Space travel may be harmful to the brain, study suggests; Prolonged cosmic radiation exposure could hasten Alzheimer's

Dec. 31, 2012 — As if space travel was not already filled with enough dangers, a new study out today in the journal PLOS ONE shows that cosmic radiation -- which would bombard astronauts on deep space missions to places like Mars -- could accelerate the onset of Alzheimer's disease.

"Galactic cosmic radiation poses a significant threat to future astronauts," said M. Kerry O'Banion, M.D., Ph.D., a professor in the University of Rochester Medical Center (URMC) Department of Neurobiology and Anatomy and the senior author of the study. "The possibility that radiation exposure in space may give rise to health problems such as cancer has long been recognized. However, this study shows for the first time that exposure to radiation levels equivalent to a mission to Mars could produce cognitive problems and speed up changes in the brain that are associated with Alzheimer's disease."

While space is full of radiation, the earth's magnetic field generally protects the planet and people in low earth orbit from these particles. However, once astronauts leave orbit, they are exposed to constant shower of various radioactive particles. With appropriate warning, astronauts can be shielded from dangerous radiation associated with solar flares. But there are also other forms of cosmic radiation that, for all intents and purposes, cannot be effectively blocked.

Because this radiation exists in low levels, the longer an astronaut is in deep space, the greater the exposure. This is a concern for NASA as the agency is planning manned missions to a distant asteroid in 2021 and to Mars in 2035. The round trip to the red planet, in particular, could take as long as three years.

For over 25 years, NASA has been funding research to determine the potential health risks of space travel in an effort to both develop countermeasures and determine whether or not the risks warranted sending men and women on extended missions in deep space.

Since that time, several studies have demonstrated the potential cancer, cardiovascular, and musculoskeletal impact of galactic cosmic radiation. The study out today for the first time examines the potential impact of space radiation on neurodegeneration, in particular, the biological processes in the brain that contribute to the development of Alzheimer's disease. O'Banion -- whose research focuses on how radiation affects the central nervous system -- and his team have been working with NASA for over eight years.

The researchers studied the impact of a particular form of radiation called high-mass, high-charged (HZE) particles. These particles -- which are propelled through space at very high speeds by the force of exploding stars -- come in many different forms. For this study the researcher chose iron particles. Unlikely hydrogen protons, which are produced by solar flares, the mass of HZE particles like iron, combined with their speed, enable them to penetrate solid objects such as the wall and protective shielding of a spacecraft.

"Because iron particles pack a bigger wallop it is extremely difficult from an engineering perspective to effectively shield against them," said O'Banion. "One would have to essentially wrap a spacecraft in a six-foot block of lead or concrete."

A portion of the research was conducted at the NASA Space Radiation Laboratory at Brookhaven National Laboratory on Long Island. NASA located its research operation at Brookhaven to take advantage of the Lab's particle accelerators which -- by colliding matter together at very high speeds -- can reproduce the radioactive particles found in space.

The researchers specifically wanted to examine whether or not radiation exposure had the potential to accelerate the biological and cognitive indicators of Alzheimer's disease, particularly in individuals who may be predisposed to developing the disease. To accomplish this they chose study the impact on animal models of Alzheimer's disease. These particular models have been extensively studied and scientists understand the precise timeframe in which the disease progresses over time.

At Brookhaven, the animals were exposed to various doses of radiation, including levels comparable to what astronauts would be experience during a mission to Mars. Back in Rochester, a team of researchers -- including URMC graduate student Jonathan Cherry, who was first author on the paper -- evaluated the cognitive and biological impact of the exposure. The mice underwent a series of experiments during which they had to recall objects or specific locations. The researchers observed that mice exposed to radiation were far more likely to fail these tasks -- suggesting neurological impairment -- earlier than these symptoms would typically appear.

The brains of the mice also showed signs of vascular alterations and a greater than normal accumulation of beta amyloid, the protein "plaque" that accumulates in the brain and is one of the hallmarks of the disease.

"These findings clearly suggest that exposure to radiation in space has the potential to accelerate the development of Alzheimer's disease," said O'Banion. "This is yet another factor that NASA, which is clearly concerned about the health risks to its astronauts, will need to take into account as it plans future missions."

Additional co-authors include Jacqueline Williams, Ph.D. and John Olschowka, Ph.D. with URMC and Bin Liu, Ph.D., Jeffrey Frost, and Cynthia Lemere, Ph.D. with Harvard Medical School. The study was funded by NASA.

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Jonathan D. Cherry, Bin Liu, Jeffrey L. Frost, Cynthia A. Lemere, Jacqueline P. Williams, John A. Olschowka, M. Kerry O’Banion. Galactic Cosmic Radiation Leads to Cognitive Impairment and Increased Aß Plaque Accumulation in a Mouse Model of Alzheimer’s Disease. PLoS ONE, 2012; 7 (12): e53275 DOI: 10.1371/journal.pone.0053275

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Differences in generic pill characteristics may lead to interruptions in essential medication use

Dec. 31, 2012 — Generic medications currently account for over 70 percent of prescriptions dispensed. However, while generic drugs are clinically bioequivalent to the brand-name version, they often differ in their physical characteristics, such as color and shape. Researchers from Brigham and Women's Hospital (BWH) have found that some patients who receive generic drugs that vary in their color are over 50 percent more likely to stop taking the drug, leading to potentially important and potentially adverse clinical effects.

The study will be published online Dec. 31, 2012 in the Archives of Internal Medicine.

"Pill appearance has long been suspected to be linked to medication adherence, yet this is the first empirical analysis that we know of that directly links pills' physical characteristics to patients' adherence behavior," explained Aaron S. Kesselheim MD, JD, MPH, assistant professor of medicine in the Division of Pharmacoepidemiology and Pharmacoeconomics at BWH, and principal investigator of this study. "We found that changes in pill color significantly increase the odds that patients will stop taking their drugs as prescribed."

The researchers conducted a case-control study of patients taking antiepileptic drugs and compared the odds that patients who did not refill their medication had been given pills that differed in color or shape from the prior prescriptions. Using a large national database of filled prescriptions, when the researchers identified a break in the patient's use of the drug, they looked at the previous two prescription fillings to see if they were the same color and shape. They found that interruptions in the prescription filling occurred significantly more frequently when the pills had different color. Interruptions in antiepileptic drug use for even a few days can raise the risk of seizure and have important medical and social consequences for patients.

These findings offer important take-home messages for physicians, pharmacists, and patients. As Kesselheim explained, "Patients should be aware that their pills may change color and shape, but that even differently-appearing generic drugs are approved by the FDA as being bioequivalent to their brand-name counterparts and are safe to take. Physicians should be aware that changes in pill appearance might explain their patients' non-adherence. Finally, pharmacists should make a point to tell patients about the change in color and shape when they change generic suppliers."

Researchers acknowledge that medication adherence is a multi-faceted issue, but suggest that taking steps to permit (or even require) similarity in pill appearance among bioequivalent brand name and generic drugs may offer a relatively simple way to contribute to better adherence.

This research was supported by a career development award from the Agency for Healthcare Research & Quality (K08HS18465-01), and a Robert Wood Johnson Foundation Investigator Award in Health Policy Research. Dr. Choudhry has received unrestricted research grants from CVS Caremark, Aetna, the Commonwealth Fund, and the Robert Wood Johnson Foundation to study medication adherence. Dr. Shrank has received unrestricted research funding from CVS Caremark, Aetna, Teva, Lilly, and the National Association of Chain Drug Stores.

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Kesselheim AS, Misono AS, Shrank WH, et al. Variations in Pill Appearance of Antiepileptic Drugs and the Risk of Nonadherence. Archives of Internal Medicine, 2012; DOI: 10.1001/2013.jamainternmed.997

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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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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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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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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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The above story is reprinted from materials provided by Rockefeller University Press, via EurekAlert!, a service of AAAS.

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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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