a process called neovascularization.

Out of the estimated 1 million people in the U.S. who suffer from chronic, severe angina -- chest pain due to blocked arteries -- about 300,000 cannot be helped by any traditional medical treatment such as angioplasty, bypass surgery or stents. This is called intractable angina, the severity of which is designated by classes. The patients in Losordo's study were class 3 or 4, meaning they had chest pain from normal to minimal activities such as brushing their teeth or even resting.

After the intractable angina patients were injected with their own stem cells, within three to six months many improved up to two classes in functional capability, a significant gain. The double-blind, randomized, placebo-controlled study included 24 patients ages 48 to 84.

Before Losordo launched the study with a procedure to extract stem cells from angina patients, he took the unusual step of testing the stem cell extraction procedure on himself. He took the drug patients were to take and underwent the stem cell extraction process.

I wanted to know what the patients were going to experience, Losordo said. I knew it was going to be harder for the patient because I don't have cardiovascular disease. But if it was tough for me, then there was no way I was going to subject the patients to it.

Rather than extract the stem cells from a patient's bone marrow, which is done in an operating room and can be a painful procedure, Losordo collected the cells from a patient's peripheral circulation. Participants first took a drug called G-CSF for five days, which stimulates the production and release of CD-34 cells from bone marrow. An intravenous line was then inserted into a patient's vein and his blood cells were processed through a machine (which resembles a dialysis machine) that removes mono-nuclear cells, a population of white blood cells that contains the CD-34s. He further processed the cells to select only CD-34s.

These cells are very powerful repair cells for ischemic tissue. They are capable of forming new blood vessels, Losordo said.

Then Losordo injected the CD-34 cells into the heart muscle. He first targeted where to inject the stem cells through a sophisticated electromechanical mapping technology that was originally developed by the Israeli army as a missile-tracking device. It identifies where the heart muscle is alive but not functioning because it is not receiving enough blood supply. This state is called hibernating myocardium. Via the mapping technique, the hibernating muscle appears as red, while the healthy muscle is blue.

It's the same way that bears hibernate because they want to decrease energy consumption, Losordo said. Muscle hibernates because it wants to decrease energy consumption to stay alive. So, it doesn't contract. It's not getting enough oxygenated blood to perform normally, so it shuts down its contractile function.

Losordo has already launched a larger, national 20-center study that will enroll 150 participants to evaluate the promising therapy. He is also about to begin a similar study in heart failure patients using the same approach.

New vaccine prevents CMV infection and disease in mice

Fri, 22 Jun 2007 04:00:00 PST

( from http://www.rxpgnews.com ) Researchers at the University of California, San Diego (UCSD) Skaggs School of Pharmacy and Pharmaceutical Sciences have patented a strategy for developing a human vaccine to prevent against Human Cytomegalovirus (hCMV) infection and disease.

CMV, a type of herpes virus, is the leading viral cause of birth defects and a serious problem in patients with compromised immune systems. The bodys natural immunity doesnt protect against infection by the virus, estimated to be present in 50 to 75 percent of all adults.

Until now, scientists havent been able to develop a vaccine to protect against CMV, said Deborah H. Spector, Ph.D., UCSD Professor of Cellular and Molecular Medicine and faculty member of the Skaggs School of Pharmacy and Pharmaceutical Sciences. Using a two-pronged approach, we successfully created and tested a vaccine in a mouse model with CMV that shows enormous promise for re-directing the bodys immune system, enabling it to fight the virus.

The mouse vaccine generates an immune response that protects against both infection and development of disease when the virus is present by completely disarming the viruss ability to replicate and establish a persistent infection. The work is currently online in advance of publication in the July issue of Journal of Virology.

Our approach generates an immune response that is different from the normal response to the virus, and we hope to have found an Achilles heel in the defenses that the virus uses to evade the immune system, said Spector. The virus has evolved to persist in the host by evading the immune responses either by hiding or by misdirecting the hosts immune responses. We found a way to teach the host immune system to not be tricked by the virus. She added that the next step is to apply this strategy to create a vaccine for use in humans.

CMV is a virus that, while carried by the majority of adults in the United States, can remain dormant for years, if not the lifetime, of a healthy individual. However, two percent of all children are born with the virus passed on by the mother in utero, and 15 percent of those children will show symptoms such as hearing loss, mental retardation, motor or learning disabilities. Because the hosts natural immune system can protect from the disease but cant rid the body of the virus, people remain infected and can become re-infected or infect others through saliva.

Children in day care settings, for example, or adults who are sexually active, can pass along the virus, explained Spector. It becomes a serious problem in developing infants during the pregnancy or in those whose immune system is compromised, such as AIDS or transplant patients.

When a persistent virus such as CMV infects an individual, it disarms the host immune system in two ways by hiding or masking the proteins that would normally provoke an immune response, or by fooling the immune system into mounting a response that doesnt work to eradicate the virus.

We needed a way to make the host defense system sit up and take notice, said Christopher S. Morello, Ph.D., first author of the study.

To do this, the researchers devised a vaccine with a one-two punch that combines a DNA immunization that targets T-cells to essential genes required for CMV replication, with a killed virus that prompts the bodys B-cells to generate an antibody response.

The vaccine contains the DNA of two essential genes that are essential for replication of the virus. These genes which are also found in other herpes viruses such as chicken pox or herpes simplex have the same or very similar sequence, structure and function whether in human or mouse viruses, and present a novel target for the hosts T-cells to muster forces and attack the virus. Secondly, the vaccine also contains a boost from an inactivated virus, which generates an antibody response. Neither approach alone would give complete protection.

In mice, the vaccine not only fought the disease, but prevented the infection from being established in the first place, Morello said.

Researchers at UCSD hope to begin pre-clinical work on development of a human vaccine. If successful, an FDA-approved, commercially licensed hCMV vaccine could be administered to specific at-risk populations, such as females prior to child-bearing years, day care providers, organ transplant recipients, or as part of regular childhood immunizations.

This approach may also be valid for a number of diseases associated with persistent or latent infections, including all types of herpes-associated diseases, AIDS, or hepatitis, said Spector. These viruses persist because immune responses generated by the viral infection are not able to eradicate the virus.

A faster way to recover from chemotherapy and marrow transplant

Wed, 20 Jun 2007 04:00:00 PST

( from http://www.rxpgnews.com ) Researchers at Childrens Hospital Boston report finding a new way to increase stem cells in blood, suggesting a possible treatment to help patients who undergo chemotherapy or bone marrow transplant for leukemia and other cancers recover their immune function more quickly. In the June 21 issue of Nature, they demonstrate that a stable analog of prostaglandin can enhance the blood-forming system, both during embryonic development and after its been damaged.

The discovery, made possible through high-volume drug screening in zebrafish, marks the first time stem-cell production has been induced by a small-molecule drug, says the studys senior author, Leonard Zon, MD, of the Childrens Hospital Boston Stem Cell Program and Division of Hematology/Oncology. Other studies, including one from Zon's own lab*, have identified ways of increasing formation of blood stem cells, which give rise to each of the bodys various blood cell types. However, the methods are technically complex and havent lent themselves to broad medical use.

The hospital now hopes to conduct a clinical trial of the drug, a long-active derivative of prostaglandin E2 known as dmPGE2. This compound was originally tested more than 20 years ago for patients with gastritis, but was never marketed as a drug.

Currently, patients undergoing bone marrow transplant must wait for marrow from a matched donor to replenish their stem cells and reproduce the full array of blood cell types, including all the cells of the immune system. When theres no suitable donor for a marrow match, patients can receive umbilical cord blood, which also contains blood stem cells. But the number of stem cells in one cord of blood is often not adequate for older children and adults, leaving them with diminished immune function and high risk for infections.

Zon and colleagues Trista North, PhD, and Wolfram Goessling, MD, PhD, both also of Childrens Stem Cell Program, zeroed in on dmPGE2 by screening more than 2,500 chemicals in zebrafish. Knowing that two genes, runx1 and cmyb, are required for blood stem cells to develop in vertebrate embryos, they looked for compounds that altered the expression (activation) of these genes. North spent six months placing 15,000+ tiny embryos in wells, each containing a different chemical five embryos to a well, 48 wells to a plate then checking each embryo 24 hours later to monitor its development and count its blood stem cells.

The screen identified 82 chemicals that markedly increased or decreased gene activity. Of these, 10 turned out to affect the prostaglandin pathway: five increased the formation of blood stem cells, and five decreased it. We werent specifically looking for prostaglandins, says Zon, a Howard Hughes Medical Institute investigator who is also a member of the Harvard Stem Cell Institute. This was a surprise finding.

A variety of experiments confirmed that prostaglandins, particularly dmPGE2, promote blood stem cell formation, while chemicals that block prostaglandin synthesis (such as aspirin or ibuprofen), suppress blood stem cell formation. Finally, in zebrafish whose marrow was depleted by irradiation, those given dmPGE2 recovered blood cell populations more quickly.

Prostaglandins are known to be released by the body when inflammation is present such as after an injury and may be among the compounds that aid recovery. So it makes some sense that prostaglandins would have the ability to enhance regrowth of cells, Zon says.

The zebrafish is ideal for investigating blood formation, says North. It reproduces quickly and in large number and has a blood-forming system that shares many similarities with that of mammals. Zebrafish embryos develop outside the mothers body and can take up chemicals through their skin, making it easy to test the developmental effects of large numbers of compounds very rapidly, while their transparent skin makes it possible to visualize the blood stem cells in live fish.

The researchers also confirmed their observations in mammalian models. When dmPGE2 was added to mouse embryonic stem cells in the lab, production of blood stem cells increased. In mice that underwent bone marrow transplant, treatment with dmPGE2 led to enhanced blood-stem-cell formation, and the stem cells remained present in the marrow more than six months after transplantation, indicating long-term engraftment. The fact that we confirmed the zebrafish discovery in a mammalian system suggests it may also be applicable in humans, says Goessling.

The clinical trial, projected to begin in 2008 at Childrens Hospital Boston in conjunction with the Dana-Farber/Harvard Cancer Center, will recruit patients undergoing cord blood transplant for leukemia. Patients will receive cord blood to replenish their blood systems, some of it treated with dmPGE2 to enhance blood-stem-cell formation. Having more stem cells should help the blood system to regrow faster and minimize complications, such as infections, says North.

Elevated pepsin levels may lead to rejection of lung transplants

Fri, 15 Jun 2007 04:00:00 PST

( from http://www.rxpgnews.com ) Researchers in the United Kingdom have demonstrated that high levels of pepsin, a digestive enzyme that is a marker for gastric aspiration, are associated with acute rejection of a lung transplant. This research provides further evidence that lung rejection may be caused by factors other than alloimmunity, the attack the body mounts to protect itself against foreign cells.

We think gastric aspiration [the taking of stomach fluids into the lung] may contribute to an overall injury to the transplanted lung, said Chris Ward, Ph.D., lead author of the study. This pattern of injury may be similar to rejection or increase the risk for further rejection.

Dr. Ward, of Newcastle University, and the other researchers reported their findings in the June 15, 2007, issue of American Journal of Respiratory and Critical Care Medicine, published by the American Thoracic Society.

The study included 36 lung transplant recipients, 17 subjects with normal lung function but unexplained cough who served as disease controls for the study, and 4 normal, nonsmoking control subjects. The researchers determined pepsin levels in all the subjects using bronchoalveolar lavage (BAL)

Our primary finding was that, compared with control subjects, wrote the researchers, BAL pepsin levels were elevated in stable lung transplant recipients, subjects with acute rejection, and subjects with bronciolitis obliterans [a common manifestation of lung transplant rejecton]. Our secondary finding was that the highest levels of pepsin appeared in the transplant recipients with clinically significant acute rejection (grade A2 or greater).

These findings support the growing recognition that gastroesophageal reflux (GER) is a potential cause for post-transplant lung injury and other airway and lung diseases. Although none of the transplant patients were formally evaluated for GER, nearly all were treated with acid suppression medications, which is standard therapy after lung transplantation.

Despite those medications, known as proton pump inhibitors, the researchers found evidence of gastric aspiration. It is important to recognize that proton pump inhibitors do not prevent reflux per se, but rather act to cut down on acidic reflux, the researchers noted. They also noted, that in addition to the damage that might be done to the new lung by acid reflux, pepsin is not targeted by these drugs and may be a separate cause of lung injury.

The researchers reported that the disease control groupthose with normal lung function, but unexplained coughdid not have pepsin in their lungs, even when 10 of 17 were diagnosed during the study as having gastroesophageal reflux disease (GERD). A diagnosis of GERD does not mean that patients are refluxing out of the esophagus and hence aspirating, they explained. Even if the refluxate reaches the upper airway, it is almost certainly cleared by a hyperactive cough reflex.

In their article, the researchers note ongoing studies being done at Duke University that appear to show lung transplant patients who undergo fundoplication, a surgical procedure that strengthens the valve between the stomach and the esophagus, before the transplant have longer survival rates and delayed onset of bronchiolitis obliterans syndrome than those who do not.

If fundoplication is confirmed as a useful prophylaxis in preventing lung rejection, they write, markers of aspiration may contribute to identifying patients who might derive clinical benefit.

Newspaper articles on organ transplantation mostly positive, study shows

Fri, 15 Jun 2007 04:00:00 PST

( from http://www.rxpgnews.com ) BUFFALO, N.Y. -- A content analysis of newspaper stories about organ and tissue donation, conducted by researchers at the University at Buffalo, found an almost 4:1 ratio of positive-to-negative articles on the subject.

In a study involving 715 stories published in 20 newspapers over two years, results showed that 57 percent of the articles were positive to organ donation, while 14 percent were negative. The remaining were neutral.

Results of the analysis appear in the current (June 2007) issue of Health Communication.

Research has shown that most of what people know about health issues they get second- or third-hand from the media or friends and family, said Thomas Hugh Feeley, Ph.D., first author on the study.

Available data suggests that organ donation is portrayed positively in the media, but it also shows a lack of knowledge about the critical shortage of organs and about how organs are procured and assigned, said Feeley, associate professor of communication in the UB College of Arts and Sciences and of family medicine in the UB School of Medicine and Biomedical Sciences.

We wanted to know if the issue was covered positively in newspapers, and what aspect of organ donation the articles concentrated on, he said. We also wondered if the content differs by newspaper or region.

Newspapers were chosen for content analysis by size of circulation and electronic access to the database. Four of the five largest U.S. daily newspapers and 13 of the top 20 were selected for the study. Nearly all the nations major dailies in the East, Midwest, South and West were included, plus USA Today, which is considered a national newspaper.

The analysis was structured to capture 17 specific categories, or references appearing in the articles, such as organ, youth, tragedy, minority, etc.

Results showed the five most frequently referenced topics in the articles were: kidneys, post-transplantation health and welfare, information on the critical shortage of organs, living donation and the actual transplant surgery process.

Negative references primarily detailed mistakes that occurred during transplantation or post-transplantation difficulties. References to family or friends as living kidney donors accounted for 88 percent of positive articles.

The New York Times published the most articles on organ donation -- 108, followed by the St. Louis Post-Dispatch with 57, analysis showed.

One theory of media influence holds that media selectively influence opinion leaders on an issue, who in turn discuss the topic with individuals who may not attend to the issue in media, Feeley noted. I think this is what happens with organ donation.

To get a fuller picture of the role of the media, future research on organ donation should examine the influence of media content on reader attitudes, and should study other sources of influence on individual belief regarding organ donation, he said.

University of Pittsburgh School of Medicine researchers develop 'off-the-shelf' vascular grafts

Fri, 15 Jun 2007 04:00:00 PST

( from http://www.rxpgnews.com ) TORONTO, June 15 University of Pittsburgh School of Medicine investigators have engineered artificial blood vessels from muscle-derived stem cells (MDSCs) and a biodegradable polymer that exhibit extensive remodeling and remain free of blockages when grafted into rats. The results of their study, which is being presented at the Tissue Engineering and Regenerative Medicine International Society (TERMIS) North America Chapter meeting being held June 13 to 16 at the Westin Harbor Castle conference center in Toronto, has potentially significant implications for the treatment of heart and kidney diseases, where there is a critical need for new sources of blood vessels for vascular grafts.

The saphenous vein taken from a patients leg continues to be the most commonly used graft for coronary artery bypass grafting even though a significant percentage of vein grafts eventually fail. Arterial grafts are the preferred conduits because they are less prone to becoming obstructed. However, they are in very limited supply, as many patients require multiple grafts. Thus, there is an ongoing search for the ideal small-caliber arterial substitute for revascularization procedures.

The University of Pittsburgh team, led by David A. Vorp, Ph.D., associate professor of surgery and bioengineering and a faculty member of the McGowan Institute for Regenerative Medicine, University of Pittsburgh School of Medicine, developed its vascular graft by bulk seeding, or spraying, MDSCs inside a biodegradable porous, tubular polyester urethane scaffold using a rotational vacuum seeding device.

After culturing their vascular constructs for seven days, the investigators then implanted them in the abdominal aortas of rats eight weeks before performing tests to determine how well the grafts had performed. The cell-seeded constructs showed a significantly higher blockage-free rate than unseeded controls (55 percent versus 0 percent). In addition, at eight weeks, there was an extensive remodeling of the MDSC-seeded polymer by surrounding tissue, exhibiting tissue formation that is consistent with a mature artery.

According to Dr. Vorp, these findings in a rat demonstrate the feasibility of developing MDSC-seeded tissue-engineered vascular grafts for eventual human application. The next step is to demonstrate the use of the tissue-engineered blood vessel in a larger animal model, such as a pig, which has a coagulation system more similar to that in humans. The advantage of our approach is that the graft could utilize the patients own stem cells and be ready for implantation almost immediately or, at most, after a relatively short culture period. This suggests that we could make these available off-the-shelf, which is an essential element for clinical translation, he explained.

University of Pittsburgh researchers culture blood-forming stem cells from human fat tissue

Thu, 14 Jun 2007 04:00:00 PST

( from http://www.rxpgnews.com ) TORONTO, June 14 Researchers at the University of Pittsburgh School of Medicine have successfully isolated and cultured human hematopoietic stem cells from fat, or adipose, tissue, suggesting that they have found another important source of cells for reconstituting the bone marrow of patients undergoing intensive radiation therapy for blood cancers. They are presenting this ground-breaking research at the Tissue Engineering and Regenerative Medicine International Society (TERMIS) North American Chapter meeting being held June 13 to 16 at the Westin Harbor Castle conference center in Toronto.

Adipose tissue has the ability to rapidly expand or contract in accordance with nutritional constraints. In so doing, it requires rapid adjustment in its blood supply and supporting connective tissue, or stroma. Based on previous reports that the stromal vascular fraction of adipose tissue contains stem cells that give rise to pericytes cells surrounding small blood vessels the University of Pittsburgh School of Medicine researchers, led by Albert D. Donnenberg, Ph.D., professor and director of the Hematopoietic Stem Cell Laboratory, University of Pittsburgh Cancer Institute, isolated the stromal vascular fraction from human adipose tissue and expanded these cells by growing them in a specialized blood-culturing medium for 21 to 42 days.

Using a cell-sorting method known as flow cytometry, the researchers detected a broad spectrum of blood-forming, or hematopoietic, cells among the cultured cells at varying stages of differentiation. In particular, they observed both early and mature red blood cells. Moreover, they detected CD34+ cells at approximately the same frequency as is present in freshly isolated bone marrow. In bone marrow, CD34+ expression indicates the presence of progenitor cells which give rise to all of the different types of blood cells.

These data indicate that hematopoietic stem cells, or cells that give rise to them, are an integral part of normal adipose tissue, according to Dr. Donnenberg. We took cells from the stromal vascular fraction of normal adipose tissue and basically gave them bone marrow food to see what would happen. We were able to culture a variety of hematopoietic cells, including blood progenitor cells.

Dr. Donnenberg said that the use of a patients own bone marrow or blood-derived stem cells for bone marrow reconstitution carries some risk that these cells are contaminated with the patients own tumor cells. Since it has been shown in some cases that tumor cells contaminating bone marrow grafts are the source of recurrent malignancies after autologous transplantation, this might be a way of giving patients who need bone marrow reconstitution their own hematopoietic cells derived from a source other than their defective bone marrow, he explained.

Carnegie Mellon scientists devise method to increase kidney transplants

Mon, 11 Jun 2007 04:00:00 PST

( from http://www.rxpgnews.com ) PITTSBURGHComputer scientists at Carnegie Mellon University have developed a new computerized method for matching living kidney donors with kidney disease patients that can increase the number of kidney transplants and save lives.

This step-by-step method, or algorithm, could significantly boost the efficiency of kidney exchanges, a mechanism for matching live donors with unrelated recipients. Kidney exchanges are now considered the best chance for boosting the number of kidney transplants in the United States. More than 70,000 Americans are on the waiting list for kidney transplants and about 4,000 die waiting each year.

The matching algorithm makes it possible to create matches for three- and four-way exchanges that is, three or four donors matched to three or four recipients as well as two-way exchanges. It is the first that is scalable so it can be used for a national pool of donors and recipients, said Tuomas Sandholm, professor of computer science.

A paper detailing the algorithm, developed by Sandholm, Computer Science Professor Avrim Blum and graduate assistant David J. Abraham, will be presented Friday, June 15, at the Association for Computing Machinerys Conference on Electronic Commerce in San Diego.

The Alliance for Paired Donation, a kidney exchange program for 50 transplant centers in 15 states, began using the matching algorithm in December. The Alliance director, Dr. Michael Rees of the University of Toledo Medical Center, said it improves on previous methods both by including three- and four-way exchanges and by factoring in so-called altruistic donors kidney donors without a specified recipient.

For instance, in a match run in early May, the algorithm identified four potential two-way exchanges, three three-way exchanges and one four-way exchange among about 100 donor-patient pairs and seven altruistic donors. Whether any of those transplants take place will depend on factors such as final compatibility testing, Rees said. With the same set of donor-patient pairs and without altruistic donors, the matching method previously used by the Alliance would have identified only one two-way exchange, he added.

About 140 paired kidney donations have occurred in the United States since 1999, Rees said. These paired donations can happen when a friend or loved one is willing to donate a kidney to a patient but is found to be incompatible. When possible, a paired donation is then arranged, in which donor A is incompatible with recipient A, but can donate to recipient B, and donor B can donate to recipient A.

Sandholm said the number of transplants could be increased by expanded use of three-way exchanges donor A gives to recipient B, donor B gives to recipient C and donor C gives to recipient A and four-way exchanges. Numbers could also be increased by enlarging the pool of donor-patient pairs, he added.

Several regional exchanges are in operation and the possibility of a national exchange has been discussed. Rees predicted that in perhaps five years a national pool could include 3,000 donor-patient pairs and accumulate 1,000 to 1,500 pairs each year. Potentially, as many as 2,000 transplants could be performed from a pool of this size if three- and four-way exchanges are arranged, he said. But existing matching algorithms can arrange only two-way exchanges for such a large pool, and current algorithms capable of arranging three- and four-way exchanges can handle no more than 600 to 900 pairs.

Computer memory is a limiting factor in optimizing kidney exchanges, Sandholm said, noting the large number of constraints, such as differing blood and tissue types, that must be considered. We work around this by using incremental problem formulation, he said. That is, the algorithm devised at Carnegie Mellon doesnt consider all of the constraints at once, but formulates them in the computers memory only as needed, enabling it to analyze up to 10,000 donor-patient pairs.

Research shows cord blood comparable to matched bone marrow

Thu, 07 Jun 2007 04:00:00 PST

( from http://www.rxpgnews.com ) University of Minnesota researchers report that umbilical cord blood transplants may offer blood cancer patients better outcomes than bone marrow transplants, according to an analysis of outcome data performed at the Center for International Blood and Marrow Transplant Research (CIBMTR), Medical College of Wisconsin, Milwaukee.

This is the first study that directly compares matched bone marrow, which is currently considered the preferred graft, with matched and mismatched umbilical cord blood. There is considerable controversy in the medical community about which source of blood stem cells (cord blood or marrow) should be considered the gold standard for treatment of childhood leukemia.

In this study, the investigators compared outcomes of pediatric leukemia patients who received unrelated bone marrow transplants with those who received umbilical cord transplants. While all bone marrow donors were matched, nearly all cord blood donors were mismatched.

The main objective of the research was to compare the results after cord blood and marrow transplantation and provide guidelines to transplant physicians on the selection of the best donor for children with leukemia. Remarkably, mismatched cord blood performed as well as matched bone marrow as measured by leukemia-free survival rates, providing the degree of mismatch was limited and the number of cord blood cells available was sufficient. Furthermore, study participants who received matched cord blood had a 20 percent higher survival rate than matched bone marrow recipients, though the number of matched cord blood transplants was small.

The research appears in the June 9, 2007, issue of The Lancet with John E. Wagner, M.D., professor of Pediatrics and director of the University of Minnesota Medical Schools division of Pediatric Hematology/Oncology and Bone Marrow Transplantation, as senior investigator.

The study was done in collaboration with the National Cord Blood Program of the New York Blood Center, New York. Mary Eapen, M.D., associate professor of Pediatrics at the Medical College of Wisconsin and Associate Scientific Director of the CIBMTR, is the first author.

What this study suggests is that cord blood need not be considered a second line therapy any longer. The fact that cord blood is banked and readily available with little notice is a great advantage. Today, leukemia patients can wait months for an appropriately matched bone marrow donor, during which time their disease might return, Wagner said. For the first time, the timing of transplantation can be dictated by the patients needs as opposed to the availability of the matched bone marrow.

The research suggests that it will become more important to invest in cord blood banks that meet certain standards in relation to cell dose (or volume of the transplanted cells) and Human Leukocyte Antigen (HLA) diversity.

Human Leukocyte Antigens (HLA) are a group of proteins on bone marrow cells that can provoke the immune system to respond. When doing bone marrow or cord blood transplants, doctors generally try to have the donors and recipients HLA types match as closely as possible.

Wagner added that increasing the inventory will increase the chance of finding donors for ethnic and racial minorities currently underrepresented in volunteer marrow registries worldwide.

While the study showed that umbilical cord blood took longer to rebuild the blood-making cells in the body, it was associated with a lower risk of graft versus host disease, a potentially lethal complication, especially when HLA types are mismatched. Rates of leukemia relapse also are lower with mismatched umbilical cord blood transplants. This study also showed that in addition to having a good match, higher cell doses for umbilical cord blood transplants improved survival rates.

The study was done by extensive review of clinical data from transplant centers around the country and reported to the CIBMTR at the Medical College of Wisconsin, Milwaukee and the National Cord Blood Program at the New York Blood Center. The analysis included transplant outcomes in 785 children younger than 16 who had the diagnosis of acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML).

Studies to find better ways to preserve human eggs, ovarian tissue under way

Wed, 06 Jun 2007 04:00:00 PST

( from http://www.rxpgnews.com ) The goal is to make human eggs, ovarian tissue, blood vessels, even whole organs available when needed.

To get there, researchers are directly comparing slow-freezing techniques, used successfully for decades to preserve sperm and embryos, to a more rapid method of cryopreservation that transforms tissues into durable glass-like structures.

Phase I trials under way at the Medical College of Georgia are comparing the two approaches in human ovarian tissue and eggs, or oocytes, as well as human-like cow ovarian tissue and eggs.

They start with reproductive tissues because young women with cancer produce a compelling need and are a good model for other tissues and organs.

What we tell patients is that right now the standard of care for people who are going through cancer therapy is to use egg donors later on, says Dr. Adelina M. Emmi, reproductive endocrinologist and medical director of MCG Reproductive Laboratories of Augusta.

Treatment for leukemia and cervical, ovarian, breast or other cancers often leaves women infertile because systemic chemotherapy and more focused radiation therapy, designed to kill rapidly spreading cancer cells, also can destroy dynamic reproductive tissue.

I dont think when you are faced with the reality that you may die, your fertility is the most important thing you are thinking or talking about, but there are a lot of women interested in talking about it, says Dr. Emmi. She hopes her work with Dr. Ying C. Song, cryobiologist, will one day give her more to say.

They are collecting ovarian tissue from volunteers age 16 to 37 who need the tissue taken for some reason other than cancer, such as a hysterectomy for benign disease, says Dr. Song, MCG clinical associate professor at MCG and director of research for Augusta-based Xytex Research/Xytex International. Collaborators at the University of Texas Health Science Center and M.D. Anderson Cancer Center are doing the same.

With some of the tissue, they are using conventional cryopreservation. Chemicals to protect cells from the hazards of freezing are added before taking tissue from the refrigerator temperature of 4 degrees Celsius to minus 80 degrees Celsius over two- and one-half hours. Later, liquid nitrogen takes it to minus 196 degrees

You put it in a control-rate freezer that takes down the temperature one degree centigrade per minute so it drops the temperature very, very slowly, says Dr. Song.

Slow cooling works well for simple tissue, such as sperm or even embryos, and for blood. In blood, for example, conventional cryopreservation freezes the liquid part but not the cells inside. Liquid freezes and the water inside the cells moves out gradually so they dehydrate, Dr. Song explains.

But, for more complex structures, such as a human egg or ovarian tissue, resulting ice formation can be destructive. Ice crystals break up your inside organelles. That is what hurts eggs, which are very delicate, he says.

When you trigger ovulation with a hormone or naturally, you get the last separation of the chromosomes, from 46 to 23, says Dr. Emmi. That separation enables a future baby to get half his chromosomes from mom and half from dad. Fragile spindles, which line up chromosomes for division, are easily broken during freezing so chromosomes cant properly divide. Typically the resulting embryo dies. Plus, fertilization is unlikely since freezing often hardens the eggs outer shell that sperm must penetrate.

That is why we have tried to develop technology without freezing, says Dr. Song, who has pioneered use of vitrification in blood vessels, cartilage and heart valves.

Vitrification, which takes tissue from room temperature to minus-100 degrees Celsius in 20 minutes, solidifies tissue into a clear, glass-like structure minus the opacity of ice cubes and frozen meats, a tell-tale sign of ice crystals within.

Dr. Song, whose research lab is in MCGs biotech incubator, has developed cryoprotectants that can be used safely in higher doses as well as agents to help protect tissue during the ultra-rapid process of de-vitrification.

People use low concentrations of cryoprotection because they are toxic, he says. The problem is, if you use lower concentrations, you cannot get true vitrification. The agents are needed to intercept water so it wont form ice. Interestingly if small ice crystals form during cooling, they can get larger during de-vitrification, which takes place in seconds.

We developed a solution where we can warm up tissue in under five minutes and still get no ice formation, says Dr. Song, adding that ice formation aside, it is difficult to thaw rock-solid tissue at room temperature in a matter of seconds, meaning the current approach could have extremely limited use.

A study he published in March 2000 in Nature Biotechnology showed the approach he uses works well, at least in blood vessels. Now we want to try this on eggs and ovarian tissue and see if we can develop a robust technology and improve outcomes, Dr. Song says.

Later, researchers will put ovarian tissue preserved both ways into mice to see if it survives and starts making proper connections.

The reason for using ovaries is when you have cancer, if you need chemotherapy, you often dont have time to go through stimulation cycles to get oocytes, says Dr. Emmi. You are concentrating on getting rid of cancer cells. Also, if a woman has breast cancer, for example, hormones needed to induce ovulation could be problematic because many breast cancer cells have estrogen receptors.

As pieces of a puzzle come together, Dr. Song notes scientists already are developing methods to stimulate ovarian tissue to produce eggs outside the body, a process that could also make in vitro fertilization a lot more affordable. Others are looking for ways to ensure there are no cancer germ cells in salvaged tissue.

If all goes as hoped with this study, the next step will have Drs. Song and Emmi taking ovarian tissue from cancer patients, vitrifying it then, after they are sure its cancer-free, re-implanting it when the woman is ready.

A concurrent phase I study is comparing standard cryopreservation to vitrification in eggs. They are using eggs from 60 women age 18-42 that would be discarded because they are not adequate for in vitro fertilization. They also are retrieving and maturing eggs from cow ovaries donated by a local slaughterhouse. Bull sperm will be used to test the viability of cow eggs afterward but human eggs will not be fertilized.

Standard cryopreservation has been tried and largely failed in human eggs, says Dr. Emmi, who believes some version of vitrification likely offers a better option for ovarian tissue and eggs. In fact, many in vitro fertilization programs, including the one she directs at MCG Health System, are moving toward vitrification, which also seems to work faster, better and cheaper in embryos.

They pursue the potential of egg preservation as well to really find out which is the best option: ovarian tissue or pure eggs. Also, a better way to preserve eggs which last about 24 hours outside the body without preservation would reduce the cost and logistical issues of coordinating donor eggs.

The long-term goal is organ banking, says Dr. Song, because even though there are insufficient numbers of donors for those on transplant lists today, another piece of the puzzle is developing techniques for growing organs. In fact, he is collaborating with scientists at Yale University and the Georgia Institute of Technology to regenerate blood vessels and pancreatic substitutes, noting studies published in Tissue Engineering and Cell Transplantation.

Regenerative medicine will help supplement the shortage of organs in the future, and we need technology to preserve those we make.

Gene expression patterns predict rapid decline in idiopathic pulmonary fibrosis patients

Wed, 30 May 2007 04:00:00 PST

( from http://www.rxpgnews.com ) PITTSBURGH, May 30 -- Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease typically characterized by the slow but progressive onset of shortness of breath or cough. Most patients live about five years after diagnosis. However, according to a new study being published today in the online journal PLoS ONE, a subset of patients with a specific genetic profile has a much more rapid progression to complete pulmonary failure and death without a lung transplant.

Based on observations in the clinic that some IPF patients display a more rapidly progressing disease course, researchers at the Simmons Center for Interstitial Lung Disease at the University of Pittsburgh School of Medicine, collaborating with pulmonary scientists in Mexico and California, used DNA microarray analysis to measure the gene expression patterns of 26 rapid progressors and 88 slow progressors. They identified 437 differentially expressed genes between the groups. Specifically, lungs of rapid progressors, who were predominantly males who smoked, overexpressed genes involved in the development of tissues and organs (morphogenesis), oxidative stress, cell migration and proliferation and genes from fibroblasts and smooth muscle cells.

According to Naftali Kaminski, M.D., director of the Simmons Center and director of the Lung Translational Genomics Center, division of pulmonary, allergy and critical care medicine, University of Pittsburgh School of Medicine, these findings offer strong evidence that rapid progressors represent a distinct clinical phenotype compared with the usual slower progressing patients.

We are only now starting to really understand IPF and to characterize it, Dr. Kaminski said. Therefore, it is critical for patients with the disease to be seen in centers that are actively involved in IPF research, so we can help them better decide a course of action.

These findings also highlight the variability in the progression and outcome of IPF and may explain, in part, the difficulty in obtaining significant and reproducible results in studies of therapeutic interventions in patients with IPF, noted first author Moisés Selman, M.D., director of research at the National Institute of Respiratory Research in Mexico City. This study suggests that physicians should pay more attention to the time of onset of symptoms in their patients, Dr. Selman said.

Although preliminary, these results may allow investigators to identify biomarkers of disease progression and, more importantly, better evaluate the effectiveness of potential therapies, added Talmadge E. King Jr., M.D., chief of medicine at San Francisco General Hospital and an internationally renowned expert in research and management of pulmonary fibrosis.

Adult stem cells from human cord umbilical cord blood successfully engineered to make insulin

Fri, 25 May 2007 04:00:00 PST

( from http://www.rxpgnews.com ) GALVESTON, Texas -- In a fundamental discovery that someday may help cure type 1 diabetes by allowing people to grow their own insulin-producing cells for a damaged or defective pancreas, medical researchers here have reported that they have engineered adult stem cells derived from human umbilical cord blood to produce insulin.

The researchers announced their laboratory finding, which caps nearly four years of research, in the June 2007 issue of the medical journal Cell Proliferation, posted online this week. Their paper calls it the first demonstration that human umbilical cord blood-derived stem cells can be engineered to synthesize insulin.

This discovery tells us that we have the potential to produce insulin from adult stem cells to help people with diabetes, said Dr. Randall J. Urban, senior author of the paper, professor and chair of internal medicine at the University of Texas Medical Branch at Galveston and director of UTMBs Nelda C. and Lutcher H. J. Stark Diabetes Center.Stressing that the reported discovery is extremely basic research, Urban cautioned: It doesnt prove that were going to be able to do this in people its just the first step up the rung of the ladder.

The lead author of the paper, UTMB professor of internal medicine/endocrinology Larry Denner, said that by working with adult stem cells rather than embryonic stem cells, doctors practicing so-called regenerative medicine eventually might be able to extract stem cells from an individuals blood, then grow them in the laboratory to large numbers and tweak them so that they are directed to create a needed organ. In this way, he said, physicians might avoid the usual pitfall involved in transplanting cells or organs from other people organ rejection, which requires organ recipients to take immune-suppressing drugs for the rest of their lives.

Huge numbers of stem cells are thought to be required to create new organs. Researchers might remove thousands of donor cells from an individual and grow them in the laboratory into billions of cells, Denner explained. Then, for a person with type 1 diabetes, researchers might engineer these cells to become islets of Langerhans, the cellular masses that produce the hormone insulin, which allows the body to utilize sugar, synthesize proteins and store neutral fats, or lipids. But were a long way from that, Denner warned.

Denner said this research, which reflects a fruitful collaboration with co-authors Drs. Colin McGuckin and Nico Forraz at the University of Newcastle Upon Tyne in the United Kingdom, used human umbilical cord blood because it is an especially rich source of fresh adult stem cells and is easily available from donors undergoing Caesarian section deliveries in UTMB hospitals. However, he added, embryonic stem cell research was absolutely necessary to teach us how to do this.

Embryonic stem cells have been engineered to produce cardiac, neural, blood, lung and liver progenitor cells that perform many of the functions needed to help replace cells and tissues injured by many diseases, the paper notes. Among the insights into cell and tissue engineering gained from work with embryonic stem cells, it adds, are those relevant to the engineering of functional equivalents of pancreatic, islet-like, glucose-responsive, insulin-producing cells to treat diabetes.

The researchers said they tested adult stem cells in the laboratory to ensure that they were predisposed to divide. Then they used a previously successful method in which complex signals produced by the embryonic mouse pancreas were used to direct adult stem cells to begin developing, or differentiating, into islet-like cells.

As they grew these adult stem cells in the laboratory, the researchers conducted other tests in which the cells to be engineered showed evidence of a characteristic, or marker, known as SSEA-4 that was previously thought to exist only in embryonic cells. They also found that, just as embryonic cells have been shown to do, these adult stem cells produced both C-peptide, a part of the insulin precursor protein, and insulin itself. Confirming the presence of the C-peptide was especially crucial, the researchers suggested, because although insulin is often found in the growth media with which the cells are nurtured and is often taken up by such cells, the presence of the C-peptide proves that at least some of the insulin was produced, or synthesized, by the engineered cells.

UPMC begins study of heart support device as a bridge to transplantation

Mon, 21 May 2007 04:00:00 PST

( from http://www.rxpgnews.com ) PITTSBURGH, May 21 Doctors at UPMC have begun a study using an investigational cardiac device, the VentrAssist Left Ventricular Assist System (LVAD) to see whether it can be used safely and effectively in patients with end-stage heart failure.

The study hopes to enroll 30 patients overall for the multi-center feasibility trial throughout nine centers in the United States. Five patients at UPMC have received the device so far, and one has successfully received a heart transplant after waiting for nearly three months on the pump, two of which were spent at home on the device.

The VentrAssist LVAD presents us with a third-generation mechanical solution for end-stage congestive heart failure that approaches the goal of minimal interference with a patient's life. In a subsequent study with this pump, we will focus on support for transplant candidates as well as permanent use for those who do not qualify for heart transplantation, hopefully demonstrating its advantages over previous technology, said Robert Kormos, M.D., co-director of heart transplantation, director of the artificial heart program, medical director of the McGowan Institute for Regenerative Medicine and professor of surgery, division of cardiothoracic surgery at the University of Pittsburgh School of Medicine.

The VentrAssist LVAD is a mechanical blood pump that is implanted in the body to assist the heart to pump blood around the body for people with end-stage heart failure. It is still an experimental investigational device that has been approved by the U.S. Food and Drug Administration only for the purposes of the study. The blood pump is made of titanium and weighs just over half a pound, compared to the 5 pounds of older pumps. The implanted blood pump is connected to the heart and the aorta by two tubes called cannulae. Blood is drawn directly from the left ventricle and returned to the aorta. The VentrAssist LVAD works in tandem with the natural heart and an external controller regulates the blood pump. Unlike other cardiac assist devices, the VentrAssist LVAD has a centrifugal design allowing it to operate in a way that responds to exercise more like the natural heart.

According to the American Heart Association, more than 5 million Americans are diagnosed with heart disease and 550,000 patients are newly diagnosed each year. Despite the significant resources for treatment of this disease, outcomes remain poor. The five-year survival for individuals diagnosed with heart failure is less than 50 percent, and in end-stage heart failure, the one-year survival may be as low as 25 percent regardless of medical therapy.

Currently, there are a limited number of LVADs that are commercially approved for a bridge to heart transplant. Although some patients have benefited from earlier models, many of these devices are large and cumbersome. Patients must be tethered to machines that severely limit their activity. The researchers hope that the VentrAssist LVAD investigational study will help reduce load on the patient's heart while awaiting transplant, improve blood flow and circulation and overall quality of life.

In some cases, the patients with earlier model LVADs demonstrated recovery of their own heart. As a result, they were able to be weaned off the LVAD and avoid heart transplant altogether. It is not known yet whether the VentrAssist LVAD will have the same effect. There is a parallel U.S. clinical trial that will look at the safety and feasibility of the VentrAssist LVAD as an alternative to transplantation.

Dr. Kormos has more than 20 years experience working with artificial heart devices. He is a leading authority in the mechanics of end-stage heart failure and recently chaired a symposium with members of the FDA on adverse reactions to investigational devices at the 27th Annual International Society of Heart and Lung Transplantation meeting.

Quality versus quantity -- transforming kidney transplant policy

Thu, 17 May 2007 04:00:00 PST

( from http://www.rxpgnews.com ) Boston May 17, 2007 -- A new article published in American Journal of Transplantation examines the dilemmas faced in trying to change kidney transplant policy; addressing the need to balance the benefits of immediate transplants with those to be had from waiting for a more suitable match. The article highlights some of the important points to be considered in any new policy-making, and suggests a new method for allocation, whereby the patients are involved in the decision process.

The majority of deceased-donor kidneys are allocated to patients with end-stage renal disease on a first-come, first-serve basis, rather than through careful matching, despite the fact that there is little risk of immediate death from renal ailments. As a result, donated kidneys in excellent condition may be given to patients who are almost certain to die long before the replacement organ wears out, while patients with longer life expectancies may be given organs with a high chance of graft failure, making second or even third transplants necessary later in life.

Recent attention has been focused on designing new methods of prioritization, one that allocates kidneys based on matches with the most favorable risk factors for long-term graft survival. Patients would be ranked based on the expected gain in years-of-life compared to continuing dialysis. However, such a system comes with a number of significant trade-offs, with some ethnic and age groups being more likely to benefit from transplants, and therefore ranking higher than others. The challenge for policy makers is to create a ranking system that takes into account those who do not meet maximum benefit requirements.

In this editorial, Richard B. Freeman, Jr., M.D. presents a solution suggesting that patients themselves decide what level of graft failure risk he or she deems acceptable. Recipients would only be offered kidneys that meet their own standards, rather than being directed by arbitrary allocation policies. Freeman claims that such a system would have many benefits, including better educating patients so that they could make informed decisions, allowing patients to personally decide where the trade-off between the qualitative and quantitative benefit of a transplant lies, as well as speeding up the organ placement program. An approach of this sort would not prevent low risk grafts from being given to patients with short life expectancies, or vice-versa, but it would ensure that the decision rests with the patient, in contrast to a system where quantitative benefit would always take priority with no patient or care giver input.

UPMC performs first beating heart transplant procedure in the US

Thu, 17 May 2007 04:00:00 PST

( from http://www.rxpgnews.com ) PITTSBURGH, May 17 Protected by its own nutrients and blood supply, a beating heart supported by an investigational organ preservation device was successfully transplanted into a 47-year-old man with congestive heart failure and pulmonary hypertension on Sunday, April 8. The surgery was performed at UPMC by Kenneth R. McCurry, M.D., assistant professor of surgery, division of cardiothoracic surgery at the University of Pittsburgh School of Medicine and director of cardiopulmonary transplantation at UPMC's Heart, Lung and Esophageal Surgery Institute.

The patient, who is from Portage, Pa., is doing well and was discharged from the hospital on Monday, April 30. The donated heart, from a 46-year-old Caucasian male, was maintained in a beating state on the investigational Organ Care System (OCS) for two hours and 45 minutes.

Dr. McCurry is principal investigator of the PROCEED Trial, at UPMC, which is evaluating the safety and efficacy of the OCS for heart transplants, manufactured by TransMedics Inc., of Andover, Mass. The OCS is designed to maintain donor hearts in a beating, functioning state during transportation from the donor to the recipient's hospital. After removal from the donor, the heart is placed into the OCS, where it is immediately revived to a beating state, perfused with oxygen and nutrient-rich blood and maintained at the appropriate temperature. Using the OCS, organs are kept in their physiological, beating state for delivery to the recipient and until implantation.

This study presents an exciting opportunity to apply the latest medical technology to help patients receive lifesaving transplants. By maintaining the organ in near perfect physiologic state, the OCS will reduce injury and help extend the life of these organs, which also will improve patient outcomes with less rejection and shorter length of ICU and hospital stay, said Dr. McCurry.

Last month, the U.S. Food and Drug Administration approved TransMedics Inc. to begin the pilot phase of a trial of the investigational device exemption at five centers in the United States. In addition to UPMC, other centers participating include Brigham and Women's Hospital in Boston, the UCLA Medical Center in Los Angeles, the University of Chicago Hospitals Cardiac Center, and the Cleveland Clinic Heart and Vascular Institute. Twenty patients will be enrolled in this phase of the PROCEED trial.

This technology has the potential to greatly reduce ischemic injury to the transplanted organ by enabling the organ to continue to be perfused and oxygenated with its own blood supply. The current standard of preserving a transplanted organ is cold preservation. In this approach the organ is initially perfused with a cold solution and then packed in sterile ice.

Ischemic injury occurs during the period between the donor and the recipient surgeries. During this time the organ is without blood or oxygen, which may cause injury to the transplanted organ, which may ultimately lead to rejection.

Results of the European PROTECT -1 Trial using the OCS were reported at the 27th Annual Meeting of the International Society of Heart Lung Transplantation in San Francisco last month. Results from the European study showed success with the device in 20 heart transplants with 30-day graft and patient survival at 100 percent.

'Nondanger' signal lowers immune reactions

Tue, 15 May 2007 04:00:00 PST

( from http://www.rxpgnews.com ) Rheumatology researchers have discovered that a well-known cell receptor sends a signal to dampen the immune system.

While not having an immediate application to treating disease, the finding raises the possibility that by targeting that receptor, physicians could stimulate a nondanger signal to rein in overzealous human immune responses. Controlling those responses could potentially protect transplant patients from rejection episodes or could relieve symptoms of autoimmune diseases such as rheumatoid arthritis and lupus.

The study, which was performed in mice, appeared in the May 15 issue of the Journal of Immunology.

Researchers from The Childrens Hospital of Philadelphia and The University of Pennsylvania reported that complement receptor 3 (CR3), a protein found on cell surfaces, inhibits dendritic cells, the sentinels of the immune system, from setting off an alarm signal that brings on a full immune response.

Normally, dendritic cells patrol different tissues and organs and look for danger signals sent by tissues undergoing stress or responding to invading microorganisms, said Stefania Gallucci, M.D., leader of the study team at The Childrens Hospital of Philadelphia. We found that when we stimulate CR3 on dendritic cells, CR3 sends a nondanger signal that suppresses the ability of dendritic cells to set off an immune response, added Dr. Gallucci, who is also an assistant professor at the University of Pennsylvania.

In their study, the researchers used a monoclonal antibody, engineered to bind to CR3, to trigger a cascade of responses that had a net result of decreasing the activation of T cells that would normally be produced. T cells are immune cells that fight infection while contributing to the inflammation seen in an immune response.

What is exciting about our research is that we have a new agent for modifying dendritic cell function, said pediatric rheumatologist Edward M. Behrens, M.D., the first author of the study. The monoclonal antibody we used is already in a form that can be used for further studies. It has anti-inflammatory effects, so it may be a potential weapon against inflammatory diseases.

One such disease is lupus erythematosus, an autoimmune disease in children and adults that may damage many organs. A next step, said Dr. Gallucci, is to test the antibody in mice that have a disease similar to lupus in humans. The study team also expects to test the antibody in animal models of rheumatoid arthritis. In addition, the researchers may investigate a possible role for the antibody as an immunosuppressant, in preventing a patients immune system from rejecting cell and organ transplants.

Nerves controlling muscles are best repaired with similar nerves

Fri, 11 May 2007 04:00:00 PST

( from http://www.rxpgnews.com ) When repairing severed or damaged motor nerves with a donor nerve graft, surgeons have traditionally used a sensory nerve from another area of the patient's body. However, these patients often do not fully regain function in the injured area.

But now a team of surgeons at Washington University School of Medicine in St. Louis and Barnes-Jewish Hospital has found that repairing a motor nerve in rats with an intact motor nerve yields better results than using a sensory nerve. The research appeared in the March issue of the journal Microsurgery.

Motor nerves control movement in the muscles, while sensory nerves receive sensory stimuli, such as pain. A significant difference between the two types of nerves is that motor nerves have much larger axons, the thread-like extensions of the nerve cell that carry nerve impulses throughout the body.

The researchers, led by Gregory H. Borschel, M.D., a plastic and reconstructive surgeon at the School of Medicine and senior author of the paper, defines the question of this work as seeking to determine why motor nerves were regenerating more successfully than sensory nerves. Was it because of the nerve's own structure, or architecture, or because supporting cells such as Schwann cells were boosting the regeneration

To find an answer, the researchers broke down the nerve architecture by chopping up motor, sensory and mixed nerves. They divided the minced nerves into groups by type, inserted the mush into tiny silicone tubes and encouraged severed motor nerves to regenerate through the mixtures in the tubes.

The researchers found that disrupting the nerve's architecture by mincing it abolished the benefit of repairing a motor nerve with an intact motor nerve. It turned out there was no difference in regeneration using motor versus sensory nerves through the chopped-nerve tissue, Borschel said.

Several factors contributed to the results, he said. We know that the axons, or nerve fibers, in the motor nerves are bigger, while the sensory nerve fibers are smaller, he said. When the nerves are trying to regenerate using a motor nerve as a graft, it's easier for them to use the larger axons of another motor nerve, although the reason why is not clear.

The results could eventually translate into improved treatment for humans who have nerve damage from industrial, recreational or auto accidents.

The research data is very compelling, Borschel said. The evidence presented through this study could represent a paradigm shift from what we currently do in the operating room. The current standard of treatment for fixing a gap in a motor nerve is to use a sensory nerve, but we believe that if you use a motor nerve instead of a sensory nerve, then the outcome would be better.

The surgeons in the Division of Plastic and Reconstructive Surgery have begun using motor nerves grafts in limited patient cases with good results, Borschel said, but to clearly demonstrate the difference between motor nerve grafting and sensory nerve grafting in humans, much more study is needed.

One obstacle to the use of more motor nerve grafts is that the human body has a limited number of expendable motor nerves. Currently, surgeons are able to use the nerve from the gracilis muscle along the inner thigh or the latissimus dorsi along the side of the torso.

This study, in conjunction with other related work from our laboratory, will likely result in a shift away from the use of traditional sensory nerve grafts to the much more permissive motor nerve grafts for reconstruction of injury, said Susan E. Mackinnon, M.D., the Sydney M., Jr. and Robert H. Shoenberg Professor and Head of the Division of Plastic and Reconstructive Surgery at the School of Medicine.

Ronald W. Busuttil receives American Surgical Association's highest honor

Thu, 10 May 2007 04:00:00 PST

( from http://www.rxpgnews.com ) Dr. Ronald W. Busuttil, professor and executive chairman of the UCLA Department of Surgery, has received the American Surgical Association's Medallion for Scientific Achievement, joining a list that includes the nation's most distinguished surgeons.

Busuttil, who is internationally recognized for his expertise in liver transplantation and surgery, received the award April 26 during the association's annual meeting in Colorado Springs, Colo.

To receive this award from the most prestigious surgical organization in the world and to consider the accomplishments of the prior recipients gives me a feeling of great humility, he said. I could never have achieved this great distinction without the incredibly dedicated and talented medical and surgical team at UCLA, with whom I have had the privilege to work for more than 25 years.

Busuttil, who also holds UCLA's William P. Longmire Jr. Chair in Surgery, is founding chief of the division of liver and pancreas transplantation and director of the Pfleger Liver Institute, which includes the DumontUCLA Transplant Center and the DumontUCLA Liver Cancer Center.

The UCLA Health System is extraordinarily proud of Dr. Ron Busuttil for this recognition by his peers as one of the foremost liver transplant surgeons in the world, said Dr. Gerald S. Levey, UCLA vice chancellor for medical sciences and dean of the David Geffen School of Medicine at UCLA. UCLA values Ron's leadership as executive chairman of the department of surgery, as well as his commitment to research and teaching the next generation of surgeons.

Busuttil graduated magna cum laude from Loyola University in New Orleans and earned his M.D. and Ph.D. degrees at Tulane University. He served his surgical residency at UCLA under Dr. William P. Longmire Jr., UCLA's first chairman of surgery, and trained in transplantation at the University of Pittsburgh with Dr. Thomas Starzl, also a Medallion recipient. Busuttil has been on the UCLA surgical faculty since 1978.

In 1984, he established the UCLA Liver Transplant Program, one of the nation's first, which has since grown into one the world's largest liver transplant centers. Busuttil has been the program's director and chief surgeon for more than two decades, and he and his team have performed more than 4,000 liver transplants.

In addition to his pioneering accomplishments in surgery, Busuttil has demonstrated a lifelong commitment to teaching and advancing the field of transplantation and surgery. His laboratory has trained many research fellows, including surgical residents and trainees in basic science disciplines. And his liver transplantation training program, considered one of the world's best, has produced more than 150 American and international transplant surgeons, many of whom now lead their own programs.

His basic science research is focused on ischemia-reperfusion injury of the liver. Studies from his lab on adhesion molecule blockade are now in Phase II clinical trials. Earlier in his career, he made seminal contributions to research in surgical infectious disease, surgery for portal hypertension and the biology of aortic aneurysms.

Busuttil serves as an editorial board member or reviewer for many prestigious journals and is co-editor of Transplantation of the Liver, the definitive textbook on the subject, now in its second edition. He has written more than 500 peer-reviewed scientific manuscripts, 60 book chapters and 400 abstracts. He is an active member of all the major national and international surgical and transplantation societies and routinely holds key committee positions. He is vice president of the American Surgical Association, a past president of the American Society of Transplant Surgeons, a member of the council of the Transplantation Society, president-elect of the International Liver Transplantation Society and a former board member of the United Network for Organ Sharing.

CT and MRI accurate for pre-transplant evaluation of patients with cirrhosis

Sat, 05 May 2007 00:29:02 PST

( from http://www.rxpgnews.com ) CT and MRI are highly accurate at determining which patients would be optimal candidates for liver transplantation, says a recent study.

The study evaluated 1,029 cirrhotic patients who underwent liver transplantation at the University of Pittsburgh Medical Center. The researchers reviewed the last imaging report before surgery (970 on CT and 59 on MRI) and the pathologic report of the explanted liver. The patients were then assessed according to the Milan and University of California San Francisco criteria which describes which patients are the best candidates for transplant.

"The purpose of our study was to focus on the medical decision making process for liver transplant candidate selection and the utilization of CT and MRI to this end," said Alessandro Furlan, MD, one of the authors of the study.

According to the study, agreement between the radiology and pathology staging was demonstrated in 96.5% and 97.5% of the patients according to the Milan and UCSF criteria. The study revealed that imaging underestimated tumor stage in 2.7% (Milan) and 1.85% (UCSF) of the patients and overestimated tumor stage in 0.8% (Milan) and 0.7% of the patients (UCSF).

"The results support the current use of CT and MRI as tools to assist with candidate selection according to criteria from the United Network of Organ Sharing/Milan and UCSF," said Dr. Furlan. "The results essentially support the validity of current clinical practice in the use of CT and MRI in the workup of liver transplant patients," he said.

The full results of the study will be presented on Thursday, May 10, 2007 during the American Roentgen Ray Society Annual Meeting in Orlando, FL.

Machine preservation may promote more organ sharing

Wed, 02 May 2007 04:00:00 PST

( from http://www.rxpgnews.com ) WINSTON-SALEM, N.C. -- Preserving the kidneys of deceased older donors on a pump as opposed to the conventional method of storing and transporting organs in a cooler may lower hospital costs, improve initial organ function, and promote greater use and more sharing of organs, according to new research by Wake Forest University Baptist Medical Center.

By placing kidneys on a portable pump, preservation times can be safely extended to permit more time for sharing organs across the country, said Robert Stratta, M.D., lead researcher of the study, which is reported in the May issue of the Journal of the American College of Surgeons.

In addition, Stratta said, the pump can be used to project the kidneys initial function allowing for more appropriate matching of donor organs and recipients.

While machine preservation, or pulsatile perfusion, is not new, it is not widely used because it is more costly and labor-intensive. According to the United Network for Organ Sharing, only 21 percent of kidneys from deceased donors are preserved on a pump.

The purpose of this study was to compare outcomes in kidney transplant patients receiving kidneys from older deceased donors based on whether organs were preserved by pump or cold storage.

The critical organ shortage poses a challenge to optimize the use and function of all organs from deceased donors, said Stratta, explaining why it is important to compare the two methods of preservation.

With machine preservation, donated organs are connected to a portable pump to maintain a constant flow of a specialized preservation solution through the organs until transplantation. With both methods of preservation, a cooling solution is pumped into the organs during organ recovery. However, with simple cold storage, the kidneys are simply immersed in preservation solution and packed on ice until transplant.

The study involved organs from expanded criteria donors (ECDs). This category was created by UNOS in 2002 so that higher risk donor organs, once considered unsuitable, could be transplanted safely. The category includes kidneys from deceased donors over age 60 years or those over age 50 with health conditions such as high blood pressure, stroke or elevated levels of a protein called creatinine. Levels of creatinine, which is produced by muscle, are used to determine kidney function.

The current study included 120 ECD kidney transplants -- 95 kidneys were preserved with machine and 25 with simple cold storage preservation techniques.

Despite the fact that the machine-preserved kidneys were out of the body for a longer period of time (a mean of 24 hours versus 19 hours for the cold stored organs), both groups of recipients had similar survival and functional outcomes. In addition, the patients receiving machine-preserved kidneys had a 50 percent reduction in the rates of viral infections and delayed graft function, which is the inability of the kidneys to start working on their own without dialysis.

The routine use of machine preservation for ECD kidneys may lower hospital costs by reducing complications, said Stratta. In addition, it may promote more sharing of organs; it is a superior means of preserving organs out of body and provides a way to assess the viability of the organ.

Stratta said machine preservation has played an important role in the Medical Centers success transplanting kidneys at the outer limits of the ECD acceptance criteria, such as organs donated after cardiac death, preserved for more than 30 hours, or from donors over age 70. In previous studies with up to four years of follow-up data, Stratta has shown that success rates with these organs are equivalent to those of conventional donors, in part because of appropriate donor and recipient matching through using the pump to assess viability and function.

Lipocalin-2 linked with inflammatory response during heart transplants.

Sat, 28 Apr 2007 12:14:24 PST

( from http://www.rxpgnews.com ) A new study, led by Felix Aigner, M.D., has identified a protein known as Lipocalin-2 (Lcn-2) as potentially responsible for regulating the bodyâs inflammatory response during heart transplants. One of the major complications involved with many transplantations is the damage done to the transplanted heart during and immediately following surgery, known as ischemia and reperfusion (IR). In particular, inflammatory cells infiltrate the donated heart, which then releases enzymes and other proteins that attack the transplanted tissue, and can seriously impair the viability of replacement organs and jeopardize the health of the patient. The identification of Lcn-2 could be a first step towards reducing this inflammatory response and increasing the success rate of heart transplants worldwide. The study appears in American Journal of Transplantation.

Building on earlier work, the study finds that Lcn-2 is released by inflammatory cells attacking transplanted hearts in mice, and suggests that the protein is responsible for attracting further inflammatory response. Inflammation was found to decrease dramatically in mice in which the production of Lcn-2 was genetically disabled.

The study also found elevated levels of Lcn-2 in the kidneys of mice that had undergone heart transplants, suggesting the proteinâs possible involvement in the systemic response to IR. âThe major goal of our research activities is therefore to understand the exact mechanisms of this injury concomitant to organ transplantation,â notes Aigner, stressing the value of this research to the development of new treatment options in organ transplantation.

LCT reports major step forward for islet transplantation in diabetes patient

Thu, 29 Mar 2007 04:00:00 PST

( from http://www.rxpgnews.com ) Living Cell Technologies Limited (ASX: LCT) today announced it has published evidence outlining the survival and identification of live porcine islet cells and insulin production in a human patient 10 years after receiving a pig islet cell transplant.

The scientific paper published in the March issue of the international journal Xenotransplantation outlines how LCT has demonstrated the long-term safety, viability and function of its encapsulated porcine islets in a human patient over an extended period of time, without the use of immunosuppression.

In 1996 a 41 year old diabetic was injected with LCTs prototype diabetes product containing pig islet cells to help regulate his blood glucose levels and control of diabetes. The transplanted cells helped reduce the patients insulin requirement by 34% for over a year, which provided better control and overall well-being. By 2005 the patients glycated hemoglobin levels remained lower than the pre-transplant levels pointing to improved long-term control of blood glucose levels.

Ten years later the patient suggested that he was still obtaining benefit from the transplant. LCT scientists assumed that the cells would not be alive or functioning after that period of time, but the patient convinced LCT scientists to organise for a laparoscopy to check. This resulted in finding both living and functioning pig islet cells in his abdomen.

This has never been achieved before. It is a profound step forward for safe, effective and long-term diabetes control and shows the ability for pig cells to survive inside a human for an extended period of time and without immune suppression, commented Prof Bob Elliott, LCT Medical Director.

Dr Christina Buchanan, a biochemist from the University of Auckland and an expert in insulin, conducted the analysis to ensure that the insulin detected in the patients blood samples were unequivocally pig and not human insulin the final proof of efficacy.

Dr John Court, a diabetologist and scientific advisor to LCT said: This is only one patients experience but it does show that pig cells can survive at least ten years in a micro-capsule coating and continue to release insulin into the patients bloodstream.

LCT has significantly advanced the encapsulation process since the 1996 clinical trial and there is an even greater understanding and control over the longevity and robustness of the encapsulation process, as well as the porcine islet cells. The product is produced under a GMP manufacturing license.

LCT will be trialing the DiabeCell® pig islet cell transplant in patients in a phase I/IIa clinical trial, expected to begin in Quarter 2, 2007. In addition, LCT is awaiting approval to conduct an additional trial in New Zealand this year with a different treatment protocol. Subsequent trials in the US or Europe are intended following initial results from these studies.

The trial will involve the simple injection of encapsulated neo-natal pig islet cells into the peritoneal (abdominal) cavity of the diabetic patients. The procedure is quite simple and carried out under local anaesthetic. Patients will then be monitored by LCTs well established protocols, which are in accordance with international xenotransplantation guidelines.

This is strong evidence that LCTs DiabeCell® product holds significant potential to address the key issues of finding renewable donor cells and not using immunosuppression, as outlined in the National Institutes of Health (USA) and Juvenile Diabetes Research Foundation (JDRF) strategic plans, said Dr Paul Tan, LCTs CEO.

LCTs clinical trial program intends to test three different treatment regimens, in order to find the most appropriate, long-lasting and effective transplant possible, Dr Tan said.

DiabeCell® is a porcine pancreatic cell product for the treatment of insulin-dependent diabetes. The neo-natal pig cells produce insulin and help regulate blood glucose levels appropriate to the amount of glucose detected in the blood stream of the diabetic recipient.

Extensive pre-clinical testing of DiabeCell® in animal models has shown no adverse effects with any dose or repeated transplants, extended survival of the islets, a significant reduction in insulin requirements, and prolonged insulin independence in some individual animals.

Outpatient medication errors common, difficult to detect among transplant patients

Mon, 19 Mar 2007 04:00:00 PST

( from http://www.rxpgnews.com ) Medication errors appear to be common, often hidden and associated with adverse events among patients receiving outpatient care after an organ transplant, according to a report in the March issue of Archives of Surgery, one of the JAMA/Archives journals. The health care system is involved with nearly one-third of these errors.

Medication use is increasingly commonmore than 60 percent of U.S. adults ages 45 to 64 reported using at least one prescription drug during the previous month when surveyed from 1999 to 2000, according to background information in the article. Medication errors are common as well, with adverse drug events reported among 6.5 percent of hospitalized patients. It seems logical that the additional degrees of freedom introduced in the outpatient setting by the patient, caretaker, outside pharmacy or third-party payer will result in greater confusion and error, the authors write. Examples of the types of serious errors anecdotally reported to date in this setting include mix-ups between sound-alike and look-alike drugs, similar looking packaging and inappropriate dosing.

Amy L. Friedman, M.D., and colleagues at the Yale University School of Medicine, New Haven, Conn., documented medication errors that occurred among all recipients of liver, kidney and pancreas transplants who were tracked by the Yale New Haven Organ Transplantation Center between April 1, 2004, and March 31, 2005. At every encounter, the home medication regimen is reviewed with the patient by a nurse-coordinator, physician associate or physician and compared with the regimen prescribed at the last interaction with the patient, the authors write. Encounters include outpatient or emergency department visits, admission to the hospital or phone conversations.

During the study period, the researchers identified 149 medication errors in 93 patients, who were taking an average of 10.9 medications each. The most frequent type of error (56 percent of all errors) was patient error. An additional 13 percent of the errors were prescription errors; 13 percent were delivery errors; 10 percent were availability errors, when a patient did not have at least a 24-hour supply of a medication; and 8 percent were reporting errors, which occurred when a patient could not give the researchers enough information to identify the type, dosage, or frequency of a medication. Adverse events were associated with 48 (32 percent) of the errors, including 17 hospitalizations, three outpatient procedures, nine episodes of rejection and six failed transplants.

The researchers also pinpointed the root causes of the errors. The root cause was defined as a specific underlying cause that can reasonably be identified, that is in the control of the transplant team to fix and for which effective recommendations for preventing recurrences could be generated, the authors write. The root causes were identified as the patient in 68 percent of the errors, financial issues in 5 percent and health care providers in 27 percent, including 10 percent caused by the transplant team itself.

Understanding the root causes of medication errors, which often stem from communication failures, should help remove the judgmental lens through which non-adherence to drug therapies is often viewed, the authors conclude. We should strive to continue to eliminate health care systembased errors through centralized records and other streamlining methods to improve processes. In doing so, it seems likely that our patients will gain confidence in us and our ability to help them navigate a complex and confusing system. This will both improve patient safety and facilitate the shift from a culture of blame to a culture of prevention, they note.

Emory algorithm improves kidney transplant chances for sensitized patients

Fri, 02 Mar 2007 05:00:00 PST

( from http://www.rxpgnews.com ) Approximately one-third of the patients on the national waiting list for kidney transplants have only a small chance of receiving a new organ, no matter how long they are on the list. Due to prior transplants, pregnancies or blood transfusions, these patients have developed antibodies that make it very difficult to match them with donor organs.

Researchers at Emory University have developed a decision process, based on innovative technology, that may help to level the transplant playing field and give new hope to these highly sensitized patients. The Emory Algorithm, as this new method is known, may even change the way kidneys from deceased donors are allocated in the United States.

Sensitized patients have developed antibodies against human leukocyte antigens (HLAs), which play an important role in the body's immune response to foreign tissue. These patients represent one-third of the national waiting list for kidney transplant patients (50 percent in Georgia), but they only receive about 15 percent of deceased-donor kidney transplants each year.

The United Network for Organ Sharing (UNOS) coordinates the nation's transplant system through a point system based primarily on wait time, sensitization and HLA matching. When a perfect match occurs, the kidney is offered to the person at the top of the national list. If there are no perfect matches nationally, the kidney becomes available to transplant centers in the region from which it came.

The Emory Algorithm, while still following these guidelines, allows a transplant center to predict which sensitized patients on the list will be compatible with any given donor. A five-year Emory study, published in the October 2006 issue of the American Journal of Transplantation, found the algorithm raised the rate of transplants from 15 percent to 25 percent in sensitized patients by accurately predicting which of these patients would be compatible with the donor kidney. The survival rate of a kidney transplant in sensitized patients in the five-year study was almost identical to that of unsensitized recipients--66 percent vs. 70 percent.

The algorithm was developed by Emory immunologists Robert Bray, PhD, and Howard Gebel, PhD, along with Emory transplant surgeons Christian Larsen, MD, DPhil and Thomas Pearson, MD, DPhil. They used a relatively new technology of single-antigen bead assays, which gives a more specific analysis of HLA antibodies by identifying a single antibody at a time versus general groups of antibodies. The algorithm allows immunologists to inform transplant surgeons with a high degree of confidence whether a kidney from a deceased donor is a compatible match with a recipient.

Each of us has a constellation of HLAs, with six major ones related to kidney transplantation and dozens of specific HLAs within each of those antigen groups, says Dr. Bray. Studies show the more antigens a donor and recipient share, the better the survival rate of the transplanted kidney. With the older technique of cross matching HLA cells with the blood of a potential recipient, we couldn't always identify which HLAs the antibodies were targeting. False readings could occur.

A decade ago Drs. Bray and Gebel helped One Lambda, Inc., an HLA diagnostic company in California, develop and test its single-antigen bead assays. Each bead is coated with a single HLA antigen produced by recombinant DNA technology. Different HLA molecules are bound onto different antigen beads. The beads are mixed with the recipient's blood and placed in a flow cytometer. A laser reads which antibodies, if any, are attached to the HLA molecules on the beads. A computer collects and organizes the results.

While some transplant centers use these same single assay tests to identify HLA antibodies, they don't incorporate the data into their cross-matching process. Prior to the Emory Algorithm, highly sensitized patients may have been at a disadvantage due to the time constraints in the organ donor process, which did not allow transplant centers to determine if they could receive the kidney that was available. At Emory, sensitized patients have an increased chance of receiving a transplant.

Kidney transplantation is the optimal treatment for end-stage renal disease, and being able to offer transplantation to this population is a significant advance, says Dr. Pearson.

Based on results of the Emory study, a UNOS committee is looking at the algorithm as UNOS reevaluates its kidney allocation system. The committee is expected to make recommendations this year, according to Mark Stegall, MD, a transplant surgeon at the Mayo Clinic who chairs this committee. Dr. Pearson also sits on the committee.

I hope the algorithm process will become national policy as part of an overall kidney allocation policy, Dr. Stegall says. Eighty percent of transplant programs are using the single-antigen bead technology, but relatively few are using that data as a way to allocate kidneys to sensitized patients. But Dr. Stegall is not ready to commit to a system based only on organ compatibility as determined by antibodies. Kidneys are a scarce resource, he says. We have to put sensitization in perspective. There is always an unsensitized patient out there.

The Emory algorithm helps equalize the allocation scheme, Dr. Pearson says. With this system everyone on the waiting list would be considered for an available kidney, but only the best match would receive it. We have to balance priorities to try and help as many people as possible, he says.

There is a perception that patients who are highly sensitized have poor outcomes, says Gebel, but that is not our experience.

Primary graft dysfunction is risk factor for a later serious lung transplant problem

Thu, 01 Mar 2007 05:00:00 PST

( from http://www.rxpgnews.com ) Primary graft dysfunction, a common complication that affects up to 25 percent of lung transplant patients shortly after surgery, constitutes a significant risk factor for later deadly bronchiolotis obliterans syndrome (BOS).

This research appears in the first issue for March 2007 of the American Journal of Respiratory and Critical Care Medicine, published by the American Thoracic Society.

Ramsey R. Hachem, M.D., of the Division of Pulmonary and Critical Care at Washington University School of Medicine in St. Louis, and eight associates examined the impact of primary graft dysfunction on the development of BOS in 320 lung transplant recipients.

BOS, a chronic scarring process that affects the small airways of the lungs years after transplant surgery, results in the progressive obliteration of the small airways with resulting obstructive lung disease. BOS is a leading cause of death after the one-year anniversary of a lung transplant.

We found that primary graft dysfunction is associated with an increased risk of BOS independent of certain other risk factors, including acute rejection and community-acquired respiratory viral infections, said Dr. Hachem.

Clinically and pathologically, primary graft dysfunction is a devastating form of acute lung injury that affects transplant patients in the first hours after they receive transplanted organs. The complication, which mimics adult respiratory distress syndrome, can be fatal for up to 50 percent of affected transplant patients.

Among the 320 recipients studied, 161 developed BOS, with the median time to onset at close to four years, said Dr. Hachem. Lung transplant recipients who did not have primary graft dysfunction had significantly greater freedom from BOS than those who developed any grade of primary graft dysfunction.

The researchers graded the severity of subjects' primary graft dysfunction according to the International Society for Heart and Lung Transplantation (ISHLT) definition. Those who did not have primary graft dysfunction immediately after transplantation were classified grade 0, while those with more severe graft dysfunction received a 1, 2 or 3.

In their analysis, the investigators found that all grades of primary graft dysfunction were associated with a significantly increased risk of BOS. Recipients with primary graft dysfunction grade 1 had the relative risk of 1.73; those with grade 2 had a relative risk of 2.13; and those with grade 3 were 2.53 times more likely to experience the later problem.

This association has important clinical implications and suggests that the immunosuppressive regimen should be optimized and that lung function should be monitored closely for patients who develop primary graft dysfunction, said Dr. Hachem.

The researchers noted that additional studies are needed to further investigate the molecular mechanisms of primary graft dysfunction and its relationship to BOS.

According to the ISHLT, this area of study is becoming increasingly important, as the number of lung transplants performed in the U.S. was a record 1,815 last year. They reported that survival was 78 percent at one year, 61 percent at three years, 49 percent at five years, and 25 percent at 10 years.

JDRF awards Emory $2.5 million to develop islet transplant technology

Mon, 26 Feb 2007 05:00:00 PST

( from http://www.rxpgnews.com ) Using a $2.5 million, three-year grant from the Juvenile Diabetes Research Foundation (JDRF), Emory transplant researchers plan to develop pig islets as an alternative to human islets for transplant into patients with Type 1 diabetes. If their research is successful, clinical trials of the porcine islet transplants into humans could begin within the next three years. Christian P. Larsen, MD, DPhil, director of the Emory Transplant Center, is principal investigator of the grant.

Individuals with Type 1 diabetes, which usually develops early in life, are unable to produce their own insulin because their pancreatic islets do not function. In 2000, researchers in Edmonton, Alberta, first reported that islet transplantation can produce a high rate of insulin independence with excellent metabolic control. This was followed over the next several years by a series of clinical trials focused on improving the islet transplant procedure. Emory was the first, and is still the only, center in Georgia thus far to transplant human islets. Emory physician/researchers have performed 16 islet transplants into nine patients since 2003.

Despite some success in helping patients forgo or cut down on insulin injections, the islet transplant procedure still faces significant challenges. Transplant recipients must take toxic immunosuppressant drugs to improve long-term survival of the islets. Emory scientists, based on research begun at the Yerkes National Primate Research Center and continued in human clinical trials, are leaders in a national effort to develop less toxic drugs for islet and solid organ transplants.

At the same time, researchers have realized the vast gap between the number of human islets available from current sources and the millions with Type 1 diabetes who could potentially benefit from safe and effective islet replacement therapy. Xenotransplants, which are transplants between two different species of animals, have been considered as an alternative that could provide much larger quantities of islets for human transplant.

While support from the JDRF has allowed us to make considerable progress in improving immunosuppressant drugs and in refining the islet transplant procedure, a significant problem remains with the available supply of islets, says Dr. Larsen. There simply will never be enough islets available for transplant if we must rely on human deceased donor pancreases. We are very optimistic that porcine islets may provide the answer to this difficult challenge.

With the JDRF grant, the Emory scientists will use a nonhuman primate model at the Yerkes Research Center to develop their porcine islet transplant strategy. This will include successfully preparing the porcine islets for transplant; circumventing the potent rejection barriers to acceptance of the xenograft; and understanding and minimizing the risk of transmission of porcine pathogens to human transplant recipients and the general population.

In 2002, the JDRF awarded Emory scientists $4.1 million to create the Emory JDRF Center for Islet Transplantation to address large-scale strategies for islet replacement. One of only a handful of such centers, it was renewed with an additional five-year grant of $8.5 million in 2006 with the goal of advancing islet transplantation to a mainstream therapy for Type 1 diabetes. More information about JDRF is available at

African-Americans receive fewer stem cell transplants than whites

Thu, 08 Feb 2007 05:00:00 PST

( from http://www.rxpgnews.com ) Lower transplant rates in ethnic communities may be explained somewhat by a lack of suitable anonymous donors, a problem the medical community has long known and been working to address. Surprisingly, the study found the discrepancy in treatment held true even when the transplant was autologous (e.g. self-donated stem cells were used) or when the cells were donated by a relative, typically a sibling.

The National Marrow Donor Program has made great strides in increasing the number of African-American donors, which is important because non-related donors are more likely to have a tissue type that matches the patient if they are of the same ethnic group, said Mary Horowitz, M.D., M.S., chief scientific director for the Center for International Blood and Marrow Transplant Research (CIBMTR) and professor of medicine at the Medical College of Wisconsin, Milwaukee. But our research shows the problem is more extensive than we thought, and if all we do is increase the number of available anonymous donors, we won't be successful in making sure that everyone who needs transplant gets one. While the shortage of appropriate anonymous donors is an understandable cause of a lower rate of unrelated donor transplantation, it should not affect the use of autologous or related donor transplants in African-Americans, yet the rates of these transplants are also lower.

Stem cell transplant (also known as blood and marrow transplant) is used to treat diseases of the blood and several types of cancer. In the study, researchers looked at the rate of stem cell transplants among African-Americans, Caucasians and men and women for the treatment of three types of cancer most commonly treated with stem cell transplants: leukemia, lymphoma and multiple myeloma. Together, these cancers account for nearly 10 percent of all cancer cases in the United States.

Patients who are candidates for stem cell transplants are most likely to find a matching donor in someone of their own ethnicity. The group of genes known as human leukocyte antigens (HLA) in the donor and patient must be closely matched for the procedure to be successful, and that is more likely to be true within ethnic groups. Because African-Americans have a greater variation of HLA types, it is estimated that three times as many African-American donors are needed to equal the chance of obtaining a Caucasian match, according to the National Cord Blood Program.

The next step is for researchers to determine why the stem cell transplant self-donation and relative-donation rates differ between Caucasians and African-Americans. Among the potential reasons:

Cord Blood Registry achieves industry-leading stem cell recovery with new automation technology

Wed, 07 Feb 2007 05:00:00 PST

( from http://www.rxpgnews.com ) San Bruno, CAFebruary 7, 2007Cord Blood Registry® (CBR) today announced that it has completed initial validation testing of the company's proprietary CellAdvantageTM system using new automation technology for cell processing, developed by ThermoGenesis and distributed by GE Healthcare. The new technology, called the AXP AutoXpressTM Platform (AXPTM), is the industry's first functionally-closed, automated cord blood stem cell processing technology.

The FDA-required validation testing demonstrated that CBR's CellAdvantage system can meet or exceed the company's current mononuclear cell (MNC) -- or stem cell -- recovery rate of 98 percent, which is the highest published cell recovery rate in the industry. CBR will present data results at an upcoming medical meeting.

Achieving these extremely high cell recovery rates through automation is a very significant advancement for our company and for the families we serve, said Tom Moore, chief executive officer of CBR. Our business is experiencing dramatic growth as expectant parents increasingly choose to preserve their baby's cord blood stem cells with us. By integrating AXP automation technology into our CellAdvantage system, CBR is the only family bank that will be able to increase our cell processing capacity and at the same time maintain or exceed our industry-leading cell recovery rates.

Cord Blood Registry is the first and only family cord blood bank to adopt this cutting-edge technology and offer it to consumers who wish to cryopreserve their own genetically-related stem cells for future therapeutic use. The world's largest public donation bank, The New York Blood Center, has also adopted AXP processing.

In our selection process, we closely evaluated the two automated cell processing systems available on the market, said Moore. We determined that only AXP can deliver cell recovery rates that can exceed our current cell separation process and do so consistently.

Published studies on the other system CBR evaluated, SEPAX, show mean MNC recovery rates ranging from 77.4 percent to 87.7 percent with a variability ranging from +/- 9.72 percent to +/- 27.8 percent.

This data did not meet CBR quality standards and fell short of our current capabilities, said Moore. We have only one chance to process these cells and every family needs to know that they can expect to get the highest possible cell recovery and quality when they bank with CBR. Studies have correlated survival rates and improved outcomes with the number of stem cells used in therapy.

How the cells are stored was another important criteria in CBR's selection of AXP.

The AXP technology uses a next-generation cryobag for storage that is constructed with a blow-molded process that eliminates seams, said Phil Coelho, chief executive officer of ThermoGenesis. A seamless storage bag is important because it greatly improves the integrity of the bag and significantly decreases the potential for breakage that has been documented to occur in traditional seamed-plastic storage bags.

We are proud of our track record of quality and innovation in the family cord blood banking industry, said Moore. CBR is pleased to partner with GE Healthcare and ThermoGenesis on creating a cell processing system that sets the standard for others to follow.

Looking at Liver Retransplantation

Sat, 03 Feb 2007 12:02:04 PST

( from http://www.rxpgnews.com ) A new study on liver retransplantation (re-LT) over a 15 year period at a clinic in Germany found that indications for the surgery had changed and there were fewer rejections, complications, and recurrence of disease during that time. The positive trend may be due to improvements in intensive care management and immunosuppressants, along with early decisions about when to retransplant despite the shortage of quality donor organs.

The results of this study appear in the February 2007 issue of Liver Transplantation, the official journal of the American Association for the Study of Liver Diseases (AASLD) and the International Liver Transplantation Society (ILTS). The journal is published on behalf of the societies by John Wiley & Sons, Inc. and is available online via Wiley InterScience at http://www.interscience.wiley.com/journal/livertransplantation.

While liver transplantation has become increasingly successful over the last two decades, liver retransplantation shows significantly inferior results. The reasons for this include infections following surgery, multiorgan failure, bleeding complications, recurrence of the underlying disease, and chronic rejections. In addition, it is more expensive than first-time transplants and presents the problem of claiming organs that might have otherwise been used by first-time recipients, who are more likely to have a better outcome. For these reasons, retransplantation is controversial, but for many patients it is the only alternative to death.

Led by Robert Pfitzmann, M.D. of Charité Virchow Clinic in Berlin, Germany, researchers conducted a study of 119 retransplant recipients in their clinic between 1989 and 2003 in order to find ways of improving treatment and results. Indications for retransplant included initial non-function of a transplanted liver, recurrence of the underlying disease, rejection, blood clots in the main artery that carries blood to the liver, and ischemic-type-biliary-lesions (ITBL), a complication of liver transplants. The mean follow-up was approximately 5 years; 65 percent of retransplants were performed within the first year of the initial transplant, the vast majority taking place within three months.

Analysis showed that coma, hemoglobin and the amount of plasma transfused during surgery were independent predictors of survival following retransplantation. In contrast to other studies, creatinine (a protein in the blood), the amount and time between the first and second transplant, donor and recipient age, ischemia time, bilirubin and hepatitis C status did not influence survival. "These results support our assumption that the recipients' clinical status immediately before re-LT plays a very important role on the outcome of our patients, whereas the donor status appears less important" the authors note. At the same time, they acknowledge that they used "high quality standard selection criteria and acceptance of donor organs," which may explain why donor status was not predictive of outcome.

Their findings led to several therapeutic measures, including lowering the dosage of immunosuppressants very early, administering medication to improve kidney function, early blood transfusions, and continuous improvements in intensive care management. They note that patient survival after retransplant very strongly depends on the reason for the transplant, with patients experiencing ITBL and rejection showing the best survival rates. They also observed that the major complications leading to death following retransplant were bacterial infections with septic complications, which indicates a variety of measures that can be undertaken to prevent infection from claiming lives. Although they achieved good results, they conclude that "further progress and improvement in the treatment of retransplanted patients is required to enchance survival after re-LT."

In an accompanying editorial in the same issue, R. Mark Ghobrial, M.D., Ph.D., F.R.C.S. of the David Geffen School of Medicine at University of California Los Angeles noted that retransplantation requires sophisticated decision-making but that accurate outcome predictors are lacking. The author suggests that the most important contribution of the current study is the determination of factors that predict outcomes in retransplants, noting that it is in agreement with previous reports stressing the influence of recipient status on retransplant outcome. However, he states that while the study minimizes the importance of donor status, these effects should not be underestimated. He questions why factors found to be independent predictors of death at other hospitals were not significant in the current study, noting that it may be due to the level of surgical expertise or the ability of the current study's authors to apply stringent selection criteria for donors and recipients. "The fruits of this selection effort are reflected in the good survival achieved in this series," he concludes. "The lessons for re-OLT may therefore be: selection, selection, selection."

New culture method for hepatitis C virus uses primary hepatocytes and patient serum

Tue, 23 Jan 2007 05:00:00 PST

( from http://www.rxpgnews.com ) Seattle, WA -- Researchers open the way for improved study of hepatitis C virus by devising a novel virus culture system that allows replication of patient-isolated virus in nontransformed hepatocytes, instead of culture-adapted virus strains in transformed cell lines. The related report by Lázaro et al, Hepatitis C virus replication in transfected and serum-infected cultured human fetal hepatocytes, appears in the February issue of The American Journal of Pathology.

Hepatitis C virus (HCV) infection affects approximately 170,000,000 people worldwide. HCV liver disease, which may induce liver inflammation, cirrhosis, and/or hepatocellular carcinoma, represents the foremost reason for liver transplantation in much of the U.S.

Study of HCV replication within liver cells, or hepatocytes, has been hampered by a lack of adequate virus culture systems. Some systems allow the virus to infect cells but do not permit prolonged replication and production of virus, while other systems rely on derivatives of permissive virus isolates for efficient replication in transformed (mutated) cell lines. Still lacking has been a system to sustain replication of novel virus isolates from patients using nontransformed hepatocytes.

Nelson Fausto of the University of Washington School of Medicine has crossed this hurdle using a human fetal hepatocyte culture system that was previously developed in his lab. Using this system, his group has demonstrated sustained replication and production of virus particles for at least 2 months, with these virus particles able to infect new cells.

In their first experiments, Fausto and colleagues transfected hepatocyte cultures with HCV genomic RNA and found replication of HCV RNA genomes and production of core protein (for virus particle formation). Release of infectious virus particles was confirmed, as media from these cells were able to infect naive hepatocytes. Finally, virus particles were examined by electron microscopy and shown to possess the expected size and shape of HCV virus particles.

Once the system was established, the group examined whether sera from patients carrying HCV could infect the human fetal hepatocytes. When sera from patients infected with different HCV strains were added to the hepatocyte culture system, viral replication occurred and new virus particles were produced.

In both transfection and infection models, virus particles were released in a cyclical manner, with bursts of virus produced every 10-14 days. This is similar to what has been reported during clinical HCV infection, possibly due to the host's natural defenses. Interestingly, cultured hepatocytes responded to viral replication by displaying signs of distress and cell death and by expressing interferon-beta, a cellular antiviral, in an effort to control the infection.

This culture system provides a breakthrough in studying HCV replication in nontransformed hepatocytes, the natural target of the virus. By allowing infection by patient serum containing a wide array of virus strains, this system may allow better understanding of the differences between different strains, further improving treatment strategies.

Operations research pioneer outlines ways to make kidney transplant allocation more equitable

Wed, 03 Jan 2007 05:00:00 PST

( from http://www.rxpgnews.com ) Stefanos A. Zenios, a professor at Stanford's Graduate School of Business, renowned for his application of Operations Research (O.R.) to tackle some of modern medicine's thorniest problems, has completed new research that could revolutionize kidney allocation for transplant waiting list candidates. The paper, Recipient Choice Can Address the Efficiency-Equity Trade-Off in Kidney Transplantation: A Mechanism Design Model, was co-written by Zenios with Xuanming Su at Berkeley's Haas School of Business. It was recently published in the journal Management Science.

For over a decade, Zenios has applied O.R., the discipline that uses advanced analytical methods to make better decisions, to find alternative ways to distribute scare resources such as the supply of human kidneys available for transplant. Using optimization, game theory, statistics and queuing theory from the O.R. tool box, Professor Zenios presents a new model which not only gives patients greater choice about their position on the transplant waiting list, but creates a more efficient and equitable system.

Zenios calls for the definition of five distinct quality grades for kidneys. When a patient joins the kidney transplant waiting list, he/she is given information on how long it would take to wait for each of these grades (higher quality is paired with longer waits and vice versa) and what the expected outcomes for transplanting each grade are, given their personal health profile. From there, the patient works with his/her physician to decide on what the minimum grade of kidney they would be willing to accept is.

In essence, Zenios' model creates a sequence of queues for kidneys of various grades and, within these queues, organs that become available are allocated based on waiting time. This contrasts with the present allocation system, determined by the United Network of Organ Sharing (UNOS), whereby kidneys are allocated based on waiting time and certain medical criteria, and choice about what quality organ you are wiling to accept is limited. (Interestingly, UNOS is currently considering changes in the kidney allocation system in which patients will be prioritized according to a utilitarian system, as proposed by earlier research from Professor Zenios).

Initial simulations indicate that the Zenios' model could give an additional 10% of waiting list patients access to organs for transplant, while cutting the current number of discarded kidneys from 11-15% to 3%. Put another way, the system could cut the current death rate on the kidney transplant waiting list (which hovers at 30%) by a third.

As an O.R. practitioner, I'm fascinated by efficiency gains, and the current national kidney transplantation waiting list is a system that cries out for optimization, says Professor Zenios. My research has shown that a purely utilitarian approach can be unfair to certain populations of patients and that more refined models involving shared decision-making between physicians and patients that also provide priority points based on waiting time would achieve a better balance on the efficiency-equity spectrum.

A transplant in time

Thu, 28 Dec 2006 05:00:00 PST

( from http://www.rxpgnews.com ) In hemophilia, a mutated gene prevents the production of a critical blood-clotting protein. Treatments for hemophilia and other such genetic diseases, when they exist, may consist of risky blood transfusions or expensive enzyme replacement therapy. But what if the body could be induced to begin producing these proteins, say by transplanting healthy tissue with the abilities that are lacking?

Prof. Yair Reisner and Ph.D. student Anna Aronovich of the Weizmann Institute's Immunology Department, together with colleagues, showed, in research recently published in the Proceedings of the National Academy of Sciences (PNAS), how such a transplant might, in the future, be made feasible.

Previous attempts to treat genetic disease by transplanting (mother to daughter) a spleen, an organ that can manufacture a number of the missing proteins in some such diseases, had made little headway due to the fact that the spleen is home to the immune system's T cells cells responsible for the severe immune responses against the recipient known as graft-versus-host disease (GVHD).

Reisner and his team revived the idea, with a twist. Over the past several years, he and members of his lab have been experimenting with tissue transplanted from pig embryos a possible substitute for human donor organs. From this, they have learned that for each type of tissue, there is a window of opportunity during which cells taken from the developing embryo can be most successfully transplanted. Tissues taken too early, when they are still fairly undifferentiated, may form tumors, while those taken too late can be identified as foreign, causing the host to reject them.

By taking spleen tissue from embryonic pigs over the course of gestation, they found that the harmful T cells are not present in the tissue prior to day 42 of gestation. The scientists also found that tissue of this age exhibits optimal growth potential as well as secreting factor VIII, the blood-clotting protein missing in hemophilic patients. Thus, the scientists fixed the ideal time for spleen transplantation at 42 days. Hemophiliac mice with spleen tissue transplanted from pig embryos at this time experienced completely normal blood clotting within a month or two of implantation.

Although a number of problems would need to be surmounted before researchers could begin to think of applying the technique to humans, the Institute team's experiment is proof of principle evidence that transplanted embryonic tissue, whether human or pig, could one day help the body to overcome genetic diseases.

Common cold virus leads to death in lung transplant patients

Fri, 15 Dec 2006 05:00:00 PST

( from http://www.rxpgnews.com ) Human rhinovirus (HRV), the leading cause of most common colds, struck two immunosuppressed lung transplant patients, leading to progressive respiratory failure, graft dysfunction and death. The two were part of a group of 11 transplant patients who suffered clinically significant respiratory infection from HRV in both the upper and lower airways, overturning the long-held belief that HRV affects only upper airway tissue.

The research appears in the second issue for December 2006 of the American Journal of Respiratory and Critical Care Medicine, published by the American Thoracic Society.

Laurent Kaiser, M.D., of the Central Laboratory of Virology at the University Hospital of Geneva, Switzerland, and 13 associates assessed the incidence of chronic rhinovirus infection and its potential clinical impact on 69 lung transplant recipients at two centers. Over a 19-month period, they screened all lung transplant patients using molecular analysis to detect 13 different respiratory viruses.

Human rhinovirus is a leading cause of respiratory infections in adults and children. Adults, on average, get infected with the virus once per year. Lung transplant patients, with impaired immune systems due to drugs to halt rejection, are at potentially higher risk from the virus.

Our evidence demonstrates that rhinoviral disease is not exclusively limited to the upper respiratory tract, said Dr. Kaiser. It can also lead to lower respiratory complications, which immunosuppressed patients can be at higher risk of developing.

Although eight lung transplant patients had transient rhinoviral infections, three showed a persistent infection. The others were able to clear the virus from their system.

We confirmed the persistence of a single strain in each of three lung transplant recipients clinically infected by rhinovirus, said Dr. Kaiser. Two of the three had chronic upper respiratory tract infections. All three had relapsing lower respiratory infections, and two subsequently died with graft dysfunction.

Dr. Kaiser noted that the persistent infection suggests that certain cases can act as viral reservoirs to sustain transmission of rhinovirus.

Therefore, in lung transplant recipients with severe immunosuppression, clinical rhinovirus infection needs to be considered, said Dr. Kaiser. This point might have substantial implications in terms of diagnostic procedures, clinical management, and anti-viral use, if available.

In an editorial on the research in the same issue of the journal, Marc B. Hershenson, M.D., of the University of Michigan, Ann Arbor, and Sebastian L. Johnston, M.D., Ph.D., of the National Heart and Lung Institute at Imperial College in London, wrote: The report by Drs. Kaiser and colleagues ends once and for all the argument that rhinovirus cannot infect the lower airways. Although interesting new data suggest that rhinoviruses may induce proinflammatory responses in lung cells independent of viral replication, replication is almost certainly required for a maximal response. However, until the present report, which includes positive bronchoalveolar cultures and lung immunochemistry, incontrovertible evidence of rhinoviral replication in the lung in the setting of spontaneous infection has been lacking. This report informs our understanding of the mechanisms underlying rhinovirus-induced exacerbations of asthma and COPD.

They continued: These exciting new data raise the possibility that patients with asthma and other patients with chronic airway disease are unusually susceptible to rhinovirus infection leading to increased rates of exacerbation. These results may also help explained the increased susceptibility of children to rhinovirus infections. Further studies on susceptibility to rhinovirus infection in the population are now required.

Researchers create genetically matched embryonic stem cells for transplantation

Thu, 14 Dec 2006 05:00:00 PST

( from http://www.rxpgnews.com ) Researchers at Children's Hospital Boston report a new and efficient strategy, using eggs alone, for creating mouse embryonic stem cells that can be transplanted without the risk of rejection because the cells are compatible with the recipient's immune system. The findings will be published online in the journal Science on December 14.

Though done in mice, the work establishes the principle of using unfertilized eggs as a source of customized embryonic stem cells that are genetically matched to the egg donor at the genes that control recognition of cells by the immune system, making them potentially useful for transplantation therapies. There are several caveats, including the fact that only females could benefit from this technique, donating their own eggs to generate the stem cells, and concerns that the tissues derived from this special type of embryonic stem cells might not function normally.

This technique, if proven effective in humans, offers an efficient way of generating customized stem cell lines from women, says George Q. Daley, MD, PhD, senior author on the paper, who is the Associate Director of the Children's Hospital Boston Stem Cell Program and a member of the Executive Committee of the Harvard Stem Cell Institute. It would eliminate tissue matching and tissue rejection problems, a major obstacle to successful tissue transplantation.

Embryonic stem cells are master cells that can generate all tissue types in the body. In 2002, Daley's laboratory collaborated with the laboratory of Rudolf Jaenisch, PhD, of the Whitehead Institute, MIT to demonstrate the first use of another method, somatic cell nuclear transfer, to create customized embryonic stem cells to repair genetic defects in mice. But somatic cell nuclear transfer (sometimes called therapeutic cloning) is a technically demanding and inefficient process that involves transferring the nucleus of a donor cell into an egg from which the nucleus has been removed.

We will not stop testing nuclear transfer, because it is the only means we know for generating embryonic stem cells that are genetically identical to a patient, says Daley, who heads one of two Harvard Stem Cell Institute-associated labs attempting to create human embryonic stem cells with that technique. However, generating embryonic stem cells from unfertilized eggs is far more efficient than nuclear transfer, and therefore may allow us to move toward human applications sooner.

In the new study, Daley, first author Kitai Kim, PhD, and colleagues at Harvard Medical School, Brigham and Women's Hospital and Massachusetts General Hospital used unfertilized eggs of mice to create so-called parthenogenetic embryonic stem cells. Parthenogenesis is a method of reproduction, common in plants and in some animals, in which the female can generate offspring without the contribution of a male. It doesn't normally occur in mice, but Daley, Kim and colleagues were able to induce unfertilized mouse eggs to develop through a series of chemical treatments, then generated embryonic stem cells.

Next, they used genetic typing to identify those embryonic stem cells that shared with the egg donor the genes responsible for tissue matching, called the major histocompatibility complex (MHC). When they injected these selected embryonic stem cells into MHC-matched mice, a variety of specialized tissues formed, with no rejection and no need to suppress the recipients' immune system.

Daley's laboratory at Children's Hospital Boston is now trying to replicate its results with human eggs.

As Daley noted, there are several potential limitations to embryonic stem cells generated by parthenogenesis. First, since parthenogenetic embryonic stem cells are made from eggs, the technique is only applicable to females. (Methods exist for deriving embryonic stem cells using sperm from men, but these techniques are as technically challenging and inefficient as somatic cell nuclear transfer, Daley says.)

There are also potential safety concerns. Embryonic stem cells created through parthenogenesis have altered expression of certain genes that are imprinted. Imprinted genes are marked for expression in a special way based on whether they are passed to offspring by the egg or the sperm. Because parthenogenetic embryonic stem cells are made from eggs only, they carry no paternally imprinted genes, and instead carry two copies of maternally imprinted genes. Altered expression of imprinted genes has been linked with cancer and poor growth in some tissues. In addition, embryonic stem cells created through parthenogenesis may have some regions of their genome that contain duplicated copies of mutant genes that have been linked with malignancies or abnormal tissue growth.

Right now this technique is useful for basic research, but we are hopeful that parthenogenetic cells might prove useful for therapies, Daley says. Our cells produce normal tissues in mice, and there is a report in the clinical literature of a human patient whose blood was derived entirely from parthenogenetic cells. However, we'll have to demonstrate the safety and durability of cells derived from parthenogenetic embryonic stem cells before we could imagine any clinical use.

Preventing graft-versus-host disease disease after bone marrow transplant -- without toxicity

Mon, 11 Dec 2006 05:00:00 PST

( from http://www.rxpgnews.com ) Unless the donor is an identical twin, patients undergoing bone-marrow transplant (also known as hematopoietic stem cell transplant, or HSCT) must first receive powerful chemotherapy drugs to wipe out their immune system and prevent their bodies from rejecting the donated cells. Research from Childrens Hospital Boston and the Dana-Farber Cancer Institute has helped demonstrate that this punishing regimen increases the risk of graft-versus-host disease (GVHD), in which the donors cells mount an immune response against the patient. But the most recent findings also suggest that the risk for GVHD can be reduced by replacing a natural antibiotic protein, known as bactericidal/permeability increasing protein (BPI), which is depleted when patients undergo chemotherapy.

Now, a multicenter study is about to test this idea in HSCT patients, using a manufactured form of BPI known as rBPI21 (XOMA Ltd.) Unlike other treatments to prevent GVHD, BPI does not suppress the immune system and has shown virtually no toxicity.

Researchers Ofer Levy, MD, PhD, of Childrens Hospital Boston, and Eva Guinan, MD, of Childrens Hospital Boston and Dana-Farber Cancer Institute, will present their most recent findings and discuss the new clinical trial on December 11 at the American Society of Hematology (ASH) Annual Meeting in Orlando, Fla. (abstract # 2856).

The new trial is the culmination of over five years of collaborative research by Levy and Guinan in human patients. Many basic and translational studies, including our own, have provided a strong rationale for a trial of BPI in patients undergoing hematopoietic stem cell transplants, says Levy. Replenishing a natural host defense factor that is deficient due to chemotherapy makes theoretical and practical sense, and we hope that bringing our bench work to patients will reduce the complications they suffer.

GVHD occurs when immune cells from donor attack the recipient, and can lead to multiple organ failure and death. It strikes some 30-60 percent of transplant patients, depending on how closely matched the donor is, and is kept in check only by eliminating otherwise useful donor immune cells or by using powerful immune-suppressing drugs.

Studies in mice had shown that the chemotherapy regimens used in HSCT not only wipe out white blood cells (with the intended effect of suppressing the immune system), but also damage the intestinal lining. This breach of the lining allows endotoxin, which is produced by bacteria living in the intestines, to enter the bloodstream. The endotoxin, in turn, provokes an inflammatory response that mobilizes donor immune cells, helping to trigger GVHD.

Levy, in Childrens Division of Infectious Diseases, had long been studying BPI, which naturally blocks and neutralizes endotoxin.(1) BPI is found in neutrophils, the very white blood cells that are virtually wiped out by pre-transplant chemotherapy. Studies in mice had shown that blocking endotoxin reduces the incidence of GVHD after chemotherapy and HSCT.(2)

Intrigued by these findings, Levy and Guinan began to study endotoxin and BPI in human patients undergoing HSCT with pre-transplant chemotherapy. In 2003 they showed, in a study of 57 children, that patients blood endotoxin levels rise markedly within a week of the transplant.(3) And now, in a study of 30 patient:donor pairs to be presented at the ASH meeting, they show that patients undergoing HSCT also have a sharp drop in BPI levels just as their endotoxin levels are rising and that BPI deficiency is associated with a greater likelihood of GVHD.

BPI is markedly deficient 100 to 1000-fold lower in our transplant patients, says Guinan, associate director of the Center for Clinical and Translational Research at Dana-Farber. If we can replenish this host defense factor, we might be able to moderate the damaging effects of GVHD.

The multicenter clinical trial, expected to begin within the next few months, will test rBPI21 (opebacan, NEUPREX® [Nasdaq: XOMA]). rBPI21 has been in phase I, II, and III human trials, with evidence of benefit in children and adolescents with serious meningococcal infections, but has not yet been approved by the Food and Drug Administration.

Levy and Guinan will first conduct a small safety trial, gradually increasing the amount of BPI given and the duration of treatment. If BPI appears safe, they will quickly mount a randomized, controlled trial in 30 to 40 patients who are undergoing HSCT for cancer or blood diseases. Childrens/Dana-Farber will be the lead center, with four to five additional pediatric and adult sites at prominent medical centers around the country.

Our ultimate goal is to reduce the downstream complications of stem-cell transplant, says Guinan. BPI would make these transplants significantly less toxic.

Pittsburgh-based team engineers muscle, bone cell differentiation with aid of ink-jet printer

Sun, 10 Dec 2006 05:00:00 PST

( from http://www.rxpgnews.com ) PITTSBURGH -- A Pittsburgh-based research team has created and used an innovative ink-jet system to print bio-ink patterns that direct muscle-derived stem cells from adult mice to differentiate into both muscle cells and bone cells. The results, which could revolutionize the design of replacement body tissues, will be presented Sunday, Dec. 10 at the 46th annual meeting of the American Society for Cell Biology in San Diego by Julie (Jadlowiec) Phillippi, a Carnegie Mellon University post-doctoral research fellow supported by the Pittsburgh Tissue Engineering Initiative.

This report is the first describing a system that can pattern the formation of multiple cell types within the same vessel from a single population of adult stem cells. The new preclinical advance in the field of regenerative medicine could one day benefit millions of people whose tissues are damaged from a variety of conditions, including fatal genetic diseases like Duchenne Muscular Dystrophy (DMD), wear and tear associated with aging joints, accidental trauma, and joint deterioration due to autoimmune disorders.

The custom-built ink-jet printer, developed at Carnegie Mellon's Robotics Institute, can deposit and immobilize growth factors in virtually any design, pattern or concentration, laying down patterns on native extracellular matrix-coated slides (such as fibrin). These slides are then placed in culture dishes and topped with muscle-derived stem cells (MDSCs). Based on pattern, dose or factor printed by the ink-jet, the MDSCs can be directed to differentiate down various cell-fate differentiation pathways (e.g. bone- or muscle-like).

Previously, researchers have been limited to directing stem cells to differentiate toward multiple lineages in separate culture vessels. This is not how the body works: the body is one vessel in which multiple tissues are patterned and formed. The ink-jet printing technology allows us to precisely engineer multiple unique microenvironments by patterning bio-inks that could promote differentiation towards multiple lineages simultaneously, explained Phil Campbell, research professor at Carnegie Mellon's Institute for Complex Engineered Systems.

Controlling what types of cells differentiate from stem cells and gaining spatial control of stem cell differentiation are important capabilities if researchers are to engineer replacement tissues that might be used in treating disease, trauma or genetic abnormalities, said Lee Weiss, research professor at Carnegie Mellon's Robotics Institute.

This system provides an unprecedented means to engineer replacement tissues derived from muscle stem cells, said Johnny Huard, professor of orthopedic surgery at the University of Pittsburgh School of Medicine and director of the Stem Cell Research Center at Children's Hospital of UPMC. Huard has long-standing research findings that show how muscle-derived stem cells (MDSCs) from mice can repair muscle in a model for Duchenne Muscular Dystrophy, improve cardiac function following heart failure, and heal large bone and articular cartilage defects.

Weiss and Campbell, along with graduate student Eric Miller, previously demonstrated the use of ink-jet printing to pattern growth factor bio-inks to control cell fates. For their current research, they teamed with Phillippi, Huard and biologists of the Stem Cell Research Center at Children's Hospital to gain experience in using growth factors to control differentiation in populations of MDSCs from mice.

The Carnegie Mellon scientists used computer-vision feedback to calibrate how bio-inks were jetted onto their targets with micrometer precision to facilitate subsequent image analysis. They stained the MDSC cultures for cell markers to confirm that muscle and bone-like lineages lined-up in register with engineered bio-ink patterns that were initially printed onto the slides with the ink-jet printer.

Our findings showed that we successfully engineered MDSCs to become subpopulations of muscle or bone-like cells that were patterned using our bio-ink-jet system, said Phillippi. This experiment represents a key first step in demonstrating the potential of this technology to learn more about not only the basic biology of how multiple cell types are patterned in the body during development, repair and regeneration, but also for translating adult stem cells into real therapies for patients in the future.

The team, along with Alan Waggoner, professor of biological sciences and director of Carnegie Mellon's Molecular Biosensor Imaging Center, is now developing novel biosensors and fluorescent-based techniques to visualize stem cell differentiation in response to the bio-ink patterns.

Because the ink-jet system employs such precision, it could be used one day to co-culture multiple MDSC lineages - including bone, muscle and other cell types - in complex, patterned configurations that could be incorporated directly into specific areas of the body in need of repair of multiple tissue types, according to the investigators.

The Pittsburgh team envisions the ink-jet technology as potentially useful for engineering stem cell-based therapies for repairing defects where multiple tissues are involved, such as joints where bone, tendon, cartilage and muscle interface. Patients afflicted with conditions like osteoarthritis might benefit from these therapies, which incorporate the needs of multiple tissues and may improve post-treatment clinical outcomes.

The long-term promise of this new technology could be the tailoring of tissue-engineered regenerative therapies. In preparation for preclinical studies, the Pittsburgh researchers are combining the versatile ink-jet system with advanced real-time live cell image analysis developed at the Robotics Institute and Molecular Biosensor and Imaging Center to further understand how stem cells differentiate into bone, muscle and other cell types.

Transplanted brain cells hold promise for Parkinson's disease

Mon, 04 Dec 2006 05:00:00 PST

( from http://www.rxpgnews.com ) Transplanted neural stem cells hold promise for reducing the destruction of dopaminergic cells that occurs in Parkinsons disease and for replacing cells lost to the disease, scientists say.

Research published in the current issue of The Journal of Neuroscience shows a human neural stem cell transplant essentially enables an animal model for Parkinsons to continue functioning normally rather than displaying the progressive loss of movement control that characterizes the disease.

We are very cautious but to us, its an indication that stem cells have promise for Parkinsons disease, says Dr. Cesario V. Borlongan, neuroscientist at the Medical College of Georgia and corresponding author of the study.

Transplants were done shortly after a neurotoxin was used to destroy neurons that make dopamine, a neurotransmitter key to movement control, Dr. Borlongan notes. This would be equivalent to a patient getting treatment very early in the disease process, which rarely happens since there is no screening test to catch it early.

Right now we are saying if you are able to identify Parkinsons in the early stage, we think this therapy will work. An important question that remains is, Can we rescue neurons that are dying from Parkinsons This would more accurately mimic what patients need. The researchers already have begun studies that delay the transplants until weeks after injury.

For this study, researchers compared animals that received placebo treatment with those that received only protective neurotrophic factors secreted by stem cells and those that had a transplant.

Animals that received transplants essentially regained control of their movement, placebo-treated animals did not recover and those that received neurotrophic factors, called stem cell factors, recovered partially.

When researchers examined the brains one month after transplant a long time in the two-year life of a rat - researchers found endogenous dopaminergic cells and transplanted neural stem cells had both survived. Also, transplanted neural cells had formed synapses to communicate with each other and ultimately the striatum, the portion of the brain dopaminergic cells act on to control movement.

When we looked at the transplanted stem cells, they had survived, had differentiated into neurons and showed some connection with the host tissue, says Dr. Borlongan.

They did additional studies in test tubes, taking commercially available rat and human dopaminergic cells, exposing them to neurotoxins and then to stem cell factors. Stem cell factor protected cells in a dose-dependent fashion. The more stem cell factor, the better the protection, Dr. Borlongan says. When the cells were co-cultured with stem cells, protection was further increased. When they used an antibody to block the stem cell factor, neuro-protection was significantly reduced. This again shows a combination of factors at work, says Dr. Borlongan. Its a synergistic effect.

Hes now following rats with transplants for six months to see if the early protection/recovery holds up; hes already past the three-month mark and to date, recovery is stable. While the rats needed immunosuppression because they received human cells, Dr. Borlongan says humans would not.

About a half-million Americans have Parkinsons disease. Typically the disease does a lot of damage to dopaminergic cells before it becomes symptomatic. Although Parkinsons is associated with abnormal movement, such as tremors, loss of these cells actually makes it difficult for people to move and, once they move, they cant control the movement, Dr. Borlongan says. The standard treatment is L-dopa, a synthetic dopamine that tends to minimize symptoms for three to five years. As the disease progresses and the drug becomes less effective, doses are increased and can produce more dyskinesia, loss of controlled movement. Centers such as MCG are exploring new ways to slow disease progression, diagnose it earlier and more accurately monitor its progression.

BIDMC's Terry Strom, M.D., honored by American Society of Nephrology

Mon, 04 Dec 2006 05:00:00 PST

( from http://www.rxpgnews.com ) BOSTON -- Terry B. Strom, MD, director of the Division of Immunology at Beth Israel Deaconess Medical Center (BIDMC) and Scientific Director of BIDMCs Transplant Center, received the 2006 Homer W. Smith Award from the American Society of Nephrology at their annual meeting last month in San Diego. Established in 1964, the award is presented annually to an individual who has made outstanding contributions which fundamentally affect the science of nephrology.

This award recognizes one of the major intellectual forces in renal physiology, says ASN President William Henrich, MD, FASN. [Smiths] use of comparative approaches to explain normal human physiology stands as a model for students of biology and scientists attempting to unravel the mysteries of normal and disordered renal function. This award is in recognition of those who follow in his footsteps and contribute to our understanding of how the kidney functions normally and in disease states.

In a career spanning more than 30 years, Strom has made critically important contributions to both nephrology and transplantation biology through his study of immune tolerance the immune systems ability to recognize and tolerate the bodys own cells and molecules in order to prevent organ rejection, a serious problem facing kidney transplant patients.

The BIDMC Transplant Centers immunology research program enjoys an international reputation for excellence in both laboratory and clinical innovation, says BIDMC Chief Academic Officer Jeffrey S. Flier, MD. Under the scientific leadership of Terry Strom, the Center has made pivotal contributions in understanding the biology of immune cells and tolerance. Terry is one of the fields leading physician-scientists and his work is a classic example of bench-to-bedside research.

Since the first successful kidney transplant was performed in the U.S. more than 60 years ago, transplant patients and their doctors have been faced with the vexing problem of organ rejection, the bodys natural immune response when faced with a foreign invader. Through his work studying activated immune T-cells, Strom has been a leader in developing new approaches to overcome rejection without the use of highly toxic immunosuppressive drugs.

Beginning with basic studies of lymphocyte growth and development, Strom identified and characterized T-cell growth factors, produced reagents to block the action of these growth factors, studied them in experimental small animal models, evaluated them in primates, and participated in clinical trials.

His most recent work has focused on the influence of inflammation on the texture of transplant rejection and autoimmunity and on investigation of a family of T-cell proteins known as TIM (T-cell immunoglobulin Mucin domain), which serve as checkpoints for the survival or activation of T-cell subsets. To date, these findings have been published in the journals Nature, Nature Immunology and the Journal of Experimental Medicine.

A graduate of the University of Illinois School of Medicine, Strom went on to receive training in medicine at the University of Illinois Hospitals, at the former Beth Israel Hospital in Boston and at Bostons Peter Bent Brigham Hospital, where he later became medical director of the hospitals kidney transplant program. Strom is currently Professor of Medicine and Surgery at Harvard Medical School, where he has been teaching for more than three decades.

Throughout his career, Strom has contributed to more than 600 publications and has been honored with numerous awards including the Lilly Lectureship of the Royal College of Physicians (London), the 1997 Sandoz Transplant Established Investigator Award of the American Society of Transplant Physicians, and the 2001 Roche American Society of Transplantation Distinguished Achievement Award. A member of more than 15 professonal societies, Strom presently serves as a Councilor for the Cell Transplant Society. He is a past-president of the American Society of Transplantation, the Clinical Immunology Society and Councilor of the International Society of Nephrology.

Review urges limited use of device to keep heart transplant hopefuls alive

Tue, 28 Nov 2006 05:00:00 PST

( from http://www.rxpgnews.com ) An implantable pump can help heart failure patients live and recover strength while they wait for a transplant. But an evaluation of the device's track record in the United Kingdom concludes that the UK's National Health Service should continue to restrict the technology's use -- at least for now.

Although we believe that the devices have been developed sufficiently to prolong life for some very sick patients who have rapidly deteriorating heart failure, we don't feel they've been developed quite enough yet for widespread use amongst the whole heart failure population, said lead researcher Linda Sharples.

When the heart's pumping chamber weakens, a ventricular assist device, or VAD, uses a battery or electricity-powered pump to send oxygen-rich blood throughout the body.

Sharples studied health outcomes and the cost effectiveness of heart assist devices for 70 UK patients who received the implant between April 2002 and December of 2004. More than 10,000 heart assist devices have been implanted worldwide.

The review is published in the latest issue of Health Technology Assessment, the international journal series of the Health Technology Assessment programme, part of the National Institute for Health Research in the United Kingdom.

Although researchers are testing ventricular assist devices as a long-term or permanent therapy, right now the heart pumps are generally used as a temporary fix for heart transplant candidates who aren't likely to survive until a suitable organ is found.

All of the cases studied in the Health Technology Assessment review were surgeries performed as a bridge to transplantation. Most of the patients received an early or first-generation model of the heart pump.

Thirty of the 70 patients with a heart assist device died before receiving a donor heart. For the people who survive the implant, we know that their heart function improves immediately, not as much as after a heart transplantation, but it certainly improves, Sharples said.

The most common complications from the surgery were blood clots, infection and respiratory distress, the review found.

Monitoring and maintaining the heart pump usually requires patients to stay in the hospital during the entire time they wait for a donated heart. That limits quality of life, Sharples said. Patients don't get back to their normal way of life, their mobility, their ambulation is restricted and there are adverse events, but it's certainly better than before VAD implantation.

The small number of heart-pump implantations performed in the United Kingdom made it impossible for the reviewers to identify a fair patient group for comparison. But as an approximation, the reviewers compared health outcomes and costs for the VAD patients with patients on the UK's heart transplant waiting list.

The review estimates the average cost of a VAD implant operation is 63,830 British pounds (roughly $116,000). The average cost for health care and the stay in a hospital's intensive care unit was 14,500 British pounds (about $26,300).

We compared the VAD group with the very sickest of the transplant candidates and found that the health care for those individuals was less costly. Those non-VAD patients also had greater survival, Sharples said.

Still, the overall survival rate for the heart assist patients was 52 percent after one year. The reviewers called that an excellent clinical achievement for a patient population with rapidly failing hearts. In the UK, what we expect is that we will continue to use the devices in selected cases, and we will continue to use them in a small number of centers that have necessary surgical, cardiological and technical expertise, Sharples said.

We recommend that the United Kingdom continue to monitor the development of the new devices, said Sharples. I think we are all quite hopeful that they will progress and we will have more cost-effective and effective devices in the future.

While the UK study results were mixed, U.S. heart-failure and transplant expert Dr. Leslie Miller said he has more promising experience with ventricular assist devices.

Miller said candidates for a heart assist device are generally the sickest of heart failure patients who are no longer helped by drug treatment. In the United States, heart failure programs are increasingly performing heart pump implantations, because there is no other alternative when these patients become unresponsive, Miller said.

These people are critically ill and would otherwise die without the heart assist device. So when you start with that group, it is quite remarkable the ability of these pumps to resurrect people, Miller said. The fact that we see a 70 to 75 percent survival to a heart transplant with these devices is really a pretty extraordinary accomplishment.

Miller heads the cardiac program at the Georgetown University School of Medicine, Georgetown University Hospital and Washington Hospital Center. He said his successful heart pump patients often recover enough to exercise for 30 minutes on a treadmill. And he said that recovery makes heart pump patients more stable when they do undergo heart transplant surgery.

It's a very dramatic change. That's why these people do as well as anybody on the transplant list. They are so stable, they are exercising daily, Miller said.

Obese kidney transplant patients twice as likely to die in the first year or suffer organ failure

Mon, 13 Nov 2006 05:00:00 PST

( from http://www.rxpgnews.com ) Survival and successful kidney transplant rates are significantly lower when people are obese, according to a study of over 2,000 patients published in the November issue of Transplant International.

A team of experts from across the Netherlands studied the medical profiles of 4,245 adults who had received kidney transplants, using data from the Netherlands Organ Transplantation Registry.

In 2067 cases there was sufficient information to calculate their Body Mass Index (BMI) based on their weight and height - at the time of their kidney transplant.

They discovered that six per cent of patients with a BMI of more than 30 died in the first year after transplant, compared with three per cent of patients with a BMI of less than 30.

By year five, the difference was even greater, with an 81 per cent survival rate for the obese patients and an 89 per cent survival rate for patients who were not obese.

The same pattern emerged when they looked at the success of the transplant itself.

A year after the transplant was carried out, 14 per cent of obese patients had experienced a transplant failure, compared with eight per cent of non obese patients.

After five years, 71 per cent of obese patients still had a successfully transplanted kidney, compared with 80 per cent of the patients with a lower BMI.

Obese patients were more likely suffer transplant failure through infection or permanent non-functioning, but the numbers for obese and non-obese patients were both fairly low.

There were no significant differences between the two groups when it came to why patients died, but there was a trend for obese patients to suffer more infections and fatal heart conditions.

Obese patients in the study group also tended to be older and were more likely to be female

The prevalence of obesity in patients with end-stage renal disease is increasingly rapidly says lead researcher Dr Jeroen Aalten from the Department of Nephrology at the University Medical Center in Nijmegen.

It's estimated that 60 per cent of renal transplant candidates in the United States and 10 per cent in the Netherlands are obese or overweight.

These figures have been rising consistently in recent years. This could be due to a general rise in obesity worldwide, but we can't rule out that it may have been affected by changes in inclusion criteria for kidney transplants.

The study which was carried out by Nephrology specialists from seven university hospitals across the Netherlands concluded that there is a significant relationship between obesity and increased transplant failure or death.

The authors acknowledge that there has been considerable debate about whether obese patients are suitable transplant candidates.

But they also point out that while obesity is preventable and fundamentally curable, compared to age and diabetes, experience shows that it can be very difficult for people with end-stage renal disease to lose weight.

Our conclusion is that it's not fair to deny obese patients the chance of a kidney transplant as they still do better after a transplant than on dialysis says Dr Aalten.

However we shouldn't disregard the increased risk for obese patients after transplantation and we also need to bear in mind that it is important to give scarce resources to patients with the lowest risk.

It is very important that patients facing kidney transplant are fully informed about the risks that they face and are encouraged to lose weight wherever possible.

Severity of diabetes is key determinant of heart transplant success

Mon, 06 Nov 2006 05:00:00 PST

( from http://www.rxpgnews.com ) Having diabetes should not automatically disqualify you from being considered for a heart transplant, according to a study published in Circulation: Journal of the American Heart Association.

During a 10-year period, heart transplant recipients with uncomplicated diabetes lived just as long as non-diabetic recipients, according to data from the United Network for Organ Sharing (UNOS), a national organization that coordinates transplant organ procurement and distribution. However, heart recipients with severe diabetes-related organ damage, such as a history of kidney disease or stroke, had significantly worse long-term survival compared to recipients without diabetes.

Previous studies examining the impact of diabetes on survival after heart transplantation involved relatively few patients who were followed for a fairly short period. In addition, these studies failed to consider that some people have more severe forms of diabetes than others. Therefore, the impact of diabetes on survival after heart transplantation remained controversial. While no national transplantation rules disqualify people with diabetes from receiving donor hearts, each transplantation center has its own rules, and some centers exclude people with diabetes.

Diabetes significantly increases the risk of heart disease, which is the leading cause of death among people with diabetes. Diabetics are also twice as likely to develop heart failure as those without diabetes.

The question is not whether a person has diabetes but how much damage the diabetes has done, said Mark Russo, M.D., M.S., one of the study's authors and a researcher at Columbia University's International Center for Health Outcomes and Innovation Research in New York and a postdoctoral residency fellow in surgery at New York-Presbyterian Hospital/Columbia University Medical Center. A person should not be disqualified from transplantation solely because of diabetes.

Russo and his co-authors examined post-transplant survival in more than 20,000 people aged 18 years and older (average age 52) who received heart transplants between 1995 and 2005, including 3,687 people who were diabetic at the time of transplantation. Because all patients undergoing heart transplantation in the United States during this period were included in the UNOS database, the study offers a nationwide perspective on the issue of diabetes and heart transplantation.

Researchers assessed the severity of the patients's diabetes by their number of diabetes-related complications. Complications were defined as stroke, kidney failure, peripheral vascular disease (diseased blood vessels in the extremities) and severe obesity (body mass index ¡Ý35). The majority (76.1 percent) of the diabetics did not have diabetes-related organ damage.

Transplant recipients with uncomplicated diabetes had a median survival of 9.3 years, which was not significantly different from recipients without diabetes who had a median survival of 10.1 years.

The presence of complications related to diabetes prior to transplantation, however, was associated with worse post-transplant survival in diabetic transplant recipients. The median survival of diabetic recipients with one complicating condition was 6.7 years, while median survival was almost half that (3.6 years) when diabetes was combined with two or more complications. Furthermore, the risk of post-transplant complications increased significantly with increasing severity of diabetes.

It is currently estimated that 60,000 people in the United States could benefit from heart replacement therapies. Median survival following heart transplantation exceeds 10 years, and many recipients live 20 years or more after receiving a transplant. However, due to a critical shortage of donor organs, fewer than 2,500 people undergo this procedure in any given year. Therefore the findings in this study have important implications for the allocation of hearts available for transplantation.

Many patients with end-stage heart failure, even those with severe diabetes, will live longer after heart transplantation, said the study's senior author, Yoshifumi Naka, M.D., Ph.D., director of Cardiac Transplantation at New York-Presbyterian Hospital and the Herbert Irving Assistant Professor of Surgery at Columbia University College of Physicians and Surgeons.

He emphasized, however, that given the limited number of organs available, it is important to understand the risks and benefits associated with various groups of patients; this will enable the benefits from these limited resources to be maximized. In the pre-transplant screening, we must identify diabetic patients who have severe end-organ damage, Naka said. Those patients do not do as well after transplantation; so we must consider alternative treatment strategies for these patients. However, diabetics with only minimal damage should be considered for transplant.

For patients with severe heart failure and severe diabetes, alternatives to transplantation include the use of left ventricular assist devices, small electrical pumps placed in the heart, or the use of alternative wait lists for high-risk heart transplant candidates.

Predicting survival in liver transplant patients

Thu, 02 Nov 2006 21:15:00 PST

( from http://www.rxpgnews.com ) A new model based on specific characteristics of the donor and the recipient may help predict survival after liver transplantation, according to a new study. Published in the November 2006 issue of Liver Transplantation, the official journal of the American Association for the Study of Liver Diseases (AASLD) and the International Liver Transplantation Society (ILTS), the author writes, "This model could be used to inform liver transplant candidates and their doctors what post-transplant survival would be expected when a given donor is offered and may be particularly helpful in marginal or high risk donors."

The journal is published by John Wiley & Sons, Inc., and is available online via Wiley InterScience.

Currently, nearly 18 million patients are awaiting liver transplants, but because organs are scarce, only about 6,000 are transplanted each year. There are no universally accepted criteria for liver donors. In addition, the importance of various recipient characteristics to post-transplant survival isn't fully understood.

George Ioannou, M.D., M.S., of the Veterans Affairs Puget Sound Health Care System in Seattle sought to identify donor and recipient characteristics that are important predictors of graft survival following liver transplantation. He then used these predictors to develop and validate a survival model.

Using information provided by the United Network for Organ Sharing, Ioannou identified all patients who had a liver transplant between 1994 and 2003. For his study, he did not include patients who had donors under age 10 or over age 75, living donors, split-liver donors, non-heart-beating donors, or donors with serum sodium concentration greater than 170 mmoles/L. He also excluded patients with multiple organ transplants, previous liver transplants and incomplete information.

For the 20,301 patients who remained, including 6,477 with hepatitis C (HCV), he used statistical models to examine the relationship between donor and recipient characteristics and survival after transplant. He then created two models that predict survival after liver transplant one for patients without HCV and one for those with HCV. He validated the models using data from patients not included in their derivation.

Ioannou found that the donor age, cold ischemia time, recipient MELD score, and cause of liver disease have the greatest impact on survival. However, the best model for patients without HCV included donor age, cold ischemia time, gender, race/ethnicity, recipient age, BMI, MELD score, status at time of transplantation, diabetes mellitus, cause of liver disease, and serum albumin. For patients with HCV, the best model included the same donor characteristics, and all recipient characteristics except cause of liver disease and serum albumin.

"Ultimately," Ioannou writes, "risk scores and predicted survivals determined from such models may be an objective way to assess the risk of a given liver donor, recipient, or donor/recipient combination." Such models could improve the fairness of organ distribution. For example, he suggests, "if two donors are expected to be available at approximately the same time, it would be more equitable for the recipient with worse predicted post-transplant survival to receive the donor with the better predicted survival and vice versa since that would make the post transplant survival of the two recipients more similar."

An accompanying editorial by Ignazio R. Marino, M.D., F.A.C.S of the Thomas Jefferson University Hospital in Philadelphia, says Ioannou's study is an excellent starting point for the debate about which patients receive the limited supply of organs. He recommends a large prospective study of liver transplant candidates to help optimize allocation criteria and define when a prospective donor should not be used for a prospective recipient. "We might not be ready to match donor and recipient yet," Marino writes, "but this should be our ultimate goal."

Three-in-one virus killer prevents common, often fatal infections

Thu, 26 Oct 2006 04:00:00 PST

( from http://www.rxpgnews.com ) A novel combination therapy drastically reduces the infection rate of three viruses and risk of death in transplant patients with compromised immune systems. The findings, to be reported in the Nov. 1 print edition of Nature Medicine, originate from a study conducted at Baylor College of Medicine, The Methodist Hospital, and Texas Children's Hospital.

The journal has posted the findings online.

The phase 1 trial, funded by the National Heart, Lung, and Blood Institute, one of the National Institutes of Health, tested the first multivirus killer of its kind, called Trivirus-specific cytotoxic T lymphocytes (CTLs), which control infections caused by three commonplace viruses cytomegalovirus (CMV), Epstein-Barr virus (EBV), and adenovirus. Although benign in people with normal immune systems, the viruses can cause life-threatening illnesses in transplant patients and others with compromised immune systems.

The CTLs proved effective and safe in all 11 bone marrow transplant patients, who recovered completely within two to four weeks of being treated without any side effects or toxicity. Preexisting therapies for adenovirus have had little success there is an 80 percent chance of death following the development of adenovirus.

Not only were patients prevented from getting these infections after transplant, but those patients who had infections responded to the T-cell therapy and did not require any other treatment, said senior author Dr. Catherine Bollard, assistant professor of pediatrics, immunology, and medicine at BCM and a researcher at the Center for Cell and Gene Therapy at BCM, Methodist and Texas Children's. To make dramatic recoveries like these was really quite something.

The research team drew cells from bone marrow donors and trained T-cells to target the three viruses before injecting them into transplant recipients.

Drugs only control the virus. They don't cure the underlying problem, said Bollard. Whereas by introducing these specialized T-cells, we are fixing the underlying problem. Using your own immune system is preferable to chemical agents, which can have toxic side effects.

Although the CTLs must undergo further testing, the early results suggest the combination therapy to be more, cost-effective, and safe than traditional therapies and more practical than cell-based therapies that target EBV and CMV separately, both of which are carried in roughly 80 percent of all people. Adenoviruses are common viruses carried in all populations.

There is no safe and effective therapy for patients with adenovirus infections at the moment, so if you get an infection after a transplant it becomes very problematic, said first author Dr. Ann Leen, BCM instructor of pediatrics at the Center for Cell and Gene Therapy. So we trained certain T-cells to target this virus.

Bollard envisions one day extending the application of CTLs to other people with compromised immune systems, such as cancer patients undergoing chemotherapy. The therapy could also potentially be used in babies, who are more susceptible to adenovirus infections than other age groups.

First Quantum Grant to fund stem cell repair of damage from stroke

Mon, 09 Oct 2006 04:00:00 PST

( from http://www.rxpgnews.com ) HOUSTON, Oct. 9, 2006 The National Institutes of Health has named researchers at Baylor College of Medicine (BCM) and Rice University in Houston as the first and only recipients of the inaugural Quantum Grant for their international research initiative to regenerate damaged brain cells and blood vessels for the treatment of stroke.

The three-year, $2.9 million grant, funded by the National Institute of Biomedical Imaging and Bioengineering (NIBIB), part of the NIH, will support research on neuro-vascular regeneration, which will make new brain tissues in the laboratory. The new brain tissue is planned to have its own blood supply to allow it to be placed into the damaged brains of stroke patients where it will provide a source of neural and vascular cells that will continue to develop and differentiate, repairing the injured tissue in the process.

This project represents an integrated effort among leading scientists who have jointly authored numerous publications, mentored students and postdoctoral fellows, as well as collaborated on Bioengineering Research Partnership grants, said Jennifer West, who is leading the project's efforts at Rice. West is the Isabel C. Cameron Professor of Bioengineering and director of Rice's Institute of Biosciences and Bioengineering.

The newly created NIBIB Quantum Grants Program supports researchers in the development of innovative biomedical technologies in hopes of making a significant impact in the prevention, diagnosis and treatment of disease. Funding was awarded to only one grant application out of more than 100 submitted.

Karen Hirschi, deputy director of the Stem Cell and Regenerative Medicine Center within the Center for Cell and Gene Therapy at BCM, is the principal investigator for the Neuro-Vascular Regeneration project, which will be conducted in conjunction with an interdisciplinary team of researchers at Rice, the National Institute for Medical Research in London, and King's College in London.

Each member of our team has made significant contributions to the advancement of their respective fields of research and will now be able to devote substantial efforts to integrating their work and developing methods of using neuro-vascular regeneration to help stroke victims, Hirschi said.

The project team members come from diverse and complementary areas of expertise in developmental neurobiology and vascular biology, stem cell biology, genetics, biomedical imaging, tissue engineering, and clinical cellular therapies. Spanning fields of science that include cell and molecular biology, animal models of disease, and hopefully human clinical trials, the Neuro-Vascular Regeneration project falls in line with the NIH roadmap for the development of multi-disciplinary and translational science.

The BCM team also includes project co-developer Mary Dickinson, assistant professor of molecular physiology and biophysics at BCM; Dr. Thomas Zwaka, assistant professor of molecular and cellular biology in the Center for Cell and Gene Therapy at BCM; and Malcolm Brenner, professor of medicine and pediatrics and director of the Center for Cell and Gene Therapy at BCM.

Robin Lovell-Badge, head of the division of developmental genetics at the National Institute for Medical Research in London, serves as co-principal investigator of the project. Other investigators in London include Jack Price and Mike Modo, both of the Centre for the Cellular Basis of Behaviour at the Institute of Psychiatry at King's College.

Children's Hospital of Pittsburgh and UPMC surgeons save two lives with domino transplant

Mon, 02 Oct 2006 04:00:00 PST

( from http://www.rxpgnews.com ) Transplant surgeons at Children's Hospital of Pittsburgh and UPMC have saved two patients with life-threatening liver conditions utilizing a technique known as a domino transplant. It is only the nation's second domino transplant involving a patient with maple syrup urine disease (MSUD).

Domino transplants are so named for the sequential nature of the transplants an organ from a deceased donor is transplanted into the first recipient. The first recipient's organ then is transplanted into a second recipient. Domino transplants are a rare but effective way of overcoming the shortage of organs available for transplant.

In this case, a liver from a cadaveric donor was transplanted into Nickolai Rudd, an adult patient at Children's with MSUD, a rare and potentially life-threatening genetic disease. Mr. Rudd's liver was transplanted into James Paulshock, an adult suffering from liver failure caused by primary sclerosing cholangitis. The MSUD that afflicted Mr. Rudd was not passed onto Mr. Paulshock through his donated liver, while Mr. Rudd's new liver metabolically cured his MSUD. Because MSUD does not originate in the liver, and is caused by a lack of enzymes, the second patient will not inherit the disease. Both patients' new livers are now functioning normally.

Mr. Rudd's transplant was led by George V. Mazariegos, MD, director of Pediatric Transplantation at Children's Hillman Center for Pediatric Transplantation and an associate professor of surgery at the University of Pittsburgh School of Medicine. Mr. Paulshock's transplant surgery was led by Amadeo Marcos, MD, clinical director of transplantation at the Thomas E. Starzl Transplantation Institute and a professor of surgery at the University of Pittsburgh School of Medicine. The transplants were performed May 30, 2006, and both patients have since been discharged.

Domino transplants are rare because there are a very limited number of diseases in which the organ of a sick patient can be transplanted into another individual without passing on the disease. MSUD is one such disease, Dr. Mazariegos said. Because Children's and UPMC are the leading transplant centers in the world for patients with MSUD, we foresee the opportunity to continue performing domino transplants in appropriate situations. We have performed more than 20 liver transplants in patients with MSUD, and in each and every patient, liver function has returned to normal, metabolically curing these patients. Domino transplants are an extremely resourceful approach to overcome the scarcity of organs available for transplant.

Only 109 domino transplants have been performed in the United States, all involving heart or liver transplants, according to the United Network for Organ Sharing.

Our novel immunosuppression therapies have enabled our live donor liver transplant recipients to recover more quickly without dependency on heavy anti-rejection medications, commented Amadeo Marcos, M.D., professor of surgery, chief, division of transplantation and clinical director of the Starzl Transplantation Institute. Furthermore, through our exceptional partnership with surgeons at Children's Hospital, we have been able to expand the donor pool to adult recipients who can benefit by receiving an MSUD liver, since the disease is not transferred to the recipient.

Landmark study of islet transplantation reveals potential benefits in uncontrolled type 1 diabetes

Wed, 27 Sep 2006 04:00:00 PST

( from http://www.rxpgnews.com ) San Francisco, CA, September 27, 2006 -- The results of the world's first multicenter clinical trial of islet transplantation have confirmed the technique's potential benefits in patients with difficult-to-control type 1 (or juvenile) diabetes. Published in the September 28, 2006 issue of the New England Journal of Medicine, the international team of investigators report that the Edmonton Protocol for islet transplantation can safely and successfully promote long-term stabilization of blood sugar levels in brittle diabetes patients and in some cases, relieve them of the need for insulin injections altogether for at least two years.

The multicenter study, begun in 2001, studied 36 volunteers diagnosed with brittle type 1 diabetes: patients who, despite their best efforts, had wide, unpredictable fluctuations in their blood sugar levels. Using the Edmonton Protocol for type 1 diabetes, each participant received up to three infusions of donated insulin-producing islet cells at one of 9 participating clinical centers in the US, Canada and Europe. The study was sponsored by the Immune Tolerance Network (ITN), with funding and support from the Juvenile Diabetes Research Foundation (JDRF), the National Institute of Allergy and Infectious Diseases (NIAID) and the National Institute of Diabetes, Digestive and Kidney Diseases (NIDDK). NIAID and NIDDK are both components of the National Institutes of Health (NIH).

Investigators found that one year after receiving the final transplant, 72% (26/36) of patients had benefited from the technique, with 16 patients achieving freedom from insulin injections and 10 requiring insulin, but maintaining improved control of blood glucose levels. After two years, five of these 26 patients remained insulin independent, while the remainder continued to require less insulin by injection and showed improved measures of blood glucose control and reversal of hypoglycemic unawareness--a condition in which people with type 1 diabetes can no longer recognize the early symptoms of low blood sugar, thus making them vulnerable to sudden and severe confusion, loss of consciousness and seizures.

According to investigators, the results are a critical step in the development of islet transplantation as a potential treatment for type 1 diabetes.

Not only does this show that islet transplantation can offer enormous benefits for brittle type 1 diabetes patients, but we now know that a single, standardized technique can be successfully applied at facilities around the world, Dr. Robert Goldstein, Chief Scientific Officer of the Juvenile Diabetes Research Foundation that helped fund the study. This is yet another milestone for diabetes research.

The multicenter study followed from research published in the NEJM in 2000 by University of Alberta, Canada professor James Shapiro, who reported that 7 out of 7 patients who received the Edmonton Protocol were free from insulin injections 1 year after receiving the treatment.

According to Shapiro, who continued as leader of the multicenter study, its most important finding is the fact that even islet transplant recipients who never get off insulin or who return to insulin use over time show real improvement.

This isn't an all-or-nothing procedure; it's not an issue of getting patients off insulin all together and keeping them that way. As we've shown, even partial survival of the transplanted islets can lead to significantly improved health in these patients. It's a tremendous result.

Patients enrolled in the study will be followed for at least another year to continue to assess the effects of the islet transplant procedure on their diabetes and overall health.

In their paper, the investigators reported no serious side effects related to the transplant procedure itself. Study related complications were generally a result of the immunosuppressive medications that patients are required to take in order to prevent the body from rejecting the transplanted islets. The development of safer, alternative means of preventing transplant rejection using immune tolerance therapies is a key JDRF research goal and the mission of the Immune Tolerance Network, the organization overseeing the study. Tolerance therapies are highly specific treatments that reprogram the immune system to prevent harmful immune responses, while leaving the disease-fighting capabilities of the immune system intact.

The bottom line is that if islet transplantation is ever to become a viable treatment option for the majority of type 1 diabetes patients, we need new tolerance therapies. said Jeffrey A. Bluestone, PhD., ITN Director and Director of the Diabetes Center at University of California, San Francisco. The results of this study give us the foothold that we need in order to investigate these safer alternatives to immunosuppression.

Such therapies may also provide additional advantages in islet transplantation, as the authors of the publication speculate that the immunosuppressive therapies could also contribute to the loss of islet function over time that led to loss of insulin independence in several of the patients.

Immune tolerance therapies are also being investigated for use as early interventions for type 1 diabetes. Several studies have now shown that they may slow or even prevent the destruction of islet cells that leads to type 1 diabetes and the dependence upon insulin injections.

The ITN is currently in the planning stages of follow-up studies designed to test emerging tolerance therapies in islet transplantation. Funding and support for clinical trials of tolerance therapies in early and established type 1 diabetes is available to researchers world-wide through the ITN JDRF Partnership in Immune Tolerance program.

Hopkins study reveals white blood cells can both hurt and help transplanted kidneys

Wed, 20 Sep 2006 04:00:00 PST

( from http://www.rxpgnews.com ) In an example of biological irony, the same white blood cell chemistry known to damage kidneys used for transplants may also help prevent such damage, according to a federally funded study in genetically engineered mice at Johns Hopkins.

Researchers have long known that when blood flow is cut off and then returned to transplanted kidneys or other organs, immune system cells called T lymphocytes produce toxic natural chemicals that contribute to ischemic reperfusion injury (IRI). Nature cannot distinguish between deliberate surgical wounds needed to remove and re-implant a donor kidney and other kinds of organ damage in which certain toxic chemicals are needed to clean up or remove bad tissue.

But in the new study published in the September issue of The Journal of Immunology, the Hopkins team reports that that T cells can also play a role in reducing cellular damage in IRI kidneys, according to Hamid Rabb, M.D., medical director of kidney and pancreas transplantation at The Johns Hopkins University School of Medicine.

IRI occurs in 30 percent to 40 percent of kidneys removed from dead donors, resulting in lower kidney survival rates, shortened kidney life and a cost increase of approximately $20,000 per patient from the initial hospital stay and treatment alone, according to Rabb. Scientists therefore are interested in identifying means of preventing or rapidly treating IRI, but one barrier to greater understanding has been the inability to detect the lymphocytes in the kidney during the first critical six hours after blood flow is returned.

In the Hopkins study, designed to try to find these cells and learn more about IRI, white blood cells were taken from mice that had undergone experimentally induced IRI. These cells were injected into mice engineered without a thymus gland, which produces T cells. A comparison group of genetically engineered mice got no injections.

After the researchers temporarily stopped blood flow to kidneys in mice in both groups for 30 minutes, they discovered that the kidneys in the injected mice were improved compared to the other group of mice.

This was an unexpected result, says Rabb. For years we have known that T cells play a role in IRI, but we assumed it was always a negative role; now we know they play a protective role as well.

Rabb said further research is needed to establish the exact mechanism for this protection, but he says it makes perfect sense in theory.

T cells are part of our immune system, and our immune system is designed to protect us from injury. Whats surprising here is that practical experience over the years has taught us that when the immune system is activated, we have increased cell damage, says Rabb.

Using a new method developed by Dolores B. Ascon, Ph.D., a postdoctoral fellow in the Department of Nephrology at Hopkins and first author on the paper, Rabb and his team successfully tracked small numbers of lymphocytes in three distinct groups of mice: normal mice, mice that underwent fake surgery without blood flow interruption to the kidneys (ischemia) and mice that underwent surgery and 30 minutes of ischemia.

The study showed elevated levels of T cells in the kidneys three hours after IRI compared to the normal mice. It also showed elevated levels of the chemicals tumor necrosis factor alpha (TNF-alpha) and interferon gamma (IFN-gamma), which are known to produce cellular damage in kidneys. These chemicals are produced by T cells.

The mice that underwent fake surgery also had an elevated level of T cells when compared to the normal mice, but these cells did not release TNF-alpha and IFN-gamma and did not cause injury to the kidneys.

In this case it appears as though the surgery triggered the movement of T cells to the region, but since there was no ischemia, these cells did not produce TNF-alpha and IFN-gamma, says Rabb. This only further illustrates the complexity of the role T cells play in IRI.

Transfusion-free surgical program reduced use of blood products for all liver transplant patients

Mon, 18 Sep 2006 04:00:00 PST

( from http://www.rxpgnews.com ) Development of a transfusion-free surgical program for Jehovah's Witness patients undergoing liver transplantation also has helped reduce the overall use of blood products for non-Jehovah's Witnesses undergoing the procedure, according to a study in the September issue of Archives of Surgery, one of the JAMA/Archives journals.

Orthotopic liver transplantation [in which a patient's diseased liver is removed and a donor liver transplanted into the same place] is typically associated with a large volume of blood loss, resulting in multiple transfusions and related complications, the authors describe in background information in the article. Transfusion-free surgery is rapidly gaining much-needed attention primarily because of the concerns surrounding transmission of diseases such as human immunodeficiency virus, hepatitis C and other viral infections. Additionally, long-term shortage of blood products and a paucity of alternatives put the system under duress, resulting in cancellation or postponement of elective cases.

Nicolas Jabbour, M.D., from the INTEGRIS Baptist Medical Center, Oklahoma City, and colleagues analyzed the medical records of 365 adult and pediatric orthotopic liver transplants performed from January 1997 through December 2004 at the University of Southern California-University Hospital in Los Angeles. The investigators evaluated the impact of the initiation of a transfusion-free program for Jehovah's Witnesses undergoing liver transplantation on the overall use of blood products in non-Jehovah's Witnesses undergoing the procedure. The pediatric and Jehovah's Witness transplant recipients were eliminated from the study, leaving only adult non-Jehovah's Witness patients who either received a liver transplant from a deceased donor or a living donor (n=272). These patients were categorized into two groups based on the initiation of the Transfusion-Free Medicine and Surgery Program at USC (for Jehovah's Witnesses) in January 2000. Group 1 consisted of recipients who received the liver transplant before January 2000 and group 2 included all patients who underwent transplantation after January 2000.

Recipients in group 1 underwent orthotopic liver transplants without intraoperative blood-saving or salvaging techniques, whereas all transplant recipients in group 2 underwent intraoperative cell salvage (ICS) and acute normovolemic hemodilution (ANH) whenever feasible, the authors report. ANH indicates a therapeutic initiative that involves simultaneously removing the patient's blood and replacing it with nonblood products

In comparing group 2 with group 1, the mean (average) MELD [model of end-stage liver disease] score was statistically significantly higher, whereas the mean number of intraoperative PRBC (packed red blood cells) and FFP (fresh frozen plasma) transfusions were significantly lower, the authors report. The MELD score describes the survival probability of a patient with end-stage liver disease, with higher scores indicating sicker patients. The number of preoperative and postoperative PRBC, FFP and platelet transfusions between the two groups was not statistically different.

The development of a transfusion-free surgical program for Jehovah's Witness patients has had a positive impact on reducing the overall blood use in non-Jehovah's Witness patients, the authors note. According to the authors, autotransfusion decreases some of the complications of transfusions, such as transmission of unknown pathogens, and also helps to preserve blood bank resources, which consequently reduces the overall procedure cost. Surgeons are the leading consumers of blood products, and it is important that we are leaders in promoting transfusion-free techniques. In conclusion, we propose that the recognized need to minimize the use of blood products be elevated to the same level as antibiotic and deep venous thrombosis prophylaxis (prevention).

SALT protocol improves quality of donor lungs significantly

Fri, 15 Sep 2006 17:50:00 PST

( from http://www.rxpgnews.com ) By performing simple clinical maneuvers to improve donor lung quality as part of the San Antonio Lung Transplant (SALT) protocol, researchers significantly increased the number of available donor lungs and transplant procedures without compromising recipient pulmonary function, length of hospital stay or survival.

The study appears in the second issue for September 2006 of the American Journal of Respiratory and Critical Care Medicine, published by the American Thoracic Society.

Implemented in 2001, the SALT donor-management protocol applied to all potential organ donors evaluated for candidacy by the Texas Organ Sharing Alliance in San Antonio during the study until 2005. Its purpose was to increase the lung procurement rate without adversely affecting the overall survival rate of lung transplant recipients.

Luis F. Angel, M.D., of the Division of Pulmonary and Critical Care Medicine at the University of Texas Health Science Center at San Antonio, and 12 associates reviewed data from 711 potential lung donors listed between September 1, 1997, and August 31, 2005.

During the four-year SALT donor management period studied, 121 lungs were transplanted, as contrasted to 53 during the prior four years before the management program started.

"Of the 98 actual lung donors during the protocol (SALT) period, 53 had initially been considered poor donors," said Dr. Angel. "These donors ultimately provided 64, or 53 percent, of the 121 lung transplants. The type of donor was not associated with significant differences in recipients' 30-day and 1-year survival rates or any clinical measures of adequate graft function."

According to the study, the problem of donor lung availability is a very serious one. In 2005, nearly 3,000 patients were on a national waiting list for lung transplantation. However, only 35 percent of these patients received transplants, while 10 percent died awaiting an organ. Approximately half of the listed patients were on the list more than two years before receiving their transplant.

The authors noted that this trend worsens each year. The number of new additions to the transplant list is nearly double the number of patients who receive lungs.

According to the SALT lung management protocol, donor organs from brain dead patients (average age 36) were classified according to lungs' oxygenation ability, whether lung tissue has collapsed or the presence of pulmonary edema (abnormal collection of fluid in the lung).

During the program, certain donor organs previously classified as poor were subjected to specialized clinical maneuvers to improve lung quality. These procedures included bronchoscopic airway clearing of secretions, new mechanical ventilation strategies and use of diuretics to increase secretion of fluid.

As a result of these efforts, 135 organs were upgraded from poor to usable, making them eligible for transplantation.

"A key strategy for increasing the number of usable donor lungs in our study was modifying donor criteria by reassessing oxygenation, chest radiography and bronchoscopic findings as absolute criteria after active donor management," said Dr. Angel.

The authors concluded that implementing a similar donor-management program on a large scale at organ banks around the U.S., with a procurement rate approaching 25 percent, would nearly double the number of lung transplantation procedures, significantly decrease lengthy wait times and potentially eliminate many of the deaths that occur among patients awaiting lung transplantation.

In an editorial on the research in the same issue of the journal, Andrew C. Chang, M.D., of the University of Michigan Medical Center, and Jonathan B. Orens, M.D., of Johns Hopkins University School of Medicine, wrote: "It is intriguing that although organ offer rates increased to over 50 percent of consented donors, transplant centers in the organ procurement organization region accepted only 25 percent, indicating the potential for improving donor organ lung use even further than reported by this group."

"The study raises another important question regarding the availability of donor lungs. Are there truly not enough lungs? Although it has been thought that the available supply is far less than the demand, the supply may be less of a problem than actual use. Some countries outside the United States boast average use rates of 50 percent, with survival and functional outcome that compare favorably to the United States."

They concluded: "It is interesting to note that there has never been a large-scale prospective study to assess adequately the criteria used to identify the 'ideal donor.' As the demand for lung transplantation increases, such studies will be of great importance to understand better which organs are truly useable, and more importantly, which organs should be discarded. The study by Drs. Angel and colleagues underscores the importance of using an organized approach to donor management, coupled with the education of donor procurement organizations to improve donor organ use."

Shorter distance on six-minute walk test points up a greater risk of death

Fri, 15 Sep 2006 04:00:00 PST

( from http://www.rxpgnews.com ) For idiopathic pulmonary fibrosis (IPF) patients awaiting lung transplantation, a simple walk test can predict mortality rates. A new study found that individuals with IPF who can cover less than 680 feet during the six-minute test are four times more likely to die than those who can walk greater distances.

The research appears in the second issue for September 2006 of the American Journal of Respiratory and Critical Care Medicine, published by the American Thoracic Society.

David J. Lederer, M.D., of the Division of Pulmonary, Allergy and Critical Care Medicine at Columbia University College of Physicians and Surgeons in New York City, and five associates examined the records of 454 adult IPF patients on U.S. transplantation waiting lists.

In IPF, lung tissue is damaged by an unknown cause. The walls of the air sacs become inflamed, which leads to scarring or fibrosis. As a result, patients with IPF frequently suffer from progressive respiratory failure. Eventually, the scarring causes permanent loss of the lungs' ability to transport oxygen.

To date, lung transplantation is the only medical therapy that has been shown to improve survival. Twenty-percent of all lung transplant procedures performed worldwide involve patients with IPF.

The investigators call the six-minute walk test a simple, safe, reliable and inexpensive way to assess the self-paced exercise capacity of IPF patients. It varies little when repeated on the same person over a short period of time.

A total of 209 patients had a six-month follow-up without undergoing lung transplantation, said Dr. Lederer. Forty-nine of these patients, 23 percent, died during that time period. The six-minute walk test's ability to separate those alive at six months from those who died was not only significantly better than chance, but also superior to the forced vital capacity percent (FVC%) predicted test.

The authors noted that a lower six-minute walking distance was associated with more severe lung disease, status as a minority and lower educational attainment in a nationwide cohort of patients with IPF who were listed for lung transplantation.

The test also predicted waitlist mortality independently of age, sex, race, lung function indices, presence of pulmonary hypertension and other potential confounders.

According to the investigators, the six-minute walk test has at least four advantages over other tests: 1) it is less costly than other tools; 2) it can be performed on patients with severe hypoxemia (inadequate amounts of oxygen in the blood) who require continuous high-flow oxygen; 3) it can be performed in any sufficiently long hallway by appropriately trained personnel; and 4) it does not require specialized equipment and expertise found only in established pulmonary function laboratories;

The authors concluded that a test like FVC% predicted might not be valid for gauging survival in patients with IPF who have been listed for lung transplantation because of the serious nature of their illness.

Upgrading donor lung quality to improve availability

Fri, 15 Sep 2006 04:00:00 PST

( from http://www.rxpgnews.com ) By performing simple clinical maneuvers to improve donor lung quality as part of the San Antonio Lung Transplant (SALT) protocol, researchers significantly increased the number of available donor lungs and transplant procedures without compromising recipient pulmonary function, length of hospital stay or survival.

The study appears in the second issue for September 2006 of the American Journal of Respiratory and Critical Care Medicine, published by the American Thoracic Society.

Implemented in 2001, the SALT donor-management protocol applied to all potential organ donors evaluated for candidacy by the Texas Organ Sharing Alliance in San Antonio during the study until 2005. Its purpose was to increase the lung procurement rate without adversely affecting the overall survival rate of lung transplant recipients.

Luis F. Angel, M.D., of the Division of Pulmonary and Critical Care Medicine at the University of Texas Health Science Center at San Antonio, and 12 associates reviewed data from 711 potential lung donors listed between September 1, 1997, and August 31, 2005.

During the four-year SALT donor management period studied, 121 lungs were transplanted, as contrasted to 53 during the prior four years before the management program started.

Of the 98 actual lung donors during the protocol (SALT) period, 53 had initially been considered poor donors, said Dr. Angel. These donors ultimately provided 64, or 53 percent, of the 121 lung transplants. The type of donor was not associated with significant differences in recipients' 30-day and 1-year survival rates or any clinical measures of adequate graft function.

According to the study, the problem of donor lung availability is a very serious one. In 2005, nearly 3,000 patients were on a national waiting list for lung transplantation. However, only 35 percent of these patients received transplants, while 10 percent died awaiting an organ. Approximately half of the listed patients were on the list more than two years before receiving their transplant.

The authors noted that this trend worsens each year. The number of new additions to the transplant list is nearly double the number of patients who receive lungs.

According to the SALT lung management protocol, donor organs from brain dead patients (average age 36) were classified according to lungs' oxygenation ability, whether lung tissue has collapsed or the presence of pulmonary edema (abnormal collection of fluid in the lung).

During the program, certain donor organs previously classified as poor were subjected to specialized clinical maneuvers to improve lung quality. These procedures included bronchoscopic airway clearing of secretions, new mechanical ventilation strategies and use of diuretics to increase secretion of fluid.

As a result of these efforts, 135 organs were upgraded from poor to usable, making them eligible for transplantation.

A key strategy for increasing the number of usable donor lungs in our study was modifying donor criteria by reassessing oxygenation, chest radiography and bronchoscopic findings as absolute criteria after active donor management, said Dr. Angel.

The authors concluded that implementing a similar donor-management program on a large scale at organ banks around the U.S., with a procurement rate approaching 25 percent, would nearly double the number of lung transplantation procedures, significantly decrease lengthy wait times and potentially eliminate many of the deaths that occur among patients awaiting lung transplantation.

In an editorial on the research in the same issue of the journal, Andrew C. Chang, M.D., of the University of Michigan Medical Center, and Jonathan B. Orens, M.D., of Johns Hopkins University School of Medicine, wrote: It is intriguing that although organ offer rates increased to over 50 percent of consented donors, transplant centers in the organ procurement organization region accepted only 25 percent, indicating the potential for improving donor organ lung use even further than reported by this group.

The study raises another important question regarding the availability of donor lungs. Are there truly not enough lungs? Although it has been thought that the available supply is far less than the demand, the supply may be less of a problem than actual use. Some countries outside the United States boast average use rates of 50 percent, with survival and functional outcome that compare favorably to the United States.

They concluded: It is interesting to note that there has never been a large-scale prospective study to assess adequately the criteria used to identify the 'ideal donor.' As the demand for lung transplantation increases, such studies will be of great importance to understand better which organs are truly useable, and more importantly, which organs should be discarded. The study by Drs. Angel and colleagues underscores the importance of using an organized approach to donor management, coupled with the education of donor procurement organizations to improve donor organ use.