F.D.A. Requires Cuts to Dosages of Ambien and Other Sleep Drugs

WASHINGTON — For two decades, millions of Americans have taken Ambien to help them sleep at night. But for years, the Food and Drug Administration has gotten complaints that people felt drowsy the morning after taking the medicine or its successors, and sometimes got into car accidents.

On Thursday, after laboratory studies and driving tests confirming the risks of drowsiness, the agency said that women should be taking half as much.

The new recommendation applies to drugs containing the active ingredient zolpidem, by far the most widely used sleep aid. Using lower doses means less of the drug will remain in the blood in the morning hours, and will reduce the risk that people who use it will be impaired while driving.

Sleeping pills have boomed in popularity with the increasingly frantic pace of modern American life. According to IMS, a health care information and technology company, about 60 million prescriptions were dispensed in 2011, up about 20 percent since 2006. About 40 million were for products containing zolpidem.

The agency’s announcement was focused on women because they take longer to metabolize the drug than men. An estimated 10 percent to 15 percent of women will have a level of zolpidem in their blood that could impair driving eight hours after taking the pill, while only about 3 percent of men do, said Dr. Robert Temple, an official in the agency’s Center for Drug Evaluation and Research.

Reports of aftereffects from sleeping pills have circulated for years, and some doctors questioned why the drug agency took so long to act. Mishaps with sleepy driving — and even strange acts of texting, eating or having sex in the night without any memory of it in the morning — have long been familiar to the medical community.

“In this case, the F.D.A. may be behind the 8-ball,” said Daniel Carlat, an associate clinical professor of psychiatry at Tufts University, referring to residual drowsiness. “This has been a known problem. Few doctors will be surprised hearing about this. They’ll say, ‘Oh yeah, we’ve already seen this in our patients.’ ”

He added that Thursday’s announcement “will be good for public health because it will get patients to ask their doctors about the appropriate dosage.”

Agency officials acknowledged that they had received about 700 reports of driving mishaps with people on zolpidem over the years, with a spike in 2007 after a change in labeling caused more people to call in complaints. But they said it was not easy to draw a direct connection between the reports and the drug. Patients often did not remember what time they took the pill. Sometimes they had been drinking.

It was not until the drug agency reviewed driving simulation studies from controlled trials of the drug Intermezzo, which was approved in 2011 for middle-of-the-night waking, that a more complete picture of the risks emerged. The agency linked the driving simulation information with data from manufacturers on the amount of zolpidem in patients’ blood and determined that levels above about 50 nanograms per milliliter increased the risk of crashing while driving, said Dr. Ellis Unger, an official at the agency’s Center for Drug Evaluation and Research.

Dr. Unger said that all makers of new sleeping drugs would now be asked to conduct driving trials; a spokeswoman clarified that it would not be required.

“A lot of people are wondering about the elephant in the room,” Dr. Unger said. “Why did this take so long? This is science, and our thinking evolves over time.”

The drug agency told manufacturers that the recommended dose for women should be lowered to 5 milligrams from 10 for immediate-release products like Ambien, Edluar and Zolpimist. Doses for extended-release products should be lowered to 6.25 milligrams from 12.5, the agency said. Most sleeping drugs containing zolpidem are now generic.

For men, the agency informed manufacturers that labels should recommend that health care providers should “consider” prescribing lower doses.

Patients taking the higher doses should continue them for the time being, officials said, but should consult with their doctors about lowering them. Doctors can still prescribe the higher dose if the lower one does not work. The lower doses are already commercially available, Dr. Unger said, as they are recommended for older patients.

Sanofi, the manufacturer of Ambien and Ambien CR, said in a statement that it agreed that people taking zolpidem “should always talk to their doctor about the most appropriate dose,” and that the label “provides important information” to determine what that is. The company added that it “stands behind the significant clinical data demonstrating the safety and efficacy of Ambien.”

The drug has also been known to cause sleepwalking incidents, and Dr. Unger said there was evidence that the lower dose might ease such events, though it is weaker than the evidence about next-morning-drowsiness. Dr. Carlat said one of his patients discovered that her weight gain while on the drug was from midnight trips to the kitchen she did not even remember taking.

Dr. Daniel Kripke, professor emeritus of psychiatry at the University of California, San Diego, and a leading critic of sleeping pills, welcomed the move but said the agency was still not doing enough to investigate other possible side effects.

“It’s a very small step in the right direction,” he said. He added that sleeping medications like zolpidem might increase total sleep time by 20 minutes a night, but that most studies suggest that the use of sleeping pills impairs a person’s performance the next day.

Critics of the drug agency said the label on Intermezzo, which very clearly denotes the risks for women, indicate that the agency was aware of these problems earlier.

But Thomas Roth, director of the sleep center at Henry Ford Hospital in Detroit who has been a consultant to sleeping pill makers, said that the drug agency had always been concerned about the potential risks with driving, “but they care about it more now.” He said he believed the lower dose would still be effective for many patients.

Agency officials say all patients are unique and doses will need to be tailored. They say the drugs should be prescribed at the lowest dose required.

Dr. Daniel J. Buysse, professor of psychiatry at the University of Pittsburgh School of Medicine, said he already prescribed the lower dose when he feels it is necessary, by telling patients to cut a tablet in half along the score.

“This just tells me, maybe be a little bit more cautious,” said Dr. Buysse, who has been a consultant for drug companies including the maker of Ambien. “But I do not think it will have a big effect on what I do.”

Andrew Pollack contributed reporting from San Francisco.

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Visit by Google Chairman May Benefit North Korea

BEIJING — As a work of propaganda, the images that North Korea circulated this week showing Google’s executive chairman, Eric E. Schmidt, touring a high-tech incubation center are hard to beat.

David Guttenfelder/Associated Press

Eric E. Schmidt, Google’s executive chairman, standing center, with Bill Richardson, standing right, and North Korean soldiers Wednesday at the Grand People’s Study House in Pyongyang.

With former Gov. Bill Richardson of New Mexico at his side, Mr. Schmidt, who is fond of describing the Internet as the enemy of despots, toured what was presented as the hub of the computer industry in one of the world’s most pitiless police states. Both men gazed attentively as a select group of North Koreans showed their ability to surf the Web.

It is unclear what the famously hermetic North Koreans hoped to accomplish by allowing the visit. But the photos of the billionaire entrepreneur taking the time to visit the nation’s computer labs were bound to be useful to a new national leader whom analysts say needs to show his people that their impoverished nation is moving forward.

It will matter little, those experts say, that the visitors were bundled against the cold, indoors — a sign of the country’s extreme privation — or that the vast majority of North Koreans have no access to computers, much less the Web beyond their country’s tightly controlled borders.

The men’s quixotic four-day trip ended Thursday much the way it began, with some analysts calling the visit hopelessly naïve and others describing it as valuable back-channel diplomacy at a time when Washington and Pyongyang are not on speaking terms (again).

“I’m still spinning my wheels to figure out a plausible motivation for why they went,” said Daniel Pinkston, a North Korea specialist at the International Crisis Group.

Mr. Schmidt and Mr. Richardson insist they accomplished some good — showing the world has not forgotten the plight of an American detained in the North, and at least trying to nudge the tightly sealed nation a bit closer to the fold of globally connected nations.

“As the world becomes increasingly connected, their decision to be virtually isolated is very much going to affect their  physical world, their economic growth and so forth,” Mr. Schmidt told reporters after arriving at Beijing International Airport. “We made that alternative very, very clear.”

The unofficial visit, however, raised hackles in Washington, and provided rich fodder for commentators and comedians. Even before the Americans left Pyongyang, someone created an account on Tumblr, the popular social blogging site, called “Eric Schmidt looking at things,” that parodied sites (themselves parodies) featuring the country’s leaders earnestly inspecting livestock, soldiers or leather insoles. (Mr. Schmidt is shown looking intently at computer screens, “the back of a North Korean Student,” and Mr. Richardson.)

Others were less kind. Senator John McCain, Republican of Arizona, took to Twitter to call the self-appointed delegation “useful idiots,” and John R. Bolton, a former United Nations ambassador, said the delegation was unwittingly feeding the North Korean propaganda mill as it sought to burnish the credentials of Kim Jung-un, the nation’s leader, who is in his 20s.

“Pyongyang uses gullible Americans for its own purposes,” Mr. Bolton wrote in The New York Daily News.

The State Department, meanwhile, called the visit “not particularly helpful” given efforts by the United States to rally international support for tougher sanctions following North Korea’s recent launching of a rocket that intelligence experts say could help in the development of missiles that could one day reach the United States.

As if on cue, the North Korean news media hailed the visit by “the Google team” — which included Jared Cohen, who leads Google’s think tank — highlighting their visit to the mausoleum where Mr. Kim’s grandfather and father lie in state. There, Mr. Richardson and Mr. Schmidt “expressed admiration and paid respect to Comrade Kim Il-sung and Comrade Kim Jong-il,” the North’s main party newspaper, Rodong Sinmun, said.

Choe Sang-Hun contributed reporting from Seoul, South Korea, Claire Cain Miller from San Francisco, and Edward Wong from Beijing.

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Iran Finding Ways to Circumvent Sanctions, Treasury Department Says

Despite onerous sanctions that have basically shut Iran out of the global financial system, the country is still finding ways to bypass them, the Treasury Department said Thursday in an acknowledgment of what it described as an “emerging threat” to the effectiveness of the sanctions effort.

Adam Szubin, director of the Treasury’s Office of Foreign Assets Control, which supervises American enforcement of the sanctions, said the Iranians were using private exchange houses and trading companies in other countries, masking transactions with fake identities and relying on the paperless practice known as hawala, common in parts of the Middle East and Asia, in which money is transferred informally and often illegally through trustworthy couriers.

Mr. Szubin’s office issued an advisory on Thursday aimed at informing American financial institutions about what it called Iranian evasion techniques to circumvent the sanctions, which have been greatly intensified partly in response to Iran’s disputed nuclear program. Iran says the program is for peaceful use, while Western nations and Israel suspect it is meant to develop the ability to make nuclear weapons.

The most vexing sanctions, from Iran’s viewpoint, are financial prohibitions that have blacklisted many Iranian banks, denied them access to international money and credit channels and severely restricted Iran’s ability to sell oil, the most important Iranian export. A new law signed by President Obama this month expands the sanctions to include shipping, shipbuilding and energy concerns, which are likely to hurt many Iranian industries, including construction, machinery and automaking.

In a conference call with reporters, Mr. Szubin described the sanctions as a large achievement that had left Iran “almost without recourse through ordinary banking channels.” At the same time, he said, “Iran is adapting.”

“Increasingly we’re seeing them turn to trading houses in third countries,” he said, “to facilitate movement of money that would ordinarily go through a bank.”

The practice of hawala, he said, is much more difficult to monitor and disrupt. “That said, hawalas are even less perfect substitutes for banks,” he said. “It’s a mechanism that only works if you have absolute trust of the individuals involved.”

Mr. Szubin declined to quantify the total amount of money he said Iran had amassed despite the sanctions. Nor would he identify the trading houses — — or even the countries — where circumventions have been carried out, but said “we are pursuing a number of cases.”

He also said the transactions in question were often in the tens of thousands of dollars range and denominated in dollars, euros, British pounds and yen. Larger sums, he said, would be more likely to attract attention.

“This is an evolving and emerging threat,” he said. “Two years ago we saw little of this because Iran was able to find banks that were able to handle its business.”

Iranian officials have increasingly acknowledged that the American sanctions, coupled with a European Union oil embargo that took effect in July, are causing severe financial difficulties and aggravating problems caused in part by the government’s own economic mismanagement. Even the oil minister, who had repeatedly denied the sanctions were having an effect, acknowledged this week that oil exports and revenue plunged by more than 40 percent last year compared with the year before.

On Wednesday, Iran’s Central Bank said the annual inflation rate reached 27.4 percent at the end of 2012, one of the highest rates ever quoted. But private economists say even that figure vastly understates the real inflation rate and fails to fully account for a plunge in the value of Iran’s currency, the rial, which lost about 50 percent of its worth against the dollar in the past year.

Steve H. Hanke, a Johns Hopkins University economics professor and senior fellow at the Cato Institute, a conservative Washington research group, who has been following Iran’s case, said the official inflation rate reflected what he called the Central Bank’s “habit of failing to release useful economic data, and what it does release often has what I would describe as an ‘Alice in Wonderland’ quality.”

By Mr. Hanke’s calculations, Iran’s inflation rate last year was 110 percent.

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2 Years Into Nokia Turnaround, Some Good News

Nearly two years ago, Stephen A. Elop, Nokia’s new chief executive, spoke of flaming ocean platforms and shark-infested waters to describe the problems he inherited as the company teetered on the brink of irrelevance.

Mr. Elop painted the bleak outlook as he prescribed a radical cure for the Finnish mobile phone pioneer: The rejection of the company’s own Symbian smartphone operating system for a shotgun wedding to Microsoft, itself stumbling badly with smartphone software. After that, sales slumped sharply, losses mounted and huge layoffs followed.

On Thursday, he delivered unexpected good news: a profit. Sales of its new smartphone line, the Lumia, powered by Microsoft’s Windows Phone operating system, soared more than 50 percent in the fourth quarter of last year, according to preliminary financial information.

In what was seen as a make-or-break quarter, Mr. Elop said Nokia would break even or turn a 2 percent profit rather than report a loss as large as 10 percent, as analysts expected.

Nokia will report its earnings on Jan. 24.

Wall Street reacted to the announcement by sending Nokia’s American depositary receipts up 18.67 percent, or 70 cents, to $4.45.

“While we definitely experienced some tough challenges in the first half of 2012, we are managing through these issues,” Mr. Elop said in a conference call with journalists.

What Nokia has accomplished under Mr. Elop is to produce a line of increasingly competitive smartphones that are starting to draw favorable comparisons with those from Samsung and Apple, the two companies most responsible for knocking Nokia from its lofty perch.

“The Lumia smartphones are night-and-day different from Nokia’s old Symbian handsets,” said Francisco Jeronimo, an analyst with the International Data Corporation in London. “I think what we are starting to see now is what will be a steady turnaround in Nokia’s fortunes.”

The company, which dominated the cellphone business until Apple introduced its iPhone in 2007, still has a long way to go to achieve its former stature. In the third quarter, Nokia held on to a 4 percent share of the global smartphone market, and was ranked a distant No. 10 in the sector, according to Strategy Analytics, a research firm.

Samsung and Apple, the No. 1 and No. 2 smartphone makers, together had 50 percent of the global smartphone market, and their sales were growing. While its competitors rose, Nokia has generated nearly 5 billion euros ($6.5 billion) in losses under Mr. Elop, and eliminated a third of its work force.

The key to its turnaround was the introduction in October of the top-of-the-line Lumia 920 and 820, which used the new Windows Phone 8 operating system. Since then, Nokia has spent heavily on advertising in Britain and Europe to promote the models. The company will not disclose how much it had spent on its campaign, but its television ads were ubiquitous over the holidays, said Neil Mawston, an analyst at Strategy Analytics in London.

The heavy promotion, which was aided by Microsoft’s own advertising, has helped the company recapture some of its lost glory, Mr. Mawston said.

But he warned that “Nokia still lacks the true killer phone that will enable it to compete with the iPhone 5 or Samsung Galaxy S III.” He expected Nokia’s share of the global smartphone market to rise to 6 percent by the end of the year.

The company’s financial position is likely to revive even more quickly as a result of the strict cost-cutting imposed by Mr. Elop, who ran Microsoft’s business software division before joining Nokia in late 2010.

Since then, Nokia has shut factories across Europe. Last month, the company sold its 540,000-square-foot glass-and-wood headquarters in the Helsinki suburb of Espoo to Finnish investors, and leased it back. The maneuver netted Nokia 170 million euros.

Besides a more competitive array of phones, Nokia has discarded its market-leader mentality. Employees are now routinely traveling in economy class and sharing rides to airports. Workers no longer use costly telephone conference calling but speak in group teleconferences using less expensive Internet calling services.

“The company is a lot smaller now but people are working better together,” said Susan Sheehan, a Nokia spokeswoman. “Everyone has been pitching in.”

Even at Nokia Siemens, the company’s long-suffering network equipment venture, the future is looking brighter than it was two years ago. On Thursday, Nokia said the unit, which contributes about 40 percent of total sales, would report an operating profit for the quarter, its third consecutive quarterly profit.

Nokia, in its announcement to investors, even revised the operating profit margin forecast at the venture to 13 to 15 percent of sales, up from a range of 4 to 12 percent.

Looking ahead, Nokia said it expected to return to an operating loss of 2 percent of sales because of the first-quarter postholiday buying lull and fierce competition. But the results for the coming three months could vary widely.

Pete Cunningham, an analyst at Canalys, a research firm in Reading, England, said that Nokia still faced challenges. “2013 could still turn out to be another very difficult year for Nokia. It is way too premature to say that the company has made a turnaround.”

Mr. Cunningham said he used the Lumia 920, Nokia’s newest smartphone, during the Christmas holidays and liked it.

“But the more I used the phone, the more apparent it became to me that there are big gaps between Lumia and its competitors in terms of the functionality and usability of its apps,” Mr. Cunningham said.

“I still think there is a lot of work to be done on Lumia.”

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Pap Test May Prove Useful at Detecting More Types of Cancer, Study Suggests

The Pap test, which has prevented countless deaths from cervical cancer, may eventually help to detect cancers of the uterus and ovaries as well, a new study suggests.

For the first time, researchers have found genetic material from uterine or ovarian cancers in Pap smears, meaning that it may become possible to detect three diseases with just one routine test.

But the research is early, years away from being used in medical practice, and there are caveats. The women studied were already known to have cancer, and while the Pap test found 100 percent of the uterine cancers, it detected only 41 percent of the ovarian cancers. And the approach has not yet been tried in women who appear healthy, to determine whether it can find early signs of uterine or ovarian cancer.

On the other hand, even a 41 percent detection rate would be better than the status quo in ovarian cancer, particularly if the detection extends to early stages. The disease is usually advanced by the time it is found, and survival rates are poor. About 22,280 new cases were expected in the United States in 2012, and 15,500 deaths. Improved tests are urgently needed.

Uterine cancer has a better prognosis, but still kills around 8,000 women a year in the United States.

These innovative applications of the Pap test are part of a new era in which advances in genetics are being applied to the detection of a wide variety of cancers or precancerous conditions. Scientists are learning to find minute bits of mutant DNA in tissue samples or bodily fluids that may signal the presence of hidden or incipient cancers.

Ideally, the new techniques would find the abnormalities early enough to cure the disease or even prevent it entirely. But it is too soon to tell.

“Is this the harbinger of things to come? I would answer yes,” said Dr. Bert Vogelstein, director of the Ludwig Center for Cancer Genetics and Therapeutics at Johns Hopkins University, and a senior author of a report on the Pap test study published on Wednesday in the journal Science Translational Medicine. He said the genomes of more than 50 types of tumors had been sequenced, and researchers were trying to take advantage of the information.

Similar studies are under way or are being considered to look for mutant DNA in blood, stool, urine and sputum, both to detect cancer and also to monitor the response to treatment in people known to have the disease.

But researchers warn that such tests, used for screening, can be a double-edged sword if they give false positive results that send patients down a rabbit hole of invasive tests and needless treatments. Even a test that finds only real cancers may be unable to tell aggressive, dangerous ones apart from indolent ones that might never do any harm, leaving patients to decide whether to watch and wait or to go through surgery, chemotherapy and radiation with all the associated risks and side effects.

“Will they start recovering mutations that are not cancer-related?” asked Dr. Christopher P. Crum, a professor at Harvard Medical School who was not involved in the research.

But he also called the study a “great proof of principle,” and said, “Any whisper of hope to women who suffer from endometrial or ovarian cancer would be most welcome.”

DNA testing is already performed on samples from Pap tests, to look for the human papillomavirus, or HPV, which causes cervical cancer. Dr. Vogelstein and his team decided to try DNA testing for cancer. They theorized that cells or DNA shed from cancers of the ovaries and the uterine lining, or endometrium, might reach the cervix and turn up in Pap smears.

The team picked common mutations found in these cancers, and looked for them in tumor samples from 24 women with endometrial cancer and 22 with ovarian cancer. All the cancers had one or more of the common mutations.

Then, the researchers performed Pap tests on the same women, and looked for the same DNA mutations in the Pap specimens. They found the mutations in 100 percent of the women with endometrial cancer, but in only 9 of the 22 with ovarian cancer. The test identified two of the four ovarian cancers that had been diagnosed at an early stage.

Finally, the team developed a test that would look simultaneously for cancer-associated mutations in 12 different genes in Pap samples. Used in a control sample of 14 healthy women, the test found no mutations — meaning no false-positive results.

Dr. Luis A. Diaz, the other senior author of the report and an associate professor of oncology at Johns Hopkins, called the research a step toward a screening test that at first blush appears very effective at detecting endometrial cancer, though obviously less so at finding ovarian cancer.

“Probably one of the most exciting features of this approach,” Dr. Diaz said, “is that we wanted a test that would seamlessly integrate with routine medical practice that could be utilized with the same test that women get every day all over the world, the Pap smear.”

But, he added: “We can’t say it’s ready for prime time. Like all good science, it needs to be validated.”

He and other members of the team said it might be possible to improve the detection rate for ovarian cancer by looking for more mutations and by changing the technique of performing Pap tests to increase the likelihood of capturing cells from the ovary. The change might involve timing the test to a certain point in a woman’s monthly cycle, using a longer brush to collect cells from deeper within the cervix or prescribing a drug that would raise the odds of cells being shed from the ovary.

The technique also needs to be tested in much larger groups of women, including healthy ones, to find out whether it works, particularly at finding cancers early enough to improve survival. And studies must also find out whether it generates false positive results, or identifies cancers that might not actually need to be treated.

Michael H. Melner, a program director in molecular genetics and biochemistry for the American Cancer Society, called the research “very promising,” in part because it is based on finding mutations.

“It tells you not just that cancer is there, but which mutation is there,” Dr. Melner said. “As we learn more and more about which mutations are associated with more or less severe forms of cancer, it’s more information, and possibly more diagnostic.”

Read More..

Pap Test May Prove Useful at Detecting More Types of Cancer, Study Suggests

The Pap test, which has prevented countless deaths from cervical cancer, may eventually help to detect cancers of the uterus and ovaries as well, a new study suggests.

For the first time, researchers have found genetic material from uterine or ovarian cancers in Pap smears, meaning that it may become possible to detect three diseases with just one routine test.

But the research is early, years away from being used in medical practice, and there are caveats. The women studied were already known to have cancer, and while the Pap test found 100 percent of the uterine cancers, it detected only 41 percent of the ovarian cancers. And the approach has not yet been tried in women who appear healthy, to determine whether it can find early signs of uterine or ovarian cancer.

On the other hand, even a 41 percent detection rate would be better than the status quo in ovarian cancer, particularly if the detection extends to early stages. The disease is usually advanced by the time it is found, and survival rates are poor. About 22,280 new cases were expected in the United States in 2012, and 15,500 deaths. Improved tests are urgently needed.

Uterine cancer has a better prognosis, but still kills around 8,000 women a year in the United States.

These innovative applications of the Pap test are part of a new era in which advances in genetics are being applied to the detection of a wide variety of cancers or precancerous conditions. Scientists are learning to find minute bits of mutant DNA in tissue samples or bodily fluids that may signal the presence of hidden or incipient cancers.

Ideally, the new techniques would find the abnormalities early enough to cure the disease or even prevent it entirely. But it is too soon to tell.

“Is this the harbinger of things to come? I would answer yes,” said Dr. Bert Vogelstein, director of the Ludwig Center for Cancer Genetics and Therapeutics at Johns Hopkins University, and a senior author of a report on the Pap test study published on Wednesday in the journal Science Translational Medicine. He said the genomes of more than 50 types of tumors had been sequenced, and researchers were trying to take advantage of the information.

Similar studies are under way or are being considered to look for mutant DNA in blood, stool, urine and sputum, both to detect cancer and also to monitor the response to treatment in people known to have the disease.

But researchers warn that such tests, used for screening, can be a double-edged sword if they give false positive results that send patients down a rabbit hole of invasive tests and needless treatments. Even a test that finds only real cancers may be unable to tell aggressive, dangerous ones apart from indolent ones that might never do any harm, leaving patients to decide whether to watch and wait or to go through surgery, chemotherapy and radiation with all the associated risks and side effects.

“Will they start recovering mutations that are not cancer-related?” asked Dr. Christopher P. Crum, a professor at Harvard Medical School who was not involved in the research.

But he also called the study a “great proof of principle,” and said, “Any whisper of hope to women who suffer from endometrial or ovarian cancer would be most welcome.”

DNA testing is already performed on samples from Pap tests, to look for the human papillomavirus, or HPV, which causes cervical cancer. Dr. Vogelstein and his team decided to try DNA testing for cancer. They theorized that cells or DNA shed from cancers of the ovaries and the uterine lining, or endometrium, might reach the cervix and turn up in Pap smears.

The team picked common mutations found in these cancers, and looked for them in tumor samples from 24 women with endometrial cancer and 22 with ovarian cancer. All the cancers had one or more of the common mutations.

Then, the researchers performed Pap tests on the same women, and looked for the same DNA mutations in the Pap specimens. They found the mutations in 100 percent of the women with endometrial cancer, but in only 9 of the 22 with ovarian cancer. The test identified two of the four ovarian cancers that had been diagnosed at an early stage.

Finally, the team developed a test that would look simultaneously for cancer-associated mutations in 12 different genes in Pap samples. Used in a control sample of 14 healthy women, the test found no mutations — meaning no false-positive results.

Dr. Luis A. Diaz, the other senior author of the report and an associate professor of oncology at Johns Hopkins, called the research a step toward a screening test that at first blush appears very effective at detecting endometrial cancer, though obviously less so at finding ovarian cancer.

“Probably one of the most exciting features of this approach,” Dr. Diaz said, “is that we wanted a test that would seamlessly integrate with routine medical practice that could be utilized with the same test that women get every day all over the world, the Pap smear.”

But, he added: “We can’t say it’s ready for prime time. Like all good science, it needs to be validated.”

He and other members of the team said it might be possible to improve the detection rate for ovarian cancer by looking for more mutations and by changing the technique of performing Pap tests to increase the likelihood of capturing cells from the ovary. The change might involve timing the test to a certain point in a woman’s monthly cycle, using a longer brush to collect cells from deeper within the cervix or prescribing a drug that would raise the odds of cells being shed from the ovary.

The technique also needs to be tested in much larger groups of women, including healthy ones, to find out whether it works, particularly at finding cancers early enough to improve survival. And studies must also find out whether it generates false positive results, or identifies cancers that might not actually need to be treated.

Michael H. Melner, a program director in molecular genetics and biochemistry for the American Cancer Society, called the research “very promising,” in part because it is based on finding mutations.

“It tells you not just that cancer is there, but which mutation is there,” Dr. Melner said. “As we learn more and more about which mutations are associated with more or less severe forms of cancer, it’s more information, and possibly more diagnostic.”

Read More..

Delegation to North Korea Urges More Access to Internet and Cellphones

PYONGYANG, North Korea (AP) — A private delegation to North Korea that includes Google’s executive chairman, Eric E. Schmidt, is urging North Korea to allow more open Internet access and cellphones, although it is unclear how that message is being heard by a leadership that has long depended on a near-total ban on outside information to maintain its totalitarian rule.

Bill Richardson, the former New Mexico governor leading the delegation, said Wednesday in an interview in Pyongyang, the North’s capital, that his nine-member group had also called on North Korea to put a moratorium on missile launchings and nuclear tests that have prompted United Nations sanctions.

He said the group had also asked for “fair and humane treatment” for Kenneth Bae, a naturalized American citizen born in South Korea who was detained by the North in November and charged with unspecified “hostile acts.”

The delegation’s visit has been criticized as appearing to hijack United States diplomacy and bolster North Korea’s profile after its latest, widely condemned rocket launching less than a month ago.

The State Department characterized the trip as unhelpful at a time when the United States is rallying support for sanctions by the United Nations Security Council as a response to the launching.

North Korea has shown no inclination to back off its nuclear program or to stop the launchings that it depicts as needed to send satellites into orbit, but that Western countries believe are tests for technology to create missiles that could eventually be used to deliver nuclear weapons.

Mr. Schmidt is the highest-profile American business executive to visit North Korea since Kim Jong-un took power a year ago. A vocal proponent of Internet freedom and openness, Mr. Schmidt has not said publicly what he hopes to get out of the visit. On Wednesday, he toured the frigid brick building in central Pyongyang that was presented as the heart of North Korea’s computer industry, at one point briefly donning a pair of 3-D goggles.

Mr. Kim has emphasized the importance of computerizing factories, many of which have fallen into disrepair in the years since the collapse of the former Soviet Union deprived the country of its main provider of technology. But he also has vowed in recent weeks to crack down on the “enemy’s ideological and cultural infiltration,” apparently a reference to the growing flow of information over the border with China.

That flow has been driven in part by North Koreans who sneak into China to bring much-needed food and goods back home, but who also bring back news of the outside world and sometimes DVDs and thumb drives containing banned South Korean dramas.

Mr. Richardson, who has described the delegation as a private humanitarian mission, said the members were bringing a message that more openness would benefit North Korea. Almost no one in the impoverished country owns computers, and even many of the computers that are allowed are not hooked up to the Internet, according to analysts who study the North. They say that even the small number of North Koreans allowed onto the Web — a group said to include party loyalists and computer science students — are severely restricted in what they can access.

On Tuesday, Mr. Schmidt, Mr. Richardson and other delegation members chatted with students who have permission to access the Internet for research at the elite Kim Il-sung University in Pyongyang.

On Wednesday, the group toured the main library in Pyongyang, the Grand People’s Study House, where people were crowded into drafty, unheated halls at computers with intranet access to the library’s archive of books, documents and newspapers.

Later, the delegation visited the Korea Computer Center, the hub of North Korea’s efforts to develop software, where a quote from the current leader’s father and predecessor as leader, Kim Jong-il, reads: “Now is the era for science and technology. It is the era of computers.”

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World Briefing | The Americas: Mexico: Killer Dog Case Widens

A pack of feral dogs may be responsible for the deaths of as many as five people in a Mexico City park, the authorities said Wednesday. Last week, the police said dogs had killed four people, including a woman and a baby boy, whose mutilated bodies were found in the park in December. Now, prosecutors are investigating if the wounds found on a fifth person, a 15-year-old girl who died in December, are consistent with dog bites. The authorities have captured several dogs, spurring an online campaign to save them, but it is not clear if any are the culprits.

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James M. Buchanan, Economic Scholar, Dies at 93

James M. Buchanan, a scholar and author whose analyses of economic and political decision-making won the 1986 Nobel in economic sciences and shaped a generation of conservative thinking about deficits, taxes and the size of government, died on Wednesday in Blacksburg, Va. He was 93.

Alex Tabarrok, the director of the Center for Study of Public Choice at George Mason University, which Mr. Buchanan founded, confirmed his death.

Dr. Buchanan, a professor emeritus at George Mason, in Fairfax, Va., was a leading proponent of public choice theory, which assumes that politicians and government officials, like everyone else, are motivated by self-interest — getting re-elected or gaining more power — and do not necessarily act in the public interest.

He argued that their actions could be analyzed, and even predicted, by applying the tools of economics to political science in ways that yield insights into the tendencies of governments to grow, increase spending, borrow money, run large deficits and let regulations proliferate.

The logic of self-interest was nothing new. Machiavelli’s 16th-century treatise “The Prince” detailed cynical rules of statecraft to extend political power. Thomas Hobbes, in his 17th-century book “Leviathan,” held that aggressive, self-serving acts were “natural” unless forbidden by law. Adam Smith’s “The Wealth of Nations,” published in 1776, noted that people pursuing their own good also produced benefits for society at large.

But Dr. Buchanan contended that the pursuit of self-interest by modern politicians often led to harmful public results. Courting voters at election time, for example, legislators will approve tax cuts and spending increases for projects and entitlements favored by the electorate. This combination can lead to ever-rising deficits, public debt burdens and increasingly large governments to conduct the public’s business.

Indeed, he said, governments had grown so vast and complex that it was no longer possible for elected officials to make more than a fraction of the policy decisions that genuinely affect the people. Thus, he said, much discretionary power is actually held by civil functionaries who can manipulate priorities, impose barriers to entitlements and pressure legislators for rules and budgets favorable to their own interests.

Dr. Buchanan did not invent the theory of public choice, an idea whose origins are obscure but that arose in modern economics literature in the late 1940s. But from the 1950s onward, he became its leading proponent, spearheading a group of economists in Virginia that sought to change the nature of the political process, to bring it more into line with what the group considered the wishes of most Americans.

In lectures, articles and more than 30 books, Dr. Buchanan amplified on the theory of public choice and argued for smaller government, lower deficits and fewer regulations — a spectrum of policy objectives that were ascendant in the 1980s conservative agenda of President Ronald Reagan.

Over the years since Dr. Buchanan won the Nobel, much of what he predicted has played out. Government is bigger than ever. Tax revenue has fallen far short of public programs’ needs. Public and private borrowing has become a way of life. Politicians still act in their own interests while espousing the public good, and national deficits have soared into the trillions.

Dr. Buchanan partly blamed Keynesian economics for what he considered a decline in America’s fiscal discipline. John Maynard Keynes argued that budget deficits were not only unavoidable but in fiscal emergencies were even desirable as a means to increase spending, create jobs and cut unemployment. But that reasoning allowed politicians to rationalize deficits under many circumstances and over long periods, Dr. Buchanan contended.

In a commentary in The New York Times in March 2011, Tyler Cowen, an economics professor at George Mason, said his colleague Dr. Buchanan had accurately forecast that deficit spending for short-term gains would evolve into “a permanent disconnect” between government outlays and revenue.

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Gaps Seen in Therapy for Suicidal Teenagers

Most adolescents who plan or attempt suicide have already received at least some mental health treatment, raising questions about the effectiveness of current approaches to helping troubled youths, according to the largest in-depth analysis to date of suicidal behaviors in American teenagers.

The study, in the journal JAMA Psychiatry, found that 55 percent of suicidal teenagers had received some therapy before they thought about suicide, planned it or tried to kill themselves, contradicting the widely held belief that suicide is due in part to a lack of access to treatment.

The findings, based on interviews with a nationwide sample of more than 6,000 teenagers and at least one parent of each, linked suicidal behavior to complex combinations of mood disorders like depression and behavior problems like attention-deficit and eating disorders, as well as alcohol and drug abuse.

The study found that about one in eight teenagers had persistent suicidal thoughts at some point, and that about a third of those who had suicidal thoughts had made an attempt, usually within a year of having the idea.

Previous studies have had similar findings, based on smaller, regional samples. But the new study is the first to suggest, in a large nationwide sample, that access to treatment does not make a big difference.

The study suggests that effective treatment for severely suicidal teenagers must address not just mood disorders, but also behavior problems that can lead to impulsive acts, experts said. According to the Centers for Disease Control and Prevention, 1,386 people between the ages of 13 and 18 committed suicide in 2010, the latest year for which numbers are available.

“I think one of the take-aways here is that treatment for depression may be necessary but not sufficient to prevent kids from attempting suicide,” said Dr. David Brent, a professor of psychiatry at the University of Pittsburgh, who was not involved in the study. “We simply do not have empirically validated treatments for recurrent suicidal behavior.”

The report said nothing about whether the therapies given were state of the art or carefully done, said Matt Nock, a professor of psychology at Harvard and the lead author, and it is possible that some of the treatments prevented suicide attempts. “But it’s telling us we’ve got a long way to go to do this right,” Dr. Nock said. His co-authors included Ronald C. Kessler of Harvard and researchers from Boston University and Children’s Hospital Boston.

Margaret McConnell, a consultant in Alexandria, Va., said her daughter Alice, who killed herself in 2006 at the age of 17, was getting treatment at the time. “I think there might have been some carelessness in the way the treatment was done,” Ms. McConnell said, “and I was trusting a 17-year-old to manage her own medication. We found out after we lost her that she wasn’t taking it regularly.”

In the study, researchers surveyed 6,483 adolescents from the ages of 13 to 18 and found that 9 percent of male teenagers and 15 percent of female teenagers experienced some stretch of having persistent suicidal thoughts. Among girls, 5 percent made suicide plans and 6 percent made at least one attempt (some were unplanned).

Among boys, 3 percent made plans and 2 percent carried out attempts, which tended to be more lethal than girls’ attempts.

(Suicidal thinking or behavior was virtually unheard-of before age 10.)

Over all, about one-third of teenagers with persistent suicidal thoughts went on to make an attempt to take their own lives.

Almost all of the suicidal adolescents in the study qualified for some psychiatric diagnosis, whether depression, phobias or generalized anxiety disorder. Those with an added behavior problem — attention-deficit disorder, substance abuse, explosive anger — were more likely to act on thoughts of self-harm, the study found.

Doctors have tested a range of therapies to prevent or reduce recurrent suicidal behaviors, with mixed success. Medications can ease depression, but in some cases they can increase suicidal thinking. Talk therapy can contain some behavior problems, but not all.

One approach, called dialectical behavior therapy, has proved effective in reducing hospitalizations and suicide attempts in, among others, people with borderline personality disorder, who are highly prone to self-harm.

But suicidal teenagers who have a mixture of mood and behavior issues are difficult to reach. In one 2011 study, researchers at George Mason University reduced suicide attempts, hospitalizations, drinking and drug use among suicidal adolescent substance abusers. The study found that a combination of intensive treatments — talk therapy for mood problems, family-based therapy for behavior issues and patient-led reduction in drug use — was more effective than regular therapies.

“But that’s just one study, and it’s small,” said Dr. Brent of the University of Pittsburgh. “We can treat components of the overall problem, but that’s about all.”

Ms. McConnell said that her daughter’s depression had seemed mild and that there was no warning that she would take her life. “I think therapy does help a lot of people, if it’s handled right,” she said.

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