Pfizer’s once-daily Lyrica trial fails to meet goal
















(Reuters) – Pfizer Inc said on Friday a late-stage trial of a once-a-day formulation of its drug pregabalin did not significantly reduce the frequency of some types of seizures in patients with epilepsy.


The drug, sold under the brand name Lyrica, is currently used to treat epilepsy when given several times a day in combination with other drugs.













Pfizer said the lack of a statistically significant improvement may have been due to a higher-than-expected response among patients taking the placebo.


The trial was the first of three trials testing the drug as a once-a-day therapy. The company is also testing it in patients with fibromyalgia and some types of nerve pain, for which it is also approved in its immediate-release formulation.


(Reporting By Toni Clarke; Editing by Gerald E. McCormick)


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China’s commerce minister voted out in rare congress snub: sources
















BEIJING (Reuters) – China‘s commerce minister was surprisingly blocked from a spot on the ruling Communist Party’s elite body during a conclave this week, sources said, a rare snub for an official that could raise questions about trade policies during his tenure.


The failure of Chen Deming to secure a seat on the 25-member Politburo marks one of the few surprises to emerge from the party’s five-yearly congress that wrapped this week with the anointing of a new slate of top leaders who will run the world’s second largest economy.













It is also the first time in more than two decades that an official designated for a Politburo spot has been voted out of the party’s 205-member Central Committee in elections. Central Committee membership is a prerequisite for a Politburo seat.


“Chen Deming was voted out during multi-candidate elections to the Central Committee,” one source told Reuters. State news agency Xinhua said there were eight percent more candidates than seats in a preliminary vote before the formal election on Wednesday.


Not being name as an alternate or full member during the party’s 18th congress means Chen, who was previously an alternate member, is almost certain to step down as commerce minister next March. Party regulations require cabinet ministers to be Central Committee members.


It is unclear why Chen, who was seen as a strong candidate for a vice premiership and at 63 is young enough to serve another five-year term under party rules, did not secure the votes for a seat on the Central Committee.


Tianjin Mayor Huang Xingguo, 58, who was elected a full member of the Central Committee, is front-runner to replace Chen as commerce minister, two sources with ties to the leadership said.


Ma Kai, 66, secretary general of the State Council, or cabinet, is tipped to become a vice premier now that Chen is out of the running, the sources said, requesting anonymity to avoid repercussions for discussing secretive elite politics.


Until now, a politician designated to become a Politburo member has not been barred from the Central Committee since 1987, when Deng Liqun, an ultra-conservative and reviled Marxist ideologue, was voted out at the 13th congress in a deeply embarrassing fall from grace.


Chen’s imminent retirement as commerce minister, a post he has held since taking over from now disgraced politician Bo Xilai in late 2007, would come as China faces growing tension with major trade partners in Europe and the United States and Chinese officials warn of increasing protectionism.


China’s leaders set a goal for 10 percent export growth this year, but it is more likely to come in at around 7 percent as the world has struggled to recover from financial crisis.


DEFENDED RECORD


Some experts suggest that Chen’s age was the main factor in his ouster.


“Minister Chen didn’t get onto the Central Committee because of his age. He was born in 1949 and that makes him too old to serve a full term,” said a Commerce Ministry official who declined to be identified.


But exceptions to the mandatory retirement age of 65 are often made for cabinet ministers and provincial governors and politicians can become a vice premier before they turn 68.


Du Qinglin, 66, a vice chairman to parliament’s advisory body, was just elected to the Central Committee.


At a news conference last week on the sidelines of the congress, Chen declined to answer questions about whether he was being considered for a vice premier post, but he defended the ministry’s record at the World Trade Organisation.


“When you consider the volume of trade cases in which China is involved, we’ve won quite a few,” Chen said. “But we haven’t bragged about our wins, whereas some of our foreign colleagues have trumpeted theirs.”


Analysts said Chen had a reputation as a competent and moderate minister, suggesting his performance may not have been at the center of his failure to secure a central committee seat, and despite the questions that are bound to arise, policy would probably not change.


“China’s overall trade policy is not set by the ministry, but by the central government,” said He Weiwen, director of the China-U.S. Trade Research Centre at the University of International Business and Economics in Beijing.


Under Chen, the ministry has increased its use of WTO legal processes, in part to gain experience. China has a relatively short history of participating in multilateral institutions and while it has lost most of WTO cases filed against it, most countries defending against complaints have the same problem.


Scott Kennedy, director of the Research Centre for Chinese Politics and Business at Indiana University said Chen’s departure from the Central Committee was puzzling and political motives could be at play.


“I don’t think he could be punished for his record as minister of commerce. I think overall he’s done a pretty decent job with the hand he has been dealt,” Kennedy said.


(Additional reporting by Lucy Hornby and Nick Edwards; Editing by Robert Birsel)


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Canada’s Carney says rate hikes “less imminent”
















TORONTO (Reuters) – Interest rate hikes have become less imminent than the Bank of Canada once expected, although rates are still likely to rise, central bank Governor Mark Carney said in an interview published on Saturday.


“Over time, rates are likely to increase somewhat, but over time, so a less imminent timing relative to our expectation,” Carney said in an interview with the National Post newspaper.













Canada’s economy rebounded better than most from the global economic recession, and the Bank of Canada is the only central bank in the Group of Seven leading industrialized nations that is currently hinting at higher interest rates.


But Carney has also made clear that there will be no rate rise for a while, despite high domestic borrowing rates that he sees as a major risk to a still fragile economy.


“We’ve been very clear in terms of lines of defense in addressing financial vulnerabilities,” he said in the interview. “And the most prominent one, obviously, in Canada, is household debt.”


He said the bank was monitoring the impact of four successive government moves to tighten mortgage lending, which aimed to take the froth out of a hot housing market without causing a damaging crash in prices.


A Reuters poll published on Friday showed the majority of 20 forecasters believe the government has done enough to rein in runaway prices, preventing the type of crash that devastated the U.S. market.


The experts expect Canadian housing prices to fall 10 percent over the next several years, but they do not expect the recent property boom to end in a U.S.-style collapse.


(Reporting by Janet Guttsman; Editing by Vicki Allen)


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Texas Instruments cuts 1,700 jobs, winds down tablet chips
















NEW YORK/SAN FRANCISCO (Reuters) – Texas Instruments is eliminating 1,700 jobs, as it winds down its mobile processor business to focus on chips for more profitable markets like cars and home appliances.


Texas Instruments said in September it would halt costly investments in the increasingly competitive smartphone and tablet chip business, leading Wall Street to speculate that part of the company’s processor unit, called OMAP, could be sold.













The layoffs are equivalent to nearly 5 percent of the Austin, Texas-based company’s global workforce.


“A sale would have been better than a restructuring but a restructuring is certainly better than nothing,” Sanford Bernstein analyst Stacy Rasgon said.


TI has been under pressure in mobile processors, where it has lost ground to rival Qualcomm Inc. Leading smartphone makers Apple Inc and Samsung Electronics Co Ltd have been developing their own chips instead of buying them from suppliers like TI.


Instead of competing in phones and tablets, TI wants to sell its OMAP processors in markets that require less investment, like industrial clients like carmakers.


TI is expected to continue selling existing tablet and phone processors for products like Amazon.Com Inc‘s Kindle tablets for as long as demand remains, but stop developing new chips.


“This year, the Kindle runs on the OMAP 4 and next year’s Kindle is slated, we believe, for OMAP 5. We believe that program is well along to completion and do not expect that the termination of OMAP will disrupt those plans,” said Longbow Research analyst JoAnne Feeney.


Amazon had reportedly been in talks to buy the mobile part of OMAP.


TI said it expects to take charges of about $ 325 million related to the job cuts and other cost reduction measures, most of which will be accounted for in the current quarter. Its previously announced financial targets for the fourth quarter do not include these costs, TI said.


The company, which has 35,000 employees around the world, expects annualized savings of about $ 450 million by the end of 2013 from the action.


TI shares rose to $ 29 in after-hours trading after closing at $ 28.76, down 2 percent on Nasdaq.


(Reporting By Sinead Carew in New York and Noel Randewich in San Francisco; editing by Carol Bishopric)


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“Twilight Saga” ends with movie love letter to fans
















LOS ANGELES (Reuters) – “Twilight” fans bid an emotional farewell this week to Bella, Edward and Jacob in “Breaking Dawn-Part 2,” the romantic book and movie franchise that ignited a pop culture infatuation with blood-sucking vampires and werewolves.


The tumultuous love triangle between human girl Bella Swan, vampire Edward Cullen and werewolf Jacob Black, that has gripped avid fans known as “Twi-hards” for seven years, comes to a tantalizing end as “Breaking Dawn-Part 2″ hits movie theaters around the world.













The “Twilight” film franchise, based on a series of novels by Stephenie Meyer, rocketed the three main stars, Kristen Stewart (Bella), Robert Pattinson (Edward) and Taylor Lautner (Jacob), into the spotlight and the first four films have grossed more than $ 2.5 billion at the worldwide box office.


For director Bill Condon, who shot both parts of “Breaking Dawn” together and split into two movies post-production, the fifth and final film was all about the fans – who get a surprise twist to the ending.


“The real challenge was to make sure it was a satisfying climax,” Condon told reporters. “The film opens with an overture of all the main scenes from all five movies, and at the end, I…brought (it) back to the spirit of the old movies.”


The movie pays homage to the angst-ridden teenage romance between Bella and Edward that was underscored by the off-screen real-life romance between Stewart, 22, and Pattinson, 26.


“Breaking Dawn-Part 2″ shifts the action from a love story to a family story, as the Cullen clan recruit their extended vampire family to protect Bella and Edward’s daughter Renesmee from an ancient vampire coven.


“I think it’s very sweet, especially the ending of it, I think it’s very close to the book as well. It seems to be that it’s really made for the fans,” Pattinson told Reuters.


GOING OFF BOOK


While the past four films have stayed true to the books, author Meyer and screenwriter Melissa Rosenberg came up with a plot twist that adds a major scene that may surprise movie-goers.


“(The action) is off screen in the novel because we only see what Bella sees, and this was just a way of making visual what some of the other characters might have seen,” Meyer told reporters.


“It does feel very surprising. There’s something new to see but to me it doesn’t seem like it’s going hugely off the page,” she added.


While the fourth film saw Bella’s human life draw to a conclusion when she died giving birth to a human-vampire hybrid baby with new husband Edward, “Breaking Dawn-Part 2,” sees Bella as a mother and a newly-transformed vampire.


“The coolest thing about vampire Bella is that I got to play her as a human for so long, and the special parts of each vampire are always informed by the great things that they were as a human and so I got to walk in those shoes,” Stewart told Reuters.


“Everything made total sense to me. I waited for so long (to play a vampire), once I finally got it, it was so comfortable, I couldn’t wait,” the actress added.


“The Twilight Saga,” first published in 2005, kicked off a wave of vampire or supernatural-themes books, films and TV shows including HBO’s “True Blood,” the CW TV network’s “The Vampire Diaries” and Richelle Mead’s “Vampire Academy” series of young adult novels.


As the sun sets on the franchise Meyer brought to life, the author said that while she didn’t rule out the possibility of finding more stories in the vampire-werewolf universe, she had closed the chapter on the Cullens.


“I don’t know if I’ll ever get back to these (stories). Someday I’ll write down what was going to happen next. It’s sad knowing I don’t have another party with the kids again, I really hope I have a chance to at least see my friends again,” she told Reuters.


(Reporting by Piya Sinha-Roy, editing by Jill Serjeant and Marguerita Choy)


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Multibillion-dollar health fund fires watchdog
















GENEVA (AP) — The board of a $ 23 billion health fund trying to restore its image fired its top internal watchdog, whose office has been uncovering financial losses.


The Global Fund to Fight AIDS, Tuberculosis and Malaria said in a statement Thursday that its board had terminated the employment of Inspector General John Parsons “after a careful review of his performance, which was found to be unsatisfactory.” It said this was based on performance and independent peer reviews and a report by the board committee that oversees Parsons’ office.













The board said it would soon name an interim inspector-general and expects to find a permanent replacement within six months.


The fund also is selecting a new executive director Thursday from among four finalists. The previous director resigned because of a review panel that the fund created after Associated Press articles last year about financial losses. The articles led some donors to withhold funding, and the fund scaled back spending.


Those losses were uncovered by the office that Parsons had headed since 2007. The office — whose teams of auditors and investigators are supposed to function independently — was created in 2005 at the urging of the fund’s biggest donor, the United States.


Before joining the Global Fund, Parsons, a British citizen, had gained more than 35 years of experience in audits, investigations and evaluations and had served as a director at U.N. agencies UNESCO and UNICEF. He headed Britain’s National Audit Office from 1989 to 1996.


Parsons could not immediately be reached for comment Thursday.


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Stock futures erase gains, Wal-Mart falls after results
















NEW YORK (Reuters) – Stock index futures were flat on Thursday, with investors again finding few reasons to buy amid weak results from retail giant Wal-Mart and tensions in the Middle East.


Futures were off their highs of the session, continuing a trend of equities having difficulty holding onto gains. Futures had also indicated gains Wednesday morning, but stocks turned lower midday and ended down more than 1 percent.













Eroding gains in Dow futures, Wal-Mart Stores fell 3.2 percent to $ 69 in premarket trading after reporting third-quarter revenue that missed expectations and saying macroeconomic conditions continued to pressure its customers.


“This is troubling because it flies in the face of other retail data we’ve seen lately, which has been positive,” said Kim Forrest, senior equity research analyst, Fort Pitt Capital Group in Pittsburgh. “There’s not much out there convincing investors that things are getting any better.”


Target Corp eased back to $ 61.36 before the bell even as the company reported higher quarterly profit.


Overseas, Israel launched a major offensive against Palestinian militants in Gaza, killing the military commander of Hamas in an air strike and threatening an invasion of the enclave. Egypt said it recalled its ambassador from Israel in response.


Crude oil may be the most directly impacted by the tensions in the region, with any disruption to oil supply leaving crude vulnerable to a spike in prices. Brent crude rose 1 percent and is up 4.7 percent over the past two weeks.


“Nothing over there seem stable, and investors are concerned other countries could be pulled into the conflict. You’re going to see oil jump on that threat,” Forest said.


S&P 500 futures were flat but still slightly above fair value, a formula that evaluates pricing by taking into account interest rates, dividends and time to expiration on the contract. Dow Jones industrial average futures fell 25 points and Nasdaq 100 futures rose 2.75 points.


With Wednesday’s drop, both the Dow and Nasdaq ended at their lowest levels since late June. The S&P 500 is down 5.1 percent in the six sessions since election night. Wednesday marked the benchmark index’s lowest close since July 25.


Investors may seek bargains at these levels, and a round of stronger economic data could prove to be a catalyst, but many analysts say strong gains may be hard to come by until at least one of the many global macroeconomic headwinds have been resolved.


“There’s all this uncertainty out there, and the market is unbalanced because those who want to buy can be very discriminate about the price they want to buy at,” Forest said.


The market will also watch the latest economic data, with weekly jobless claims, October consumer prices and a November read on New York manufacturing all due out at 8:30 a.m. (1330 GMT). The Philadelphia Federal Reserve Bank releases its November business activity survey at 10 a.m.


Claims are seen rising by 20,000 to 375,000 while consumer prices are seen up 0.1 percent, compared with a 0.6 percent rise in September, according to a Reuters poll. The Empire State manufacturing survey is seen coming in at -6.7, compared with -6.16 in October. The Philly Fed survey is seen dropping to 2 from 5.7 in October.


While the President and Congress are unlikely to reach a definitive agreement for weeks, investors will continue to monitor the situation regarding the fiscal cliff, a series of mandated tax increases and spending cuts will start to take effect early next year that could push the U.S. economy into a recession.


President Barack Obama Wednesday reiterated his position that marginal tax rates would have to rise to tackle the nation’s deficits. Taxes on capital gains and dividends also could rise as part of the negotiations, pushing investors to sell this year and pay lower taxes on their gains.


(Editing by Theodore d’Afflisio)


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Beating tax cheats key to Italy’s recovery plan
















ROME (AP) — Good plumbers may be worth their weight in gold, but when one was spotted zipping around in a bright red Ferrari, Italian tax police were fast on his trail.


Stamping out entrenched tax evasion is crucial to Premier Mario Monti‘s quest to keep Italy from succumbing to the European debt crisis, and it is critical to fellow eurozone members in more dire straits, such as Greece and Spain — which are also notorious for making cheating the taxman a way of life.













Indeed, Greece’s international rescue creditors have been pressing Greece for two years to reform its ailing tax system, citing poor collection as a key factor keeping the country mired in crisis. In Spain, where tax fraud is rampant, as much as €90 billion ($ 150 billion) is lost each year to tax fraud — the equivalent of the country’s national debt, according to Spain’s main tax inspectors union.


To succeed in Italy, authorities will have to catch the legions of self-employed and small business owners who brazenly lie about their earnings, like the plumber in the eastern town of Pescara, who socked away undeclared income in 30 bank accounts, or a successful pastry shop owner in Calabria, who on his tax return claimed he was earning next to crumbs.


And those are the less sophisticated schemers.


Tax police officials say that wealthy Italians, their companies and foreigners who make their money in Italy are increasingly trying to avoid taxes by using such strategies as falsely declaring that their base of operations or residence is abroad.


Another daunting challenge is the so-called “submerged” economy, a term embracing Italians who declare only a fraction or nothing at all of their earnings — and dentists, lawyers, doctors and other big-earning professionals are frequently among the worst offenders.


Tax evasion of all types in Italy totals about euros 240 billion ($ 300 billion), or 15 percent of the country’s gross domestic product of €1.6 trillion ($ 2 trillion), tax police estimate. Winning the war on tax cheats could therefore more than wipe out the country’s budget deficit, which is expected to increase to euros 42 billion ($ 53 billion), or 2.6 percent of GDP this year. That would start knocking away at the nation’s colossal public debt of €2 trillion ($ 2.5 trillion), or 125 percent of GDP.


But “big international frauds are up,” lamented Lt. Col. Gianluca Campana, in charge of the income tax unit revenue protection office at the Guardia di Finanza, Italy’s financial police corps which reports to the Economy Ministry.


The entrenched practice by many cafes, eateries, hair dressers and similar small business of neglecting to give customers mandatory cash register receipts commonly grabs the attention in crackdowns on tax evasion in Italy.


But, cautioned Campana, “one false (big business) invoice can equal no cash register receipts for coffees for two months.”


Over all of 2011, the total of non-declared income discovered by tax police amounted to some €50 billion ($ 65 billion), of which some 20 percent was due to international tax evasion, he said. By comparison, in the first nine months of this year, tax police discovered some €40 billion in undeclared income, with 30 percent of that blamed on international tax evasion, Campana said.


With the economic crisis shrinking bottom lines, and Italy increasingly on the hunt for big-time evasion, especially by big businesses, “there is a tendency to move capital abroad, using maneuvers apparently legal but which really are not,” Campana said. A classic technique consists of declaring one’s formal residence abroad in tax havens like Monte Carlo. Also common are companies that clearly have their business base in Italy but claim it is abroad in countries with far lower tax brackets.


Campana is armed with three degrees, including a masters in tax law from Milan’s Bocconi University, the prestigious economics institute formerly headed by Monti. He brings skills to this specialized police corps that are as finely tuned as sharp-shooting.


“We are going after the big cases (of evasion) in order to rake in more money,” Campana said.


The Ferrari-driving plumber hid some €2 million ($ 2.6 million) of his income over several years by giving his customers invoices — for jobs ranging from fixing leaks to installing new bathrooms — for the actual cost of his work, but kept a second, false registry of much lower figures for tax purposes, said Pescara tax police Col. Mauro Odorisio.


Armed with a 2008 law, authorities confiscated assets belonging to the plumber equivalent to the approximately €1 million ($ 1.3 million) they contend he owed in taxes, Odorisio said.


With Ferraris in red or yellow, and snazzy Porsches parked inside, Guardia di Finanza garages practically resemble luxury car dealerships.


The cars get sold to help recoup unpaid taxes and interest.


Overall, tax revenues in Italy were up by 4.1 percent, says the Economy Ministry, when comparing figures from the first eight months of 2012 with the same period in 2011, but much of that was due to new taxes, and not necessarily a revolution in citizens’ consciences about tax obligations.


Monti’s recipe relies heavily on taxes that are nearly impossible to avoid, such as sales tax. He also revived a property tax that his populist predecessor, Premier Silvio Berlusconi, had abolished in a promise to voters.


The ministry’s report last month noted that the property tax figured prominently in the “tendency toward growth” in tax revenues. But sales tax revenue dropped slightly despite higher sales tax rates, indicating that consumers were feeling the pinch of the stagnant economy.


The heavier fiscal burden seems to have driven some honest citizens to rebel against the engrained culture of tax evasion.


The number of phone calls from the public to the tax police’s hotline to report stores, restaurants and other businesses that didn’t give customers sales receipts has almost doubled in the first nine months of this year, compared with the same period in 2011.


It’s apparently dawning on Italians that shirking taxes in the end only costs them, in terms of ever-higher levies and cutbacks in public services.


Citizens now increasingly understand that “the lack of revenue over time caused by tax evaders forced the government to stiffen the tax burden on categories where you can’t evade taxes,” Campana said, referring to workers whose taxes are deducted from paychecks. Another area where evasion is close to impossible is real estate ownership.


Odorisio noted the crackdown included extending the statute of limitations on tax evasion from six to eight years and establishing prison as a penalty for big-time evasion.


Other weapons include a measure promoted by the Monti government that limits cash payments to no more than €1,000. Paying by credit card or personal check is a relatively new habit for Italians, who are used to carrying wads of cash in their pockets, even for big-ticket items like home renovations or vacations.


Past governments in Italy sometimes resorted to tax amnesties to try to boost revenues. But critics, contending some Italians counted on such a possibility, described that strategy as only perpetuating the tax cheat culture.


Spain hasn’t had much success with its own tax amnesty introduced by the conservative government in March. That measure, expiring soon, allows undeclared assets or those hidden in tax havens to be repatriated by paying a 10 percent tax without criminal penalty. The amnesty is estimated to recuperate far less than the expected €2.5 billion ($ 3.25 billion).


Greece saw demands for tax system reform from international rescue creditors added on to conditions for future rescue loan payments, as Greek authorities acknowledged that a high-profile campaign to crack down on major tax cheats has produced disappointing results.


The cash-strapped government over the last 10 months recovered just €19 million ($ 25 million) of the €13 billion ($ 17 billion) of arrears on the list. A prominent Greek magazine publisher recently tapped anger over rich tax evaders by publishing a list of people allegedly holding Swiss bank accounts. He was acquitted this month of breaching privacy laws.


Meanwhile, Italian tax police are chasing after cheats who have shown some of the most chutzpah about not paying their fair share of taxes, like the Padua woman who advertised on the Internet that she had a couple of “cash-only” bed and breakfast rooms to let.


Tax police discovered the lodgings are part of an apartment in public housing she was given after falsely declaring she was indigent on her annual tax forms.


____


AP reporters Derek Gatopoulos in Athens and Ciaran Giles in Madrid contributed to this report.


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Anne Hathaway reveals oatmeal paste diet for ‘Les Miserables’
















LOS ANGELES (Reuters) – Hollywood starlet Anne Hathaway credits a strict diet of dried oatmeal paste for helping her shed some 25 pounds (11 kg) for her role in the forthcoming big screen musical “Les Miserables.”


“I had to be obsessive about it – the idea was to look near death,” Hathaway told Vogue about preparing for her role as the consumptive prostitute Fantine in the musical version of Victor Hugo‘s classic 19th century French novel.













Hathaway, 30, told the December edition of the magazine, that she first lost 10 pounds (5 kg) to begin filming and then later dropped another 15 pounds (7 kg) by eating nothing but two thin pieces of oatmeal paste a day.


“Looking back on the whole experience – and I don’t judge it in any way – it was definitely a little nuts,” said “The Dark Knight Rises” actress. “It was definitely a break with reality, but I think that’s who Fantine is anyway.”


Extreme body changes have become part of Hollywood lore, even factoring into the marketing of films. Natalie Portman received much publicity for dropping some 20 pounds (9 kg) for her Oscar-winning role as a ballerina in 2010′s “Black Swan.”


Jennifer Lawrence, who plays the famished star of the life-or-death thriller “The Hunger Games,” made waves last week vowing never to diet for a role.


Hathaway said it was a rocky transition back into everyday life after filming.


“I was in such a state of deprivation – physical and emotional,” she said. “When I got home, I couldn’t react to the chaos of the world without being overwhelmed. It took me weeks till I felt like myself again.”


Directed by Tom Hooper (“The King’s Speech”), “Les Miserables” is scheduled to be released on December 25 in the United States and is seen as a strong contender for Oscar nominations. The film version of the stage musical also stars Hugh Jackman and Russell Crowe.


(Reporting By Eric Kelsey; Editing by Jill Serjeant and Mohammad Zargham)


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New Hope For ‘Man on Fire Syndrome’
















Pamela Costa has never known a day without agonizing pain in her legs and feet.


At age 11, the Seattle native was diagnosed with inherited erythromelalgia, a genetic condition that causes such severe pain and redness some call it “Man on Fire Syndrome.”













“Think of the feeling that you get when you come in from the cold and your hands and feet are rewarming too fast,” said Costa, 47. “I have that feeling all of the time.”


Inherited erythromelalgia is a disease of small nerves and blood vessels that causes severe pain in response to heat, pressure, exertion or stress.


“These people feel excruciating, scalding pain while putting on shoes or putting on a sweater,” said Dr. Stephen Waxman, a neuroscientist at Yale University and the West Haven Veterans Affairs Hospital. “They will keep their feet on ice to the point of getting gangrene, just to relieve the sensation.”


When Costa was growing up, playing outside would trigger the unbearable burning sensation.


“I used to come in from recess and just hold my hands on the cool metal of my school desk,” said Costa, who has more than two dozen relatives with the same affliction. “I have had cousins suffer devastating injuries from over-cooling themselves.”


Although the disease is rare, researchers are searching for clues to its cause with hopes of uncovering treatments for chronic pain of all kinds. The story starts at the molecular level within tiny nerves that conduct pain signals.


An Overactive Channel Protein


Pain comes in different forms, depending on the type of nerve that senses it. And for chronic pain patients, the pain is not quick and specific, but instead slow and sharp.


This slow pain is transmitted from the limbs and body to the brain along small nerves in the spinal cord called C-fibers. Messages move along these nerve fibers due to the action of special proteins in their membranes called channels. One specific type of channel is the Nav1.7 sodium channel, which is present in great numbers in the C-fibers of the spinal cord.


Work by Waxman and others has shown that patients with inherited erythromelalgia have a defect in their Nav1.7 channels that allows too many sodium ions to enter the C-fibers, causing an increase in the sensitivity of the nerves.


The specific atomic structure of the Nav1.7 channel has been modeled by Waxman’s lab, and the results are detailed in the current issue of Nature Communications. Armed with this new model of the Nav1.7 channel, the lab has been able to show why some patients with inherited erythromelalgia respond well to an anti-epileptic drug called Carbamazepine.


Furthermore, in studying the channel structure in many different people, Waxman and colleagues have found variations in the channel from person to person. These variations may cause some people to be more likely to experience chronic pain than others.


A New Drug Target


Patients with a completely defective Nav1.7 suffer from the opposite condition, known as congenital indifference to pain. These people do not experience pain at all, with case reports of being able to walk on hot coals without pain.


As the role of Nav1.7 in the mechanism for pain sensation becomes clearer, biotechnology and pharmaceutical companies will likely take notice, according to Waxman.


“I anticipate a race to develop Nav1.7 specific blockers,” he said.


Current drug therapies for pain include medicines like morphine, as well as aspirin and ibuprofen. While all of these decrease the sensation of pain, they also interact with other tissues such as the brain, heart and stomach, causing side effects.


Nav1.7 does not appear to be present in large quantities outside of the C-fibers of the spinal cord. As such, new drugs targeting this protein could herald a new class of pain treatments with many fewer side effects than our current drugs for pain.


Costa said she hopes to see a day where such a medicine would be available to her, providing her with full relief for the first time in her life.


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