Hydrogen peroxide vapor enhances hospital disinfection of superbugs

Dec. 31, 2012 — Infection control experts at The Johns Hopkins Hospital have found that a combination of robot-like devices that disperse a bleaching agent into the air and then detoxify the disinfecting chemical are highly effective at killing and preventing the spread of multiple-drug-resistant bacteria, or so-called hospital superbugs.

A study report on the use of hydrogen peroxide vaporizers -- first deployed in several Singapore hospitals during the 2002 outbreak of severe acute respiratory syndrome, or SARS, and later stocked by several U.S. government agencies in case of an anthrax attack -- is to be published Jan. 1 in the journal Clinical Infectious Diseases.

In the study, the Johns Hopkins team placed the devices in single hospital rooms after routine cleaning to disperse a thin film of the bleaching hydrogen peroxide across all exposed hospital equipment surfaces, as well as on room floors and walls. Results showed that the enhanced cleaning reduced by 64 percent the number of patients who later became contaminated with any of the most common drug-resistant organisms. Moreover, researchers found that protection from infection was conferred on patients regardless of whether the previous room occupant was infected with drug-resistant bacteria or not.

"Hydrogen peroxide vapor, as spread around patients' rooms by these devices, represents a major technological advance in preventing the spread of dangerous bacteria inside hospitals and, especially, from one patient occupant to the next, even though sick patients were never in the same room at the same time," says infectious disease specialist and study senior investigator Trish Perl, M.D., M.Sc.

Of special note, researchers say, was that enhanced cleaning with the vapor reduced by 80 percent a patient's chances of becoming colonized by a particularly aggressive and hard-to-treat bacterium, vancomycin-resistant enterococci (VRE).

In what is believed to be the first head-to-head comparison between traditional hand-cleaning and mopping with bleaching agents and robotic vaporizers, researchers routinely tested patients and their surroundings not only for VRE, but also for the more common methicillin-resistant Staphylococcus aureus, or MRSA, and lesser-known bacteria, including Clostridium difficile and Acinetobacter baumannii.

Some 6,350 patient admissions to JHH were closely tracked as part of the two-and-a-half-year analysis, as patients moved into and out of 180 private hospital rooms. Almost half the rooms received enhanced cleaning with hydrogen peroxide vapor in between patients, while the rest did not. Overall, multiple-drug-resistant organisms were found on room surfaces in 21 percent of rooms tested, but mostly in rooms that did not undergo enhanced cleaning.

Perl says that patients bringing in or picking up drug-resistant organisms while undergoing treatment in hospitals is a persistent and growing problem, and previous research has shown that patients who stay in a hospital room previously occupied by an infected patient are at greater risk of becoming infected.

"Our study results are evidence that technological solutions, when combined with standard cleaning, can effectively and systematically decontaminate patients' rooms and augment other behavioral practices, such as strict hospital staff compliance with hand-washing and bathing patients in disinfecting chlorhexidine when they are first admitted to the hospital," says Perl, senior hospital epidemiologist for the Johns Hopkins Health System and a professor at the Johns Hopkins University School of Medicine.

"Our goal is to improve all hospital infection control practices, including cleaning and disinfection, as well as behavioral and environmental practices, to the point where preventing the spread of these multiple-drug-resistant organisms also minimizes the chances of patients becoming infected and improves their chances of recovery," says Perl.

The paired robot-like devices, each about the size of a washing machine and weighing nearly 60 pounds, as well as supplies used in the study, were provided by their manufacturer, Bioquell Inc. of Horsham, Pa.

After the room has been cleaned, the vents are covered and the two devices are placed inside. The sliding door is closed, and the room is sealed. Then, the larger of the two devices disperses hydrogen peroxide into the room, leaving a very tiny, almost invisible layer (only 2 microns to 6 microns in thickness) on all exposed surfaces, including keyboards and monitors, as well as tables and chairs.

Because hydrogen peroxide can be toxic to humans if ingested or corrosive if left on the skin for too long, the second, smaller device is activated to break down the bleach into its component water and oxygen parts. The combined operation takes the devices about an hour and a half to complete.

"What is so exciting about this new method of infection control is that the devices are easy to use and hospital staff embrace it very quickly," says surgeon and study co-investigator Pamela Lipsett, M.D., M.H.P.E. Lipsett, a professor and director of surgical and critical care fellowship training at Johns Hopkins, says that during the study and before room cleanings, staff were "wheeling in" other pieces of equipment so these, too, could be decontaminated by the hydrogen peroxide vapor.

As a result of the study and the researchers' recommendation, JHH has purchased two of the Bioquell decontaminating units, which cost more than $40,000 per pair. The devices, already in use at some 20 other hospitals across the country, will be used at Johns Hopkins to decontaminate rooms typically housing high-risk patients under strict isolation precautions because of severe infection with a multiple-drug-resistant organism.

Researchers say they next plan to study the devices' effectiveness at decontaminating the outside packaging of unused but potentially exposed hospital supplies, which are typically discarded even though their seals remain intact. The research team also wants to coordinate study testing among other hospitals to validate their Johns Hopkins findings. Larger and longer studies may also be planned, to precisely measure and determine how well the devices work against the spread of each hospital superbug. The current study had only sufficient numbers to statistically validate the paired unit's effectiveness against VRE.

In addition to Perl and Lipsett, other Johns Hopkins University investigators involved in this study were study lead investigator Catherine Passaretti, M.D.; Nicholas Reich, Ph.D.; Jessica Meyers, M.P.H.; John Shepard, M.B.A.; and Karen Carroll, M.D. Additional study assistance was provided by Jonathan Otter, at Bioquell Inc., and Tracy Ross, at the University of Massachusetts, in Amherst.

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Journal Reference:

C. L. Passaretti, J. A. Otter, N. G. Reich, J. Myers, J. Shepard, T. Ross, K. C. Carroll, P. Lipsett, T. M. Perl. An Evaluation of Environmental Decontamination With Hydrogen Peroxide Vapor for Reducing the Risk of Patient Acquisition of Multidrug-Resistant Organisms. Clinical Infectious Diseases, 2012; 56 (1): 27 DOI: 10.1093/cid/cis839

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Paired CT scans catch chemo-killing of liver tumors in real time

Dec. 31, 2012 — Using two successive pairs of specialized CT scans, a team of Johns Hopkins and Dutch radiologists has produced real-time images of liver tumors dying from direct injection of anticancer drugs into the tumors and their surrounding blood vessels. Within a minute, the images showed whether the targeted chemotherapy did or did not choke off the tumors' blood supply and saved patients a month of worry about whether the treatment, known as chemoembolization, was working or not, and whether repeat or more powerful treatments were needed.

The Johns Hopkins team's report about this novel use of dual-phase cone-bean computed tomography, or DPCBCT, an imaging technique developed at Johns Hopkins, is set to appear in the January 2013 edition of the journal Radiology. The diagnostic scans were performed on 27 men and women with inoperable liver cancer.

"This new scanning method is giving us almost instant feedback about the value of injecting antitumor drugs directly into large liver tumors and their surrounding blood vessels in an effort to quickly kill them, and to prevent the cancer from spreading," says senior study investigator and interventional radiologist Jean-Francois Geschwind, M.D.

Geschwind says if further testing proves equally successful, the paired use of cone-beam CT scans, which are already approved for single-scan use by the U.S. Food and Drug Administration, could supplant the current practice of MRI scanning a month after chemoembolization to check its effects.

"Patients should not have to endure the uncertainty of waiting weeks or more to find out if their chemoembolization was successful in fighting their liver cancer," says Geschwind, a professor in the Russell H. Morgan Department of Radiology at the Johns Hopkins University School of Medicine and its Kimmel Cancer Center.

"Dual-phase cone-beam CT avoids such delays, which also could allow the cancer to grow and spread and, ultimately, compromise chances of remission," he says.

Avoiding delays is particularly important, he says, for people with moderate to advanced stages of the disease, when liver tumors are too large or too numerous to surgically remove, and for whom chemoembolization is the main treatment option. Half of such liver cancer patients succumb within nine months, and liver transplantation is only an option for a quarter of those whose tumors have not spread outside the liver.

The newer DPCBCT scans, in which X-rays are detected by a device the size of a large laptop that can be placed directly below or above the operating room table, have the added advantage of being performed in the same room, or interventional radiology suite, as patients getting chemoembolization.

In their new study, Geschwind and his colleagues found that the initial shrinkage seen with DPCBCT scans taken before and after chemoembolization matched up almost perfectly with MRI scans taken a month later. Tumor death was 95 percent, the same as that seen by MRI. A total of 47 tumors were closely monitored in the study to assess how well DPCBCT tracked tumor death after chemoembolization.
All study participants were treated at The Johns Hopkins Hospital between March and December 2009.

In DPCBCT scanning, a chemical contrast dye is injected into the artery that supplies blood flow to the liver and tumor right before the chemotherapy drug is injected, to enhance the X-ray image. The first set of scans highlights key blood vessels feeding the tumor, as dye flows in and out of the tumor. The second set of scans is performed immediately after chemoembolization, to gauge tumor and key blood vessel death. Computer software is used to sharpen and analyze differences between the images.

The entire DPCBCT scanning time, researchers say, is between 20 seconds and 30 seconds, and the total amount of radiation exposure from the dual scanning averages 3.08 milliseiverts, which is less than half the amount of radiation involved in a modern abdominal 64-CT scan. Cone-beam CT scanners also emit an X-ray, but unlike other CT scanners, the cone-beam type of X-ray is projected onto one large, rectangular detector, roughly a foot and a half long -- and produces a telltale conical shape. The size of the cone-beam CT detector allows for single scans that can capture images the size of most people's entire liver. More powerful 64-CT and 320-CT scanners involve multiple detector rows.

Chemoembolization entails the use of tiny beads containing the chemotherapy drug doxorubicin injected directly into liver tumors.

Ultrathin catheters, about the width of a human hair, are threaded through blood vessels to deliver the drugs, which seep from the beads for several weeks.

Geschwind is leading clinical trials under way at Johns Hopkins and other centers to assess whether the combination drug treatment works for liver cancer patients. Early results have shown promise, with patients with advanced disease living 10 months to 15 months longer.

Geschwind says they plan improvements in image quality in DPCBCT scans, hoping further refinements will encourage physicians to adopt the technique. They also plan updates to the navigational software that, like GPS, can track blood vessels feeding each tumor, and provide more precise and greater numbers of targets.

Liver cancer kills nearly 20,000 Americans each year, and is much more prevalent outside the United States, where it is among the top three causes of cancer death in the world. Experts cite the rising numbers of hepatitis C infections, which cause chronic liver inflammation and are a leading risk factor for liver cancer.

Funding support for this study was provided by the French Society of Radiology and Philips Research North America in Briarcliff Manor, N.Y. Philips, whose parent company is based in the Netherlands, manufactures the CBCT device used in the study. Additional funding support was provided by the U.S. National Cancer Institute, a member of the National Institutes of Health. The corresponding grant numbers are NCI R01-CA160771 and UL1 RR-025005.

The study lead investigators were Romaric Loffroy, M.D., a radiology fellow at Johns Hopkins, and MingDe Lin, Ph.D., a Philips biomedical engineer based at Johns Hopkins who has been collaborating with Geschwind for the past five years to perfect the DPCBCT technique.

In addition to Geschwind, Loffroy and Lin, other Johns Hopkins researchers involved in this research were Gayane Yenokyan, Ph.D., at the university's Bloomberg School of Public Health; and Pramod Rao, M.D.; Nikhil Bhagat, M.D.; and Eleni Liapi, M.D., all at the School of Medicine. Philips investigators involved were Niels Noordhoek, Ph.D.; Alessandro Radaelli, Ph.D.; and Jarl Blijd, M.Sc.

The chemoembolization research study was funded by Bayer HealthCare and Onyx Pharmaceuticals, manufacturer of sorafenib, and Biocompatibles, makers of the microbeads. Geschwind is a consultant to Bayer HealthCare Pharmaceuticals, and to Biocompatibles. The terms of these arrangements are being managed by The Johns Hopkins University in accordance with its conflict-of-interest policies.

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R. Loffroy, M. Lin, G. Yenokyan, P. P. Rao, N. Bhagat, N. Noordhoek, A. Radaelli, J. Blijd, E. Liapi, J.-F. Geschwind. Intraprocedural C-Arm Dual-Phase Cone-Beam CT: Can It Be Used to Predict Short-term Response to TACE with Drug-eluting Beads in Patients with Hepatocellular Carcinoma? Radiology, 2012; DOI: 10.1148/radiol.12112316

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Rare genetic faults identified in families with bowel cancer

Dec. 30, 2012 — Rare DNA faults in two genes have been strongly linked to bowel cancer by Oxford University researchers, who sequenced the genomes of people from families with a strong history of developing the disease.

The researchers sequenced the entire DNA genomes of 20 people from families with a strong history of bowel cancer. Eight of the 20 people had developed bowel cancer, while the rest had a first-degree relative who had developed the disease. The findings are published in the journal Nature Genetics.

They found that everyone who had a faulty POLE or POLD1 gene developed bowel cancer or had a precancerous growth in the bowel.

To confirm their findings they then looked for faults in these two genes in almost 4,000 people with bowel cancer, and 6,700 people without the disease.

Neither of the genetic faults was found in people without bowel cancer. However, 12 people with a fault in the POLE gene were found in the bowel cancer group, and one person had a POLD1 gene fault.

The POLD1 fault was also found to increase the risk of getting womb cancer and possibly brain cancer, with seven people in the study being diagnosed with womb cancer and one developing two brain tumours.

Professor Ian Tomlinson, who led the research at the Wellcome Trust Centre for Human Genetics at Oxford University, said: 'These are two rare faults, but if you inherit them your chance of bowel cancer is high. By testing people with a strong family history of the disease for these, we can identify those who are at high risk and try to prevent the disease by using colonoscopy and other methods.'

POLE and POLD1 are genes involved in processes that repair damage to DNA. Without these genes functioning properly, affected individuals can build up damage in their DNA which accumulates and it is thought this may lead to changes that cause bowel cancer.

'This research highlights how much more we still have to find out about the rare gene faults that can increase a person's risk of bowel cancer,' said Dr Julie Sharp, senior science information manager at Cancer Research UK, which part-funded the work.

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Journal Reference:

Claire Palles, Jean-Baptiste Cazier, Kimberley M Howarth, Enric Domingo, Angela M Jones, Peter Broderick, Zoe Kemp, Sarah L Spain, Estrella Guarino Almeida, Israel Salguero, Amy Sherborne, Daniel Chubb, Luis G Carvajal-Carmona, Yusanne Ma, Kulvinder Kaur, Sara Dobbins, Ella Barclay, Maggie Gorman, Lynn Martin, Michal B Kovac, Sean Humphray, Huw J W Thomas, Eamonn Maher, Gareth Evans, Anneke Lucassen, Carole Cummings, Margaret Stevens, Lisa Walker, Dorothy Halliday, Ruth Armstrong, Joan Paterson, Shirley Hodgson, Tessa Homfray, Lucy Side, Louise Izatt, Alan Donaldson, Susan Tomkins, Patrick Morrison, Selina Goodman, Carole Brewer, Alex Henderson, Rosemarie Davidson, Victoria Murday, Jaqueline Cook, Neva Haites, Timothy Bishop, Eamonn Sheridan, Andrew Green, Christopher Marks, Sue Carpenter, Mary Broughton, Lynn Greenhalge, Mohnish Suri, Peter Donnelly, John Bell, David Bentley, Gilean McVean, Peter Ratcliffe, Jenny Taylor, Andrew Wilkie, Peter Donnelly, John Broxholme, David Buck, Jean-Baptiste Cazier, Richard Cornall, Lorna Gregory, Julian Knight, Gerton Lunter, Gilean McVean, Jenny Taylor, Ian Tomlinson, Andrew Wilkie, David Buck, Lorna Gregory, Sean Humphray, Zoya Kingsbury, Gilean McVean, Peter Donnelly, Jean-Baptiste Cazier, John Broxholme, Russell Grocock, Edouard Hatton, Christopher C Holmes, Linda Hughes, Peter Humburg, Alexander Kanapin, Gerton Lunter, Lisa Murray, Andy Rimmer, Anneke Lucassen, Christopher C Holmes, David Bentley, Peter Donnelly, Jenny Taylor, Christos Petridis, Rebecca Roylance, Elinor J Sawyer, David J Kerr, Susan Clark, Jonathan Grimes, Stephen E Kearsey, Huw J W Thomas, Gilean McVean, Richard S Houlston, Ian Tomlinson. Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas. Nature Genetics, 2012; DOI: 10.1038/ng.2503

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Transfusions add risk in some heart attacks, finds study of patients with anemia

Dec. 24, 2012 — When heart attack patients present in the emergency department with some degree of anemia, or anemic patients have a heart attack, physicians have a tendency, but not much guidance, about whether to provide a blood transfusion. The idea is that a transfusion could help more oxygen get to the heart. Recent national guidelines suggested that there simply isn't good evidence to encourage or discourage the common practice, but a new meta-analysis of 10 studies involving more than 203,000 such patients comes down on the side of it increasing the risk of death.

The next step for determining when the practice could be appropriate needs rigorous randomized trials that will generate more decisive, high-quality data, said lead author Dr. Saurav Chatterjee, a cardiology fellow at the Alpert Medical School of Brown University and the Providence VA Medical Center.

For the analysis published Dec. 24 in the Archives of Internal Medicine, Chatterjee and his co-authors combined and analyzed data from studies in which anemia patients with heart attacks either received "liberal" transfusions or received more restricted versions of the treatment or no transfusions at all. Liberal transfusions were defined as cases in which patients either received two units of blood or more or had a transfusion even with a hematocrit reading (a measure of red blood cell concentration) higher than 30 percent (normal is in the low 40s).

What the researchers found, after statistical adjustments to control for important medical factors, was that the risk of death was 12 percent higher for people who received the liberal transfusions than those who did not. Moreover, the group that received liberal transfusions had twice the odds of having another heart attack.

"What we found is that the possibility of real harm exists with transfusion," Chatterjee said. "It is practiced in emergency departments all across the United States. I think it is high time that we need to answer the question definitively with a randomized trial."

Of the 10 papers that Chatterjee and his co-authors reviewed, all but one were observational studies. The only randomized trial was a small pilot experiment.

Searching for an answer

Chatterjee began the study when he was a resident at Maimonides Medical Center in New York. He noticed a paper by the AABB (formerly the American Association of Blood Banks) in which the association said there was not enough clinical evidence for or against transfusions in heart attack patients.

For clinicians, the practice has always been a tough judgment call. Some transfusions are clearly necessary, for example when a patient's troubles include not just a heart attack but also severe ongoing bleeding, Chatterjee said. But transfusions also create health risks, such as an increase in potential clotting because platelets may clump together more, or from an inflammatory immune response to the introduction of blood of a "foreign" source into the body.

Chatterjee and his co-authors decided to comb the literature to determine whether, if properly combined and analyzed, existing data could provide some insight. They found 729 potentially relevant studies, but only 10 that had the right data to help answer the question.

Few as they were, Chatterjee said, the studies all told much the same story.

"One of the things that struck us is that there were very few studies in evidence of transfusion at all," Chatterjee said. "In our case, though, we found that the effect was pretty consistently harmful across the spectrum of studies, spectrum of time, and spectrum of patients that were enrolled in the individual studies."

Chatterjee said the study should not be taken to mean that transfusions should be stopped altogether for anemic heart attack patients. Instead, he said, doctors must continue exercising their clinical judgment, at least until results from a large, well-designed randomized trial can be produced. Mindful of the risk his study found, however, they might just want to shift their thinking about where the border is among borderline cases.

"Before a definitive trial is out there, we should be conservative, especially considering the high risk of harm," he said.

In addition to Chatterjee, the paper's other authors are Jorn Wetterslev of the Centre for Clinical Intervention Research in Copenhagen, Denmark; Abhishek Sharma and Edgar Lichstein of Maimonedes Medical Center; and Debabrata Mukherjee of Texas Tech University.

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Journal Reference:

Chatterjee S, Wetterslev J, Sharma A, Lichstein E, Mukherjee D. Association of Blood Transfusion With Increased Mortality in Myocardial Infarction: A Meta-analysis and Diversity-Adjusted Study Sequential Analysis. Archives of Internal Medicine, 2012; DOI: 10.1001/2013.jamainternmed.1001

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A model-free way to characterize polymodal ion channel gating

Dec. 27, 2012 — Two studies in The Journal of General Physiology (JGP) help pave the way for a "shortcut" model-free approach to studying activation of "polymodal" ion channels -- channels that open in response to multiple stimuli. Transmembrane ion channels respond to various physiological stimuli to regulate numerous cellular functions.

Different classes of channels respond to different types of stimuli; some channels, for instance, respond to changes in membrane potential whereas others are activated by ligand binding. Polymodal channels integrate different cellular signals, enabling them to mediate a more precise and flexible physiological response. Understanding the mechanisms involved in polymodal channel activation has been a challenge, however, in part because of the complexity of the models required.

Now, two studies in the January issue of JGP use straightforward thermodynamically rigorous analysis to parse the free energy of polymodal voltage- and ligand-dependent ion channels. In one study, University of Wisconsin-Madison researchers Sandipan Chowdhury and Baron Chanda examine the BK channel -- a channel activated by both changes in membrane potential and calcium binding to an intracellular domain. In the second study, Daniel Sigg (dPET Professional Services) explores gating of polymodal ion channels in general. Specifically, the authors show how to use G-V (conductance-voltage), Q-V (charge-voltage) and conductance vs. ligand concentration measurements to extract the free energies of interaction of the modules of a polymodal channel that respond to these distinct modalities

This new approach opens the door for a model-independent way to studying ion channel gating, which could be useful both for constraining future atomic-scale models of channel gating, and in understanding the disruptions that result from disease causing genetic mutations.

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Journal References:

S. Chowdhury, B. Chanda. Free-energy relationships in ion channels activated by voltage and ligand. The Journal of General Physiology, 2012; DOI: 10.1085/jgp.201210860D. Sigg. A linkage analysis toolkit for studying allosteric networks in ion channels. The Journal of General Physiology, 2012; DOI: 10.1085/jgp.201210859O. Yifrach. No model in mind: A model-free approach for studying ion channel gating. The Journal of General Physiology, 2012; DOI: 10.1085/jgp.201210929

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Doctors call for evidence-based appropriateness criteria for elective procedures

Dec. 26, 2012 — Many of the most common inpatient surgeries in the United States are performed electively. These surgeries are expected to significantly increase with the enactment of the Affordable Care Act. In a new perspectives article, published in the Dec. 27 edition of The New England Journal of Medicine, a team of Weill Cornell Medical College researchers are recommending the nation's health care leaders and medical community join forces to establish evidence-based appropriateness criteria to determine which patients are most in need of elective procedures, such as joint replacement surgery, to slow the projected surge in demand and rising costs. Currently, there are no appropriateness criteria for most of the common elective procedures.

Total joint replacement surgeries -- such as hip and knee replacements -- are among the most common inpatient surgeries in the United States and are used as a prime example of elective surgeries that could benefit from implementing appropriateness criteria. Patients requesting joint replacement surgery vary from those disabled by their joint arthritis to those who do so to maintain an active lifestyle without pain. Total joint replacement surgeries are expected to quadruple over the next two decades in the United States, contributing to the rise in health care costs and increasing the risk of medical complications.

"The purpose behind establishing criteria is to use evidence-based metrics to prioritize patients most in need," says lead author Dr. Hassan M.K. Ghomrawi, assistant professor of public health at Weill Cornell and an outcomes research scientist at Hospital for Special Surgery. "We don't want to sacrifice necessary care when thinking of cost-containment."

There were more than 1 million total joint replacement procedures performed in 2009. Experts predict that the number of these surgeries will grow drastically, exceeding 4 million by 2030, with more than half the patients younger than 65. The growing obesity epidemic, coupled with an aging population, is projected to fuel increased demand for total joint replacement surgery. These projections don't reflect the increase in the number of patients who will gain health insurance coverage under federal health care reform when the Affordable Care Act is fully implemented in 2014.

Current cost-containment proposals focus primarily on payment reforms, such as pay-for-performance and bundled payments. But in their perspective, titled "Appropriateness Criteria and Elective Procedures -- Total Joint Arthroplasty," the authors posit that developing and implementing evidence-supported criteria that identifies the appropriate patients who are most likely to benefit from surgery will also slow the growing costs of these procedures.

"Identifying patients who are likely to benefit the most from these procedures could help to combat increasing health care costs while enhancing access and quality," says senior author Dr. Alvin I. Mushlin, the Nanette Laitman Distinguished Professor and chairman of the Department of Public Health and professor of medicine at Weill Cornell and public health physician-in-chief at NewYork-Presbyterian Hospital/Weill Cornell Medical Center. "We believe that the case of total joint arthroplasty offers a prime example of the opportunities and challenges for appropriateness criteria."

"Although implementing appropriateness criteria for total joint arthroplasty has not succeeded in the past, there are reasons why it is more likely to work now," says co-author Dr. Bruce R. Schackman, chief of the Division of Health Policy and associate professor of public health at Weill Cornell. "Opinion leaders in the U.S. orthopedics community recognize the importance of such criteria, and health information technology has developed to allow more sophisticated appropriateness criteria to be integrated into decision-support tools."

According to the researchers, criteria will enable physicians to determine which patients' surgeries are medically necessary, which ones are elective, and which ones are inappropriate, and then tie reimbursement to the analysis. Procedures deemed truly inappropriate would then not be reimbursed by health insurers. The researchers believe this would decrease the number of inappropriate procedures performed, as only a minority of patients would be willing or able to pay out of pocket for them. A secondary, but just as important, result of appropriateness criteria is the potential to enhance the overall quality of care by increasing access to the procedure for those most in need and by preventing complications that might have occurred in operations that were inappropriate to begin with.

In order for the criteria to be successful and credible to physicians and patients and not limit necessary care, clinical opinion leaders and patient representatives must be involved in developing the guidelines, the researchers say. Also, although integrating appropriateness criteria into the reimbursement and care delivery systems could help "bend the cost curve," achieving savings will depend on acceptance of the criteria by physicians and patients. The researchers believe criteria generated for total joint replacement surgery could lead the way for other elective procedures, reducing their cost and enhancing quality of care.

"Evidence-based criteria, if applied wisely and fairly, may be the most powerful tool for controlling the cost and enhancing the quality of elective procedures," says Dr. Ghomrawi.

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Hassan M.K. Ghomrawi, Bruce R. Schackman, Alvin I. Mushlin. Appropriateness Criteria and Elective Procedures — Total Joint Arthroplasty. New England Journal of Medicine, 2012; 367 (26): 2467 DOI: 10.1056/NEJMp1209998

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Genetic clues to insulin production: Genomic analysis method helps track genetic contributors relevant to diabetes

Dec. 23, 2012 — In research published online Dec. 23, 2012 in the journal Nature Genetics, scientists have found three new and relatively rare genetic variants that influence insulin production, offering new clues about the genetic factors behind diabetes.

"Studying genetic variants -- even rare ones -- helps us learn how genes affect health and disease," said Karen Mohlke, PhD, one of the study's senior authors and associate professor of genetics at the University of North Carolina School of Medicine. "In this study, we've implicated new genes as playing a role in insulin processing and secretion."

The study is also the first time genetic insights have been reported using exome array genotyping, a new tool that is less costly than genetic sequencing. This analysis allows scientists to quickly screen DNA samples for known variants in specific genes. It is especially helpful for testing variants that are rare.

"The exome array allowed us to test a large number of individuals -- in this case, more than 8,000 people -- very efficiently," said Mohlke. "We expect that this type of analysis will be useful for finding low-frequency variants associated with many complex traits, including obesity or cancer."

The scientists pulled data from a large health study directed by researchers at the University of Eastern Finland. A research team including postdoctoral scientist Jeroen Huyghe at the University of Michigan, Ann Arbor led the statistical analysis, which integrated genetic data and detailed health records for a sample of 8,229 Finnish males.

Diabetes, which affects more than 25 million people in the United States, results from problems with the body's ability to produce or use insulin. Rather than pinpointing one gene behind the disease, scientists believe there are a whole host of genes that interact with health and lifestyle factors to influence a person's chances of getting the disease.

The study revealed that certain variants of three genes -- called TBC1D30, KANK1 and PAM -- are associated with abnormal insulin production or processing, even in people without diabetes. The genes may predispose such individuals to developing the disease.

As a next step, the researchers plan to continue to investigate how these genes may lead to diabetes. They also expect the results will inspire other scientists to use exome analysis to look at the genetic factors behind other complex diseases.

In addition to Mohlke, the study's co-Principal Investigators included Michael Boehnke, PhD, of the University of Michigan, Ann Arbor and Markku Laakso, MD, of the University of Eastern Finland and Kuopio University Hospital.

In the U.S., funding for the research came from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and the National Human Genome Research Institute (NHGRI), components of the National Institutes of Health.

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The above story is reprinted from materials provided by University of North Carolina School of Medicine, via Newswise.

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Jeroen R Huyghe, Anne U Jackson, Marie P Fogarty, Martin L Buchkovich, Alena Stancáková, Heather M Stringham, Xueling Sim, Lingyao Yang, Christian Fuchsberger, Henna Cederberg, Peter S Chines, Tanya M Teslovich, Jane M Romm, Hua Ling, Ivy McMullen, Roxann Ingersoll, Elizabeth W Pugh, Kimberly F Doheny, Benjamin M Neale, Mark J Daly, Johanna Kuusisto, Laura J Scott, Hyun Min Kang, Francis S Collins, Gonçalo R Abecasis, Richard M Watanabe, Michael Boehnke, Markku Laakso, Karen L Mohlke. Exome array analysis identifies new loci and low-frequency variants influencing insulin processing and secretion. Nature Genetics, 2012; DOI: 10.1038/ng.2507

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US cancer screening rates decline over the last 10 years, finds new study

Dec. 27, 2012 — The rate of people who seek preventive cancer screenings has fallen over the last ten years in the United States with wide variations between white-collar and blue-collar workers, according to a University of Miami Miller School of Medicine study published on December 27 in the open-access journal Frontiers in Cancer Epidemiology.

While earlier diagnoses and improved treatments have increased the number of survivors, cancer remains one of the most prominent chronic diseases and, last year alone, claimed the lives of more than 570,000 people in the U.S.

"There is a great need for increased cancer prevention efforts in the U.S., especially for screening as it is considered one of the most important preventive behaviors and helps decrease the burden of this disease on society in terms of quality of life, the number of lives lost and insurance costs," said lead author Tainya Clarke, M.P.H., research associate in the Department of Epidemiology and Public Health.

"But despite this," Clarke continued, "our research has shown that adherence rates for cancer screenings have generally declined with severe implications for the health outlook of our society."

For their NIH-funded study, Clarke and her team evaluated the cancer screening behaviors of the general public and cancer survivors to see if government-recommended screenings goals were achieved.

The study looked at cancer screening adherence rates for colorectal, breast, cervical and prostate cancers and compared the screening rates among the general public to all cancer survivors and to the subpopulation of employed survivors.

Results showed that the general public did not meet government recommendations for cancer screenings for any cancer types except colorectal cancer. About 54 percent of the general public underwent colorectal screenings, exceeding the 50 percent goal of the government's "Healthy People 2010" national health promotion and disease prevention initiative.

By contrast, cancer survivors, who are at an increased risk of developing the disease, had higher screening rates and underwent the recommended cancer screenings for all types except cervical cancer, which decreased to 78 percent over the last decade. The study also showed a decline among cancers survivors who sought cancer screenings over the last three years.

The researchers used the recommended cancer screening rates set by the U.S. Department of Health and Human Services and looked at data from the National Health Interview Survey between 1997 and 2010. In total, 174,393 people were included in the study analysis, with 7,528 employed cancer survivors and 119,374 people representing the general population.

In addition, the study showed that among survivors, white collar workers had higher screening rates than blue collar workers -- a crucial discovery that Clarke hopes will help change current job-related policies and overcome disparities within different professions of working cancer survivors.

The researchers speculated that ongoing disagreements among the United States Preventive Services Task Force, American Cancer Society and others over screening guidelines, as well as the decrease in worker insurance rates over the decade may have influenced the decline in screening rates.

Clarke hopes that more comprehensive research will assess the combined factors affecting screening rates and lead to more effective workplace interventions and increase screening within each occupational sector.

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Tainya C. Clarke, Hosanna Soler-Vila, Lora E. Fleming, Sharon L. Christ, David J. Lee, Kristopher L. Arheart. Trends in Adherence to Recommended Cancer Screening: The US Population and Working Cancer Survivors. Frontiers in Oncology, 2012; 2 DOI: 10.3389/fonc.2012.00190

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Genetic differences may influence sensitivity to pain, according to new study

Dec. 20, 2012 — The study, published in PLOS Genetics on 20 December, adds to growing evidence that particular genes are involved in chronic pain and highlights this pathway as a potential target for more effective pain relief treatments for patients.

The collaborative study between King's, Pfizer Ltd and the Beijing Genomics Institute (BGI), used a new method to study and compare DNA, called 'exome sequencing', to identify genetic variations relating to pain sensitivity.

Lead author Dr Frances Williams, from the Department of Twin Research and Genetic Epidemiology at King's College London said: 'Chronic pain is a significant personal and socio-economic burden, with nearly one in five people experiencing it at some time in their lives. Current pain treatments often have either limited efficacy or side effects for many, so the possibility of a new approach to pain relief is an exciting development.

It is known that people who are most sensitive to pain encountered in everyday life are more likely to go on to develop chronic pain. To identify sensitivity levels, researchers tested 2,500 volunteers using a heating probe on the arm. Volunteers were asked to press a button when the heat became painful for them, which allowed the scientists to determine individuals' pain thresholds. Exome sequencing was then used to analyse the DNA of 200 of the most pain sensitive and 200 of the least pain sensitive people.

Xin Jin, project manager from BGI, said: 'More and more evidence supports our theory that rare variants, which were overlooked in genome-wide association study, play a very important role in complex diseases and traits. The next generation of sequencing will make it possible to explore these rare variants and will lead to a wave of new discoveries in biomedical research.'

The results showed different patterns of genetic variants in each group -- the pain sensitive people had less variation in their DNA than those who were pain insensitive. Serena Scollen, Geneticist from Pfizer and co-author on the work said: 'Further studies are needed to understand fully the genetics that underlie pain sensitivity in humans, but early studies in this area are promising.'

Ruth McKernan, Chief Scientific Officer of Pfizer's Research Unit in Cambridge that works on new pain drugs said: 'This study demonstrates the value of collaborative efforts between academia and industry. The genetic influence on normal pain processing in human volunteer populations will add to other approaches and help us prioritise potential new mechanisms for treating pain.'

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Frances M. K. Williams, Serena Scollen, Dandan Cao, Yasin Memari, Craig L. Hyde, Baohong Zhang, Benjamin Sidders, Daniel Ziemek, Yujian Shi, Juliette Harris, Ian Harrow, Brian Dougherty, Anders Malarstig, Robert McEwen, Joel C. Stephens, Ketan Patel, Cristina Menni, So-Youn Shin, Dylan Hodgkiss, Gabriela Surdulescu, Wen He, Xin Jin, Stephen B. McMahon, Nicole Soranzo, Sally John, Jun Wang, Tim D. Spector. Genes Contributing to Pain Sensitivity in the Normal Population: An Exome Sequencing Study. PLoS Genetics, 2012; 8 (12): e1003095 DOI: 10.1371/journal.pgen.1003095

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Scientists discover new diagnostic markers for Kawasaki disease

Dec. 18, 2012 — Researchers have discovered proteins in human urine that offer new opportunities for the diagnosis, study and maybe even the treatment of Kawasaki disease. Mass spectrometry-based proteomic analysis of the human urine proteome, the entire set of proteins found in human urine, uncovered molecular markers that offer significant improvements for the diagnosis of the disease.

The results are reported in a new study published in EMBO Molecular Medicine.

"There is no diagnostic test for Kawasaki disease. Currently available diagnostic markers lack the specificity and sensitivity needed for reliable detection of the disease which has motivated our decision to use proteomics to identify new, improved biomarkers," said Susan Kim, a rheumatologist at Boston Children's Hospital and an instructor at Harvard Medical School. "Kawasaki disease is often difficult to diagnose and is the most prevalent cause of acquired childhood heart disease in the developed world. Failure to detect it can lead to coronary artery aneurysms and in some cases death, particularly in children who are not diagnosed early enough or when the diagnosis is not considered and acted upon due to the presence of only some of the classic symptoms."

Kawasaki disease can occur at any age but is most commonly found in children under the age of five years. The disease appears to influence the immune system in such a way that it attacks its own tissues. This leads to inflammation that can damage blood vessels, most notably around the heart. If untreated, Kawasaki disease leads to coronary artery aneurysms in up to 25% of cases.

The researchers used highly sensitive mass spectrometry techniques to profile the proteome of urine samples collected from children who had symptoms of Kawasaki disease. Several molecules were discovered that were exclusively present in the urine of patients with the disease. In particular, elevated levels of filamin C and meprin A were detected in both human blood and urine samples and show considerable potential for use as diagnostics.

Filamin C is a protein that helps maintain the structural integrity of heart and skeletal muscle. Meprin A is an enzyme that breaks down proteins and which is known to regulate the activities of other proteins linked to inflammation. Both of these markers could be used to identify patients with Kawasaki disease accurately using tests that are readily amenable for routine medical use.

"The urine proteome consists of thousands of protein molecules. Patients with Kawasaki disease have a unique urinary proteome that is distinct from the proteome observed for children with other causes of fever," remarked Hanno Steen, director of the Proteomics Center at Boston Children's Hospital and associate professor at Harvard Medical School. "In a group of 107 patients, we were able to distinguish children with Kawasaki disease from those with mimicking conditions much more reliably and accurately than currently available testing by measuring their levels of meprin A and filamin C in urine." The researchers note that further validation of the diagnostic markers is needed and this work is in progress.

The researchers suggest that the development of clinical tests using these new markers may improve the accuracy of diagnosis of children with suspected Kawasaki disease and assist in the development of new treatments. For this purpose, the scientists have made the analyzed proteomes openly available at the Peptide Atlas (www.peptideatlas.org).

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Alex Kentsis, Andrew Shulman, Saima Ahmed, Eileen Brennan, Michael C. Monuteaux, Young-Ho Lee, Susan Lipsett, Joao A. Paulo, Fatma Dedeoglu, Robert Fuhlbrigge, Richard Bachur, Gary Bradwin, Moshe Arditi, Robert P. Sundel, Jane W. Newburger, Hanno Steen, Susan Kim. Urine proteomics for discovery of improved diagnostic markers of Kawasaki disease. EMBO Molecular Medicine, 2012; DOI: 10.1002/emmm.201201494

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Game-changing diagnostic and prognostic prostate cancer genetic tests developed

Dec. 20, 2012 — Researchers at the Kimmel Cancer Center at Jefferson (KCC) have developed potentially game-changing diagnostic and prognostic genetic tests shown to better predict prostate cancer survival outcomes and distinguish clinically-relevant cancers.

The team, led by Richard G. Pestell, M.D., Ph.D., Director of the KCC and the Chair of the Department of Cancer Biology at Thomas Jefferson University, report their preclinical findings from a blinded, retrospective analysis of over 350 patients and mouse study in a recent issue of the journal of Cancer Research.

Using an oncogene-specific prostate cancer molecular signature, the researchers were able to separate out men who died of prostate cancer versus those who lived, and more specifically, identifying men who died on average after 30 months (recurrence free survival). The diagnostic test distinguished patients with clinically relevant prostate cancer from normal prostate in men with elevated prostate-specific antigen (PSA) levels.

The researchers worked with three oncogenes previously associated with poorer outcomes in prostate cancer: c-Myc , Ha-Ras, and v-Src.

The test, the researchers say, is superior to several previously published gene tests and to the Gleason scale, which is a rating given to prostate cancer based upon its microscopic appearance and currently used to help evaluate the prognosis of men with the disease.

Given the diversity of prostate cancer outcomes -- some men live two years after diagnosis, others live for more than 20 more years -- a new oncogene-specific signature like this could not only help better identify prostate cancer risk but also test targeted therapies -- by way of a new prostate cancer cell line.

These studies describe the first isogenic prostate cancer cell lines that metastasize reliably in immune competent mice. Previous studies were in immune deficient mice.

"This oncogene signature shows further value over current biomarkers of prediction and outcomes," said Dr. Pestell. "Such a signature and cell line may also enable the identification of targets for therapies to better treat prostate cancer, which takes the lives of over 27,000 men a year."

In breast cancer, the identification of tumor subsets with various gene signatures has improved clinical care for patients because of targeted therapies.

The work here by the KCC aims to identify gene patterns and subsequent tests in prostate cancer that could serve similar purposes. But to help develop such therapies, model systems that closely resemble human disease are required. To date, there have been several limitations with currently available cell lines.

Although important transplantation experiments have been conducted using human prostate cancer cell lines in immune deficient animals, the immune system plays an important role in prostate cancer onset and progression making it imperative to develop prostate cancer cell lines that can be studied in immune competent animals.

Also, although the transgenic mouse has been an effective model to study the molecular basis of human cancers, the prostate cancer mouse models have long latency and often unpredictable metastasis.

Here, the researchers succeeded in overcoming these issues.

The oncogene-specific prostate cancer molecular signatures were recapitulated in human prostate cancer and validated in distinct populations of patients as a prognostic and diagnostic test.

What's more, the researchers demonstrated how the isogenic prostate cancer cell lines metastasized in immune-competent mice.

"Identification of gene signatures in breast cancer has allowed for a deeper understanding of the disease, and this paper moves us steps closer to being able to follow a similar trajectory with prostate cancer. Today, such an understanding and a formidable testing ground for new therapies is lacking for this disease," Dr. Pestell said. "With this new oncogene-specific prostate cancer molecular signature, we have a valuable prognostic and diagnostic resource that could help change the way we manage and treat prostate cancer."

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X. Ju, A. Ertel, M. Casimiro, Z. Yu, H. Meng, P. A. McCue, R. Walters, P. Fortina, M. P. Lisanti, R. G. Pestell. Novel Oncogene Induced Metastatic Prostate Cancer Cell Lines Define Human Prostate Cancer Progression Signatures. Cancer Research, 2012; DOI: 10.1158/0008-5472.CAN-12-2133

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Diabetes, blood pressure link to colon cancer recurrence, survival, research shows

Dec. 20, 2012 — By all accounts, a combination of colon cancer, diabetes and high blood pressure can be a recipe for medical disaster. Now, a new study led by a surgical oncologist and researcher at Temple University School of Medicine and Fox Chase Cancer Center has shown just how deadly this mix can be. In a retrospective analysis of more than 36,000 patients with colon cancer, investigators showed that those with early stage disease and diabetes or high blood pressure -- two components of metabolic syndrome -- have a greater risk for the cancer returning after treatment and of dying compared to patients with colon cancer who do not have either condition.

"Although metabolic syndrome has been linked to colon cancer, the third leading cause of cancer death in the U.S., previous work looking at its effect on mortality has not adequately accounted for cancer stage or treatment," said senior author Nestor Esnaola, MD, MPH, MBA, Chief of the Division of Surgical Oncology, Professor of Surgery, and Vice-Chair of Clinical and Academic Affairs in the Department of Surgery at Temple University School of Medicine. "Our results suggest that patients with early stage colon cancer who also have diabetes or hypertension may need to be followed more closely for recurrence and could potentially benefit from broader use of adjuvant chemotherapy." Dr. Esnaola and his team reported their findings December 20, 2012 in an early online publication in the journal Cancer.

Metabolic syndrome is a cluster of conditions that affects one in five American adults and which can include diabetes, obesity, high blood pressure, low levels of good cholesterol and high amounts of lipids in the blood.

To better understand the effect of metabolic syndrome on colon cancer outcomes, Dr. Esnaola and his team linked data from the National Cancer Institute's Surveillance, Epidemiology and End Results (SEER) program, a large population-based database, to Medicare data from 1998 to 2006 on 36,079 patients with colon cancer, including 7,024 patients (19.5 percent) who were identified as having metabolic syndrome. They analyzed the effect of metabolic syndrome and its components on colon cancer recurrence and overall survival, controlling for various sociodemographic factors, tumor factors, other medical conditions and cancer treatment received.

"Metabolic syndrome as a whole had no apparent effect on colon cancer recurrence or survival," said Dr. Esnaola, who is also an attending surgeon at Fox Chase Cancer Center. "When we teased out and analyzed the effect of each of its components, however, the data told a different story."

The researchers found that among patients with early stage disease, patients with diabetes or high blood pressure had a significantly greater risk of cancer recurrence rate and death after treatment. For example, 47.7 percent of patients who did not have diabetes were still alive five years after diagnosis compared to only 41.3 percent of patients with diabetes. When the researchers looked more closely, they also found that cancer recurrence rates at five years were approximately 8 percent higher in patients with diabetes or hypertension.

In contrast, the analysis showed that patients with abnormally high levels of lipids in the blood had a lower risk of recurrence and death from colon cancer. Overall, 39 percent of patients with normal lipid levels were still alive after five years, compared to 52.7 percent of patients with abnormal levels. Cancer recurrence rates were approximately 11 percentage points lower in patients with abnormal lipid levels.

"Although we did not have data on medication for these patients, we suspect that the higher survival and lower recurrence rates observed in patients with high lipid levels in our study group were likely due to the protective effects of statins," Dr. Esnaola said. Statins are drugs that are widely used to lower cholesterol and lipid levels and have been shown to lower the risk of developing colon cancer in people.

"To our knowledge, this is the largest study to date controlling for cancer stage and treatment that has analyzed the effect of metabolic syndrome and its components on colon cancer recurrence and survival," said Dr. Esnaola. "The adverse effects of diabetes and hypertension in early stage patients and apparent protective effect of high blood lipids observed in our cohort suggest that when it comes to metabolic syndrome and cancer outcomes, the devil is in the details."

Dr. Esnaola currently is investigating the effect of metabolic syndrome and its components on other cancer types, and plans to confirm these results in a larger set of data that contains information on cancer stage, treatment and medication. "In the interim, our results underscore the need for clinical trials to define the true benefits of (the diabetes drug) metformin and statins in patients with early stage colon cancer," he said.

Other investigators contributing to this research include: Yang Yang and Baorui Liu, Comprehensive Cancer Center of Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China; and Patrick D. Mauldin, Myla Ebeling, Thomas C. Hulsey, Melanie B. Thomas, and E. Ramsey Camp, Medical University of South Carolina, Charleston.

This research was supported in part by the Nanjing Drum Tower Hospital Health, Education, and Research Foundation.

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Yang Yang, Patrick D. Mauldin, Myla Ebeling, Thomas C. Hulsey, Baorui Liu, Melanie B. Thomas, Ernest R. Camp and Nestor F. Esnaola. Effect of metabolic syndrome and its components on recurrence and survival in colon cancer patients. Cancer, 2012; DOI: 10.1002/cncr.27923

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New insights into how immune system fights atherosclerosis

Dec. 21, 2012 — A study led by Columbia University Medical Center (CUMC) researchers has found that an important branch of the immune system, in reaction to the development of atherosclerotic lesions, mounts a surprisingly robust anti-inflammatory T cell response that helps prevent the disease from progressing. The findings may help inform the design of anti-atherosclerosis vaccines and other therapies that can take advantage of this aspect of the immune system. The study was published December 21 in the online edition of the Journal of Clinical Investigation.

When the body encounters viruses, bacteria, or other potential threats, dendritic cells -- the sentinels of the immune system -- are dispatched to take a sample of the pathogen and present it to T cells. This activates the production of pro-inflammatory effector T cells (which attack the pathogen) and anti-inflammatory regulatory T cells (which keep the pro-inflammatory response in check).

"Normally, the pro-inflammatory response dominates, and that is what people assumed to be the case in atherosclerosis," said study leader Ira Tabas, MD, PhD, the Richard J. Stock Professor, Department of Medicine, and professor of pathology & cell biology (in physiology and cellular biophysics) at CUMC. "However, we found that the T cell response to atherosclerosis is mostly anti-inflammatory."

The researchers, led by postdoctoral scientist Manikandan Subramanian, PhD, used mice whose dendritic cells lacked MYD88, a signaling protein that initiates the cells' maturation. Since immature dendritic cells cannot activate T cells, the elimination of MYD88 effectively disabled the production of both effector and regulatory T cells. The mice were also bred to lack the LDL receptor, leaving them prone to the development of atherosclerosis.

The net effect of these changes in the mice was to increase the size of atherosclerotic lesions. "What this means is that the dominant effect of dendritic cells in the setting of atherosclerosis is to promote the development of protective regulatory T cells," said Dr. Tabas.

Earlier studies had suggested just the opposite: that effector T cells dominate in response to atherosclerosis. "In those studies, researchers disabled dendritic cells at an earlier stage, creating all sorts of compensatory processes," said Dr. Tabas. "That's probably why they came to a different conclusion. In our model, we were able to knock out only the step involved in activating T cells, leaving everything else alone."

The researchers found that T regulatory cells act by suppressing pro-inflammatory effector T cells and macrophages, which was expected. They also identified a new mechanism that directly links regulatory-T-cell activation with protection from atherosclerosis. According to Dr. Tabas, regulatory T cells secrete TGF-beta (a cytokine, or signaling molecule), which suppresses MCP-1 (monocyte chemoattractant protein-1), a protein that recruits monocytes, a type of white blood cell.

"Now we have a specific mechanism that could explain the preclinical success of dendritic vaccines and that provides a new understanding of how these vaccines might be improved," said Dr. Tabas.

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Manikandan Subramanian, Edward Thorp, Goran K. Hansson, Ira Tabas. Treg-mediated suppression of atherosclerosis requires MYD88 signaling in DCs. Journal of Clinical Investigation, 2012; DOI: 10.1172/JCI64617

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Liver mitochondria improve, increase after chronic alcohol feeding in mice

Dec. 20, 2012 — Scientists at the Keck School of Medicine of USC have found evidence that liver mitochondria in mice adapt to become better metabolizers of alcohol and increase in number after chronic exposure, which may raise the potential for free radical damage associated with aging and cancer over time.

The liver is a vital organ, playing a major role in metabolism and detoxification in the body. Overconsumption of alcohol has long been tied to liver diseases such as fatty liver, alcoholic hepatitis and cirrhosis, but how the substance damages the organ is not fully understood. USC research published in the Dec. 7, 2012, issue of the Journal of Biological Chemistry, a peer-reviewed scientific journal, suggests that mitochondria play an important role in the liver's response to the metabolic stress caused by alcohol intake. If scientists observe the same results in human mitochondria, it could help pinpoint targets for therapy.

"The liver has to adapt quickly to various toxins and drugs to meet the demands we place on the body," said Derick Han, Ph.D., assistant professor of research medicine at the Keck School of Medicine of USC and first author of the study. "We've found that mitochondrial plasticity -- the mitochondria's ability to change -- is probably central to the liver's response to alcohol intake. This gives us a better understanding of how the liver works and how it adapts to stress."

Mitochondria are cellular organelles that generate most of the cell's energy; they have been implicated in certain neurological disorders and have been tied to aging. The metabolism of oxygen by the mitochondria normally generates reactive oxygen species, or free radicals, which in excess can be highly damaging to cells.

"In the short term, it looks like mitochondria adapt to metabolize alcohol better, but as they increase in number and use more oxygen to help metabolize that alcohol, it could be harmful to the body," Han said.

Han and his team of scientists fed alcohol to mice over four weeks, isolated the liver mitochondria and measured levels of respiration and changes in the mitochondrial structure. They found significant increases in oxygen consumption by mice fed the alcohol in comparison to control mitochondria as early as one week after feeding. Changes were greater and more extensive with higher alcohol intake.

USC co-authors include Maria Ybanez, Heather Johnson, Jeniece McDonald, Lusine Mesropyan, Harsh Sancheti, Lily Dara and Enrique Cadenas. The study's senior investigators include Hidekazu Tsukamoto, director of the Southern California Research Center for Alcoholic Liver and Pancreatic Diseases (ALPD) and Cirrhosis, and Neil Kaplowitz, director of the USC Research Center for Liver Diseases. The study was supported by the National Institute on Alcohol Abuse and Alcoholism of the National Institutes of Health (grants AA016911, AA14428, and AA011999).

A team led by Kaplowitz is set to launch a four-year clinical trial in 2013 to study two potential new treatments for alcoholic hepatitis. Han hopes to collect data from that trial to further examine mitochondrial function in human livers exposed to alcohol.

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The above story is reprinted from materials provided by University of Southern California - Health Sciences. The original article was written by Alison Trinidad.

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D. Han, M. D. Ybanez, H. S. Johnson, J. N. McDonald, L. Mesropyan, H. Sancheti, G. Martin, A. Martin, A. M. Lim, L. Dara, E. Cadenas, H. Tsukamoto, N. Kaplowitz. Dynamic Adaptation of Liver Mitochondria to Chronic Alcohol Feeding in Mice: Biogenesis, Remodeling, and Functional Alterations. Journal of Biological Chemistry, 2012; 287 (50): 42165 DOI: 10.1074/jbc.M112.377374

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Protein kinase Akt identified as arbiter of cancer stem cell fate

Dec. 20, 2012 — The protein kinase Akt is a key regulator of cell growth, proliferation, metabolism, survival, and death. New work on Akt's role in cancer stem cell biology from the lab of senior author Honglin Zhou, MD, PhD and Weihua Li, co-first author, both from the Center for Resuscitation Sciences, Department of Emergency Medicine, Perelman School of Medicine, University of Pennsylvania, and Xiaowei Xu, Department of Pathology and Laboratory Medicine, appears in Molecular Cell.

The findings were also highlighted in Nature and Science reviews.

This new research shows that Akt may be the key as to why cancer stem cells are so hard for the body to get rid of. It has been documented that frequent hyperactivation of Akt kinases occurs in many types of human solid tumors and blood malignancies. Prior to this work, Akt was also shown to play a pivotal role in the fate of other types of stem cells, though those cellular mechanisms are still unclear.

"When I came to Penn in 2009, my lab first found that Akt regulates the activity of the protein Oct4," explains Zhou. Oct4 is one of the four transcriptional factors used to generate induced pluripotent stem cells, or iPS cells. In 2006, Kyoto University researcher and Nobel Prize winner Shinya Yamanaka expressed four proteins -- Oct 4 was one of the -- in mouse somatic cells to rewind their genetic clocks, converting them into embryonic-like iPS cells.

The biochemical experiments outlined in the Molecular Cell paper confirmed that Oct4 interacts directly with Akt and the adding of phosphate molecules to Oct4 by Akt regulates its stability, where it localizes in a cell, and its effect on gene expression. Akt phosphorylating Oct4 has the effect of making Oct4 migrate into the nucleus, where it interacts with other transcription factors and regulates target genes transcription.

The findings were further extended into embryonal carcinoma cells, which are derived from teratocarcinomas and often considered the malignant counterparts to embryonic stem cells (ESCs). The team showed that embryonal carcinoma cells with deregulated Akt activation and more phosphorylated Oct4 are more resistant to cell death signals such as ultraviolet irradiation and high glucose treatment.

Since Akt activation is often deregulated in cancer and Oct4 expression is upregulated in cancer stem cells of various types of cancer, the researchers are studying whether the Akt/Oct4 pathway plays similar roles in other types of cancer stem cells in addition to embryonal carcinoma cells. If true, Akt inhibitor may be developed as a new drug for killing cancer stem cells in cancer therapy.

The Molecular Cell work was been done in collaboration with Binghui Shen and Yingjie Wang from Zejiang University in China.

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Yuanji Lin, Ying Yang, Weihua Li, Qi Chen, Jie Li, Xiao Pan, Lina Zhou, Changwei Liu, Chunsong Chen, Jianqin He, Hongcui Cao, Hangping Yao, Li Zheng, Xiaowei Xu, Zongping Xia, Jiangtao Ren, Lei Xiao, Lanjuan Li, Binghui Shen, Honglin Zhou, Ying-Jie Wang. Reciprocal Regulation of Akt and Oct4 Promotes the Self-Renewal and Survival of Embryonal Carcinoma Cells. Molecular Cell, 2012; 48 (4): 627 DOI: 10.1016/j.molcel.2012.08.030Felix Cheung. Stem cells: Caught in the act. Nature China, 2012; DOI: 10.1038/nchina.2012.74E. Andrianantoandro. Oct4 Connects Akt to Cancerous Stem Cells. Science Signaling, 2012; 5 (253): ec310 DOI: 10.1126/scisignal.2003837

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Two novel treatments for retinitis pigmentosa move closer to clinical trials

Dec. 20, 2012 — Two recent experimental treatments -- one involving skin-derived induced pluripotent stem (iPS) cell grafts, the other gene therapy -- have been shown to produce long-term improvement in visual function in mouse models of retinitis pigmentosa (RP), according to the Columbia University Medical Center (CUMC) scientists who led the studies. At present, there is no cure for RP, the most common form of inherited blindness.

"While these therapies still need to be refined, the results are highly encouraging," said Stephen H. Tsang, MD, PhD, associate professor of pathology & cell biology and of ophthalmology at Columbia University Medical Center and an ophthalmologist at NewYork-Presbyterian Hospital/CUMC, the leader of both studies. "We've never seen this type of improvement in retinal function in mouse models of RP. We hope we may finally have something to offer patients with this form of vision loss."

The stem cell study was published in the journal Molecular Medicine. The gene therapy study was published in Human Molecular Genetics.

RP encompasses a group of inherited eye diseases that cause progressive loss of photoreceptor cells, specialized neurons found in the retina. While RP can appear during infancy, the first symptoms typically appear in early adulthood, beginning with night blindness. As the disease progresses, affected individuals lose peripheral vision. In later stages, RP destroys photoreceptors in the macula, which is responsible for fine central vision. Mutations in at least 50 genes have been found to cause the disease, which affects about 1.5 million people worldwide.

In the Molecular Medicine study, the CUMC researchers tested the long-term safety and efficacy of using iPS cell grafts to restore visual function in a mouse model of RP. Like embryonic stem cells, iPS cells are "pluripotent" -- that is, they are capable of developing into any cell type. However, iPS cells are not derived from embryos but from adult cells, in this case from human skin cells. The cells were administered, via injection directly underneath the retina, when the mice were five days old.

The iPS cells assimilated into the host retina without disruption, and none of the mice receiving transplants developed tumors over their lifetimes, the researchers reported. The iPS cells were found to express markers specific to retinal pigmented epithelium (the cell layer adjacent to the photoreceptor layer), showing that they had the potential to develop into functional retinal cells. Using electroretinography, a standard method for measuring retinal function, the researchers found that the visual function of the mice improved after treatment and the effect was long lasting. "This is the first evidence of lifelong neuronal recovery in an animal model using stem cell transplants, with vision improvement persisting throughout the lifespan," said Dr. Tsang.

In 2011, the FDA approved clinical trials of embryonic stem cell transplants for the treatment of macular degenerations, but such therapy requires immunosuppression. "Our study focused on patient-specific iPS cells, which offer a compelling alternative," said Dr. Tsang. "The iPS cells can provide a potentially unlimited supply of cells for functional rescue and optimization. Also, since they would come from the patient's own body, immunosuppression would not be necessary to prevent rejection after transplantation."

In theory, iPS cell transplants could also be used to treat age-related macular degeneration, the leading cause of vision loss among older adults, said Dr. Tsang.

In the Human Molecular Genetics study, the CUMC researchers tested whether gene therapy could be used to improve photoreceptor survival and neuronal function in mice with RP caused by a mutation to a gene called phosphodiesterase-alpha (Pde6a) -- a common form of the disease in humans. To treat the mice, the researchers used adeno-associated viruses (AAV) to ferry correct copies of the gene into the retina. The AAV were administered by a single injection in one eye, with the other eye serving as a control.

When the mice were examined at six months of age (over one-third of the mouse lifespan), photoreceptor cells were found in the treated eyes but not in the untreated eyes, the researchers reported. More important, the treated eyes showed functional visual responses, while the untreated eyes had lost all vision.

"These results provide support that RP due to PDE6a deficiency in humans is also likely to be treatable by gene therapy," said Dr. Tsang.

CUMC and its teaching-hospital affiliate, NewYork-Presbyterian Hospital, are part of an international consortium that was recently formed to bring this PDE6A gene therapy to patients. Pending FDA approval, Phase I/II clinical trials could begin within a year.

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The above story is reprinted from materials provided by Columbia University Medical Center.

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Journal References:

K. J. Wert, R. J. Davis, J. Sancho-Pelluz, P. M. Nishina, S. H. Tsang. Gene therapy provides long-term visual function in a pre-clinical model of retinitis pigmentosa. Human Molecular Genetics, 2012; DOI: 10.1093/hmg/dds466Stephen H. Tsang et al. Stem Cell (iPS) Grafts in a Preclinical Model of Retinitis Pigmentosa. Molecular Medicine, 2012 (in press)

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Preventing prostate cancer through androgen deprivation may have harmful effects

Dec. 20, 2012 — The use of androgen deprivation therapies to prevent precancerous prostate abnormalities developing into aggressive prostate cancer may have adverse effects in men with precancers with specific genetic alterations, according to data from a preclinical study recently published in Cancer Discovery, a journal of the American Association for Cancer Research.

"The growth and survival of prostate cancer cells are very dependent on signals that the cancer cells receive from a group of hormones, called androgens, which includes testosterone," said Thomas R. Roberts, Ph.D., co-chair of the Department of Cancer Biology at the Dana-Farber Cancer Institute and professor of biological chemistry and molecular pharmacology at Harvard Medical School in Boston, Mass.

Previous findings from two major randomized, placebo-controlled prostate cancer chemoprevention trials revealed that androgen deprivation therapy reduced the overall risk for low-grade prostate cancer. However, both trials also revealed a high cumulative risk for high-grade prostate cancers that has caused concern among experts.

High-grade prostatic intraepithelial neoplasia is a prostate abnormality that is considered to be a major precursor to prostate cancer. Loss of the tumor suppressor PTEN is detected in 9 to 45 percent of clinical cases.

Using a mouse model of PTEN-driven high-grade prostatic intraepithelial neoplasia, Roberts and his colleagues investigated whether surgical or chemical androgen deprivation could prevent the cancer precursor from progressing to more aggressive disease.

"When we castrated the animals, we thought the tumors would shrink and they did initially," Roberts said. "However, they then grew back and became invasive."

The results of this preclinical study suggest that prophylactic reduction of the most active form of androgen, or blocking androgen receptor function, might have unintended consequences in some men.

"Stretching our data even further, these findings suggest that as men age and their testosterone levels decrease, loss of testosterone might actually encourage indolent prostate tumors to become more aggressive," Roberts said. "This suggests that testosterone supplements might be a good thing for the prostate, even though current wisdom suggests the opposite."

Roberts noted that these results should be interpreted with caution because the prostate glands of mice are different from their human counterparts. More data on human tumors are needed to evaluate whether the data from this mouse study are applicable to men.

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The above story is reprinted from materials provided by American Association for Cancer Research, via Newswise.

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Shidong Jia, Xueliang Gao, Sang Hyun Lee, Sauveur-Michel Maira, Xiaoqiu Wu, Edward C. Stack, Sabina Signoretti, Massimo Loda, Jean J. Zhao, and Thomas M. Roberts. Opposing Effects of Androgen Deprivation and Targeted Therapy on Prostate Cancer Prevention. Cancer Discovery, 2012; DOI: 10.1158/2159-8290.CD-12-0262

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Cholesterol boosts the memory of the immune system

Dec. 21, 2012 — The memory of the human immune system is critical for the development of vaccines. Only if the body recognizes a pathogen with which it has already come into contact in the case of a second infection, the immune system can combat it more effectively than it did the first time. The Freiburg immunobiologist Prof. Dr. Wolfgang Schamel from the Institute of Biology III of the University of Freiburg and his colleagues have succeeded in demonstrating how the memory of the immune system functions. Their findings have now been published in the journals Immunity and Journal of Biological Chemistry (JBC).

The immune system becomes acquainted with a pathogen during an initial infection and understands that it must be combated. When the T cell receptors of the immune system come across the same pathogen a second time, they are much more sensitive toward them than during the first encounter, and it thus takes less pathogens to activate the immune system. It was previously unclear why the receptors become more sensitive.

In 2011, Schamel's research group and a team led by Prof. Dr. Balbino Alarcon from the Autonomous University of Madrid, Spain, found the answer to this fundamental question. In a publication in the journal Immunity, they showed that the increased sensitivity is caused by a clustering of the T cell receptors: In a naive cell that has not yet met the pathogen, the receptors are arranged individually on the cell membrane, each fending for itself. A large number of receptors thus needs to be confronted by a large number of pathogens in order for the immune system to react. In a so-called memory cell, which remembers the pathogen, the receptors are arranged in groups on the membrane. When a pathogen binds to a receptor from a cluster, all of the receptors within the cluster are activated at once. This makes the immune system more sensitive.

Now, as reported in the journal JBC, a team of researchers in Freiburg under Schamel and Prof. Dr. Rolf Schubert, professor for pharmaceutical technology and biopharmaceutics at the Institute of Pharmaceutical Sciences of the University of Freiburg, have succeeded in demonstrating how a cell forms these receptor clusters. The critical factors for the success of this endeavor were Schamel's expertise in biochemical research on T cell receptors and Schubert's expertise in the production of liposomes. The collaboration between the two teams was made possible by a project funded by BIOSS Centre for Biological Signalling Studies, a Cluster of Excellence at the University of Freiburg.

Dr. Eszter Molnár, a postdoctoral researcher in Schamel's team, and Dr. Martin Holzer from Schubert's research group isolated the receptors and reconstructed them in a synthetic membrane. After one and a half years of work, the scientists achieved a breakthrough: They discovered that the composition of the lipids of a membrane is responsible for the clustering of the receptors. The lipid composition of a naive cell differs from that of a memory cell. Cholesterol is the key factor in this process, as it is present in higher concentrations in a memory cell. This higher concentration of cholesterol leads to the aggregation of receptors, because the cholesterol joins them together like glue.

Schamel and Schubert are members of the Freiburg Cluster of Excellence BIOSS Centre for Biological Signalling Studies. Schamel is also a member of the Spemann Graduate School of Biology and Medicine and the Center for Chronic Immunodeficieny of the Freiburg University Medical Center and director of the EU network SYBILLA, which also supported this project.

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The above story is reprinted from materials provided by Albert-Ludwigs-Universität Freiburg.

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Journal References:

E. Molnar, M. Swamy, M. Holzer, K. Beck-Garcia, R. Worch, C. Thiele, G. Guigas, K. Boye, I. F. Luescher, P. Schwille, R. Schubert, W. W. A. Schamel. Cholesterol and Sphingomyelin Drive Ligand-independent T-cell Antigen Receptor Nanoclustering. Journal of Biological Chemistry, 2012; 287 (51): 42664 DOI: 10.1074/jbc.M112.386045Rashmi Kumar, María Ferez, Mahima Swamy, Ignacio Arechaga, María Teresa Rejas, Jose M. Valpuesta, Wolfgang W.A. Schamel, Balbino Alarcon, Hisse M. van Santen. Increased Sensitivity of Antigen-Experienced T Cells through the Enrichment of Oligomeric T Cell Receptor Complexes. Immunity, 2011; 35 (3): 375 DOI: 10.1016/j.immuni.2011.08.010

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Research offers new targets for stroke treatments

Dec. 20, 2012 — New research from the University of Georgia identifies the mechanisms responsible for regenerating blood vessels in the brain.

Looking for ways to improve outcomes for stroke patients, researchers led by the UGA College of Pharmacy assistant dean for clinical programs Susan Fagan used candesartan, a commonly prescribed medication for lowering blood pressure, to identify specific growth factors in the brain responsible for recovery after a stroke.

The results were published online Dec. 4 in the Journal of Pharmacology and Experimental Therapeutics.

Although candesartan has been shown to protect the brain after a stroke, its use is generally avoided because lowering a person's blood pressure quickly after a stroke can cause problems-like decreasing much-needed oxygen to the brain-during the critical period of time following a stroke.

"The really unique thing we found is that candesartan can increase the secretion of brain derived neurotrophic factor, and the effect is separate from the blood pressure lowering effect," said study coauthor Ahmed Alhusban, who is a doctoral candidate in the College of Pharmacy. "This will support a new area for treatments of stroke and other brain injury."

Alhusban and Fagan worked with Anna Kozak, a research scientist in the college, and Adviye Ergul, a professor and director of the physiology graduate program at Georgia Health Sciences University. They are the first to show that the positive effects of candesartan on brain blood vessel growth are caused by brain derived neurotrophic factor, or BDNF.

The research shows that when candesartan blocks the angiotensin II type 1 receptor, which lowers blood pressure, it stimulates the AT2 receptor and increases the secretion of BDNF, which encourages brain repair through the growth of new blood vessels.

"BDNF is a key player in learning and memory," said Fagan, the Albert W. Jowdy Professor. "A reduction of BDNF in the brain has been associated with Alzheimer's disease and depression, so increasing this growth factor with a common medication is exciting."

AT2 is a brain receptor responsible for angiogenesis, or the growth of new blood vessels from pre-existing vessels. Angiogenesis is a normal and vital process in human growth and development-as well as in healing.

For the study, the investigators used both living rat models and human brain cells. Groups were treated with either a low or high dose of angiotensin II alone or in combination with a dose of candesartan. Candesartan promoted angiogenesis, but this effect was entirely prevented by blocking BDNF or inactivating the AT2 receptor. This method identified the involvement of the AT2 receptor in BDNF secretion.

"This target is a key to enhance recovery and reduce the subsequent disability in stroke victims," said Alhusban. "We know angiogenesis proteins are upregulated in the week after a brain injury. Stimulation of the AT2 receptor with a medication is likely to enhance this part of the brain's own recovery mechanisms."

Medications proven to kick-start BDNF will not only benefit stroke victims but could have a role in other brain injury, particularly veterans with combat-related traumatic brain injuries.

There are currently medications in development activating the AT2 receptor as a mechanism for brain protection, but drug development will take five to 10 years before such a therapy is available to the public.

The research was funded by grants from the National Institutes of Health's National Institute of Neurological Disorders and Stroke and Veterans Affairs Merit Review and a pre-doctoral fellowship from the Jordan University of Science and Technology.

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The above story is reprinted from materials provided by University of Georgia. The original article was written by April Reese Sorrow.

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Journal Reference:

A. Alhusban, A. Kozak, A. Ergul, S. C. Fagan. AT1 receptor antagonism is proangiogenic in the brain: BDNF a novel mediator. Journal of Pharmacology and Experimental Therapeutics, 2012; DOI: 10.1124/jpet.112.197483

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