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The investigators conducted a family linkage study in which they searched for commonalities in the genomes of family members with bipolar disorder and a history of attempted suicide. The same gene region on chromosome 2 that was identified by this bipolar disorder and attempted suicide study was recently identified by two complementary family studies that looked at attempted suicide in families with major depression and alcohol dependence. "Family linkage studies are not always consistent, so the fact that all three studies, including ours, point to the same region of the genome is a good indication that we are on the right track toward identifying a gene or genes that play a role in why a person chooses to take his or her own life," says Willour. In a multi-institutional study, the researchers examined data from 162 families with bipolar disorder. They looked at attempted suicide in this sample because it is an important clinical problem that tends to occur more often in some of these families than in others, suggesting a distinctive genetic basis, according to senior author James B. Potash, M.D., M.P.H., of the Department of Psychiatry at Johns Hopkins. This technique, of looking at sub-types of illness, is used by genetic researchers as a way to reduce genetic complexity. From the 162 families, the researchers selected 417 subjects who were diagnosed with schizoaffective/bipolar disorder, bipolar I disorder or bipolar II disorder. These subjects were asked whether they had ever attempted suicide and the degree of intent of the most serious attempt. One hundred fifty-four subjects said they had attempted suicide, and 122 stated that they had "definite" intent. For the purpose of this study, the latter were considered to have a history of attempted suicide. Data for all 417 subjects was entered into a computer program that looks for genetic similarities between subjects with similar psychological profiles. Results indicated that family members with a history of attempted suicide and bipolar disorder showed a high degree of genetic similarity at a specific area -- DNA marker D2S1777 -- on a section of chromosome 2 referred to as 2p12. This is the same marker implicated in a 2004 study from the University of Pittsburgh School of Medicine that looked at attempted suicide and major depression. And it is close to another marker, D2S1790, located in the 2p11 region of chromosome 2, which was identified in a 2004 study from the University of Connecticut School of Medicine that looked at alcoholism and attempted suicide. Willour says that although the study does not pinpoint a specific gene responsible for attempted suicide, it does suggest a "neighborhood" in which the gene might be found. She adds that the next step is to further narrow the search and find the "address." "Once we have located the specific gene," she says, "we can better identify people who might be at risk of suicide and offer drug companies a target for possible therapies." Funding for this study came from the National Institute of Mental Health.   GENE HUNTERS CLOSE IN ON LOU GEHRIG'S DISEASE   In the first genome-wide search for the genetic roots of the most common form of amyotrophic lateral sclerosis (ALS), Johns Hopkins scientists have newly identified 34 unique variations in the human genetic code among 276 unrelated subjects with ALS. "Although we haven't located the exact gene responsible for sporadic ALS, our results seriously narrow the search and bring us that much closer to finding what we need to start developing treatments for the disease," says Bryan J. Traynor, M.D., of the Department of Neurology at The Johns Hopkins University School of Medicine. ALS, also known as Lou Gehrig's disease for the legendary Yankee first baseman who succumbed to its paralyzing assault on the nervous system, kills 10,000 Americans a year. An estimated one in 2,000 people is at risk of developing the disease. Genes behind inherited forms of ALS -- responsible for about only 5 percent of all cases -- were discovered a decade ago, but no genetic roots have previously been found for sporadic ALS, which occurs in people without a family history of the disease. In the Johns Hopkins study, Traynor and his team scanned the entire genome of 276 adult male and female subjects with sporadic ALS and 271 adult male and female subjects with no history of neurological disease. The researchers found 34 genetic variants that ALS patients were more likely to have compared to normal individuals without the disease. "This is the first major step toward understanding how genetics may influence the most common form of ALS," says co-researcher Jeffrey D. Rothstein, M.D., Ph.D., professor in the Department of Neurology at Johns Hopkins. "The results will not only help us to better understand sporadic ALS but also to tailor tools that will reveal therapies for it." Traynor cautioned that the 34 SNPs are not guaranteed trail markers for ALS genes. "If you roll dice 555,352 times, you are bound to get lucky by chance alone on some of those throws," he says. "The next step is to go back and figure out which of these 'hits' are real and which are false." Traynor says a follow-up study is in the works that will replicate the research using a similar number of patients and controls. Traynor, who has a joint affiliation with the National Institute of Mental Health in Bethesda, Md., collaborated in this study with lead author Jennifer Schymick and fellow researcher John Hardy, Ph.D., both of the Laboratory of Neurogenetics at the National Institute on Aging in Bethesda. This study was supported by funding from the National Institute of Neurological Disorders and Stroke, the Packard Center for ALS Research at Johns Hopkins and the ALS Association.   WIDELY USED HEPATITIS B DRUG SPURS HIV DRUG RESISTANCE   A Johns Hopkins study has proven false established medical practice that an antiretroviral drug widely used to treat hepatitis B liver infections was safe to use on its own in patients co-infected with HIV. Their findings demonstrate that treatment with entecavir leads to cross-resistance to other antiviral drugs used to treat the AIDS virus. "Our results show that entecavir is no different from any other that has been shown to be active against HIV -- it breeds resistance rapidly, despite its ability to reduce the amount of HIV in the body," says senior study author and infectious disease specialist Chloe Thio, M.D. Researchers say the findings have serious implications for the more than 4 million people worldwide believed to be infected with both viral illnesses but who need to treat their hepatitis B and are not yet on anti-HIV drugs. Authors of the study have informed the U.S. Food and Drug Administration of their results so that prescribing physicians can be notified and so that drug labeling can be changed. They have also notified Bristol-Myers Squibb, which makes and sells entecavir under the brand name Baraclude. "The alert should go out to co-infected people to consult with their physicians immediately about entecavir to see if it is the right drug to treat their hepatitis B in the first place and to evaluate alternative therapies," says Thio, an associate professor of medicine at the Johns Hopkins University School of Medicine. Thio says she has stopped prescribing entecavir as her first option in treating hepatitis B in co-infected patients who are not already using drugs to suppress HIV. "The good news is that co-infected patients already on HIV therapy can still use entecavir to treat their hepatitis B, but the bad news is that there are now fewer options for treating hepatitis B first," she adds. Hepatitis B infection attacks the liver and can lead to cirrhosis, liver cancer or even death from liver failure. According to Thio, some co-infected patients decide first to treat their hepatitis B infection if HIV has not yet weakened their immune system and to avoid the debilitating side effects of anti-HIV medications. In the Johns Hopkins study, researchers found in both laboratory and clinical tests that within six months of entecavir therapy, a so-called M184V mutation of HIV develops. Thio says viruses with this mutation are known to be resistant to lamivudine, better known as 3TC, a medication that prevents HIV replication and "is a cornerstone of most drug-combination therapies used to fight the immune system disease." Because lamivudine is in the same category of HIV therapies as another widely used drug, emtricitabine, its effectiveness is also compromised by entecavir, she says. Thio began to investigate entecavir's effects on HIV in fall 2006 after noticing reports of anti-HIV activity in two co-infected patients, one at the Johns Hopkins Moore Clinic, which specializes in HIV/AIDS care, and another at a San Diego medical center. The patients (and there is now a third case) were taking only entecavir yet showed a tenfold decrease in the amount of HIV in their blood. Previous studies had shown entecavir not to have any significant effects on HIV, but they were based on older tests that could not quantify the effects of HIV on individual immune cells or detect mutations. Thio believed that the recent patient cases called for a more thorough investigation with more advanced techniques. The lab test, developed at Johns Hopkins by study co-author Robert Siliciano, M.D., Ph.D., a professor at Johns Hopkins and a Howard Hughes Medical Institute investigator, specifically tests what drugs affect HIV and can be tailored to probe effects on any particular mutant of HIV. Lab results showed that entecavir, in concentrations less than a tenth of what is used in humans, cut the number of newly infected cells in half. However, at increasing concentrations, the drug had no greater impact on suppressing HIV replication. HIV is a virus renowned for its ability to change form and thus evade or develop resistance to therapies designed to stop its action. When researchers tested the blood of one of the co-infected patients for the M184V mutation, they found none in samples taken at the start of entecavir therapy. But they did find it in 61 percent of viral samples tested after four months of therapy, and 96 percent at six months. More than 1.2 million Americans are infected with hepatitis B. A vaccine against the virus has been available in the United States since 1982, but an estimated 60,000 new infections occurred in the United States in 2004 alone. Hepatitis B is transmitted by contact with blood and other body fluids of an infected person, through sexual activities, injection drug use, sharing of personal care items or direct contact.   RX FOR WRONG-SITE SURGERY: TWO MINUTES OF CONVERSATION   A study of Johns Hopkins surgeons, anesthesiologists and nurses suggests that hospital policies require a brief pre-operation "team meeting" to make sure surgery is performed on the right patient and the right part of the body could decrease errors. In the study, Johns Hopkins OR personnel were "very positive" about the briefings, according to surgeon Martin Makary, M.D., M.P.H., director of the Johns Hopkins Center for Surgical Outcomes Research and lead author of the study. "Although we lack systems for uniform reporting of wrong-site surgeries to understand the extent of the problem, we observed team meetings increase the awareness of OR personnel with regard to the site and procedure and their perceptions of operating rooms safety," says Makary. He stressed that wrong-site surgery is exceptionally rare but entirely preventable. A study published last year in the Archives of Surgery that looked at 2.8 million operations in Massachusetts over a 20-year period suggests that the rate of "wrong-site" surgery anywhere other than the spine is one in every 112,994 operations. The study excluded the spine because researchers defined wrong-site surgeries as operations conducted on a different organ or body part than intended by the surgeon and patient. Since the spine is one body part, even though a surgeon may have operated on the wrong part of the spine, technically it is still the right part of the body. The Joint Commission, which evaluates and accredits nearly 15,000 health care organizations and programs in the United States, requires hospitals to have a presurgical conversation in the OR before every surgery. Although Makary says no national standard was set by the Joint Commission, he and others led efforts at Johns Hopkins to enforce the mandate, developing a standardized OR briefing program that became Johns Hopkins Hospital policy in June 2006. Since then, he has collaborated with Rochester University, Yale, Columbia and Cornell and the World Health Organization to broaden the use and reach of the Johns Hopkins program. The briefing consists of a two-minute meeting during which all members of the OR team state their name and role, and the lead surgeon identifies and verifies such critical components of the operation as the patient's identity, the surgical site and other patient safety concerns. The briefing is performed after anesthesia is administered and prior to incision. A survey, among 147 surgeons, 59 anesthesiologists, 187 nurses and 29 other OR staff, was given twice -- before implementing the policy and after it had been in effect for three months. After training, a 13.2 percent increase in those who believed the policy would be effective was recorded among the OR personnel. And more than 90 percent agreed that "a team discussion before a surgical procedure is important for patient safety." "The Joint Commission identified communication breakdowns as the most common root cause of wrong-site surgeries," says Makary. "Our research indicates that OR personnel see presurgical briefings as a useful tool to help prevent such errors." Before the new policy was implemented, Makary notes, many surgeons would walk into the OR and start working without a conversation of any kind and without even knowing the names of the nurses and other staff who were assisting them. The survey is based on a similar questionnaire designed by the airline industry to assess programs designed to reduce safety errors. Johns Hopkins faculty members Peter J. Pronovost, M.D., Ph.D., and Bryan Sexton, Ph.D., also contributed to the article.   HOPKINS SCIENTISTS UNCOVER CAUSE OF ANTIPSYCHOTIC DRUG WEIGHT GAIN   Johns Hopkins brain scientists have hit on how and why some powerful drugs used for treating mental illnesses cause patients to gain so much weight that they often develop life-threatening complications such as diabetes and heart disease. "We've now connected a whole class of antipsychotics to natural brain chemicals that trigger appetite," says Solomon H. Snyder, M.D., professor of neuroscience at the Johns Hopkins School of Medicine. "Our identification of the molecular players that link such drugs to increased food intake means there's now hope for finding a newer generation of drugs without the weight-gain side effects." Previous research already had fingered increased levels and actions of one particular enzyme, AMPK, in brain cells as a control lever for appetite in mice and presumably humans. Suspecting that antipsychotic drugs might spike AMPK in the brain to overact, the Johns Hopkins team injected mice with clozapine (Clozaril), which, with olanzapine (Zyprexa) and risperidone (Risperdal), is commonly prescribed for schizophrenia and bipolar disorder in people who do poorly on conventional drugs. Mice given clozapine showed quadrupled AMPK activity compared to activity measured pre-drug. The researchers then gave the mice leptin, a hormone that suppresses appetite, and as suspected, saw lowered AMPK levels. Drilling down further into what controls AMPK and its boost of hunger, Sangwon Kim, Ph.D., a research associate and lead author of the study, "rounded up the usual suspects, brain proteins known to relay communication from cell to cell." Systematically manipulating these cell-signaling proteins, Snyder's team found that blocking one in particular, a receptor site for histamine, a well-known player in triggering classic allergy symptoms, activates AMPK to the same extent as clozapine. To confirm that the histamine receptor connects the drug, AMPK activity and appetite, the team gave clozapine to mice genetically engineered without a histamine receptor. Results? Peace. No heightened AMPK activity. "Histamine also has a long history as a suspect in weight control, but no one ever could put a finger on the exact link," says Snyder. "The connection we've made between its receptor and appetite control is incredibly intriguing and opens new avenues for research on weight control, possibly including drugs that suppress appetite safely." The research was funded by the U.S. Public Health Service, Canadian Institute of Health Research, National Institutes of Health and National Multiple Sclerosis Society.   CALL MADE FOR CHANGES IN WOMEN'S HEART DISEASE RISK-FACTOR LIST   Johns Hopkins cardiologists are calling for an expansion of the criteria widely used by physicians to detect and assess a postmenopausal woman's chances of developing cardiovascular disease, the leading cause of death among women in the United States. Roger Blumenthal, M.D., and colleagues say that a family history of heart disease and blood levels of a protein tied to vessel inflammation, C-reactive protein, should quickly be added to traditional assessments of women's risk of suffering a heart attack, stroke or severe chest pain (angina). "Physicians should incorporate these factors into their testing and decision-making about which women are most likely to develop cardiovascular disease," says Blumenthal, an associate professor and director of the Ciccarone Preventive Cardiology Center at The Johns Hopkins University School of Medicine and its Heart Institute. "And physicians should intervene with lifestyle changes and drug treatment before symptoms start to appear," he adds. "Our best means of prevention is through early identification of those most at risk." Blumenthal says these changes could help ameliorate the discrepancy between the death rate for men and women from cardiovascular disease, which has steadily declined for men over the last 20 years, but has remained relatively the same for women. The new risk-factor list would strengthen existing assessment tools, including the Framingham Risk Estimate, which gauges how likely a person is to suffer a fatal or nonfatal heart attack within 10 years and calculates risk based on a summary score of such factors as age, blood pressure, cholesterol levels and smoking. Clear evidence was found that only family history and C-reactive protein, or hsCRP for short, had significant, additional predictive value in determining women really at moderate or high risk of future cardiovascular disease. The new method changed risk scores for at least 20 percent of the women studied. "These are the best data yet to show how we should be assessing our female patients," says Blumenthal, whose own research showed in 2005 that the gold standard Framingham tool failed to identify approximately one-third of women over age 60 who had advanced hardening and narrowing of the arteries for their age and sex. The latest findings are not surprising, the Johns Hopkins team says. Family history - where either a parent or a sibling suffered a coronary event - doubles a woman's own chances of arterial disease. High blood levels of C-reactive protein, in excess of 3 milligrams per liter, also double the risk. And the effects are multiplied if both factors are present, with a woman's risk rising almost fourfold. Also in 2005, Blumenthal and his team suggested additional screening, using CT scans of the arteries and calcium scoring to better find women who would likely benefit from aspirin and statin therapy. Such additional tests, he says, should still be considered for those women with no symptoms and at least two traditional risk factors who are also undergoing lifelong drug therapy with aspirin and lipid-lowering drugs. But, he notes, the latest analysis, which was funded by the Donald W. Reynolds Foundation, provides a thorough review of many potential risk factors and should be applied for all postmenopausal women. Results are available online at http://www.reynoldsriskscore.org Evaluation of the women in the current study included analysis of race, age, body mass index, menopause status, frequency of exercise, alcohol use, postmenopausal hormone use and dietary supplements of vitamin E, other multivitamins and aspirin. Blood factors studied were equally varied and included levels of homocysteine, creatinine, fibrinogen and hemoglobin A1C levels. "Our goal is to make heart attacks less likely to occur and to do so by strongly considering therapies such as aspirin, cholesterol-lowering medications and, possibly, blood pressure medications for individuals at higher risk," says editorial co-author and cardiologist Erin Michos, M.D., a clinical fellow at Johns Hopkins. In addition to researchers' call for change, Michos says that existing treatment guidelines, the 2001 National Cholesterol Education Program Adult Treatment Panel, which currently emphasize the Framingham score, should be revised to incorporate family history and hsCRP.   PATRICK WALSH SELECTED PHYSICIAN OF THE YEAR   Castle Connolly Medical Ltd., the publishing company behind the well-known medical directory America's Top Doctors, has named Johns Hopkins urologist Patrick C. Walsh, M.D., one of three honorees to receive the organization's "Physician of the Year" award. Walsh was selected from a pool of more than 600,000 physicians from around the country. "These awards are really meant to honor those who are at the top of the top, and Dr. Walsh's many contributions to the field of medicine make him truly deserving of this attention," said John J. Connolly, Ed.D., president and CEO of Castle Connolly Medical Ltd. Walsh, University Distinguished Service Professor at Johns Hopkins, was the director of the institution's Brady Urological Institute for three decades. Castle Connolly will honor him in March at an awards dinner in New York City, highlighting his commitment to "clinical excellence." "To be chosen from such a vast pool of worthy award candidates is certainly an honor," says Walsh, who is best known for his pioneering nerve-sparing prostatectomy and meticulous anatomical approach to improving the diagnosis and surgical treatment of benign and malignant prostate tumors. "This is honor not only bestowed upon me, but on all of my colleagues I have worked with through the years, on Johns Hopkins, as the kind of place where translational research happens, and most of all on my patients who have been my loyal partners in discovery." Walsh is the author of several best-selling books and the winner of many distinguished awards honoring his contributions to prostate cancer research, including the Charles F. Kettering Gold Medal from the General Motors Cancer Research Foundation. Nominations for the Physician of the Year category were solicited from the executive and medical leadership of the nation's leading medical centers and specialty hospitals, and from all the physicians profiled in America's Top Doctors. Castle Connolly was founded in 1991. According to company literature, its physician-led research team conducts extensive annual surveys of the medical leadership of leading hospitals and physicians in private practice as part of its overall selection and screening process, before identifying physicians who are among the very best in the nation. The first Physician of the Year Awards was held last year. The event was created to honor doctors who share "an unwavering dedication to their patients and medicine as a whole." The organization's medical advisory board selects three recipients from hundreds of peer-nominated applicants.