Diets low in polyunsaturated fatty acids may be a problem for youngsters

Sep. 13, 2013 — In the first study to closely examine the polyunsaturated fatty acid (PUFA) intake among U.S. children under the age of 5, Sarah Keim, PhD, principal investigator in the Center for Biobehavioral Health at The Research Institute at Nationwide Children's Hospital, has found what might be a troubling deficit in the diet of many youngsters. The study, published online today by Maternal and Child Nutrition, used data on nearly 2500 children age 12 to 60 months from the U.S. National Health and Nutrition Examination Survey.

PUFAs are essential to human health. A proper ratio of omega-6 to omega-3 PUFAs plays an important role in cell function, inflammation, eye development and neural functioning. However, the ideal dietary intake of PUFAs for young children is unclear. Knowing that infants often receive significant amounts of key PUFAs through breast milk and infant formula during the first year of life, Dr. Keim and her colleague, Amy Branum, PhD, MSPH, of the Centers for Disease Control and Prevention, decided to estimate the average intake of PUFAs in the diet for children between infancy and kindergarten.

"The ratio of omega-6 to omega-3 intake was high -- about 10. Some experts use this as an indicator of diet quality, with a high ratio being less healthy," says Dr. Keim. "In addition, intake of a key fatty acid known as DHA in children 12 to 60 months of age was low -- lower than what infants generally consume -- and it did not increase with age."

Dr. Keim's study was also the first to examine the primary dietary sources of PUFA intake among children under the age of 5 and to examine age, race and ethnicity in relation to fish intake in this age group. Fish are an excellent source of fatty acids, such as DHA and EPA, and were shown to be the richest sources of PUFAs in children's diets.

"Only about 54 percent of children ate fish at least once in the previous month. Non-Hispanic black children were more likely than non-Hispanic white children to have eaten fish," says Dr. Keim. "Because diet can be an important contributor to many diseases, it's important to understand how such disparities might contribute to disease risk."

The swift physical and neurological development during this period of childhood may mean that variations in PUFA intake could have important implications for growth, she adds.

"This work could help inform dietary recommendations for children, and may be particularly important for the preterm population," Dr. Keim says. "We are currently carrying out a clinical trial to see if DHA supplementation when children are 1 year of age can help cognitive development in those born preterm."

At present, there is no official dietary recommendation in the U.S. for DHA and EPA intake or supplementation among children, although the Institute of Medicine has issued what they call a "reasonable intake" level of two 3-oz servings of fish per week for children. "According to our research, however, children are clearly not consuming this much fish," says Dr. Keim. In addition, the researchers found that overall intake of key fatty acids, such as DHA and EPA, among U.S. children is only a fraction of what is regularly consumed by young children in certain other countries, including Canada. Other studies suggest that similarly low intakes exist in kids age 5 and older. By incorporating key omega-3 PUFAs into a child's diet at a very early age, Dr. Keim says, it may be more likely to become part of a lifelong diet.

Dr. Keim hopes her work will contribute to a more detailed understanding of the diets of young children in the U.S. and will motivate health professionals to start considering the specific nutritional needs of children for healthy growth and development. "We'd like to continue our work examining dietary patterns in very young children, since they are often excluded from dietary studies," she says.

Ideally, Dr. Keim says she would like to see families expose their children to a variety of fresh foods as soon as they are old enough to eat solids. "Dietary habits can form very early, so starting with a balanced diet may have long-lasting effects for children's health." According to Dr. Keim, this balanced diet should include fish and other good sources of healthy fatty acids.

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Can drinking orange juice aid in cancer prevention?

Sep. 13, 2013 — In a forthcoming review article from Nutrition and Cancer: An International Journal, a publication of Routledge, researchers review available evidence that links orange juice with cancer chemoprevention. The review article, "Orange Juice and Cancer Chemoprevention" discusses the putative mechanisms involved in the process, the potential toxicity of orange juice, and the available data in terms of evidence-based medicine.

Orange juice has many potential positive effects when it comes to cancer, particularly because it is high in antioxidants from flavonoids such as hesperitin and naringinin. Evidence from previous in vitro studies has indicated that orange juice can reduce the risk of leukemia in children, as well as aid in chemoprevention against mammary, hepatic, and colon cancers. Biological effects of orange juice in vitro are largely influenced by the juice's composition, which is dependent on physiological conditions of the oranges such as climate, soil, fruit maturation, and storage methods post-harvest.

The researchers acknowledge potential toxicity from orange juice if consumed in excess amounts -- especially for children, hypertensive, kidney-compromised, and diabetics. Excessive drinking of orange juice for individuals from these groups has the potential to create noxious effects, hyperkalemia, and has been associated with both food allergies and bacterial outbreaks in cases where the juice was unpasteurized. "Excessive intake of any food, even for the healthiest, can lead to oxidative status imbalance," wrote the researchers.

Further research is highly recommended to determine the biological connection between orange juice and cancer chemoprevention. Issues such as the type of cultivar and the amount consumed will also need clarification.

Overall, the review article summarizes several biological effects of orange juice that can contribute to chemoprevention, including antioxidant, antimutagenic and antigenotoxic, cytoprotective, hormonal, and cell signaling modulating effects. Orange juice has antimicrobial and antiviral action and modulates the absorption of xenobiotics. "OJ could contribute to chemoprevention at every stage of cancer initiation and progression," the researchers explained. "Among the most relevant biological effects of OJ is the juice's antigenotoxic and antimutagenic potential, which was shown in cells in culture and in rodents and humans."

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Dozens dead in fire at Russian psychiatric hospital

By Steve Gutterman

MOSCOW (Reuters) - A fire killed 37 people in a Russian psychiatric hospital on Friday, the second deadly blaze at such a facility this year, heightening concerns about Russia's treatment of the mentally ill and other vulnerable wards of the state.

Fires have frequently claimed high tolls among residents of hospitals, schools and other state institutions over the past decade, raising questions about safety standards.

The pre-dawn fire razed a dilapidated ward for severely ill male patients at the hospital in a provincial village north of Moscow, apparently killing some while under sedation as fog slowed firefighters travelling from 45 km (28 miles) away.

Emergency and law enforcement authorities had recently sought to have the run-down wood, brick and concrete building condemned as unfit for use, a senior official said. Federal investigators began a criminal inquiry into suspected negligence.

State television showed firefighters spraying water on the smoking, blackened ruins of the hospital ward.

A female orderly died while trying to save patients at the hospital in the village of Luka, which is in Novgorod province between Moscow and St Petersburg, the regional branch of the federal Investigative Committee said in a statement.

It said 37 people were killed, and the Emergency Situations Ministry said 34 bodies had been recovered by 10 p.m. on Friday.

"Psychiatric hospitals are the worst of all," said Yuri Savenko, president of the Independent Psychiatric Association of Russia. "Their condition is pathetic. It's inevitable that such things will occur increasingly often."

More than 20 patients were evacuated after the fire broke out shortly before 3 a.m. (2300 GMT on Thursday). The fire left little but the concrete foundation of the single-story building standing.

BLAME GAME

Volunteer firefighters began battling the blaze minutes after it started, but the nearest fire station is 45 km away and it took a crew 45 minutes to arrive on fog-shrouded roads, Interfax cited a top regional emergency official as saying.

Investigators and the chief doctor at the hospital said they suspected a patient started the fire, Russian news agencies reported, but regional governor Sergei Mitin said it might have been accidental.

"Medical personnel saw a patient who was shrouded in flames. ... It's possible that he was smoking in bed and the mattress caught fire," Mitin said, according to Interfax. He said the ward that caught fire housed severely ill patients.

"Sedatives were given to patients for whom they had been prescribed," Interfax quoted the chief doctor, Gusein Magomedov, as saying.

Emergency officials and prosecutors had sought to have the building condemned as unsafe, but a court instead ordered management to correct unspecified flaws by August 2014, the head of safety oversight for the emergencies ministry said.

"The building that burned was unfit for use," the official, Yuri Deshevykh, told state-run Itar-Tass news agency.

A doctor said there had been plans to move the patients to a newly renovated building elsewhere in two years, RIA reported.

Fires with high death tolls have struck state institutions including drug treatment centres, dormitories and homes for the disabled over the past decade. In April, a fire at a psychiatric hospital outside Moscow killed 38 people.

Fires killed 11,635 people in Russia and caused more than 14 billion roubles ($430 million) in losses last year, according to the Emergency Situations Ministry. The death rate is much higher than in the United States and other Western countries.

(Additional reporting by Gabriela Baczynska; Editing by Mark Heinrich)

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Measles cases on the rise in US, experts encourage vaccine

Sep. 13, 2013 — Prior to the use of the measles-mumps-rubella vaccination, hundreds of those infected with the measles would die yearly, tens of thousands would be hospitalized and around 1,000 cases would result in chronic disability. Decades later, after believing that endemic transmission of this highly contagious illness was eradicated in the United States in 2000, cases are on the rise again, according to the Centers for Disease Control and Prevention.

“It is heartbreaking to watch something happen that is completely preventable,” said David Kimberlin, M.D., University of Alabama at Birmingham professor of pediatrics and the American Academy of Pediatrics’ liaison to the CDC's Advisory Committee on Immunization Practices.

“This would not be happening if people trusted us and got their measles vaccinations,” said Kimberlin, who sees patients at Children's of Alabama. “Someone eventually will die from measles, leaving many asking why it couldn't have been prevented, but it can be.”

Kimberlin said measles cases are making it into the United States through international travelers, but it is finding fertile ground in communities because of the percentage of people in those communities who are not vaccinated against measles.

The CDC reports 159 cases between Jan. 1 and Aug. 24, 2013, with 82 percent of the cases in unvaccinated persons, and 9 percent with unknown vaccination status. Ninety-nine percent of the cases were import-related.

“It is like tossing a lit match on dry grass,” Kimberlin said. “The message to take home from this is quite simple: get vaccinated against all vaccine-preventable diseases and be protected from them, or do not get vaccinated and run the very-real risk of getting those diseases and possibly dying.”

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Obama senior adviser hospitalized twice last week

WASHINGTON (Reuters) - President Barack Obama's senior adviser, Dan Pfeiffer, was hospitalized twice last week with what doctors determined was high blood pressure, a White House official said on Friday.

Pfeiffer, 37, one of Obama's original inner circle when he ran for president in 2008, has received treatment and is back at work in the White House, where his blood pressure is being monitored.

"We are happy and relieved to have Dan back at work full time. He's feeling better, listening to his doctors, and focused on helping implement the president's very full domestic and foreign policy agenda," said White House spokeswoman Amy Brundage.

Pfeiffer initially became ill while having dinner at a Washington restaurant on September 4. After an overnight stay at a hospital, he went back to work but fell ill again and spent nearly two days in the hospital.

(Reporting by Steve Holland)

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Car Ventilation Settings May Reduce Exposure to Pollution

FRIDAY, Sept. 13 (HealthDay News) -- Your car ventilation settings have a major effect on the levels of exposure to particulate pollution while driving, according to a new study.

Particulate pollution is the black, sooty smoke produced by diesel engines and coal-fired power plants.

In this study, researchers from the University of Southern California (USC) measured in-vehicle particulate pollution exposure in a wide range of car types and operating conditions.

"Short of driving less, putting your ventilation to 'recirculate' is the best way to reduce exposure to all types of vehicle-related particulate pollution," study senior author Scott Fruin, an assistant professor of preventive medicine at USC, said in a university news release.

"Otherwise, an hour-long commute to work or school can double your daily exposure to traffic-related particulate air pollutants," he added.

Compared to ventilation settings that bring in outside air, the "recirculate" setting reduced in-vehicle pollution from 80 percent of on-road levels to 20 percent for small-particle pollution and from 70 percent to 30 percent for larger particles, the researchers found.

The windows of the cars were always kept closed for the study. Keeping windows open while driving quickly raises inside pollutant concentrations to the same levels as on-road levels, the researchers said.

They also found that particulate pollution levels are lower in newer cars, at slower speeds and when driving on arterial roads instead of freeways. Pollution levels are five to 10 times higher on highways than in other locations, according to the researchers.

Leaving the windows closed over 30-minute or longer drives with several passengers raised carbon dioxide levels in the cars, Neelakshi Hudda, a research associate in the environmental health department at USC's Keck School of Medicine, said in the news release.

"Some people are sensitive to high [carbon dioxide] concentrations," Hudda said. "To prevent this, outside air should be pulled in every 10 or 15 minutes for a minute or two, especially if there are two or more people in the vehicle."

The study was published online recently in the journal Environmental Science & Technology.

More information

The U.S. Environmental Protection Agency has more about particulate pollution.

Copyright c 2013?HealthDay. All rights reserved.

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Research points to promising treatment for macular degeneration

Sep. 13, 2013 — Researchers at the University of North Carolina School of Medicine have published new findings in the hunt for a better treatment for macular degeneration. In studies using mice, a class of drugs known as MDM2 inhibitors proved highly effective at regressing the abnormal blood vessels responsible for the vision loss associated with the disease.

"We believe we may have found an optimized treatment for macular degeneration," said senior study author Sai Chavala, MD, director of the Laboratory for Retinal Rehabilitation and assistant professor of Ophthalmology and Cell Biology & Physiology at the UNC School of Medicine. "Our hope is that MDM2 inhibitors would reduce the treatment burden on both patients and physicians."

The research appeared Sept. 9, 2013 in the Journal of Clinical Investigation.

As many as 11 million Americans have some form of macular degeneration, which is the most common cause of central vision loss in the western world. Those with the disease find many daily activities such as driving, reading and watching TV increasingly difficult.

Currently, the best available treatment for macular degeneration is an antibody called anti-VEGF that is injected into the eye. Patients must visit their doctor for a new injection every 4-8 weeks, adding up to significant time and cost.

"The idea is we'd like to have a long-lasting treatment so patients wouldn't have to receive as many injections," said Chavala. "That would reduce their overall risk of eye infections, and also potentially lower the economic burden of this condition by reducing treatment costs." Chavala practices at the Kittner Eye Center at UNC Health Care in Chapel Hill and New Bern.

All patients with age-related macular degeneration start out with the "dry" form of the disease, which can cause blurred vision or blind spots. In about 20 percent of patients, the disease progresses to its "wet" form, in which abnormal blood vessels form in the eye and begin to leak fluid or blood, causing vision loss.

While anti-VEGF works by targeting the growth factors that lead to leaky blood vessels, MDM2 inhibitors target the abnormal blood vessels themselves causing them to regress -- potentially leading to a lasting effect.

Chavala and his colleagues investigated the effects of MDM2 inhibitors in cell culture and in a mouse model of macular degeneration. They found that the drug abolishes the problematic blood vessels associated with wet macular degeneration by activating a protein known as p53. "p53 is a master regulator that determines if a cell lives or dies. By activating p53, we can initiate the cell death process in these abnormal blood vessels," said Chavala.

MDM2 inhibitors also have conceivable advantages over another treatment that is currently being investigated in several clinical trials: the use of low-dose radiation for wet macular degeneration. Radiation works by causing DNA damage in cells leading to an increase in p53 and cell death. MDM2 inhibitors activate p53 without causing DNA damage. Also, MDM2 inhibitors can be given by eye injection, which is advantageous over some forms of radiation treatment that require surgery to administer.

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Sanofi could acquire L'Oreal's stake, buy more of Regeneron

By Natalie Huet and Ben Hirschler

PARIS/LONDON (Reuters) - Repurchasing L'Oreal's 9 percent stake in Sanofi might make sense for the French drugmaker if the $12 billion holding is put up for sale, Sanofi's chief executive said on Friday.

Chris Viehbacher told an investor conference the group had the resources to do "opportunistic" share buybacks, as well as making bolt-on acquisitions and potentially increasing its stake in U.S. biotech firm Regeneron Pharmaceuticals.

Shares in Regeneron jumped more than 5 percent to an all-time high of $288.50 in New York after his comments, also buoyed by Lazard Capital Markets and RBC raising their price targets for the stock. Sanofi and L'Oreal shares were little changed.

Speculation over the fate of L'Oreal's stake in Sanofi has been fuelled by last month's comments from L'Oreal's CEO that the cosmetics company could buy back the 23-billion-euro ($30-billion) stake Nestle holds in it if L'Oreal in turn sold the 9-billion-euro stake it owns in Sanofi.

The comments have weighed on Sanofi shares, already dragged down by disappointing quarterly results, but some analysts say the drugmaker could use the opportunity to repurchase the shares with cheap debt, thereby boosting its earnings.

Asked about his potential interest in buying back L'Oreal's stake from next year, Viehbacher said it was difficult to comment because the issue was highly conditional.

"We certainly have cash flow to do some things," he told a Bank of America Merrill Lynch healthcare conference in London.

"Whether we would intervene in that or not is going to be a function of - if it does happen - what at that given point in time is the best use of capital. It may well be opportune to have a look at it."

Restrictions on Nestle selling its L'Oreal stake end in April.

More generally, Viehbacher said he did not exclude other share buybacks, but said these would depend on opportunities for acquisitions.

He said Sanofi could also look at raising its stake in Regeneron to as much as 30 percent. Sanofi holds about 16 percent of Regeneron and said in February it has the right to increase this to a maximum 30 percent under its decade-long partnership with Regeneron.

"The Regeneron relationship has become extremely productive for us," Viehbacher said. "Over time, it could well make sense to build our stake up to 30 percent. How fast we do that, whether or not we do that is a function of a number of different factors - but it is a bulky chunk of money to use."

Regeneron's market value is about $27 billion.

Regeneron is best known for its eye drug Eylea, co-marketed with Bayer. But it has also successfully developed the cancer treatment Zaltrap with Sanofi and is working with the French group on a new kind of cholesterol drug.

The drug, which is in late-stage trials, has cut levels of "bad" LDL cholesterol by 60 percent through a new mechanism - blocking a protein called PCSK9.

(Editing by Louise Ireland and Bob Burgdorfer)

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Software may be able to take over from hardware in managing caches

Sep. 13, 2013 — In today's computers, moving data to and from main memory consumes so much time and energy that microprocessors have their own small, high-speed memory banks, known as "caches," which store frequently used data. Traditionally, managing the caches has required fairly simple algorithms that can be hard-wired into the chips.

In the 21st century, however, in order to meet consumers' expectations for steadily increasing computational power, chipmakers have had to begin equipping their chips with more and more cores, or processing units. And as cores proliferate, cache management becomes much more difficult.

Daniel Sanchez, an assistant professor in MIT's Department of Electrical Engineering and Computer Science, believes that it's time to turn cache management over to software. This week, at the International Conference on Parallel Architectures and Compilation Techniques, Sanchez and his student Nathan Beckmann presented a new system, dubbed Jigsaw, that monitors the computations being performed by a multicore chip and manages cache memory accordingly.

In experiments simulating the execution of hundreds of applications on 16- and 64-core chips, Sanchez and Beckmann found that Jigsaw could speed up execution by an average of 18 percent -- with more than twofold improvements in some cases -- while actually reducing energy consumption by as much as 72 percent. And Sanchez believes that the performance improvements offered by Jigsaw should only increase as the number of cores does.

Location, location, location

In most multicore chips, each core has several small, private caches. But there's also what's known as a last-level cache, which is shared by all the cores. "That cache is on the order of 40 to 60 percent of the chip," Sanchez says. "It is a significant fraction of the area because it's so crucial to performance. If we didn't have that cache, some applications would be an order of magnitude slower."

Physically, the last-level cache is broken into separate memory banks and distributed across the chip; for any given core, accessing the nearest bank takes less time and consumes less energy than accessing those farther away. But because the last-level cache is shared by all the cores, most chips assign data to the banks randomly.

Jigsaw, by contrast, monitors which cores are accessing which data most frequently and, on the fly, calculates the most efficient assignment of data to cache banks. For instance, data being used exclusively by a single core is stored near that core, whereas data that all the cores are accessing with equal frequency is stored near the center of the chip, minimizing the average distance it has to travel.

Jigsaw also varies the amount of cache space allocated to each type of data, depending on how it's accessed. Data that is reused frequently receives more space than data that is accessed infrequently or only once.

In principle, optimizing cache space allocations requires evaluating how the chip as a whole will perform given every possible allocation of cache space to all the computations being performed on all the cores. That calculation would be prohibitively time-consuming, but by ignoring some particularly convoluted scenarios that are extremely unlikely to arise in practice, Sanchez and Beckmann were able to develop an approximate optimization algorithm that runs efficiently even as the number of cores and the different types of data increases dramatically.

Quick study

Of course, since the optimization is based on Jigsaw's observations of the chip's activity, "it's the optimal thing to do assuming that the programs will behave in the next 20 milliseconds the way they did in the last 20 milliseconds," Sanchez says. "But there's very strong experimental evidence that programs typically have stable phases of hundreds of milliseconds, or even seconds."

Sanchez also points out that the new paper represents simply his group's "first cut" at turning cache management over to software. Going forward, they will be investigating, among other things, the co-design of hardware and software to improve efficiency even further and the possibility of allowing programmers themselves to classify data according to their memory-access patterns, so that Jigsaw doesn't have to rely entirely on observation to evaluate memory allocation.

"More and more of our computation is happening in data centers," say Jason Mars, an assistant professor of computer science at the University of Michigan. "In the data-center space, it's going to be very important to be able to have the microarchitecture partition and allocate resources on an application-by-application basis."

"When you have multiple applications that are running inside a single box," he explains, "there's a point of interference where jobs can hurt the performance of each other. With current commodity hardware, there are a limited number of mechanisms we have to manage how jobs hurt each other."

Mars cautions that a system like Jigsaw dispenses with a layer of abstraction between chip hardware and the software running on it. "Companies like Intel, once they expose the microarchitectural configurations through the software layer, they have to keep that interface over future generations of the processor," Mars says. "So if Intel wanted to do something audacious with the microarchitecture to make a big change, they'll have to keep that legacy support around, which can limit the design options they can explore."

"However," he adds, "the techniques in Jigsaw seem very practical, and I could see some variant of this hardware-software interface being adopted in future designs. It's a pretty compelling approach, actually."

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Study establishes human model of influenza pathogenesis

Sep. 13, 2013 — A National Institutes of Health (NIH) clinical study of healthy adult volunteers who consented to be infected with the 2009 H1N1 influenza virus under carefully controlled conditions has provided researchers with concrete information about the minimum dose of virus needed to produce mild-to-moderate illness. The study also gives a clearer picture of how much time elapses between a known time of infection, the start of viral shedding (a signal of contagiousness), the development of an immune response, and the onset and duration of influenza symptoms. The data obtained from this study provide a basis for more rapid, cost-effective clinical trials to evaluate new influenza drugs or to determine the efficacy of candidate vaccines for both seasonal and pandemic influenza.

In the study, 46 volunteers were divided into five groups and exposed to influenza virus in escalating doses. The virus, synthesized in the lab under Good Manufacturing Practice conditions, was genetically identical to the virus that caused 2009 H1N1 pandemic influenza. The volunteers all gave informed consent and subsequently were admitted to an isolation unit at the NIH Clinical Center in Bethesda, Md., for a minimum of eight days following virus exposure. The volunteers' health was closely monitored throughout their stay in the clinic and for two months afterward. The researchers sought to determine the minimum dose of virus needed to produce both shedding of live virus in nasal secretions and mild or moderate flu symptoms in 60 percent or more of dosed volunteers. When the scientists administered an influenza virus dose of 107 TCID50 (a measure of the amount of virus required to produce cell death in 50 percent of cultured cells inoculated with virus) to 13 volunteers, 9 (or 69 percent) shed virus and developed symptoms. Lower dosages did not generate responses that met this threshold, thereby establishing the minimum dose of influenza virus needed to produce mild-to-moderate illness.

Researchers from NIH's National Institute of Allergy and Infectious Diseases (NIAID) presented the preliminary study results at the Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) meeting in Denver in September 2013.

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New technique in RNA interference cuts time and cost in genetic screens

Sep. 13, 2013 — There is a new contender in the field of gene discovery, and it's giving knockout mice a run for their money. Researchers at The Rockefeller University have shown that a new technique using RNA interference is able to find genes that cause epidermal tumor growth in months rather than the decades it may take using traditional methods employing specially bred, genetically altered mice. They recently revealed the first genome-wide RNA interference screen of a mouse in an article published in Nature.

RNA interference is a natural process by which RNA molecules inhibit gene expression, but it can also be used by scientists to block a gene's function and look for those that contribute to certain diseases.

"For years, fruit flies and worms have been great model organisms because of the ability to carry out rapid genetic screens," says Elaine Fuchs, Rebecca C. Lancefield Professor. "Genetic screens in mammalian cells have been limited to petri dishes, where cells are exposed to stress and nonphysiological growth conditions."

Doing the screen involves using short pieces of RNA, called small hairpin RNAs, which are inserted into the cell and are able to halt messages from specific genes, keeping the genes from making proteins. A genetic screen might look at 15,000 genes -- meaning thousands of petri dishes or fruit flies -- a task deemed far too large, time-consuming and costly to do with current mouse knockout technology. But researchers led by Slobodan Beronja, a former postdoc in Fuchs's Laboratory of Mammalian Cell Biology and Development, created a special method of RNA interference, where the small hairpin RNAs are all pooled together and injected into the embryos of pregnant mice using a virus.

"We've now devised a technology where we can effectively treat the surface of living mouse embryos as a petri dish of cells, and carry out genome wide screens on mouse cells in their native environment in vivo," says Fuchs. "Previously, genome-wide screens were only possible in lower animals, such as flies, worms and yeast, where it is often difficult to assess the relevance to human disorders such as cancer."

After allowing for normal or pre-cancerous tissues to grow, the researchers quantified the number of individual small hairpin RNAs in the animals, and used it as a measure of their relative importance to the growth process, Beronja, now an assistant member at the Fred Hutchinson Cancer Research Center, explains. The result is the ability to screen more genes with fewer mice. The team screened over 16,000 genes using just 100 litters of mice, and identified about 200 genes that were uniquely important to oncogenic growth in the skin.

"We wanted to identify new genes that are worthy of creating drugs against in cancer treatment," says Beronja. "The greater the complexity of the drug treatment, the greater its success. If you attack several genes, it's more effective."

The researchers found several genes that were already known to cause tumor growth, but many, including one known as Mllt6, surprised them. Although there has been some research on it in leukemia, the gene had never been linked to solid tumors.

"The next step is to validate the list of 200-plus genes and narrow it down to the true candidates for drug therapy. Mllt6 is one that needs further exploration," says Beronja. "But we have shown that this method of genetic screening is cheaper, easier and more informative. It was a risky undertaking that Dr. Fuchs entrusted me to take, and it paid off."

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U.S. court temporarily blocks a competitor to AstraZeneca's Nexium

NEW YORK (Reuters) - A federal U.S. judge issued a temporary injunction against Hanmi Pharmaceutical Co Ltd on Friday, preventing the South Korean drugmaker from launching a close relative of AstraZeneca Plc's Nexium stomach-acid drug in the United States.

Judge Timothy Dyk of the U.S. Court of Appeals for the Federal Circuit approved AstraZeneca's request for the injunction on Friday. He ordered Hanmi to respond within a week and AstraZeneca to reply no later than September 24.

AstraZeneca has accused its South Korean rival of patent infringement for developing Esomezol, a drug that treats gastroesophageal reflux disease, which is caused by stomach acid moving up into the esophagus.

In August, Hanmi received tentative approval from the U.S. Food and Drug Administration for Esomezol, which was developed based on Nexium.

Hanmi's potential encroachment poses a threat to AstraZeneca, which is facing the near-term expiration of U.S. patents covering its two top-selling drugs - Nexium, which loses U.S. protection in 2014, and the cholesterol pill Crestor, which will go off-patent in 2016. As a result, sales at the company are set to fall by several billion dollars.

(Reporting by Lauren Tara LaCapra in New York, Deena Beasley in Los Angeles and Zeba Siddiqui in Bangalore; Editing by Tim Dobbyn)

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Unions fail to get fix from White House on key 'Obamacare' concern

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Can drinking orange juice aid in cancer prevention?

Sep. 13, 2013 — In a forthcoming review article from Nutrition and Cancer: An International Journal, a publication of Routledge, researchers review available evidence that links orange juice with cancer chemoprevention. The review article, "Orange Juice and Cancer Chemoprevention" discusses the putative mechanisms involved in the process, the potential toxicity of orange juice, and the available data in terms of evidence-based medicine.

Orange juice has many potential positive effects when it comes to cancer, particularly because it is high in antioxidants from flavonoids such as hesperitin and naringinin. Evidence from previous in vitro studies has indicated that orange juice can reduce the risk of leukemia in children, as well as aid in chemoprevention against mammary, hepatic, and colon cancers. Biological effects of orange juice in vitro are largely influenced by the juice's composition, which is dependent on physiological conditions of the oranges such as climate, soil, fruit maturation, and storage methods post-harvest.

The researchers acknowledge potential toxicity from orange juice if consumed in excess amounts -- especially for children, hypertensive, kidney-compromised, and diabetics. Excessive drinking of orange juice for individuals from these groups has the potential to create noxious effects, hyperkalemia, and has been associated with both food allergies and bacterial outbreaks in cases where the juice was unpasteurized. "Excessive intake of any food, even for the healthiest, can lead to oxidative status imbalance," wrote the researchers.

Further research is highly recommended to determine the biological connection between orange juice and cancer chemoprevention. Issues such as the type of cultivar and the amount consumed will also need clarification.

Overall, the review article summarizes several biological effects of orange juice that can contribute to chemoprevention, including antioxidant, antimutagenic and antigenotoxic, cytoprotective, hormonal, and cell signaling modulating effects. Orange juice has antimicrobial and antiviral action and modulates the absorption of xenobiotics. "OJ could contribute to chemoprevention at every stage of cancer initiation and progression," the researchers explained. "Among the most relevant biological effects of OJ is the juice's antigenotoxic and antimutagenic potential, which was shown in cells in culture and in rodents and humans."

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Vaccination does not improve outcome of melanomas patients

Sep. 13, 2013 — Results of an EORTC study published in the Journal of Clinical Oncology show that vaccination with GM2/KLH-QS-21 does not benefit patients with stage II melanoma. Vaccination with GM2/KLH-QS-21 stimulates the production of antibodies to the GM2 ganglioside, an antigen expressed by many melanomas. Serological response to GM2 was shown to be a positive prognostic factor in patients with melanoma and was the rationale for this trial.

The idea of treating cancer with a vaccine has been around since the first vaccines against infectious disease were developed. The GM2 ganglioside, an antigen expressed in most melanomas but with limited expression in normal tissues, was thought to offer a suitable target for such therapeutic vaccination. Previous studies had shown that serological response against GM2 was a favorable prognostic factor. The five and ten year survival rates for patients with melanoma having primary tumors with a Breslow thickness greater than 1.5 mm are just of 74% and 61%, respectively, so EORTC trial 18961 was launched to compare vaccination to observation in these patients.

Prof. Alexander M.M. Eggermont of the Institut Gustave Roussy, Villejuif, Paris-Sud, and Universite Paris-Sud, Kremlin Bicetre, France and Coordinator of this study says, "These results clearly indicate that we do not fully comprehend the impact, on the whole, of multiple vaccinations. The effects of such vaccinations might well be detrimental as was clear at the time of the interim analysis that stopped this trial. Now that we have entered a new era in immunotherapy in melanoma with checkpoint inhibitors like anti-CTLA4, and especially with anti-PD1/PDL1, a new opportunity for vaccine development may have arrived."

In this phase III EORTC 18961 trial, 1314 patients with stage II melanoma (primary melanoma thicker than 1.5 mm, T3-4N0M0; AJCC Stage II) were randomized to either vaccination with GM2-KLH-QS21, 657 patients, or observation, 657 patients. The vaccination treatment consisted of subcutaneous injections given once a week during the first month, then once every three months for the first two years, and once every six months during the third year.

Analyses were by intent to treat, and at a median follow-up of 1.8 years the trial was stopped for futility and patients did not receive further vaccinations. For relapse-free survival, the primary endpoint, the hazard ratio (HR) was 1.00 and P = 0.99, and an unfavorable outcome was seen for patients in the vaccination arm compared to the observation arm in terms of overall survival (HR 1.66; P=0.02). Following the IDMC recommendations, all patients in the vaccination arm stopped their treatment.

At final analysis, the median follow-up was 4.2 years. There were 400 relapses, nine deaths without relapse, and a total of 236 deaths. Decreases in both the relapse-free, 1.2%, and overall, 2.1%, survival rates were observed in the vaccination arm at 4 years. For these two endpoints, the estimated HRs were 1.03 and 1.16, respectively.

Toxicity was acceptable; 4.6% of patients went off study because of toxicity.

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37 dead in fire at Russian psychiatric hospital

MOSCOW (AP) — Russia's top investigative agency says 37 people have died in a fire in a Russian psychiatric hospital.

The fire in the one-story hospital in the village of Luka in the northwestern Novgorod region erupted around 3 a.m. Friday and quickly engulfed the structure, which dates back to the 19th century, the Emergency Situations Ministry said.

The Investigative Committee said Friday that rescuers so far have recovered 10 bodies. It did not explain how it knew about the other deaths.

The agency added that the blaze was apparently sparked by a patient.

Authorities had long warned that the mostly wooden building was unsafe.

Copyright c 2013 The Associated Press. All rights reserved. This material may not be published, broadcast, rewritten or redistributed.

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Investigators say 37 dead in Russian mental hospital fire

MOSCOW (Reuters) - A fire at a Russian psychiatric hospital on Friday killed 37 people, the top investigative agency in the province where the blaze occurred said.

The bodies of 10 of the 37 victims were recovered from the ruins of the building that burned down in a pre-dawn fire, the Novgorod regional branch of Russia's Investigative Committee said in a statement, without giving details on the other 27 victims.

(Writing by Steve Gutterman, Editing by Thomas Grove)

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UN: 6.6 million children under 5 died last year

LAGOS, Nigeria (AP) — Childhood death rates around the world have halved since 1990 but an estimated 6.6 million children under the age of 5 still died last year, the U.N. children's agency said Friday.

Nearly half of all children who die are in five countries: Nigeria, Congo, India, Pakistan and China, it said in a report.

"Progress can and must be made," said Anthony Lake, UNICEF's executive director. "When concerted action, sound strategies, adequate resources and strong political will are harnessed in support of child and maternal survival, dramatic reductions in child mortality aren't just feasible, they are morally imperative."

The top killers are malaria, pneumonia and diarrhea, the report said, taking the lives of about 6,000 children under age 5 daily. A lack of nutrition contributes to almost half of these deaths, the U.N. said.

Eastern and Southern Africa have reduced their death rates for children under 5 by more than 50 percent since 1990. West and Central Africa are the only regions not to have at least halved the number of children under 5 dying over the past 22 years, the U.N. said.

Nigeria bears more than 30 percent of early childhood deaths for malaria and 20 percent of the deaths associated with HIV. Globally, the country accounts for one in every eight child deaths, the U.N. said.

While these numbers are grim, the rate of improvement globally seems to have plateaued at about 4 percent improvement per year since 2005, the report said. The estimated numbers are based on solid data from about half the world's countries. And for regions with the biggest problems, they had to rely on modeling techniques.

Countries like Bangladesh, Ethiopia and Brazil showed tremendous progress, due in part to increased community health care. Affordable and increased interventions — like treated mosquito nets, medicines, rehydration treatments and improved access to safe water — helped improve the early childhood death rate in other countries as well.

But improvements were not as bold in countries like Nigeria, Congo, Sierra Leone and Pakistan, the report showed.

Lake said a new sense of urgency was needed to improve the figures.

"Yes, we should celebrate the progress," he said. "But how can we celebrate when there is so much more to do?"

Copyright c 2013 The Associated Press. All rights reserved. This material may not be published, broadcast, rewritten or redistributed.

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Kerry, Lavrov hope Syria chemical talks will revive peace conference

GENEVA (Reuters) - U.S. Secretary of State John Kerry and Russian Foreign Minister Sergei Lavrov said on Friday they were hopeful that talks on Syria's chemical weapons would help revive an international plan for a "Geneva 2" conference to end the war in Syria.

Kerry, who said the ongoing talks on chemical weapons were "constructive", told a news conference in Geneva that he and Lavrov planned to meet in New York around Sept 28 and hoped to agree a date for the Geneva 2 conference then.

(Reporting by Tom Miles and Stephanie Nebehay)

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Dozens feared dead after fire at Russian psychiatric hospital

By Steve Gutterman

MOSCOW (Reuters) - A fire raged through a Russian psychiatric hospital on Friday, killing at least six people and leaving dozens missing, the second such blaze this year and one likely to increase criticism of the state's treatment of the mentally ill.

Police were searching the area in the village of Luka north of Moscow for survivors of the pre-dawn fire at a ward for severely incapacitated patients, according to emergency and law enforcement officials.

Emergency authorities had recently sought to have the run-down wood, brick and concrete building condemned as unfit for use, a senior official said. In response to the fire, a federal criminal investigation into suspected lethal negligence began.

State television showed firefighters spraying water on the smoking, blackened ruins of the ward at the hospital - footage that has become sickeningly familiar after a number of deadly fires at state institutions in Russia in recent years.

An orderly died while trying to save patients at the hospital in Luka, which is in Novgorod province between Moscow and St Petersburg, the federal Investigative Committee said. It said 35 people were unaccounted for.

Six bodies had been found by mid-morning, the Emergency Situations Ministry said.

Some of the missing may have escaped the hospital, ministry official Oleg Voronov said on Ekho Moskvy radio, but none had been found hours after the blaze, which broke out before 3 a.m. (2300 GMT on Thursday), by police combing the area.

The fire left little but the concrete foundation of the single-story building housing male patients at the hospital. Voronov said there were about 60 people in the building, most of them patients, when the blaze broke out.

Officials said more than 20 patients were evacuated.

Investigators and the chief doctor at the hospital said they suspected a patient started the fire, Russian news agencies reported, but regional governor Sergei Mitin said it might have been accidental.

"Medical personnel saw a patient who was shrouded in flames. ... It's possible that he was smoking in bed and the mattress caught fire," Mitin said, according to Interfax. He said the ward that caught fire housed severely ill patients.

BLAME GAME

Critics of the government say state authorities frequently blame the victims of fires in order to avoid culpability.

Emergency officials and prosecutors had sought to have the building condemned as unsafe, but a court instead ordered management to correct unspecified flaws by August 2014, the head of safety oversight for the Emergencies Ministry said.

"The building that burned was unfit for use," the official, Yuri Deshevykh, told state-run Itar-Tass news agency.

There have been many fires with high death tolls at state institutions such as hospitals, schools, drug treatment centers and homes for the disabled in the past decade, raising questions about safety measures, conditions and emergency exit routes.

In April, a fire at a psychiatric hospital outside Moscow killed 38 people.

The death rate from fires is much higher in Russia than in Western countries including the United States.

The nation of 142 million is also plagued by accidents on its roads, rails, rivers and in the workplace, taking the shine off a post-Soviet recovery for which President Vladimir Putin - in power since 2000 - claims a measure of credit.

Critics say Putin's top-down ruling style fosters a culture of negligence and that he has made little progress stemming the corruption and corner-cutting that is blamed for many deadly accidents.

Yuri Savenko, president of the independent psychiatric association of Russia, said the dilapidated state of psychiatric hospitals was pushing up death tolls from fires. He said a third of the buildings at such facilities had been declared unfit for use since 2000.

(Editing by Mark Heinrich)

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Rhoen-Klinikum to sell hospitals to Fresenius in $4 billion deal

By Jonathan Gould and Ludwig Burger

FRANKFURT (Reuters) - Germany's Rhoen-Klinikum is to sell most of its hospitals to rival Fresenius SE for 3.07 billion euros ($4.1 billion), in an attempt by Rhoen's founder to outflank opponents to an outright sale of the company.

The deal follows a long struggle by Rhoen-Klinikum's founder Eugen Muench to sell the business to Fresenius in the face of opposition from rebel shareholders, an industry rival and a supplier.

The 43 hospitals and 15 outpatient facilities being sold account for about two thirds of Rhoen's revenues, with mainly specialized clinics and university teaching hospitals remaining with Rhoen.

Rhoen and Fresenius have wanted to create a country-wide network of hospitals large enough to provide a form of medical insurance.

The transaction, which according to Rhoen does not require a shareholder vote, would make Fresenius unit Helios the largest private hospital operator in Europe, Fresenius said in a statement.

The hospital deal comes a year after Fresenius dropped an initial 3.1 billion euro plan to take over Rhoen.

Shares in Rhoen jumped 9.9 percent at the open, while those of Fresenius were up 5.2 percent.

Rhoen founder and chairman Muench last year initiated the sale of the entire group, in which he and his wife hold 12.5 percent, to diversified healthcare company Fresenius.

But rival hospitals operator Asklepios and a medical supplies maker B. Braun weighed in with the purchase of enough shares to fend off the suitor.

Muench, who has continued to campaign for a sale, and he and his detractors have engaged each other in legal action.

Sources have said B. Braun saw the deal as putting it at risk of losing Rhoen as a client to Fresenius while Asklepios feared that a dominant player would be able trump rivals when public-sector hospitals were put up for auction.

B. Braun and Asklepios declined to comment on Friday.

The acquisition would boost Helios' sales by about 2 billion euros and earnings before interest, tax, depreciation and amortization (EBITDA) by about 250 million, Fresenius said.

Helios would have 117 hospitals across Germany and sales of nearly 5.5 billion euros after integration of the Rhoen facilities.

Fresenius said the purchase price would be entirely debt financed and it would not assume any of Rhoen's debt.

The ratio of the Fresenius group's net debt to core earnings would temporarily rise above 3.0 this year but remain below 3.5 before returning to the 2.5-3.0 target range next year, the company added.

Rhoen said in a separate statement that it planned to pay a special dividend of up to 1.9 billion euros, funded by transaction proceeds and reserves, on top of its regular dividend. It was also mulling buying back its own shares.

Proceeds also would be used to repay debt, with a further 200 million euros slated for investments, it said.

After the sale, Rhoen would still control several hospitals, including university hospitals in the cities of Giessen and Marburg, and have revenue of about 1 billion euros, it said.

The deal requires approval by antitrust authorities as well as minority shareholders in some of the hospitals concerned.

(Editing by Stephen Coates and Jane Merriman)

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Forcing cancer to digest itself

Sep. 12, 2013 — When tumour cells no longer degrade themselves, cancer may develop. Using black skin cancer as an example, Bern Researchers have now shown that a protein plays an important role in the process of degradation of tumour cells. By reactivating this degradation therapeutically, you can virtually force tumours to digest themselves.

Cells are able to degrade damaged molecules as well as entire areas of cells by self-digestion and use the resulting degradation products to gain energy and to produce new molecules or parts of cells. This process of self-digestion is called autophagy and can be considered a renovation of the cell.

Energy production through autophagy plays an important role for cells when they are lacking nutrients, oxygen or growth factors. A team of researchers of the University of Bern under the direction of Hans-Uwe Simon of the Institute of Pharmacology has now found out that a reduced self-digestion of tumour cells may contribute to the development of a melanoma. The discoveries demonstrate new therapy approaches for the treatment of black skin cancer. The study is being published today in "Science Translational Medicine."

Nipping the tumour "in the bud"

The researchers examined the importance of autophagy for the formation of tumours. They particularly studied a central autophagy-regulating protein (ATG5) in a group of nearly 200 patients with melanoma. They found out that changes in the chromosomes -- so-called epigenetic changes -- resulted in the presence of an insufficient quantity of ATG5 in the tumour cells and thus in a restriction of their self-digestion. In addition, the group with Hans-Uwe Simon was able to show experimentally that the formation of tumours can be prevented through a therapeutic normalisation of self-digestion. This reveals a new approach for the future therapy of melanomas and perhaps also other types of cancer at an early stage: "In the future, ATG5 might not only play a role in the diagnosis of melanomas; we also hope for new therapies in order to force tumours at an early stage to digest themselves," Simon explains.

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The above story is based on materials provided by University of Bern, via AlphaGalileo.

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Journal Reference:

1. H. Liu, Z. He, T. von Rutte, S. Yousefi, R. E. Hunger, H.-U. Simon. Down-Regulation of Autophagy-Related Protein 5 (ATG5) Contributes to the Pathogenesis of Early-Stage Cutaneous Melanoma. Science Translational Medicine, 2013; 5 (202): 202ra123 DOI: 10.1126/scitranslmed.3005864

Note: If no author is given, the source is cited instead.

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Youth more likely to be bullied at schools with anti-bullying programs

Sep. 12, 2013 — Anti-bullying initiatives have become standard at schools across the country, but a new UT Arlington study finds that students attending those schools may be more likely to be a victim of bullying than children at schools without such programs.

The findings run counter to the common perception that bullying prevention programs can help protect kids from repeated harassment or physical and emotional attacks.

"One possible reason for this is that the students who are victimizing their peers have learned the language from these anti-bullying campaigns and programs," said Seokjin Jeong, an assistant professor of criminology and criminal justice at UT Arlington and lead author of the study, which was published in the Journal of Criminology.

"The schools with interventions say, 'You shouldn't do this,' or 'you shouldn't do that.' But through the programs, the students become highly exposed to what a bully is and they know what to do or say when questioned by parents or teachers," Jeong said.

The study suggested that future direction should focus on more sophisticated strategies rather than just implementation of bullying prevention programs along with school security measures such as guards, bag and locker searches or metal detectors. Furthermore, given that bullying is a relationship problem, researchers need to better identify the bully-victim dynamics in order to develop prevention policies accordingly, Jeong said.

Communities across various race, ethnicity, religion and socio-economic classes can benefit from such important, relevant Department of Criminology and Criminal Justice research, said Beth Wright, dean of the UT Arlington College of Liberal Arts.

"This important discovery will result in improvements in health, in learning, and in relationships, with unlimited positive impact," Wright said.

A growing body of research shows that students who are exposed to physical or emotional bullying experience a significantly increased risk of anxiety, depression, confusion, lowered self-esteem and suicide. In addition to school environmental factors, researchers wanted to know what individual-level factors played a key role in students who are bullied by peers in school.

For their study, Jeong and his co-author, Byung Hyun Lee, a doctoral student in criminology at Michigan State University, analyzed data from the Health Behavior in School-Aged Children 2005-2006 U.S. study. The HBSC study has been conducted every four years since 1985 and is sponsored by the World Health Organization. The sample consisted of 7,001 students, ages 12 to 18, from 195 different schools.

The data preceded the highly publicized, 2010 "It Gets Better" campaign founded by syndicated columnist and author Dan Savage and popularized by YouTube videos featuring anti-bullying testimonials from prominent advocates.

The UT Arlington team found that older students were less likely to be victims of bullying than younger students, with serious problems of bullying occurring among sixth-, seventh- and eighth-graders. The most pervasive bullying occurred at the high school level.

Boys were more likely than girls to be victims of physical bullying, but girls were more likely to be victims of emotional bullying. A lack of involvement and support from parents and teachers was likely to increase the risk of bullying victimization. These findings are all consistent with prior studies.

Notably, researchers found that race or ethnicity was not a factor in whether students were bullied.

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Treat the fungus among us with nontoxic medicinal compound

Sep. 12, 2013 — A Kansas State University microbiologist has found a breakthrough herbal medicine treatment for a common human fungal pathogen that lives in almost 80 percent of people.

Govindsamy Vediyappan, assistant professor of biology, noticed that diabetic people in developing countries use a medicinal herb called Gymnema slyvestre to help control sugar levels. He decided to study the microbiological use of Gymnema slyvestre -- a tropical vine plant found in India, China and Australia -- to see if it could treat a common human fungal pathogen called Candida albicans.

The investigation was successful on two levels: Vediyappan's research team found the medicinal compound is both nontoxic and blocks the virulence properties of the fungus so that it is more treatable. The results are important for human health, biomedical applications and potential drug development.

"We have shown that this compound is safe to use because it doesn't hurt our body cells, yet it blocks the virulence of this fungus under in vitro conditions," Vediyappan said. "Taking the medicine could potentially help patients control the invasive growth of the fungus and also help bring their sugar levels down."

Candida albicans is one of the major fungal pathogens in humans because it lives in oral and intestinal areas as a normal flora, Vediyappan said. But the fungus can overgrow and can cause oral, intestinal and genital infections. The fungus kills almost 30 percent of people who have it and it is a concern among cancer patients -- especially patients with neck or oral cancer -- HIV patients, organ transplant patients and other people with compromised immune systems.

The fungus can grow in two forms: a treatable yeast and a difficult-to-treat hyphal form. Once the fungus transforms from a yeast to a hyphal growth it becomes difficult to treat because the hyphal growth has long filament-like structures that can spread into various organs. Vediyappan's study aimed to block the hyphal growth form.

"Once it gets into the tissue, it spreads like roots and is difficult to contain by our immune system," Vediyappan said.

If the fungus remains in yeast form, it is easy to manage and does not invade tissues. Vediyappan's research team purified gymnemic acid compounds that prevented the transition stage from occurring and stopped the fungus spread. The gymnemic acids come from the leaves of Gymnema sylvestre, a traditional medicinal plant.

The research appears in the peer-reviewed journal PLOS ONE in an article titled "Gymnemic acids inhibit hyphal growth and virulence in Candida albicans."

Gymnema extract is commonly used to treat diabetes and other ailments because it is a cost-effective treatment, Vediyappan said. Often, people drink the extract to control their sugar levels or to lose weight.

Although Vediyappan's research team is not the first to discover gymnemic acid compounds, the team is the first to discover that the compounds block the fungal transition. The researchers found that the compounds work quickly, too, which was an important characteristic. The treatable fungal yeast can transition to a hyphal growth within 30 minutes of an infection. When the hyphal transition has occurred, it will grow into branched filaments.

The gymnemic acid compounds are nontoxic, which is especially important for cancer patients and other immunocompromised patients. The gymnemic acids can stop the unwanted invasive infection while preserving important healthy cells.

The Candida albicans fungus also makes a biofilm, which is a fungal cell collection that can be difficult to treat. The researchers found that the gymnemic acid compounds converted the biofilm back to treatable yeast cells.

"This compound prevents the biofilm formation because hyphae are the major builders of biofilms and biofilms are resistant to antifungals," Vediyappan said. "Yeast cells by themselves cannot make biofilms and are sensitive to antifungal treatments."

Another interesting aspect: The gymnemic acid compounds also stopped the growth of Aspergillus, another fungal pathogen that can affect heart transplant patients and leukemia patients.

Vediyappan plans future studies to research mode of action, potential drug development, diabetes applications and other ways to improve treatment for Candida albicans and other fungal pathogens.

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Analysis: House Republicans go for broke in fiscal battles

By Richard Cowan and David Lawder

WASHINGTON (Reuters) - Another down-to-the-wire fight, potentially more toxic than usual, is rapidly shaping up in the U.S. Congress as conservatives prepare to exploit looming fiscal deadlines to derail President Barack Obama's signature healthcare reform law.

Like previous congressional spending battles, this one involves two measures that were once relatively routine: a bill to continue funding the government to avert a shutdown, and another to increase the government's borrowing power so it can pay its debts and avoid default.

But the conflict is particularly volatile this time as, unlike the budget cuts demanded by Republicans in earlier fiscal showdowns, their demands for concessions on Obamacare on the eve of its October 1 insurance exchanges launch are non-negotiable for Democrats.

And this time, it's not just Republicans versus Democrats, but Republican against Republican. Party elders, lacking the power to make rebellious conservatives back off, have been reduced to pleading with them to do so. The conservatives, braced by the passion of Tea Party activists as the 2014 election approaches, are not inclined to cooperate.

The deadline for funding the government is September 30, when a so-called "continuing resolution" enacted last March expires. By mid-October or early November, the U.S. Treasury likely will run out of borrowing authority. Without an increase of the $16.7 trillion cap that is written into law, the federal government faces an historic default on its debt that would create havoc in global financial markets.

There is increasing talk among Republicans about a whopper bill that would fund the government from October 1 through September 30, 2014, raise the debt ceiling by giving the Treasury Department enough borrowing authority to last for a year, and impose a one-year delay of Obamacare.

"Let's give them something and we get something in exchange," Tea Party Republican Representative John Fleming of Louisiana told reporters.

It's not so simple, said Republican Senator Jeff Flake of Arizona, who spent 12 years as a House member and made his reputation as a fiscal conservative. Flake questioned his former colleague's wisdom in pushing their fight against Obamacare.

"The notion that you're going to get this (Democratic) Senate and this president to pass a repeal right now is I don't think practical," Flake said. He added, "I quit trying to understand that place (the House) as soon as I left."

FISCAL BRINKMANSHIP

Opponents to Obamacare, which will provide insurance to millions of Americans, say the law will damage healthcare as well as the nation's economy. After three years of trying and failing to repeal the law, some conservatives in the House of Representatives are willing to go for broke - literally - in their drive to prevail.

Apart from the futility of linking Obamacare to the fiscal issues, the concern of senior Republicans is that their party will take a huge public relations hit if they are blamed for the fiscal strife, as it did in the mid 1990s after successive government shutdowns precipitated by Republican budget demands.

In a CNN/ORC survey taken between September 6-8, 51 percent said Republicans would be more responsible for a shutdown, and 33 percent said Obama would take the blame.

There are risks for Democrats and Obama too. While polling results showed the public more upset with Republicans then Obama after the "fiscal cliff" fight that led to across-the-board budget cuts, Obama's Gallup approval rating started on a downward trend then from which it has yet to recover, with other polls suggesting that Americans hold all parties in Washington as well as the president responsible for "gridlock."

With the deadlines fast-approaching, the maneuvering is well underway.

The White House announced that Obama would speak to the Business Roundtable group of big-company chief executives next week. White House spokesman Jay Carney did not offer any details about what Obama will say, but he has used business groups in the past to pressure Congress to avoid fiscal brinkmanship.

"We will never accept anything that delays or defunds" Obamacare, Carney stressed again on Thursday.

In the U.S. Capitol, the top four Republican and Democratic leaders of the Senate and House met in the office of House of Representative Speaker John Boehner on Thursday to try to plot out a happy ending to their government spending and debt limit challenges.

Afterward, Boehner told reporters "there are a million options that are being discussed by a lot of people."

But while Republicans control the House, Boehner does not control Republicans.

HIGH-STAKES MANEUVER

The intra-party fight on such a high-stakes maneuver as coupling Obamacare changes to the debt limit hike is seen as pushing negotiations on the legislation right up to the October or November deadline.

In the meantime, Democrats, who control the White House and the Senate, are content to demand a no-strings-attached debt limit increase and watch Republicans tear themselves apart over this legislation, as well as the more pressing bill to keep the government running beyond September 30.

"The strategy is to watch the meltdown. This is an internal Republican dilemma, and Mr. Boehner has the hardest job in the Capitol," Democratic Representative Peter Welch, of Vermont, told Reuters.

And so, as Congress revs up for yet another gut-wrenching fiscal fight, partisan participants and non-partisan observers alike see more evidence of a dysfunctional legislature that already is the laughing stock of the country.

"The anarchists have taken over," declared Senate Majority Leader Harry Reid, a Democrat, referring to the fiscal fights. "We're in a position here where people who don't believe in government - and that's what the Tea Party is all about - are winning," said Reid.

Chris Krueger, of the Guggenheim Partners financial services firm, observed on Thursday: "The House Republican caucus is borderline ungovernable."

(Additional reporting by Mark Felsenthal, Rachelle Younglai and Caren Bohan; Editing by Fred Barbash and Tim Dobbyn)

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Americans living longer, more healthy lives

Sep. 12, 2013 — Thanks to medical advances, better treatments and new drugs not available a generation ago, the average American born today can expect to live 3.8 years longer than a person born two decades ago. Despite all these new technologies, however, is our increased life expectancy actually adding active and healthy years to our lives? That question has remained largely unanswered -- until now. In a first-of-its-kind study, researchers at the University of Massachusetts Medical School (UMMS) have found that the average 25-year-old American today can look forward to 2.4 more years of a healthy life than 20 years ago while a 65-year-old today has gained 1.7 years.

Synthesizing data from multiple government-sponsored health surveys conducted over the last 21 years, Allison Rosen, MD, associate professor of Quantitative Health Sciences at UMMS, Susan Stewart, researcher at the National Bureau of Economic Research, and David Cutler, professor of economics at Harvard University, were able, for the first time, to measure how the quality-adjusted life expectancy (QALE) of all Americans has changed over time. The study's findings are described in a paper published today in the American Journal of Public Health.

"QALE tells us more than how long a person can expect to live," said Dr. Rosen, senior author on the study. "It tells us what the relative quality of those added years are in terms of physical, emotional and mental well-being. Though many studies have measured this in different ways, this is really the first time we've been able to capture this type of information across the whole U.S. population over an extended period."

The data shows that Americans are living longer, reporting fewer symptoms of disease, have more energy and show fewer impairment in everyday tasks such as walking than a generation ago. According to the study authors, a 25-year-old person today can expect to live 6 percent or 2.4 quality years longer than their 1987 counterpart. Meanwhile, a 65-year-old person will gain 1.7 quality years, a 14 percent increase from a generation ago.

Thanks to improvements in health care, many conditions are far more treatable today than 25 years ago, Rosen said. Heart disease, for instance, was potentially much more debilitating a generation ago and patients often suffered a decline in quality of life as a result. "Today, it is far less likely that a patient recovering from a heart attack will become institutionalized or need around-the-clock care the way they once might have," Rosen said. They also found that health gains made as a result of smoking cessation programs were being off-set, in part, by increases in obesity.

Today, Americans are more likely to see quality of life declines related to chronic, degenerative diseases such as Alzheimer's and dementia, while younger Americans appear to be experiencing problems related to a sedentary lifestyle.

The authors also identified some troubling health trends. Among these was an increase in anxiety among young and middle-aged people beginning in 2001. Problems with walking have increased significantly among non-elderly over the last decade.

In the past, researchers have had a difficult time measuring population health beyond simple life expectancy because quality of life incorporates so many variables -- physical well-being, mental health, pain, vitality, energy, emotional state -- that it's difficult to bring all these things together cohesively into a single number. Making it even more challenging, the surveys that measure quality of life are rarely consistent with each other because they all define health and quality of life differently.

Using multiple national surveys that asked Americans about their health in various ways over the last 21 years, the authors solved this problem by identifying areas where the studies overlapped, allowing them to build a single, large data set which covered the entire adult population over more than two decades.

"Comprehensive measures of the overall health of the nation are practically nonexistent," said Rosen. "This study shows how existing national data can be used to systematically measure whether the population is getting healthier -- not just living longer."

As the Affordable Care Act goes into effect in 2014, the value of a single, consistent way of measuring improvements in health over a large population will be invaluable in assessing the impact of these pending changes according to the authors.

"Having a consistent measure of population health represents a major advance in our ability to measure the impact of health care reform on the health -- not just the health care use -- of all Americans," said Rosen. "The bottom line in assessing the success of the ACA is whether or not we are getting the most health from our investment of increasingly limited resources. Are we getting the most health bang for our bucks?"

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Current pledges to reduce greenhouse gas emissions put over 600 million people at risk of higher water scarcity

Sep. 12, 2013 — Our current pledges to reduce greenhouse gas emissions, which are projected to set the global mean temperature increase at around 3.5°C above pre-industrial levels, will expose 668 million people worldwide to new or aggravated water scarcity.

This is according to a new study published today, 13 September, in IOP Publishing's journal Environmental Research Letters, which has calculated that a further 11 per cent of the world's population, taken from the year 2000, will live in water-scarce river basins or, for those already living in water-scarce regions, find that the effects will be aggravated.

The results show that people in the Middle East, North Africa, Southern Europe and the Southwest of the USA will experience the most significant changes.

The results show that if the global mean temperature increases by 2°C -- the internationally agreed target -- then eight per cent of the world population (486 million people) will be exposed to new or aggravated water scarcity, specifically in the Near and Middle East.

Lead author of the research Dr Dieter Gerten, from the Potsdam Institute for Climate Impact Research, said: "Our global assessments suggest that many regions will have less water available per person.

"Even if the increase is restricted to 2°C above pre-industrial levels, many regions will have to adapt their water management and demand to a lower supply, especially since the population is expected to grow significantly in many of these regions."

"The unequal spatial pattern of exposure to climate change impacts sheds interesting light on the responsibility of high-emission countries and could have a bearing on both mitigation and adaption burden sharing."

According to Dr Gerten, the main driver of new or aggravated water scarcity is declining precipitation; however, increased temperatures will also lead to an increase in evapotranspiration of water and, thus, decrease the resources.

The anticipated increase in population will have even stronger effects on the ratio of water demand and water availability in some regions.

To assess the impacts of different mean global warming levels, the international group of researchers combined existing simulations from 19 climate change models with eight different global warming trajectories. The latter ranged from 1.5°C to 5°C increases above pre-industrial levels, resulting in a total of 152 climate change scenarios that were examined.

In addition to water shortages, the researchers assessed the impact that future climatic changes may have on global terrestrial ecosystems. They sought to discover what areas will be affected by strong ecosystem changes, and whether these areas are rich in biodiversity and/or contain unique species.

"At a global warming of 2°C, notable ecosystem restructuring is likely for regions such as the tundra and some semi-arid regions. At global warming levels beyond 3°C, the area affected by significant ecosystem transformation would significantly increase and encroach into biodiversity-rich regions," continued Dr Gerten.

"Beyond a mean global warming of 4°C, we show with high confidence that biodiversity hotspots such as parts of the Amazon will be affected."

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Molecular structure reveals how HIV infects cells

Sep. 12, 2013 — In a long-awaited finding, a team of Chinese and US scientists has determined the high-resolution atomic structure of a cell-surface receptor that most strains of HIV use to get into human immune cells. The researchers also showed where maraviroc, an HIV drug, attaches to cells and blocks HIV's entry.

"These structural details should help us understand more precisely how HIV infects cells, and how we can do better at blocking that process with next-generation drugs," said Beili Wu, PhD, professor at the Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences. Wu was the senior investigator for the study, which was published in Science Express on September 12, 2013.

The study, which focused on the CCR5 receptor, was supported by both US and Chinese research funding agencies. "International collaborations like this one are increasingly needed to solve big problems in science," said study co-author Raymond C. Stevens, PhD, a professor at The Scripps Research Institute (TSRI) in California. "Now that we have both human CXCR4 and CCR5 HIV co-receptor three-dimensional structures, it is likely we will see the next generation of HIV therapeutics."

A Major Target

The CCR5 receptor is one of the most sought-after targets for new anti-HIV drugs. Although the AIDS-causing virus was initially discovered to infect cells via another receptor, CD4, researchers found in 1996 that HIV infection also requires a co-receptor -- usually CCR5, which sits alongside CD4 on a variety of immune cells.

CCR5's importance to HIV infection is underscored by the fact that certain genetic variants of it can dramatically raise or lower HIV infection risk, as well as the speed of the disease process after infection. One shortened CCR5 variant, found in about 10 percent of Europeans, is not expressed at all on immune cell surfaces -- and people who produce only this variant are almost invulnerable to HIV infection.

Scientists therefore have sought to develop anti-HIV drugs that block the virus from binding to CCR5 or otherwise render the receptor inactive. Yet only a handful of CCR5-inhibiting compounds have been developed so far -- and no one knows exactly how they work. "One thing that we've lacked is a high-resolution molecular 'picture' of the CCR5 receptor structure that we can use for precise drug design," Wu said.

A Six-Year Quest

Wu came to the Stevens laboratory at TSRI in 2007 to conduct postdoctoral research on the two HIV co-receptors, CCR5 and the alternate HIV co-receptor CXCR4. A minority of HIV strains use CXCR4 instead of CCR5 as a co-receptor with CD4 for their initial infiltration of cells.

"Her goal from the beginning was to determine the structures and understand the functions of these two HIV co-receptors and she was very determined which was inspiring," said Stevens.

Wu spent her postdoctoral years focusing on CXCR4, which posed fewer technical challenges than CCR5. Her landmark study of the CXCR4 structure was published in Science in 2010. After moving back to China to start her own laboratory at SIMM, she returned to the "unfinished business" of the CCR5 structure.

Both CCR5 and CXCR4 belong to a large family of cell receptors known as G protein-coupled receptors (GPCRs). GPCRs are notoriously hard to produce in useful amounts for structural analysis. With their floppy structures, they are also very hard to coax into the ordered, solid lineups of individual molecules -- "crystals" -- needed for structure determination by X-ray crystallography. Eventually, however, with help from insights gained during the CXCR4 project, Wu, as a new professor, and her young team of students used a novel "fusion partner" molecule that would hold CCR5 proteins together enough to form usable crystals, together with efforts of computational modeling, compound synthesis and cell signaling assays from Drs. Hualiang Jiang, Hong Liu and Xin Xie's groups at SIMM, which led to the structure determination of CCR5.

As in most receptor-structure projects, Wu and her colleagues further stabilized CCR5 with a compound that is known to bind to it, in this case the Pfizer drug maraviroc (sold under the brand name SelzentryR or CelsentriR outside the US). Marketed for HIV infection since 2007, maraviroc grabs hold of CCR5 in a way that prevents HIV from using the receptor to get into cells. "Maraviroc was thought to lock CCR5 into an inactive conformation, and so we wanted to 'see' that conformation at high resolution," said Wu.

The resulting crystallography data provided that fine-grained picture of CCR5's HIV-resistant conformation. The data also revealed maraviroc's precise binding site on CCR5 -- a site from which the drug molecule clearly influences how the receptor works, even though it is separate from the sites on the receptor that are thought to be used by HIV. The maraviroc binding site is also different from the site used by CCR5's natural binding-partners, a set of immune proteins called chemokines. Maraviroc thus appears to work against HIV indirectly -- not by physically blocking the virus, but by locking the receptor structure into an HIV-insensitive conformation.

"Structural details can offer tremendous insight into how proteins and drugs work, also aiding the development of therapeutic agents," said Peter Preusch, PhD, of the National Institute of General Medical Sciences, which helped fund the research along with another component of the National Institutes of Health, the National Institute of Allergy and Infectious Diseases. "This study provides knowledge about the interactions between maraviroc and CCR5, a target for anti-HIV therapy, that helps us understand how the drug works at the molecular level and could enable further explorations of HIV biology and approaches to improve drugs targeting such interactions."

Useful Insights

Comparison of the CCR5 structure with the previously determined CXCR4 structure also provided hints about an important aspect of HIV evolution during infections. Most HIV infections start by using only CCR5 as a co-receptor for cell entry, but in time the virus often switches its co-receptor usage from CCR5 to CXCR4. That opens up more cell types to HIV infection, and the further spread of the virus inside the body is liable to speed up the disease progression towards full-blown AIDS and death.

The new data suggest that the distinction between CCR5 and CXCR4 as co-receptors for HIV infection boils down to relatively subtle differences in structural shapes and electric charge distributions in the HIV binding region -- differences that will be of interest to HIV drug developers.

"Knowing the CXCR4 structure and now the CCR5 structure at this level of detail should accelerate the development of drugs that can block HIV by using both of these co-receptors," said Wu.

She and her colleagues now plan to follow up with structural studies of CCR5 and CXCR4 in complex with the HIV envelope protein gp120 and CD4 to obtain even more informative pictures of the process of viral infection.

Soon after the structure determination of CCR5, SIMM performed structure-based drug design and has obtained several drug lead compounds with more potent antiviral efficacies than maraviroc, which further proves the importance of CCR5 structure on the development of HIV theraputics.

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