A Magnetic Shortcut to Clinical Trials

Even the most promising drug will fail if it never reaches its target. So before starting large clinical trials, pharmaceutical companies must determine, among other things, the precise dosage to use, a process that can be expensive and time-consuming. Scientists investigating a drug for Parkinson's disease have now shown how an MRI scan can quickly determine the optimal dosage for drugs that act on the brain.

The most precise way to track drugs as they move through the body is a PET (positron emission tomography) scan, in which a drug is a radioactively tagged, injected into the body, and tracked with a scanner. But PET scans have several drawbacks, notes Kevin Black, associate professor of psychiatry at Washington University in St. Louis, Missouri, who led the new research, published in the December issue of The Journal of Neuroscience. PET scanners, and PET scans, are very costly. And because they expose subjects to radioactivity, multiple PET scans can pose a health risk. As an alternative to PET scans, drug companies sometimes spend months to years assessing optimal dosages via clinical measures such as mood questionnaires or tests of patients' manual dexterity.

The Washington University study, funded by Synosia Therapeutics, is the first to track a drug's effect with an MRI technique called arterial spin labeling (ASL). Using this approach, the researchers determined the optimal dosage of the Parkinson's drug noninvasively, without injections or radioactivity, in four months.

The researchers focused the MRI machine on subjects' neck arteries to tag water molecules in the blood by changing their magnetic properties. These water molecules were visible in subsequent scans, providing a picture of arterial blood flow to particular parts of the brain.

The researchers took scans before and after the administration of different doses of the drug. When they compared the shots, Black and colleagues could see immediately which areas of the brain implicated in Parkinson's showed increased blood flow, owing to the action of the drug. This allowed them to identify the most effective dosage for further testing.

Using ASL to accelerate the move to large trials will interest drug companies as a cost-cutting measure, says the University of Pennsylvania's John Detre, a neurologist who developed ASL in the early 1990s and was not involved in the new research. "A key go/no-go decision in drug development early on is whether the drug is getting into the brain and doing what you think it's doing," he says. "This study is a fantastic proof of principle."

ASL doesn't have the specificity of PET scans, which can track the way drugs act at a molecular level, says Luis Hernandez of the University of Michigan's MRI Research Facility. "But if you want to know if the drug is changing the part of the brain it should be reaching," he remarks, "then this works well."

An obvious target for ASL is antidepressants, which take two to six weeks or longer to show a clinical effect. With ASL, it is possible to see very quickly whether the drug is affecting the brain?an indication that it could be effective in alleviating depression. Detre adds that the technique could see more use in other areas of drug development: "You might be able to use this one technique to look at the effects of a very broad range of drugs on the brain."

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U.S. Envoy in Critical Condition After Surgery

Doctors at George Washington University Hospital completed the surgery on Saturday morning, and Mr. Holbrooke has been joined there by members of his family, according to the statement from the department?s spokesman, Philip J. Crowley. He did not provide further details.

Mr. Holbrooke, 69, a veteran diplomat who helped broker the peace accord that ended the war in Bosnia, became ill on Friday during a meeting with Secretary of State Hillary Rodham Clinton, administration officials said. He was able to walk out of Mrs. Clinton?s office to seek medical attention.

As the senior policy maker on the administration?s most pressing foreign policy issue, Mr. Holbrooke helped shape the civilian component of the administration?s Afghanistan strategy, deploying more than 1,000 diplomats and aid workers to help the Afghans rebuild its state institutions.

Mr. Holbrooke travels regularly to Afghanistan and Pakistan, conducting often difficult negotiations with President Hamid Karzai of Afghanistan and Pakistan?s civilian and military leaders.

Before his current post, Mr. Holbrooke was an investment banker, author, and commentator. He has held an array of diplomatic posts, including United States ambassador to the United Nations and ambassador to Germany, and he was twice an assistant secretary of state, for East Asia and for Europe.

Mr. Holbrooke began his career in Vietnam, where he worked as a staff assistant to two ambassadors, Maxwell D. Taylor and Henry Cabot Lodge Jr. At the age of 35, he was the youngest person ever to hold the position of assistant secretary for East Asian and Pacific affairs.

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Weekend Open Forum: Gadgets you can't live without

Those of you born more than a couple of decades ago can probably remember a time when cell phones, personal computers, cable television, and other modern conveniences werent something youd take for granted or outright didnt even exist. Some say those were simpler times, but as a technology lover I certainly wouldnt want to live without many of these things. Truth is, in most cases they also make life so much easier.

Digital video recorders, like TiVo, for example, changed the way a lot of people consume television programming and this continues to evolve with the proliferation of broadband connectivity and streaming content. Cell phones are much more than omnipresent communication devices -- which is already amazing by itself -- and now double as anything from real-time GPS navigation systems, to workout companions, gaming handhelds and much more.


Granted, some things are not particularly vital and others we may get just for bragging rights, but Im sure most of you own at least a handful of gadgets that are part of your everyday lives. Having just moved to another country, I had to leave some things behind and my arsenal is rather limited at the moment -- its mainly a unibody MacBook, which I dual boot between Windows 7 and Mac OS X, an iPhone 4, a flat-screen TV and a digital SLR camera. My laptop is due for an update soon, I plan to buy a speaker dock, and Im still considering if I should get a tablet sometime next year (oh yeah, and probably a nice coffee maker). How about you? What are the gadgets you absolutely cant live without?

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Blog - A Lego Reconstruction of the World's Earliest Computer

Here's a brand new stop motion video of a reconstruction of the world's first mechanical computer, directed by occasional Technology Review contributor John Pavlus. It's entirely self-explanatory: watch it and read on.

One hundred years before the birth of Christ, when agriculture and the wheel was for most of human civilization the apex of technological achievement, the Greeks built a mechanical computer so sophisticated that it could add and subtract--all in the name of predicting the next lunar eclipse.

In 2010, Apple engineer Andrew Carol created, based on previous reconstructions of the so-called "Antikythera" mechanism, which was discovered in a shipwreck in 1901, a fully functioning Lego replica of the device. Like the original, it accurately predicts solar eclipses.

Its secrets are explained at length in a feature in Nature and its Wikipedia entry, which, not surprisingly for a device that is catnip for geeks, is as exhaustive as the plot exegeses of old episodes of Lost.

The Antikythera is such a marvelous device--Michael Edmunds of Cardiff University, who led the most recent study of the device, says it is more historically valuable than the Mona Lisa--that it continues to inspire great works of its own: first the historically faithful reconstructions of it, then the lego reconstruction, and now this stop motion video, which, like all stop motion, was an enormous effort in itself.

Here's a sped-up, behind the scenes video of the shoot:

And if you want to really dig deep, Pavlus has conducted an interview with the creator of the Lego version of the Antikythera. It includes fascinating details about managing the friction generated by the more than 100 gears in the mechanism. Here's Carol's account of how it works:

It's pretty simple; it's all about ratios between the numbers of teeth on two gears meshed together. If one gear has 50 teeth and another has 25, that's a 2-to-1 ratio -- which means that turning the axle one full revolution on the first gear will multiply by two, because it turns the second gear twice as fast.

But the tradeoff is that when you make it go fast, you lose power. It's fast, but it's not strong, and vice versa -- and those mechanical effects pile up quickly when you've got over 100 gears working together in exotic ratios. When I have to multiply by 127, it's got to turn very fast, but with little power, which means that whatever amount of friction there is, I've effectively multiplied it by 127. So I had to put a lot of thought into designing the optimal layout of gears that would minimize the friction enough to make that kind of calculation physically work.

Finally, there's Pavlus's account of how he brought the video project itself together. For anyone interested in how to explain complicated technology to a lay audience, it's quite a ride:

But how to actually execute that idea? Obviously some kind of animation would be necessary. Several people I consulted urged me to use computer graphics. But that felt wrong: Legos are wonderfully tactile, and I really wanted to highlight the machine's intricate physical detail ? to make you feel like you could literally reach out and touch the gears or turn the crank. CGI would feel too weightless and abstract ? too perfect. Andy's model was the quintessence of DIY hacking: he didn't even diagram it out before starting to build it. I needed animation that was physical, craft-ey, and a little bit rough around the edges. Stop-motion was the clear choice.

For even more background on the Antikythera mechanism check out this illuminating video from 2008, produced for Nature by a director with decades of experience at the BBC.

Follow Mims on Twitter or contact him via email.

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Mozilla patches 11 security flaws in Firefox

Mozilla has released the latest stable version of Firefox, now at version 3.6.13. The latest version fixes various security bugs, 11 advisories to be exact, and stability issues, 68 bug fixes in all.

More specifically, the 11 Security Advisories are broken down as such: nine are rated "Critical," one is marked "High," and the last one is classified as "Moderate." The critical vulnerabilities include a Java security bypass, multiple memory safety hazards, buffer overflow security issue, as well as a crash and remote code executing issue while using HTML tags inside of a XUL tree. The two non-critical vulnerabilities are related to character encodings and location bar SSL spoofing.

To download the latest version, you can use the "Check for Updates" option in the browser. Alternatively, you can download it directly for Windows, Mac, or Linux.

The new stable release of Firefox comes as the company is pushing forward with Firefox 4, which is currently at Beta 7. Firefox 4 was originally slated to be released by now, but Mozilla has since delayed it until 2011.

Mozilla also released Thunderbird 3.1.7, an update for its e-mail client. Thunderbird follows Firefox updates because it can display HTML formatted e-mails. The update also has several additional bug fixes to improve performance, security, and stability.

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Mozilla patches 11 security flaws in Firefox

Mozilla has released the latest stable version of Firefox, now at version 3.6.13. The latest version fixes various security bugs, 11 advisories to be exact, and stability issues, 68 bug fixes in all.

More specifically, the 11 Security Advisories are broken down as such: nine are rated "Critical," one is marked "High," and the last one is classified as "Moderate." The critical vulnerabilities include a Java security bypass, multiple memory safety hazards, buffer overflow security issue, as well as a crash and remote code executing issue while using HTML tags inside of a XUL tree. The two non-critical vulnerabilities are related to character encodings and location bar SSL spoofing.

To download the latest version, you can use the "Check for Updates" option in the browser. Alternatively, you can download it directly for Windows, Mac, or Linux.

The new stable release of Firefox comes as the company is pushing forward with Firefox 4, which is currently at Beta 7. Firefox 4 was originally slated to be released by now, but Mozilla has since delayed it until 2011.

Mozilla also released Thunderbird 3.1.7, an update for its e-mail client. Thunderbird follows Firefox updates because it can display HTML formatted e-mails. The update also has several additional bug fixes to improve performance, security, and stability.

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Obama Weighs a Broad Tax Overhaul

While administration officials cautioned on Thursday that no decisions have been made and that any debate in Congress could take years, Mr. Obama has directed his economic team and Treasury Department analysts to review options for closing loopholes and simplifying income taxes for corporations and individuals, though the study of the corporate tax system is farther along, officials said.

The objective is to rid the code of its complex buildup of deductions, credits and exemptions, thereby broadening the base of taxes collected and allowing for lower rates ? much like a bipartisan majority on Mr. Obama?s debt-reduction commission recommended last week in its final blueprint for reducing the debt through 2020.

Doing so would offer not only an opportunity to begin confronting the growth in the national debt but also a way to address warnings by American business that corporate tax rates and the costs of complying with the tax code are cutting into their global competitiveness.

Mr. Obama signaled his inclination in off-the-cuff remarks on Wednesday as he was defending the tax cuts deal negotiated with Congressional Republicans this week. ?We?ve got to have tax reform,? he said.

Economic and political advisers say the process is in its early stages, and Mr. Obama ultimately could decide against such action, given the pitfalls, both political and substantive. In the past, any effort to alter the tax code has provoked powerful opposition among interest groups, and the picking of winners and losers.

Yet proponents within the administration and among some outside advisers say that Mr. Obama, by putting tax reform atop the national agenda, could seize an opportunity to take the offensive in dealing with the newly empowered Republicans in Congress, repair his strained relations with business and embrace a potentially powerful theme heading into his re-election campaign.

Democrats have long struggled to define battles over taxes on their terms. The revolt by many members of the president?s party in Congress over his deal with Republicans, which would extend the Bush-era tax cuts for the rest of his term and create his own tax cuts for lower-income people and for businesses, has underscored anew the deep ideological divisions in Washington on the subject. Should that deal be enacted, it could add to pressure for simplifying the tax system because its mix of breaks for taxpayers of all incomes would further complicate the tax code, at least for the next year or two.

Administration officials and lawmakers in both parties also took note last week of the bipartisan show of support within the fiscal commission for changes of the type being considered by Mr. Obama. That suggested a potential break in the long-solid Republican wall of opposition to anything that smacked of a tax increase.

Rather than increase individual and corporate tax rates to raise more revenues, a majority of the panel proposed eliminating or reducing many of the popular tax breaks for businesses and individuals that cost $1 trillion annually and using the additional revenues to lower rates and reduce deficits. The majority included five Republicans, among them two of the Senate?s most conservative members, Tom Coburn of Oklahoma and Michael D. Crapo of Idaho.

According to commission officials, the Treasury secretary, Timothy F. Geithner, expressed interest in the panel?s approach. With tax breaks ended or restricted in return for lower rates, businesses and individual taxpayers would know that for each credit or deduction they wanted put back into the code, their marginal tax rates would go up by an amount sufficient to make up the revenues that would be lost.

Some Democrats argue that the White House should take the lead, before Republicans do. Even as administration officials deliberate over their course, a growing number of conservative economists and strategists are urging Congressional Republicans to quit fighting the decade-old fight over the Bush tax rates and take up the reform mantle.

?Declare Bush tax cuts, like the Bush administration itself, over,? Kevin A. Hassett, the director of economic policy studies at the American Enterprise Institute, a conservative-leaning research organization, wrote recently in a Bloomberg News column.

?The fact is,? he added, ?if we extend the Bush tax cuts, it locks in the status quo. Earth to Washington: The status quo stinks. With the economy still limping forward, much more significant fiscal-policy medicine is in order.?

Mr. Obama, in his brief remarks on Wednesday during a meeting with the president of Poland, suggested that Republicans would still be defending the Bush tax rates for the next two years while he is looking forward to a new, better code.

?We?re going to have a big debate about taxes and we?re going to have a big debate about the budget and we?re going to have a big debate about deficits,? he said. ?And Republicans are going to have to explain to the American people over the next two years how making those tax cuts for the high end permanent squares with their stated desire to start reducing deficits and debt.?

?I?ll have the opportunity,? he added, ?to make the case that we?ve got to have tax reform, that we?ve got to simplify the system, that we do have to cut spending where it makes sense. But we?re also going to have to make sure that we?ve got a tax code that is fair and that looks after the interest of middle-class Americans and continues to grow the economy.?

Next year will be the 25th anniversary of the previous overhaul of the income tax code that lowered rates and wiped away many tax breaks in return. As administration officials point out ? by way of lowering expectations for action soon ? the process leading to the 1986 act was begun nearly three years earlier, when President Ronald Reagan called for a fairer, simpler code in his 1984 State of the Union address. And the legislation several times seemed dead.

The earlier effort also involved a president of one party facing a Congress partly controlled by the opposition party.

While the overhaul of a quarter-century ago raised taxes for many corporations, the legislation was designed to be ?deficit neutral? ? it neither increased nor reduced the government?s tax collection over all. But people in both parties agree that the next tax-overhaul effort would almost certainly have to raise revenues to address the nation?s growing fiscal problems.

?I think it is important to understand that that is not a process that will happen overnight,? Robert Gibbs, the White House press secretary, said Thursday. ?That will take ? as it did I think in the last major tax code revision in the mid ?80s ? that will take some time.? But, he added, Mr. Obama and his economic team ?certainly believe that it?s good to start that long process.?

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Blog - A Lego Reconstruction of the World's Earliest Computer

Here's a brand new stop motion video of a reconstruction of the world's first mechanical computer, directed by occasional Technology Review contributor John Pavlus. It's entirely self-explanatory: watch it and read on.

One hundred years before the birth of Christ, when agriculture and the wheel was for most of human civilization the apex of technological achievement, the Greeks built a mechanical computer so sophisticated that it could add and subtract--all in the name of predicting the next lunar eclipse.

In 2010, Apple engineer Andrew Carol created, based on previous reconstructions of the so-called "Antikythera" mechanism, which was discovered in a shipwreck in 1901, a fully functioning Lego replica of the device. Like the original, it accurately predicts solar eclipses.

Its secrets are explained at length in a feature in Nature and its Wikipedia entry, which, not surprisingly for a device that is catnip for geeks, is as exhaustive as the plot exegeses of old episodes of Lost.

The Antikythera is such a marvelous device--Michael Edmunds of Cardiff University, who led the most recent study of the device, says it is more historically valuable than the Mona Lisa--that it continues to inspire great works of its own: first the historically faithful reconstructions of it, then the lego reconstruction, and now this stop motion video, which, like all stop motion, was an enormous effort in itself.

Here's a sped-up, behind the scenes video of the shoot:

And if you want to really dig deep, Pavlus has conducted an interview with the creator of the Lego version of the Antikythera. It includes fascinating details about managing the friction generated by the more than 100 gears in the mechanism. Here's Carol's account of how it works:

It's pretty simple; it's all about ratios between the numbers of teeth on two gears meshed together. If one gear has 50 teeth and another has 25, that's a 2-to-1 ratio -- which means that turning the axle one full revolution on the first gear will multiply by two, because it turns the second gear twice as fast.

But the tradeoff is that when you make it go fast, you lose power. It's fast, but it's not strong, and vice versa -- and those mechanical effects pile up quickly when you've got over 100 gears working together in exotic ratios. When I have to multiply by 127, it's got to turn very fast, but with little power, which means that whatever amount of friction there is, I've effectively multiplied it by 127. So I had to put a lot of thought into designing the optimal layout of gears that would minimize the friction enough to make that kind of calculation physically work.

Finally, there's Pavlus's account of how he brought the video project itself together. For anyone interested in how to explain complicated technology to a lay audience, it's quite a ride:

But how to actually execute that idea? Obviously some kind of animation would be necessary. Several people I consulted urged me to use computer graphics. But that felt wrong: Legos are wonderfully tactile, and I really wanted to highlight the machine's intricate physical detail ? to make you feel like you could literally reach out and touch the gears or turn the crank. CGI would feel too weightless and abstract ? too perfect. Andy's model was the quintessence of DIY hacking: he didn't even diagram it out before starting to build it. I needed animation that was physical, craft-ey, and a little bit rough around the edges. Stop-motion was the clear choice.

For even more background on the Antikythera mechanism check out this illuminating video from 2008, produced for Nature by a director with decades of experience at the BBC.

Follow Mims on Twitter or contact him via email.

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Rumor: Apple ditching Nvidia for Intel and AMD

Apple has outfitted its notebooks with Nvidia's graphics chips for years, including the existing MacBook line, but that may not be the case in future systems. According to sources cited by CNET, Apple plans to drop Nvidia's mobile graphics chips for the integrated solution in Intel's upcoming Sandy Bridge processors.

Intel's IGPs are generally associated with lackluster performance, but early benchmarks suggest that Sandy Bridge's integrated graphics core is on par with basic discrete cards such as the Radeon HD 5450. If true, that's a substantial leap forward and would at the very least be sufficient for entry-level MacBooks.

"Historically, if you look at those low-end devices, the 13-inch class products, there's not a lot of room for a discrete GPU. So, going forward, if [Apple was] going to use Sandy Bridge in a low-end product, I think they would have to rely exclusively on the Sandy Bridge integrated graphics," said an Insight64 analyst.


Using the graphics core built into Intel's processors would presumably reduce system costs, and assuming Apple passes that on to the consumer, we could see more mainstream pricing for lower-tier MacBooks. By cutting Nvidia's discrete parts, there's also potential for increased battery life and slimmer machines.

We imagine Cupertino will continue to ship premium notebooks with discrete graphics chips, but not necessarily Nvidia's. CNET's sources say that Apple will rely on AMD to supply it with graphics processors for future MacBook Pros, with the possibility of AMD's upcoming Fusion chips appearing in low-end MacBooks.

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Android Market Gets Usability Updates [TNW Google]

Well maybe the Apple App Store won?t be able to claim it?s the coolest store around. According to the Android Developers Blog the Android Market is going to get some nice improvements ? well now:

With a focus on improving discoverability and merchandising, we?ve introduced a new carousel on the home and category screens. Users can quickly flip through the carousel to view promoted applications and immediately go to the download page for the application they want. Developers have been very active in creating great Widgets and Live Wallpapers. To make it easier for users to find their favorites, we?re introducing two new categories for Widgets and Live Wallpapers. Applications that include Widgets and Wallpapers will be automatically added to those new categories. We?ll also be adding more categories for popular applications and games in the weeks ahead. In addition, the app details page now includes Related content, which makes it easier for users to quickly find apps of similar interest.
via Android Developers Blog: Android Market Client Update.

Over the next two weeks the new Android Market Client will be pushed out to all devices running Android 1.6 and higher. Google is smartly starting to make sure their app market place makes it easy for people to find great apps. It?s worked for Apple, I think it?s working for RIM. My personal experience with the BlackBerry App World hasn?t been great or bad, just there.

I think it says a lot about the industry over all that only Microsoft doesn?t have an app market out or planned. Apple App Store and soon Mac App Store. Chrome has an App Gallery and the Android Marketplace. Windows Phone 7 has their own ways to find and get apps. RIM, of course, has theirs. I wonder, then, how long it will take before Microsoft comes up with their own solution for Windows itself.

One of the biggest challenges with all devices and operating systems is finding out what apps and tools to use with it. Maybe Apple rightly deserves flack for the tight control over the App Store, but there is no doubt that Apple makes it easy to find great great apps for iOS devices. Google?s updates to the Android Marketplace see the same potential. Now, let?s see if Microsoft can step up with a great solution of their own.

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