If you need another reason to quit smoking, consider that it may diminish your chances of being a parent or grandparent. Scientists at the University of Rochester Medical Center have found that women exposed to second hand smoke, either as adults or children, were significantly more likely to face fertility problems and suffer miscarriages.

An epidemiologic analysis of more than 4,800 non-smoking women showed those who were exposed to second hand smoke six or more hours per day as children and adults faced a 68 percent greater chance of having difficulty getting pregnant and suffering one or more miscarriages. The study is published online in Tobacco Control and is one of the first publications to demonstrate the lasting effects of second hand smoke exposure on women during childbearing years.

“These statistics are breathtaking and certainly points to yet another danger of second hand smoke exposure,” said Luke J. Peppone, Ph.D., research assistant professor at Rochester’s James P. Wilmot Cancer Center.

In the study, four out of five women reported exposure to second hand smoke during their lifetime. Half of the women grew up in a home with smoking parents and nearly two-thirds of them were exposed to some second hand smoking at the time of the survey.

More than 40 percent of these women had difficulty getting pregnant (infertility lasting more than a year) or suffered miscarriages, some repeatedly.

“We all know that cigarettes and second hand smoke are dangerous. Breathing the smoke has lasting effects, especially for women when they’re ready for children,” said Peppone, who analyzed information in the Patient Epidemiology Data System, a well-studied cohort that has yielded information on a variety of cancers.

Peppone analyzed surveys collected from 4,804 women who visited Roswell Park Cancer Institute for health screenings or cancer care from 1982-1998. The 16-page survey focused on lifestyle, habits, family and personal health history, and occupational and environmental exposures. Each participant in this study reported that they had never smoked, and had been pregnant at least once or tried to become pregnant.

Participants reported whether one or both of their parents smoked and if they lived with or worked with smokers as adults. They also estimated the amount of time they were exposed to second hand smoke.

Peppone acknowledges that the data is based upon self-reporting and that is not perfect. However, he said “Women, especially mothers, have extremely accurate recall. Mothers can easily recall details like how long they breastfed, what vitamins they took during prenatal care, and childhood activities.”

Many of the women in the study grew up in the 1940s and 1950s, long before the surgeon general issued the first warning about the dangers of cigarette smoking in 1964. Since then, millions of dollars were spent to study the dangers of cigarette smoking. Tobacco use contributes to more than nearly 90 percent of all deadly lung cancers and 30 percent of all cancer deaths in the U.S., and a host of other health problems

Since the mid-1960s, smoking bans and government-funded, anti-smoking campaigns have encouraged smokers to quit and discouraged others from starting using a number of passive and aggressive techniques. Smoking rates have declined, however people continue to use tobacco and suffer the health risks.

The study was funded by a National Cancer Institute grant and was previously presented at the Society for Behavioral Medicine and Society of Research of Nicotine and Tobacco conferences.

Brand-name drugs used to treat cardiovascular disease are no better than generics, a new review of available evidence shows. Yet a number of editorials in medical journals, written by specialists, have urged against substituting the less expensive generics for their designer counterparts.

“We found no evidence that brand-name drugs are any better in terms of clinical outcomes than generic drugs,” said Dr. Aaron S. Kesselheim, lead author of a study appearing in the Dec. 3 issue of the Journal of the American Medical Association and an instructor in medicine at Brigham and Women’s Hospital in Boston. “The FDA [U.S. Food and Drug Administration] has approved all generic drugs and certifies that they are bioequivalent, meaning equivalent in all biological and chemical characteristics of the drug.”

The challenge then becomes one of perception, Kesselheim said, with this new paper itself representing “hopefully another step in helping combat the misperception that brand-name drugs are clinically superior,” he said.

The findings come closely on the heels of another study which found that there is often little evidence that off-label prescribing (prescribing a drug to treat a disease or condition different from the one it was approved for) is effective or safe.

Generic drugs have the same active ingredient as their brand-name counterparts, but may differ in terms of the color or shape of the pill and some of the inert binders (which are not clinically active).

The advantage to generic medications, of course, is that they cost substantially less.

The developers of drugs are permitted to exclusively market the drug for a finite period of time after its approval, at least partly to recoup the costs of developing the medication. After that time, however, other manufacturers may produce the same drug as a generic.

“There are a number of studies out there saying that generic drugs should be an important part of a physicians prescribing treatment, that they’re able to reduce costs and improve patient adherence which can lead to better patient outcomes,” Kesselheim said. “Generic drugs are available for nearly every condition but generally are underused in the marketplace, and one of the reasons they’re underused is that there is a perception out there among physicians and patients that brand-name drugs are better than generic drugs.”

Kesselheim and his colleagues decided to investigate the data to see if brand-name drugs really were superior.

They searched for articles comparing the clinical efficacy of brand-name and generic cardiovascular drugs published between January 1984 and August 2008.

All of the studies involving beta blockers, antiplatelet agents, statins, ACE inhibitors and alpha-blockers showed clinical equivalence, while 91 percent of randomized controlled trials showed clinical equivalence for diuretics, and 71 percent showed the same for calcium-channel blockers.

Yet 53 percent of 43 editorials had a negative take on substituting generic drugs.

“We found no evidence that a brand-name drug is clinically superior,” Kesselheim said.

Almost half of the trials and nearly all of the editorial and commentaries failed to identify funding sources.

“The key is, are the drugs therapeutically equivalent. In other words, do you get the same result,” said Robert Stanberry, an assistant professor of pharmacy practice at Texas A&M Health Science Center Irma Lerma Rangel College of Pharmacy at Kingsville. “I would tend to agree, that’s mostly true.”

More information

The U.S. Food and Drug Administration has more on generic drugs.

SOURCES: Aaron S. Kesselheim, M.D., J.D., instructor, medicine, division of pharmacoepidemiology, Brigham and Women’s Hospital, Boston; Robert Stanberry, J.D., Pharm.D., assistant professor, pharmacy practice, Texas A&M Health Science Center Irma Lerma Rangel College of Pharmacy at Kingsville; Dec. 3, 2008, Journal of the American Medical Association

The pace at which Americans are getting cancer has started to decline, marking what could be a long-awaited turning point in the battle against the disease, according to an annual report that tracks progress in the war on cancer.

Cancer deaths have also continued a decline that began in the early 1990s, meaning that for the first time both trend lines are dropping.

“It is a significant milestone,” said Otis W. Brawley, chief medical officer at the American Cancer Society, which produces the report with the National Cancer Institute, the Centers for Disease Control and Prevention, and the North American Association of Central Cancer Registries.

The drop in new cancer diagnoses has been driven largely by declines in many of the leading forms of cancer: lung, prostate and colorectal cancer in men, and breast and colorectal cancer in women.

The analysis found that the overall incidence of cancer began inching down in 1999, but not until the data for 2005 were analyzed was it clear that a long-term decline was underway.

“The take-home message is that many of the things we’ve been telling people to do to be healthy have finally reached the point where we can say that they are working,” Brawley said. “These things are really starting to pay off.”

Brawley and others cautioned, however, that part of the reduction could be the result of fewer people getting screened for prostate and breast cancers. In addition, the rates at which many other types of cancer are being diagnosed are still increasing, he said, and overall far too many Americans are still getting and dying from cancer.

Cancer is still being diagnosed in about 1.4 million Americans each year, and 560,000 die from it.

“We still have a lot to do,” Brawley said. “If you look at the data, it’s clear that we could still do much better — much, much better.”

Some experts said the drop was not surprising, noting that it was primarily the result of a fall in lung cancer because of declines in smoking that occurred decades ago. They criticized the ongoing focus on detecting and treating cancer and called for more focus on prevention.

“The whole cancer establishment has been focused on treatment, which has not been terribly productive,” said John C. Bailar III, who studies cancer trends at the National Academy of Sciences. “I think what people should conclude from this is we ought to be putting most of our resources where we know there has been progress, almost in spite of what we’ve done, and stop this single-minded focus on treatment.”

Bailar and others argue that research should emphasize identifying the underlying causes of cancer, such as environmental exposures, to prevent it from occurring in the first place.

A study performed by the team of Dr. Nabil G. Seidah, Director of the Biochemical Neuroendocrinology Research Unit at the IRCM, shows for the very first time that the degradation by PCSK9 of the LDLR receptor, which is responsible for removing the bad cholesterol (LDL-cholesterol) from the bloodstream, may be inhibited by a third protein, annexin A2.

This major discovery co-authored by Gaétan Mayer, a postdoctoral fellow, Steve Poirier, a doctoral student, and Dr. Seidah was published on November 14 in the Journal of Biological Chemistry (JBC).

Genetic studies on humans have clearly shown that PCSK9 is a prime therapeutic target for the prevention and treatment of cardiovascular diseases. PCSK9 proprotein convertase promotes the degradation of the receptor responsible for eliminating LDL-cholesterol particles. Thus, the presence of PCSK9 leads to a surplus of bad cholesterol in the bloodstream and contributes to plaque formation, leading to blockage of blood vessels and arteries.

This phenomenon is a major risk factor that can lead to cardiovascular diseases, such as heart attack, atherosclerosis and stroke. Mutations of human genes have demonstrated that a rise in PCSK9 activity results in a major increase in LDL-cholesterol and familial hypercholesterolemia. Conversely, in people with a non-functional mutation in the gene coding for PCSK9, a decrease in its activity brings down the LDL-cholesterol concentration levels in the bloodstream and diminishes by up to 88% the risks of developing cardiovascular diseases.

“By performing a series of biochemical experiments, we discovered that annexin A2 binds strongly to PCSK9 and inhibits its function,” remarks Gaétan Mayer, the article’s first author.

This discovery should pave the way toward the development of a new drug that would lower blood cholesterol to recommended levels. Currently, cholesterol lowering drugs known as “statins” are used by more than 25 million people worldwide. Statins decrease cholesterol synthesis and increase the number of LDL-receptors, thus efficiently decreasing plasma cholesterol levels; however, they also increase the amount of PCSK9, which degrades those receptors, thus reducing the effect of statins.

A drug that would block PCSK9 could either be used alone or jointly with statins and would be highly beneficial to patients in whom statins do not work or are unable to take this drug.

This work was supported by the Canadian Institutes of Health Research (CIHR) and by a Canada Research Chair.

1. Mayer G, Poirier S, and Seidah NG. Annexin A2 Is a C-terminal PCSK9-binding Protein That Regulates Endogenous Low Density Lipoprotein Receptor Levels. Journal of Biological Chemistry, 2008; 283 (46): 31791 DOI: 10.1074/jbc.M805971200

Adapted from materials provided by Institut de recherches cliniques de Montreal.

New research by The University of Texas School of Public Health shows that a medication for high blood pressure called a diuretic or water pill is particularly effective at reducing the risk for a type of heart failure that affects women more often than men.

Heart failure is a clinical syndrome characterized by an inadequate supply of oxygen rich blood as a result of impaired cardiac pump function. More than 5 million Americans are living with heart failure and most had high blood pressure before developing this potentially deadly condition.

While much research has been focused on the impact of antihypertensive medications on the prevention of heart failure associated with reduced pumping capacity in the heart’s all-important left ventricle, comparatively little research has been performed on the prevention of heart failure wherein the heart muscle is clearing a normal or preserved percentage of blood with each heart beat. This percentage is called left ventricular ejection fraction (LVEF).

“We showed that a diuretic was as good as or better than other classes of medication for high blood pressure in reducing the occurrence of heart failure in people with a wide range of left ventricular ejection fraction,” said Barry Davis, M.D., Ph.D., the study’s lead author, the Guy S. Parcel Chair in Public Health and director of the Coordinating Center for Clinical Trials at the UT School of Public Health.

The study involved 910 hypertensive adults who had been taking antihypertensive medications and who were subsequently diagnosed with heart failure in a hospital. Those with an ejection fraction of 50 percent or more were defined as Heart Failure Preserved Ejection Fraction (HFPEF) and those with an ejection fraction of 49 percent or less as Heart Failure Reduced Ejection Fraction (HFREF). Forty-four percent had preserved ejection fraction and 56 percent reduced ejection fraction.

Participants treated with a thiazide-type diuretic (chlorthalidone) had reduced risk of Heart Failure Preserved Ejection Fraction compared to those taking a calcium channel blocker (amlodipine), an angiotensin-converting enzyme inhibitor (lisinopril), or an alpha-adrenergic blocker (doxazosin). Chlorthalidone reduced the risk in people with reduced ejection fraction compared with amlodipine or doxazosin. Chlorthalidone was similar to lisinopril in preventing heart failure with reduced ejection fraction. “On the basis of the data from many heart failure trials, a combination of the last two agents would be expected to be particularly effective in preventing heart failure in this group,” the authors wrote.

“In both heart failure with preserved and reduced ejection fraction, the diuretic is helping to remove excess fluid - which can reduce both pre load and after load and thus increase ejection fraction,” Davis said.

Heart failure patients with preserved ejection fraction may still have big problems, Davis said. “Let’s say the heart normally should pump 70 milliliters (ml) of blood. It fills up with 100 ml and pumps 70 for an EF of 70 percent (which is good). However with reduced ejection fraction it only pumps 30 ml or has an EF of only 30 percent. On the other hand you could have preserved ejection fraction and in this case the heart fill up with just 50 ml of blood but pumps 30 ml. The EF would be 60 percent. In both cases, only 30 ml is reaching the body.”

Davis said heart failure is sometimes characterized as either systolic or diastolic heart failure. In systolic heart failure, there is reduced cardiac contractility, whereas in diastolic heart failure there is impaired cardiac relaxation and abnormal ventricular filling. Heart Failure Preserved Ejection Fraction is typically associated with the filling blood phase and Heart Failure Reduced Ejection Fraction with the forcing blood out phase.

Participants with preserved ejection fraction compared to those with reduced ejection fraction were more likely to be women (52 percent versus 38 percent) and less likely to have a history of coronary heart disease (32 percent versus 39 percent). People with heart failure with preserved ejection fraction have a subsequent mortality rate almost as high as those with reduced ejection fraction, about 50 percent at five years.

Participants in the study were from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), a randomized, double-blind, multi-center clinical trial that compared four classes of medications for high blood pressure. More than 42,000 people 55 years of age or more with hypertension were in the trial between 1994 and 2002.

Davis’ collaborators from the UT School of Public Health were Charles E. Ford, Ph.D., associate professor of biostatistics and Lara M. Simpson, Ph.D., faculty associate. Also contributing were: John B. Kostis, M.D., UMDNJ-Robert Wood Johnson Medical School, New Brunswick, N.J. ; Henry R. Black, M.D., New York University School of Medicine, New York, N.Y.; William C. Cushman, M.D., Memphis Veteran’s Affairs Medical Center, Memphis, Tenn.; Paula T. Einhorn, M.D., Division of Prevention and Population Sciences, National Heart, Lung, and Blood Institute, Bethesda, Md.; Michael A. Farber, M.D., Crozer Keystone Health Network, Upland, Pa.; Daniel Levy, M.D., Framingham Heart Study/National Heart, Lung and Blood Institute Framingham, Mass.; Barry M. Massie, M.D., San Francisco Veterans Affairs Medical Center, San Francisco, Calif.; and Shah Nawaz, M.D., private practice in Sudbury, Ontario, Canada.

Research was supported by the National Heart, Lung, and Blood Institute, National Institutes of Health and the U.S. Department of Health and Human Services, Bethesda, Md.

1. . Heart Failure With Preserved and Reduced Left Ventricular Ejection Fraction in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. Circulation: Journal of the American Heart Association, Nov. 10 online issue

Adapted from materials provided by University of Texas Health Science Center at Houston.

Statins, the class of drugs commonly used for lowering cholesterol, are now showing promise at preventing deep vein thrombosis (DVT) or blood clots, an affliction that occurs in nearly 2 million Americans each year.

New research presented at CHEST 2008, the 74th annual international scientific assembly of the American College of Chest Physicians (ACCP), suggests that the use of statins may be associated with a significant reduction in the occurrence of venous thromboembolism (VTE), a condition that includes DVT and pulmonary embolism, in patients with solid organ tumors, including breast, lung, and colon cancers.

“The results of our research are interesting and thought provoking,” said study author Danai Khemasuwan, MD, Albert Einstein Medical Center, Philadelphia, PA. “We hope that our research alerts the scientific community to the potential of statins in reducing VTE.”

Dr. Khemasuwan and his colleagues from Albert Einstein Medical Center evaluated the influence of statins use on the incidence of VTE by reviewing 740 consecutive patients admitted to the hospital between October 2004 and September 2007 with a diagnosis of breast, lung, colon, prostate, stomach, esophagus, pancreas, ovary, kidney, or brain cancer. The occurrence of VTE, risk factors for VTE, and use of statins were recorded. Patients who either used statins for less than 2 months or who never used statins were allocated to the control group.

The mean age of the entire study population was 65 years, 52 percent of subjects were women, and 76 percent were African-American. A total of 26 percent of patients received statins, and the overall incidence of VTE was 18 percent. The analysis revealed that patients receiving statins were significantly less likely to develop VTE than the control group, with 8 percent of patients receiving statins developing VTE compared with 21 percent in the control group. A logistical regression analysis yielded the same results irrespective of smoking, documented metastatic disease, current use of chemotherapy, immobilization, and use of aspirin.

Although the authors could not draw conclusions about the cause and effect relationship between statins and VTE, Dr. Khemasuwan feels the data are promising. “If the results of our study are confirmed in a prospective randomized, controlled trial, this could have very significant implications for the medical community.”

“Recent studies have examined the use of statins for the prevention of lung disease, stroke, and other neurologic disorders,” said James A. L. Mathers, Jr., MD, FCCP, President of the American College of Chest Physicians. “The results of this study are promising and suggest a potential role for statins in the prevention of thromboembolism.”

CHEST 2008 is the 74th annual international scientific assembly of the American College of Chest Physicians, held October 25-30 in Philadelphia, PA.

The brains of individuals with major depressive disorder appear to react more strongly when anticipating pain and also display altered functioning of the neural network that modifies pain sensitivity, according to a new report.

“Chronic pain and depression are common and often overlapping syndromes,” the authors write as background information in the article. Recurring or chronic pain occurs in more than 75 percent of patients with depression, and between 30 percent and 60 percent of patients with chronic pain report symptoms of depression “Understanding the neurobiological basis of this relationship is important because the presence of comorbid pain contributes significantly to poorer outcomes and increased cost of treatment in major depressive disorder.”

Irina A. Strigo, Ph.D., of the University of California San Diego, La Jolla, and colleagues studied 15 young adults with major depressive disorder (average age 24.5) who were not taking medication and 15 individuals who were the same age (average 24.3 years) and had the same education level but did not have depression. Patients with depression completed a questionnaire that evaluated their tendencies to magnify, ruminate over or feel helpless in the face of pain. All participants underwent functional magnetic resonance imaging (fMRI) while their arms were exposed to a thermal device heated to painful levels (an average of 46.4 degrees to 46.9 degrees Celsius, or about 115 degrees to 116 degrees Fahrenheit) and also to non-painful temperatures. Visual cues (a green shape for non-painful warmth and a red shape for painful warmth) were presented before the heat was applied.

Compared with the controls, patients with depression showed increased activation in certain areas of their brain—including the right amygdala—during the anticipation of painful stimuli. They also displayed increased activation in the right amygdala and decreased activation in other areas, including those responsible for pain modulation (adjusting sensitivity to pain), during the painful experience.

To examine whether the activation of the amygdala was associated with passive coping styles, the researchers compared the percentage change in the activations of the amygdala with the helplessness, rumination and ramification reported by the participants with depression. “Significant positive correlations were observed in the major depressive disorder group between greater helplessness scores and greater activity in the right amygdala during the anticipation of pain,” the authors write.

“The anticipatory brain response may indicate hypervigilance to impending threat, which may lead to increased helplessness and maladaptative modulation during the experience of heat pain,” the authors write. “This mechanism could in part explain the high comorbidity of pain and depression when these conditions become chronic.”

“Future studies that directly examine whether maladaptive response to pain in major depressive disorder is due to emotional allodynia [a pain response to a non-painful stimulus], maladaptive control responses, lack of resilience and/or ineffectual recruitment of positive energy resources will further our understanding of pain-depression comorbidity,” they conclude.

This study was supported by Barrow Neurological Foundation, grants from the National Institute of Mental Health, the National Association for Research in Schizophrenia and Depression and the University of California San Diego Center of Excellence for Stress and Mental Health.

1. Irina A. Strigo, PhD; Alan N. Simmons, PhD; Scott C. Matthews, MD; Arthur D. (Bud) Craig, PhD; Martin P. Paulus, MD. Association of Major Depressive Disorder With Altered Functional Brain Response During Anticipation and Processing of Heat Pain. Arch Gen Psychiatry, 2008;65(11):1275-1284

Adapted from materials provided by JAMA and Archives Journals.

The diabetes medication metformin may be associated with a lower risk of death from cardiovascular disease, according to a meta-analysis of previously published studies. No associations were found between other diabetes medications and beneficial or harmful cardiovascular effects, in part because of insufficient data, the authors note.

“A wide variety of oral diabetes medications are currently available for the treatment of type 2 diabetes mellitus,” they write as background information in the article. “With the addition of newer oral therapies to the market in the late 1990s (e.g., thiazolidinediones and meglitinides), it is critical to evaluate how these agents compare with older medications. This is particularly important in light of the expense of many of the newer therapies.” The specific effects of these medications on cardiovascular health remains unclear, and recent controversy has surrounded possible cardiac risks associated with one newer drug, rosiglitazone.

Elizabeth Selvin, Ph.D., M.P.H., of the Johns Hopkins Bloomberg School of Public Health, Baltimore, and colleagues performed a meta-analysis of data from 40 clinical trials published on or before Jan. 19, 2006. All the trials assessed the benefits or harms of oral diabetes medications approved for use in the United States, including combinations of therapies commonly prescribed by physicians, and included information about heart attack, stroke or other cardiovascular events. The average age of participants ranged from 52 to 69 and 27 of the studies (68 percent) were less than one year in duration.

“Treatment with metformin hydrochloride was associated with a decreased risk of cardiovascular morality [death] compared with any other oral diabetes agent or placebo; the results for cardiovascular morbidity [illness] and all-cause mortality were similar but not statistically significant,” the authors write. “No other significant associations of oral diabetes agents with fatal or non-fatal cardiovascular disease or all-cause mortality were observed. When compared with any other agent or placebo, rosiglitazone was the only diabetes agent associated with an increased risk of cardiovascular morbidity and mortality, but this result was not statistically significant.”

Poor quality and inconsistent reporting of cardiovascular data, along with the lack of long-term studies, make it difficult to draw firm conclusions, the authors note. “Our study demonstrates that there have been few trials of oral diabetes therapies that have lasted longer than six months and that reporting of adverse events for cardiovascular disease is poor,” they continue.

“There is a critical need for studies of oral diabetes medications with long-term outcomes. The relatively modest differences in blood pressure, cholesterol levels and weight observed after treatment with oral diabetes medications in short-term trials may not translate to changes in long-term cardiovascular risk. Only long-term trials can provide definitive conclusions regarding the comparative efficacy of oral diabetes medications and long-term risks.”

This article is based on research conducted by the Johns Hopkins Evidence-Based Practice Center under a contract with the Agency for Healthcare Research and Quality. This study was also supported by grants from the National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases.

Editorial: Innovative Approaches Needed to Ensure Safety of Diabetes Medications

“Selvin et al noted that, when it comes to choosing the safest oral agents, the quality of the data are problematic,” writes David M. Nathan, M.D., of Massachusetts General Hospital, Boston, in an accompanying editorial.

“The current approach to assessing the relatively rare but clinically important adverse effects of diabetes management is unsatisfactory,” he continues. “The vagaries of meta-analyses make them unreliable. On the other hand, increasing the size and duration of controlled clinical trials to provide adequate statistical power to detect relatively infrequent events would potentially bankrupt the pharmaceutical industry that supports most of the trials and delay the development of new drugs.”

New approaches are needed to ensure the safety of drugs without slowing development, Dr. Nathan concludes. “For example, the phased introduction of new medications with uniform, standardized collection of adverse outcome data might identify relatively rare complications before the drugs are used by millions. Similarly, the use of clinical databases may provide an early alert regarding adverse outcomes,” he writes. “In the meantime, there are well-established and safe treatments that, if used aggressively, can improve the long-term health of patients with type 2 diabetes.”

1. Elizabeth Selvin; Shari Bolen; Hsin-Chieh Yeh; Crystal Wiley; Lisa M. Wilson; Spyridon S. Marinopoulos; Leonard Feldman; Jason Vassy; Renee Wilson; Eric B. Bass; Frederick L. Brancati. Cardiovascular Outcomes in Trials of Oral Diabetes Medications: A Systematic Review. Arch Intern Med., 2008;168(19):2070-2080 [link]

Adapted from materials provided by JAMA and Archives Journals.

Individuals who take cholesterol-lowering statins before being hospitalized with pneumonia appear less likely to die within 90 days afterward, according to a new report.

In the United States and Europe, pneumonia hospitalization rates have increased 20 percent to 50 percent over the past decade, according to background information in the article. About 10 percent to 15 percent of those with pneumonia die from the disease. A recent review article indicated that statins may benefit patients with sepsis (infection of the bloodstream) or bacteremia (presence of bacteria in the bloodstream), possibly due to the medications’ anti-clotting, anti-inflammatory or immune-modifying properties.

Reimar W. Thomsen, M.D., Ph.D., of Aarhus University and Aalborg Hospital, Aalborg, Denmark, and colleagues reviewed data from 29,900 adults hospitalized with pneumonia between 1997 and 2004. Of these, 1,371 (4.6 percent) were taking statins at the time.

“Mortality [death] among statin users was lower than among non-users: 10.3 percent vs. 15.7 percent after 30 days and 16.8 percent vs. 22.4 percent after 90 days,” the authors write. The lowest relative death rate associated with statins was observed in patients older than 80 and in those with bacteremia. “The differences became apparent during the first few weeks of hospitalization, a period associated with a high number of pneumonia-related deaths, and they increased only minimally between 30 and 90 days after admission, which suggests that statin use is beneficial primarily in the early phase of infection.”

Previous statin use, or the use of any other preventive medication for cardiovascular health, was not associated with a reduced death rate from pneumonia.

“Several biological mechanisms may explain our results,” the authors write. Statins change the immune response, beneficially affect processes associated with blood clotting and inflammation and inhibit dysfunction in blood vessels. These effects may especially benefit patients with sepsis and bacteremia, which are associated with early death from pneumonia.

“Our study adds to the accumulating evidence that statin use is associated with improved prognosis after severe infections,” the authors write. “The decrease in mortality associated with statin use seems to be substantial in patients with pneumonia requiring hospital admission. Randomized trials are needed to examine causality of the associations found in observational studies. Given the availability of statins, with their relatively low cost and mild adverse effects, positive results of statin therapy trials in patients with pneumonia would have substantial clinical and public health implications.”

This study was supported by the Western Danish Research Forum for Health Sciences and by the Clinical Epidemiological Research Foundation at Aarhus University Hospital, Aarhus, Denmark.

Editorial: Combining Statins and Antibiotics May Prove Effective Against Infection

“These data suggest a substantial decrease in mortality with statin use,” writes Kasturi Haldar, Ph.D., of the University of Notre Dame, South Bend., Ind., in an accompanying editorial.

The resulting data “raises the question of whether statins should be used to improve anti-infective therapy. They are not optimal for treating acute infection because it takes days to achieve the desirable concentrations in plasma,” Dr. Haldar continues.

“However, because statins target the host, drug resistance, a major problem in treating bacterial infections, is not likely to develop. Thus, it may be useful to consider clinical research testing of combinations of statins with existing antibiotic agents to evaluate whether it is possible to develop optimized combination therapies effective against both acute and persistent infections.”

This editorial was supported by a Department of Veterans Affairs Merit Award, Great Lakes Research Center of Excellence and by the National Institutes of Health.

1. Reimar W. Thomsen; Anders Riis; Jette B. Kornum; Steffen Christensen; Soren P. Johnsen; Henrik T. Sorensen. Preadmission Use of Statins and Outcomes After Hospitalization With Pneumonia: Population-Based Cohort Study of 29 900 Patients. Arch Intern Med., 2008;168(19):2081-2087 [link]

Adapted from materials provided by JAMA and Archives Journals.

Adding corticosteroids to traditional antimicrobial therapy might help people with pneumonia recover more quickly than with antibiotics alone, UT Southwestern Medical Center scientists have found.

Unlike the anabolic steroids used to bulk up muscle, corticosteroids are often used to treat inflammation related to infectious diseases, such as bacterial meningitis. Used against other infectious diseases, however, steroid therapy has been shown to be ineffective or even harmful.

In a study available online and in a future issue of the Journal of Infectious Diseases, researchers at UT Southwestern show that mice infected with a type of severe bacterial pneumonia and subsequently treated with steroids and antibiotics recovered faster and had far less inflammation in their lungs than mice treated with antibiotics alone.

“Some people might think that if you give steroids, it would counteract the effect of the antibiotic,” said Dr. Robert Hardy, associate professor of internal medicine and pediatrics and the study’s senior author. “But it turns out you need the antibiotic to kill the bug and the steroid to make the inflammation in the lung from the infection get better. The steroids don’t kill the bugs, but they do help restore health.”

Pneumonia is a lung infection typically characterized by breathing difficulties and spread by coughing and sneezing. Symptoms include headache, fever, chills, coughs, chest pain, sore throat and nausea. Pneumonia caused by the Mycoplasma pneumoniae bacterium is generally a less severe form of the disease that can occur in any age group. It accounts for 20 percent to 30 percent of all community-acquired pneumonia cases.

In the current study, mice infected with the M pneumoniae bacterium were treated daily with a placebo, an antibiotic, a steroid, or a combination of the antibiotic and steroid in order to investigate the effect on M pneumoniae-induced airway inflammation. The animals were then evaluated after one, three and six days of therapy.

“It turns out that the group that got both the antibiotic and the steroids did the best,” Dr. Hardy said. “The inflammation in their lungs got significantly better.”

Although antimicrobials remain the primary therapy for M pneumoniae infection, there have been several reports in recent years about physicians adding steroids to the treatment regimen of patients with severe cases, Dr. Hardy said. The problem, he said, is that those were individual case reports.

“They never had a control group, so it was impossible to tell what impact the addition of steroids had on recovery,” he said.

The new findings not only suggest that giving antibiotics with steroids can help individuals with pneumonia get better faster, but also suggest a potentially more effective therapy for someone in the midst of an asthma attack due to M pneumoniae infection. Up to 20 percent of asthma attacks in children and adults have been shown to be triggered by this bacterium.

Dr. Hardy said it’s too early to recommend steroids as standard treatment for people with this type of bacterial pneumonia, but the work does support the need for a clinical trial.

“Or if there are very sick patients, this combination treatment doesn’t seem to worsen the disease,” he said. “The good thing about our results is the data alone support moving on to a clinical study.”

Research presented at the 20th annual Transcatheter Cardiovascular Therapeutics (TCT) scientific symposium, sponsored by the Cardiovascular Research Foundation (CRF), found that coronary heart disease (CHD) symptoms presented in the context of a stressful life event were identified as psychogenic in origin when presented by women and organic in origin when presented by men. The study could help explain why there is often a delay in the assessment of women with heart disease.

“We know that there is a delay in diagnosing CHD in women and this is an important step forward in understanding why,” said Alexandra J. Lansky, M.D., director of the Women’s Health Initiative at CRF, director of Clinical Services at the Center for Interventional Vascular Therapy, a cardiologist at NewYork-Presbyterian Hospital/Columbia University Medical Center, and an associate professor of clinical medicine at Columbia University College of Physicians and Surgeons.

The investigation – “Gender Bias in the Diagnosis, Treatment, and Interpretation of CHD Symptoms: Two Experimental Studies with Internists and Family Physicians,” was led by Gabrielle R. Chiaramonte, Ph.D., postdoctoral associate at the Weill Medical College of Cornell University and Clinical Fellow at NewYork-Presbyterian Hospital. The study examined the effects of patients’ gender and the context of how CHD symptoms are presented (with/without mention of life stressors and anxiety) on primary care physicians’ patient evaluations.

“The selection of internists and family physicians was particularly relevant as they are generally the first medical professionals to assess patients’ symptoms and to make treatment recommendations. A greater understanding of factors contributing to gender bias in CHD assessment in this group would thus be especially meaningful,” said Dr. Chiarmonte.

The researchers hypothesized that the presence of life stressors/anxiety would shift the interpretation of women’s – but not men’s – CHD symptoms, so that these would be perceived to have a psychogenic etiology.

“The greater prevalence of anxiety disorders in women, along with the greater likelihood that women will discuss stressors with their physicians, and the overlap of CHD and anxiety symptoms, contribute to this shift in interpretation,” Dr. Chiaramonte said.

In the studies, 87 internists (Study 1) and 143 family physicians (Study 2) read a vignette of a 47-year-old male or a 56-year-old female (by age at equal risk for CHD) presenting a multitude of CHD symptoms and risk factors. Half the vignettes included sentences indicating the patient had recently experienced a life stressor and that they appeared anxious. Each physician read one version of the vignette and then specified a diagnosis, made treatment recommendations, and indicated the etiology of symptoms.

As the investigators predicted, results showed a gender bias when CHD symptoms were presented in the context of stress, with fewer women receiving CHD diagnoses (15% versus 56%), cardiologist referrals (30% versus 62%), and prescriptions of cardiac medication (13% versus 47%) than men. No evidence of a bias was observed when CHD symptoms were presented without the stress. Results also showed that the presence of stress shifted the interpretation of women’s chest pain, shortness of breath and irregular heart rate so that these were thought to have a psychogenic origin. By contrast, men’s symptoms were perceived as organic whether or not stressors were present.

Dr. Chiaramonte stated, “For women, the presence of stress or anxiety drives the interpretation of accompanying symptoms so that symptoms such as chest pain or shortness of breath undergo a ‘meaning shift’ when presented in the context of stress or anxiety and they are perceived as a manifestation of the stress or anxiety and not as CHD symptoms. For men, cardiac symptoms drive the interpretation of accompanying symptoms so that anxiety or stress is perceived (rightly so) as a risk factor for CHD and may in fact augment the CHD assessment. The presence of anxiety or stress in men does not deter from the CHD assessment; for women, it appears to preclude a CHD assessment.”

Dr. Chiaramonte warned that, “Given the overlap of CHD and anxiety symptoms (e.g., chest tightness common in both) and given the higher prevalence of anxiety symptoms or disorders in women, physicians need to be aware of gender differences in symptom presentation and they need to be especially careful to rule out CHD before considering an anxiety diagnosis. In the case of women, anxiety appears to have a pervasive influence on medical judgments regardless of the gender of the health care provider making the evaluations.”

Ronald Friend, Ph.D., co-investigator, Professor of Psychology at Stony Brook University and Oregon Health & Sciences University, School of Nursing, added: “The assessment of women’s CHD is further complicated by evidence that women sometimes present with ‘atypical’ CHD symptoms and that chest pain, a hallmark symptom in men, is less common in women. We recently conducted an additional study with 142 family physicians examining the influence of stress on the assessment of patients presenting atypical CHD symptoms. Results showed a different dynamic in this case: Women were more likely than men to receive a GI rather than a CHD diagnosis regardless of the presence of stress; the addition of stress increased GI diagnoses in both men and women. Given that women are more likely to present with atypical symptoms (and stress), these preliminary results are cause for concern.”

Prior to conducting the two studies reported here, the researchers had tested their hypothesis with 99 first year medical students, 82 third and fourth year medical students, and 122 physician assistant students. The investigators were surprised to find nearly identical results whether the participants surveyed were first year medical students or experienced practicing family physicians and internists.

Dr. Chiaramonte concluded, “The consistent results observed with participants of varying clinical experience attest to the strength of the research and the pervasiveness of the effect. Our results suggest the need for the development of educational initiatives aimed at improving health care providers’ understanding of gender differences in symptom presentation.”

The research team included: Gabrielle R. Chiaramonte, Ph.D., of Weill Medical College of Cornell University/NewYork-Presbyterian Hospital; Ronald Friend, Ph.D., of Stony Brook University and Oregon Health & Sciences University, School of Nursing; Arnold S. Jaffe, Ph.D., and Jeffrey S. Trilling, M.D., of Stony Brook University Medical Center; Gil Weitzman, M.D., B. Robert Meyer, M.D., Susan Evans, Ph.D., and JoAnn Difede, Ph.D., of Weill Medical College of Cornell University/NewYork-Presbyterian Hospital; and Alexandra J. Lansky, M.D., of NewYork-Presbyterian Hospital/Columbia University Medical Center.

About 44 percent of individuals who had bipolar disorder as children continue to have manic episodes as young adults, according to a report in the October issue of Archives of General Psychiatry, one of the JAMA/Archives journals. This rate, along with the severity of the disease at young ages, strongly suggest that bipolar disorder can be continuous from childhood to adulthood, the authors note.

Recent data has demonstrated an enormous increase in the diagnosis of pediatric bipolar disorder, a severe mood disorder involving episodes of mania and depression, according to background information in the article. However, skepticism continues to exist regarding the existence of the condition in children. Given increased media attention to the issue, there is a need to further increase the validity of childhood diagnoses.

Barbara Geller, M.D., and colleagues at Washington University in St. Louis studied 115 children (average age 11.1) diagnosed with bipolar disorder beginning in 1995 to 1998. At the beginning of the study and again during nine follow-up visits conducted over eight years, the children and their parents were interviewed separately about their symptoms, diagnoses, daily cycles of mania and depression and interactions with others.

A total of 108 (93.9 percent) of the children completed the study (average age at follow-up, 18.1 years). During the eight-year follow-up, they spent 60.2 percent of weeks with any mood episodes and 39.6 percent of weeks with episodes of mania. Although 87.8 percent recovered from mania, 73.3 percent relapsed. The researchers also examined the characteristics of children’s second and third episodes of mania and found that like the first episodes, they were characterized by psychosis, daily cycling between mania and depression and a long duration (55.2 weeks for the second and 40 weeks for the third episode).

At the end of the follow-up period, 54 patients were age 18 or older. Of those, 44.4 percent continued to have manic episodes and 35.2 percent had substance use disorders, a rate similar to those diagnosed with bipolar disorder as adults.

“In grown-up subjects with child bipolar disorder I, the 44.4 percent frequency of manic episodes was 13 to 44 times higher than population prevalences, strongly supporting continuity between child and adult bipolar disorder I,” the authors write. “Subjects with child bipolar disorder I who were grown up at the eight-year follow-up constituted approximately half the sample. However, even if all subjects younger than 18 years at the eight-year follow-up never had episodes of bipolar disorder I as adults, the overall significance of the findings would be similar, because the rate would still be six to 22 times higher than population prevalences.”

“In conclusion, mounting data support the existence of child bipolar disorder I, and the severity and chronicity of this disorder argue strongly for large efforts toward understanding the neurobiology and for developing prevention and intervention strategies,” they write.

Editorial: Examination Lays Groundwork for Future Research

“Extending previous seminal work on pediatric bipolar disorder, Geller et al present the first longitudinal study following up a large sample of youth diagnosed with pediatric bipolar disorder into adulthood,” writes Ellen Leibenluft, M.D., of the National Institute of Mental Health, Bethesda, Md., in an accompanying editorial.

“Just as the children in this important study have matured over the last decade, so has research on pediatric bipolar disorder,” Dr. Leibenluft writes. More articles on the condition were published in January 2008 than in the decade between 1986 and 1996.

“This upsurge both results from and contributes to a growing awareness that serious mental illnesses do not emerge de novo when individuals reach adulthood, but rather reflect early developmental processes. This awareness has profound implications for future research, highlighting the need for longitudinal studies such as that of Geller et al as well as pathophysiological research in children, studies comparing adults and youth with bipolar disorder and studies of youth at familial risk for bipolar disorder,” Dr. Leibenluft concludes.

1. Barbara Geller, Rebecca Tillman, Kristine Bolhofner, Betsy Zimerman. Child Bipolar I Disorder: Prospective Continuity With Adult Bipolar I Disorder; Characteristics of Second and Third Episodes; Predictors of 8-Year Outcome. Arch Gen Psychiatry, 2008; 65 (10): 1125-1133 [link]
2. Ellen Leibenluft. Pediatric Bipolar Disorder Comes of Age. Arch Gen Psychiatry, 2008; 65 (10): 1122-1124 [link]

Adapted from materials provided by JAMA and Archives Journals.

Take a kidney out of the body and it still knows how to filter toxins from the blood. But all bets are off in the face of high blood pressure.

“How does the kidney know how to do it and why does it break in hypertension?” says Dr. Edward W. Inscho, physiologist in the Medical College of Georgia Schools of Medicine and Graduate Studies.

The kidneys filter about 200 quarts of plasma daily, eliminating about two quarts of waste product and extra water as urine, according to the National Institute of Diabetes and Digestive and Kidney Diseases.  But the complete physiology remains a mystery.

He challenged colleagues to fill in important blanks in how this process works normally and how to make it work better in disease during the Sept. 19 Lewis K. Dahl Memorial Lecture at the 62nd High Blood Pressure Research Conference and Workshop in Atlanta.

One thing is clear: Hypertension takes a serious toll on the kidneys and damaged kidneys worsen hypertension. Dr. Inscho believes the kidneys’ million hard-working filters, or glomeruli, are direct victims of high pressure. His research focuses on the minute arteries, or arterioles, that feed blood into each of them. These afferent arterioles are responsible for keeping blood pressure at a comfortable 60 mmHg inside glomeruli. At a healthy blood pressure of 120/80 mmHg, blood enters the artery at a mean pressure of 100 mmHg, but higher pressures mean the arterioles must work even harder to reach the 60 mmHg target. They seem up to the task at least initially, contracting to make it harder for blood to pass and reducing pressure in the process. “We want to know how it does that,” Dr. Inscho says as he watches the near instantaneous contraction.

He thinks he may at least know the messenger. The first reaction to high pressure actually is for the small vessel to stretch. That stretch prompts smooth muscle cells on the vessel wall to release ATP, a common molecule known as an energy source but also gaining acceptance as an extracellular messenger, he theorizes. “It’s an action-reaction kind of event.”

When he puts ATP on the vessel it rapidly constricts; when he blocks the ATP receptor it won’t. Unfortunately ATP works best in the face of normal pressures: constricting pressure about 25 percent as opposed to 2-3 percent when it’s high. Still there are plenty of questions. Whether ATP is really released by the initial stretching is a critical one, he says. Whether ATP really comes from smooth muscle cells is another.

University of Southern California researcher Dr. Janos Peti-Peterdi thinks high pressures tugging the tethers connecting smooth muscle cells to others in the blood vessel wall may really be what releases ATP, a theory Dr. Inscho presented during the Sept. 19 meeting. It may be that hypertension changes the attachment of those tethers so they don’t respond and the blood vessel can’t either.

“We are trying to figure out how all this fits together,” says Dr. Inscho. Figuring out the critical steps of this “amazingly elegant, amazingly precise and very complicated” process will lead to better understanding of what gets corrupted by diseases such as hypertension and diabetes and maybe how to stop kidney destruction.

As scientists are finding with many diseases, Dr. Inscho says inflammation likely plays a big role.  “We know we can make these animals hypertensive, treat them with anti-inflammatories and prevent this whole process from occurring,” he says of glomeruli destruction. “I think that’s pretty exciting, but we don’t know exactly how we are doing that.” Blood pressure is not affected, just the negative impact on the kidneys. Inflammation, he notes, is likely well-intended but ultimately ends up thickening blood vessel walls and hampering flexibility.

The Lewis K. Dahl Memorial Lecture was established in 1988 by the Council for High Blood Pressure Research to honor Dr. Dahl’s pioneering work in the relationship between salt, the kidneys and hypertension. His contributions include development of the Dahl salt sensitive rat, a genetically engineered model of hypertension.

The Sept. 17-20 hypertension conference in Atlanta was sponsored by the Council for High Blood Pressure Research and the Council on Kidney in Cardiovascular Disease.

About 1 in 3 adults has high blood pressure, but many people don’t do a good job of controlling the problem because medications can be pricey. And doctors may not be doing all they can, either. According to new research, released last week during the annual meeting of the American Heart Association’s Council for High Blood Pressure Research, many doctors fail to follow national guidelines that call for treating people above the 120/80 level. Here, then, is an online calculator from the American Heart Association that will help you calculate your risk, as well as five low-cost ways to lower your blood pressure.

1. Take a diuretic. A major study that examined commonly prescribed medications—including ACE-inhibitors, alpha blockers, and calcium channel blockers—found that diuretics, an older class of drugs, were more effective than the others at treating hypertension. You should talk to your doctor before trying a diuretic; most types require a prescription. Thiazide diuretics are an especially affordable and often effective option.

2. Cut back on salt. Again and again researchers have proved that eating too much salt causes blood pressure to rise. The National Heart Lung and Blood Institute suggests that even healthy adults eat no more than 2,400 milligrams of sodium—or about a teaspoon of table salt—a day; people with high blood pressure will want to eat about half of that. Try substituting spices such as bay leaf, nutmeg, pepper, basil, curry powder, garlic, ginger, oregano, and rosemary.

3. Use the DASH diet. The name of this diet—Dietary Approaches to Stop Hypertension—says it all. Research has proven that the DASH diet, which emphasizes fruits, vegetables, whole grains, and low-fat dairy foods, can reduce blood pressure in just 14 days.

4. Drink less alcohol. If you’re a heavy drinker, cutting back to one or two drinks a day can lower systolic blood pressure by 2 to 4 millimeters of mercury (mm Hg). (Blood pressure readings—110/70, for example—are measured in millimeters of mercury; systolic blood pressure is the top or first number, the maximum pressure exerted when the heart contracts.) In addition, avoiding alcohol can help you avoid unwanted calories and keep your weight down.

5. Exercise. In a recent analysis of more than 50 research trials, regular physical activity reduced blood pressure by an average of 4/3 mm Hg. Other research has shown that every 2.2 pounds of weight loss causes blood pressure to drop by about 1/1 mm Hg. Experts recommend at least 30 minutes on most days of the week.

Thousands of patients with high blood pressure could benefit from changing their drug treatment regimen to reduce their risk of cardiac death.

The current U.S. hypertension treatment guidelines recommend using a thiazide diuretic – a drug that increases the volume of urine – alone as the initial drug therapy for high blood pressure. But a failure of diuretic drugs to decrease deaths from heart attacks, an important consequence of hypertension, prompted Vanderbilt University Medical Center researchers to analyze data from existing clinical trials of diuretic drugs.

They found that combining a thiazide diuretic with a “potassium-sparing” drug to treat hypertension reduced both sudden cardiac death and total coronary mortality by 40 percent. The findings call into question the current treatment guidelines.

“The recommendations can now be re-examined in light of these new findings,” said John Oates, M.D., senior author of the study published in the September/October issue of the Journal of the American Society of Hypertension. The Joint National Committee, under the direction of the National Heart, Lung, and Blood Institute, publishes clinical practice guidelines for hypertension – new guidelines are expected in 2009.

Thiazide diuretics successfully reduce blood pressure for many patients, but they are also known to deplete potassium, said Oates, a professor of Medicine and hypertension specialist. This potassium “wasting” has sparked concern over the years with studies suggesting a link between potassium loss and sudden cardiac death.

Oates and colleagues examined data from controlled clinical trials that compared a thiazide diuretic/potassium-sparing (ENaC inhibitor) drug combination to placebo. They generated new, previously unpublished data on sudden death in these trials, and then analyzed the results of the trials in a meta-analysis – a statistical evaluation of data combined from multiple trials. They found a 40 percent reduction in total cardiac mortality and in sudden cardiac death in elderly patients with hypertension taking the drug combination, compared with those receiving placebo.

“It was very striking,” Oates said.

The investigators also performed a new meta-analysis of the clinical trials of thiazides given without a potassium-sparing drug, adding new trials to the mix. They found no benefit in coronary mortality and a 26 percent increase in sudden death. Even though the increase was not statistically significant, it was “going in the direction in which you didn’t want to go,” Oates said.

Observational studies previously had found an increase in sudden cardiac death in patients taking a thiazide diuretic alone, and one showed that sudden death was greater at higher doses of thiazides, he said. Studies in animal models of heart attacks also have demonstrated that low potassium levels (caused by thiazide diuretics) can spark the abnormal heart rhythms that lead to sudden death.

Do thiazide diuretics given alone have an adverse effect of increasing the risk of sudden cardiac death in patients with high blood pressure? It’s possible.

“There’s biologic plausibility for an adverse effect of the thiazides,” Oates said. “If it’s true, it’s probably the largest adverse effect in the history of modern pharmacology. The number of individuals affected over the last 50 years would be staggering.”

And since the current U.S. clinical practice guidelines for hypertension recommend a thiazide diuretic without a potassium-sparing drug, millions of patients may be at increased risk of coronary death, Oates pointed out.

Oates acknowledges that potassium-sparing drugs may reduce coronary mortality through a mechanism unrelated to their prevention of potassium loss. As studies proceed to determine how these drugs reduce death risk, he said, it’s time to add them to thiazides as recommended first-line treatment for high blood pressure in the elderly.

Patricia Hebert, Ph.D., Christopher Coffey, Ph.D., Daniel Byrne, Theresa Scott, Rogert Fagard, M.D., Ph.D., Jeffrey Rottman, M.D., and Katherine Murray, M.D., participated in the current study. The National Institute of General Medical Sciences supported the research. Oates is the Thomas F. Frist Sr. Professor of Medicine.