Medicine Man

Lack of oxygen isn't the only way that carbon monoxide (CO) damages the heart, say researchers at Rhode Island Hospital.

According to the findings of a new study, published in the January issue of Academic Emergency Medicine, CO also causes direct damage to the heart muscle, separate from the effects of oxygen deprivation, which reduces the heart's pumping capacity and permanently impairs cardiac function.

"These findings suggest that heart damage caused by carbon monoxide may have long-lasting effects even after its been eliminated from the blood, making the diagnosis of carbon monoxide poisoning even more critical," said lead author Selim Suner, M.D., M.S., director of emergency preparedness and disaster medicine at Rhode Island Hospital.

"While this research puts us one step in the right direction, there is still much more we need to know about the underlying mechanisms if we hope to someday develop targeted treatments," added Suner, who's also an associate professor of emergency medicine, surgery and engineering at The Warren Alpert Medical School of Brown University.

The study is the first to show that CO's effect on heart muscle is unrelated to oxygen deprivation in the recovery phase, even when all CO is out of the system.

When inhaled, CO - the leading cause of accidental poisoning deaths across the country - displaces oxygen in the blood and deprives organs such as the heart, brain and other vital organs of life-sustaining oxygen. Based on previous studies, researchers have speculated that there may be other mechanisms besides oxygen deprivation that lead to CO-related heart damage, although these have not been clearly defined.

In the study, Suner and colleagues examined an animal model in which blood and other systemic factors were eliminated in order to determine the direct effects of CO on cardiac function in the recovery phase. This model used three groups: a control group; a nitrogen control group designed to induce oxygen deprivation; and a group exposed to a combination of CO and oxygen, which best simulates the environmental conditions of CO poisoning. The pressure generated in the left ventricle of the heart was used as an indicator of heart function.

Left ventricular-generated pressure was decreased in both the nitrogren control and CO groups compared to the control group. However, the group exposed to CO did not recover cardiac function - including blood pressure - to the extent that the nitogren control group did after treatment with 100 percent oxygen. These findings suggest that CO has an independent toxic effect on the heart separate from oxygen deprivation.

Known as the "invisible killer," CO exposure is responsible for an estimated 15,000 emergency department visits and 500 unintentional deaths each year. It is an odorless, colorless gas produced by common household appliances that burn fuel, such as gasoline, oil and wood. When not properly ventilated or used incorrectly, CO emitted by these appliances can build up to dangerous levels. CO poisoning can be very difficult to diagnose, since its symptoms resemble those of the flu and other common illnesses. Pregnant women, children and the elderly are most susceptible to CO poisoning.

http://www.lifespan.org/

Heart surgeons at Johns Hopkins have evidence to support further tightening rather than easing of standards used to designate hospitals that are best at performing heart transplants.

In a study to be presented Jan. 29 at the 44th annual meeting of the Society of Thoracic Surgeons in Fort Lauderdale, Fla., the Hopkins team recommends that the benchmark for designation as a high-volume hospital rise from 10 heart transplants per year to 14. High-volume centers consistently show higher survival and fewer complication rates.

However, the standard, which is officially set by the U.S. Centers for Medicare and Medicaid Services and which qualifies medical centers for federal reimbursement, was recently lowered from 12 per year to 10.

"The bar for patient safety, quality of care and survival needs to be set pretty high," says senior study investigator and cardiac surgeon John Conte, M.D. "Our national health care system has to rethink which hospitals should do heart transplants, and in consultation with their physicians, patients need to evaluate these surgical volumes to see for themselves which hospitals have teams operating at their peak skill level."

Conte and his team reviewed the patient records of 14,401 men and women who received a heart transplant in the United Stats between 1999 and 2006.

The study is believed to be the largest and most thorough review of survival rates after heart transplantation in hospitals, based on volume.

"Our results clearly demonstrate that current standards have been arbitrarily set too low," says Conte, who is director of heart and lung transplantation at The Johns Hopkins Hospital.

"There is a certain threshold, a minimum number of surgeries needed to maintain the expertise of the entire transplant team," he says, noting that a dozen or more highly specialized professionals are involved in each transplant case, including cardiac surgeons, cardiologists, anesthesiologists, transplant coordinators, intensive care nurses, immunologists, pathologists, pulmonologists, and technicians.

In the new study, researchers found that death rates one month and one year after transplant increased steadily at hospitals that performed fewer than 14 heart transplants per year, which was the case for a majority of the 143 U.S. medical centers licensed to perform them. Roughly a dozen institutions perform more than 20 cases annually - including The Johns Hopkins Hospital and the University of Maryland Medical Center - and fewer than 10 hospitals do more than 30 procedures, with no more than five sites performing more than 40.

Study results showed that the overall average death rate one year after surgery was 12.6 percent. However, patients had a 16 percent greater chance of dying in a hospital that performed fewer than five heart transplants per year and had the best chances of surviving, with a 30-day mortality rate of less than 1 percent, at a hospital that performed over 40 procedures per year. Patients at hospitals with volumes of less than 10 had an 80 percent greater chance of dying within a month.

Using a graph and statistical analysis, researchers showed that death rates flattened for the majority of patients in hospitals with heart transplant volumes at 14 or more per year.

Conte, an associate professor of surgery at The Johns Hopkins University School of Medicine and its Heart Institute, says heart-failure patients on transplant wait lists should consult with their cardiologists about hospital and surgeon volumes when making decisions about transplants.

Hopkins cardiologist and study co-investigator Stuart Russell, M.D., who has personally cared for more than 360 transplant patients in the past decade, says patients should also look for consistently high volumes over several years as well as overall survival rates for transplant programs.

One-year survival rates at The Johns Hopkins Hospital, he notes, consistently average above 90 percent.

Despite the team's findings, Russell says it will take a clear shift in public health policy to move American medicine toward further concentration of volumes for complex procedures such as heart transplantation.

In the United Kingdom, he points out, centers designated to performed heart transplants are severely restricted, and volumes soar past 50 for each center.

"In the United States, too many low-volume hospitals have a program that they won't let go of, no matter how poor the results," says Russell, an associate professor at Hopkins.

More than 2,000 people undergo heart transplants each year in the United States. Nearly 3,000 remain on wait lists, and up to 20 percent of those on the list to receive a heart will die while waiting. Costs for a heart transplant often run as high as $260,000.

http://www.sts.org/

A University of Kentucky research team reports that loss of an important DNA repair function, called DNA mismatch repair (MMR), is responsible for refractory/relapsed Acute Myeloid Leukemia (AML).

The study, "Preferential Loss of Mismatch Repair Function in Refractory and Relapsed Acute Myeloid Leukemia: Potential Contribution to AML Progression," was published in advance online on Jan. 29 by Cell Research of Nature Publishing group. The team was led by Liya Gu, a professor in the Graduate Center for Toxicology of the UK Medical Center.

Acute Myeloid Leukemia (AML) is an aggressive hematological cancer. Although most AML patients achieve complete remission after chemotherapy, they eventually undergo relapse. The molecular basis of the relapse remains unclear.

The researchers looked into blood samples from different development stages of AML patients, i.e., at initial diagnosis, remission (recovered after chemotherapy), relapse, and persistence (no remission because of resistance to chemotherapy), for mutations in MMR genes and found that MMR defects are preferentially associated with relapsed and persistent AML patients.

This study reveals for the first time that loss of MMR function contributes to AML relapse/persistence. In addition, this study has a significant impact on AML and other leukemia treatments. The researchers provide compelling evidence suggesting that AML relapse may be due to minimal residual disease (MRD), a small number of drug-resistant leukemia cells persist in the patient after achieving complete remission.

The researchers found that the phenotype of these drug-resistant MRD cells is similar to cells that have lost the MMR function. Therefore, an understanding of how MMR-deficient cells sensitize to chemotherapeutics would lead to a successful treatment for leukemia patients.

The research team also includes Guogen Mao, Fenghua Yuan, Kimberly Absher, C. Darrell Jennings and Dianna S. Howard of University of Kentucky and Craig T. Jordan at University of Rochester Medical Center.

http://www.uky.edu/

Scientists at Cold Spring Harbor Laboratory (CSHL) have reported new findings about how the mammalian brain interprets and fashions representations of sound that may help explain how we are able to focus on one particular sound among many in noisy environments such as offices or cocktail parties.

Neurons in the brain's auditory cortex interpret incoming sound signals and send them to the rest of the nervous system, in the brain and spinal cord. Using rats, the CSHL team discovered that a very small minority of available auditory neurons react strongly when exposed to any specific sound.

"This finding challenges the standard model of sound representations in the auditory cortex, which predicts that neural representations of stimuli often engage a large fraction of neurons," said Anthony Zador, Ph.D., CSHL professor and corresponding author of a research paper published today in the journal Public Library of Science: Biology.

The researchers used a new technique called "in vivo cell-attached patch clamp recording" which measures the reaction of individual neurons. This recording technique samples neurons in a fair and unbiased way, unlike traditional approaches, which favored the largest and most active neurons. Using this technique, the team found that only 5% of neurons in the auditory cortex had a "high firing rate" when receiving a range of sounds of varying length, frequency, and volume. The experiment included white noise and natural animal sounds.

The team's objective was to quantify the relative contributions of different sub-populations of neurons in response to the range of sounds. Most of what is known about the auditory cortex of the mammalian brain comes from studies of the anesthetized cortex. The results of the experiments reported today are important partly because they measure the response of neurons in rats that were not anesthetized. In animals that are awake, it's possible to measure the response over an interval of time to one sound among many that are co-occurring.

This is the approach the Zador lab has taken to explain "selective attention," or what Dr. Zador calls "the cocktail party problem." Half of the neurons measured in the reported experiments showed no reaction at all to incoming stimuli. The researchers hypothesize that each neuron in the auditory cortex may have an "optimal stimulus" to which it is particularly sensitized.

"Your entire sensory apparatus is there to make successful representations of the outside world," said Dr. Zador, who is director of the CSHL Swartz Center for Computational Neuroscience. "Sparse representations may make sensory stimuli easier to recognize and remember." Recognizing the brain's ability to distinguish "optimal stimuli" could help scientists find ways to improve how sounds are learned. Prior research has already yielded similar results when measuring sight, movement, and smell. This is the first evidence of a correlation between sparse representations and hearing.

"The goal of sensory processing is to take a signal, like a sound or a vision, from your environment and use it to drive behavior," said Dr. Zador. "The brain needs to recognize and learn about these inputs in order to survive."

http://www.cshl.org/

Preliminary research has found an association between certain microRNA expression patterns and poor survival and treatment outcomes for colon cancer, according to a study in the January 30 issue of JAMA: The Journal of the American Medical Association.

Colon cancer is a major cause of cancer death worldwide. Colorectal cancer is the third most common and second leading cause of cancer death in the United States. "Even though 5-year mortality rates have modestly declined over the last 3 decades, there is still a need to identify new prognostic biomarkers and therapeutic targets for this disease," the authors write. They add that microRNAs have potential as diagnostic biomarkers and therapeutic targets in cancer.

MicroRNAs are 18 to 25 nucleotide, noncoding RNA (ribonucleic acid) molecules that have been found to regulate a variety of cellular processes and may also have a role in the development of cancer cells. The prognostic potential of microRNAs has been demonstrated for chronic lymphocytic leukemia, lung cancer and pancreatic cancer, according to background information in the article. No study has evaluated the association between microRNA expression patterns and colon cancer prognosis or therapeutic outcomes.

Aaron J. Schetter, Ph.D., M.P.H., and Curtis C. Harris, M.D., of the National Cancer Institute, National Institutes of Health, Bethesda, Md., and colleagues evaluated microRNA profiles of colon tumors and paired nontumorous tissue to study their potential role in tumor formation, diagnosis and therapeutic outcome in colon cancer. The study included 84 patients from Maryland; associations were validated in a second, independent group of 113 patients from Hong Kong.

Thirty-seven microRNAs were differentially expressed in tumor tissues by microRNA microarray analysis in the Maryland test cohort. Expression patterns of five tested microRNAs were validated in the Hong Kong cohort. "The discriminatory power of 5 microRNAs to differentiate between tumor and nontumorous tissue suggests that predictable and systematic changes of microRNA expression patterns may occur during tumorigenesis and may be representative of sporadic colon adenocarcinomas," the authors write.

"We found systematic differences in microRNA expression patterns between colon tumors and paired nontumorous tissue. Tumors with high expression of miR-21 [a microRNA] was associated with poor survival outcome and poor response to adjuvant chemotherapy in 2 independent cohorts, independent of staging and other clinical covariates suggesting that miR-21 may be a useful diagnostic biomarker for colon adenocarcinomas and survival prognosis including response to therapy."

"Additional studies are required to demonstrate a causal link with miR-21 and the progression of colon cancer to determine the potential of miR-21 as either a biomarker or therapeutic target," the researchers write.

http://jama.ama-assn.org/