Sep
10
The Most Powerful Doctor You Never Heard Of
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Doctors don’t know what they are doing
wrong. A Yale cardiologist is working
to change that.
FORBES.com, September 10, 2010, by Matthew Herper – Medicine is flying blind. Thousands of medical journal articles are published every month on potential new treatments and diagnostic tests. Precious few of them measure how well doctors are doing in the real world, outside of controlled trials–what they are doing right, what they are doing wrong and what they are forgetting to do entirely. No wonder our medical system wastes billions of dollars a year.
Yale cardiologist Harlan Krumholz, age 52, has spent two decades shining a light into this broken system. When he started, the kind of “outcomes” research he does was deeply unfashionable. Doctors figured that it would merely confirm the obvious fact that some doctors and hospitals are better than others.
But Krumholz proved the skeptics wrong. By figuring out what to measure and how, he showed that even top hospitals were systematically underperforming, largely because no one was tracking the results. In 2004 he proved that only one-third of American hospitals were treating heart attack patients quickly enough. His work laid the groundwork for the system the Medicare program now uses to compare hospitals. Another line of research proved that heart-failure patients are frequent flyers: They end up back in the hospital almost as soon as they leave. This result led to a provision in Obama’s new health reform law that will allow Medicare to dock hospitals’ pay starting in 2012 if that revolving door is moving too fast. The new law even creates a Patient-Centered Outcomes Research Institute that aims to extend the type of work Krumholz does in cardiology to other medical arenas such as cancer and psychiatry.
“Every day millions of patients are being treated, and the lessons from their experiences are lost because there is no systematic effort to learn from them,” says Krumholz. “If I’m sitting down with a patient, I should be able to take advantage of everything we have learned up until yesterday to treat them.”
Krumholz’s basic idea is that if you ask the right question and pick the right measurement, you can figure out a way to get the answer, often using billing records or existing databases. This frequently involves partnering with insurers or Medicare. He has a knack for focusing on performance metrics that hold hospitals accountable. For heart attack patients, Krumholz picked “door to balloon time,” or how fast the patient is treated upon arrival. Hospitals that are doing badly on this measure can’t blame it on how long the ambulance took to get there.
For big corporations the idea that “you can’t manage it if you can’t measure it” is an old chestnut. General Electric, Toyota and other companies have had data-driven quality-improvement efforts for years. But medicine–supposedly a more scientific profession–has been slow to measure itself. Krumholz has been one of a small handful of pioneers behind the scenes pushing to do this. “There’s no one else who has been more of a leader in allowing us to understand what we are doing” right and wrong, says Ralph Brindis, the chair of the American College of Cardiology. Adds Memorial Sloan-Kettering Cancer Center pulmonologist Peter Bach: “He’s one of the most prominent quality-of-care researchers in the world. He’s trained countless researchers everywhere.”
Krumholz was inspired to be a doctor by his father, a pulmonologist who took him on rounds when he was a child. “It’s the most amazing profession,” he says. “You’re making decisions that are so important to people, and they have to trust you to help them.” As a biology student at Yale in the late 1970s he studied how the rural poor in America and foreign countries like India and China often didn’t get care that was available to richer folks in cities. He learned low-tech solutions often could help. At Harvard Medical School in the 1980s he rode the subway to housing projects to teach residents there to give basic emergency care.
His career got off to a quick start. On his first day as a Yale professor in 1992, he published a study in the New England Journal of Medicine defending a then controversial Genentech clot-buster drug. But after that he wasn’t sure what to do next until he heard about Qualidigm, a nonprofit that paid moonlighting doctors to go over patient records and find mistakes for Medicare. He went to one of its meetings and met the group’s chief executive, Marcia K. Petrillo. She was talking about using the Medicare billing system to identify ways patient care was being hurt.
As she was talking, the idea that the medical system itself keeps doctors from adequately caring for patients snapped into Krumholz’s head. “In medical school you never thought, Gee, how will the system affect me?” Krumholz says. “The lesson of medical school was that you are a singular crusader. It’s about how the individual operates. If you were lucky a smart nurse would tell you if you were about to do something really dumb.”
Krumholz convinced Medicare in 1995 to give him access to detailed patient data it had just started collecting from heart doctors in Alabama, Connecticut, Iowa and Wisconsin. The result was a database of 16,000 patients that became the basis for Medicare’s hospital comparison projects, including its public site, hospitalcompare.hhs.gov.
The same year he showed that aspirin was being given to only 75% of heart patients who should get it. He studied blood pressure pills called beta blockers and found that only half of the heart patients who needed them were getting them. In 1997 he found that half the patients hospitalized for heart failure returned to the hospital within six months after their first visit.
Krumholz’s biggest hit came in 2004. Angioplasty, a procedure in which a balloon-tipped catheter is used to reopen a clogged artery, saves lives if performed soon after a heart attack. Guidelines recommend doing it within 90 minutes of a patient’s arrival at the hospital. Using two drug company databases, Krumholz showed that only 33% of patients were getting angioplasty in that time frame. He also showed that the delays increased the death rate.
Working with Yale management researcher Elizabeth Bradley, his team visited the fastest and slowest hospitals. He found speed was often the result of taking simple steps like letting the emergency room doc call for an angioplasty without consulting a cardiologist or putting electrocardiograms in ambulances so the heart attack would be confirmed before the patient arrived. He led an effort by the ACC and the American Heart Association to push hospitals to change their ways. Today 90% of heart attack patients have their arteries opened within 90 minutes of hospital arrival (unless they end up at a hospital that can’t perform angioplasty).
Krumholz is branching out beyond heart disease. He played a key role in a 2009 study showing 4 million Americans each year get high radiation doses from routine scans, potentially boosting cancer risk.
Krumholz’s hunger for new data sources can get him into trouble. He was paid $225,000 over three years to be a witness for plaintiff lawyers suing Merck over its arthritis drug Vioxx after it was recalled for causing heart attacks. This gave him access to Merck’s e-mails and other data. Krumholz used them to publish articles that show Merck might have identified Vioxx’s risks earlier.
Merck says the payments are a conflict of interest. But doctors trust him because he speaks his mind and puts patients first. When Merck’s anticholesterol drug Zetia failed to clear artery plaque in a key study in 2008, Krumholz addressed a big conference of cardiologists and bluntly told them to use better-proven drugs. Merck lost $22 billion in market cap that afternoon.
Sep
10
Seniors relax by the sea in Andernos, Southwestern France,
June 23, 2010. REUTERS/Regis Duvignau
ScienceDaily.com, GoogleNews.com, by Kate Kelland – LONDON, Sep. 9, 2010 (Reuters) — Daily tablets of large doses of B vitamins can halve the rate of brain shrinkage in elderly people with memory problems and may slow their progression toward dementia, data from a British trial showed on Wednesday,
Scientists from Oxford University said their two-year clinical trial was the largest to date into the effect of B vitamins on so-called “mild cognitive impairment” — a major risk factor for Alzheimer’s disease and other forms of dementia.
Experts commenting on the findings said they were important and called for larger, longer full-scale clinical trials to see if the safety and effectiveness of B vitamins in the prevention of neurodegenerative conditions could be confirmed.
“This is a very dramatic and striking result. It’s much more than we could have predicted,” said David Smith of Oxford’s department of pharmacology, who co-led the trial.
“It is our hope that this simple and safe treatment will delay development of Alzheimer’s in many people who suffer from mild memory problems.”
Mild cognitive impairment (MCI) affects around 16 percent of people aged over 70 worldwide and is characterized by slight problems with memory loss, language or other mental functions.
MCI does not usually interfere with daily life, but around 50 percent of people diagnosed with it go on to develop the far more severe Alzheimer’s disease within five years. Alzheimer’s is a mind-wasting disease for which there are few treatments and no cure, and which affects 26 million people around the world.
Smith and colleagues conducted a two-year trial with 168 volunteers with MCI who were given either a vitamin pill containing very high doses of folic acid, vitamin B6 and vitamin B12, or a placebo dummy pill.
These B vitamins are known to control levels of an amino acid called homocysteine in the blood, and high blood levels of homocysteine are linked to an increased risk of developing Alzheimer’s disease.
Helga Refsum, who also worked on the trial, stressed that vitamins were given in extremely high doses.
“This is a drug, not a vitamin intervention,” she said.
The pills, called “TrioBe Plus” contained around 300 times the recommended daily intake of B12, four times daily advised folate levels and 15 times the recommended amount of B6.
Brain scans were taken at the beginning and the end of the trial to monitor the rate of brain shrinkage, or atrophy.
The results, published in the Public Library of Science (PLoS) One journal, showed that on average the brains of those taking the vitamin treatment shrank at a rate of 0.76 percent a year, while those taking the dummy pill had an average brain shrinkage of 1.08 percent.
People who had the highest levels of homocysteine at the start of the trial benefited the most from the treatment, with their brains shrinking at half the rate of those on the placebo.
Although the trial was not designed to measure cognitive ability, the researchers found those people who had lowest rates of shrinkage had the highest scores in mental tests.
Commenting on the study, Paul Matthews, a professor of clinical neurology at Imperial College London said that although the vitamins used are generally safe and inexpensive, the study “should not drive an immediate change in clinical practice”
“Instead, it sets out important questions for further study and gives new confidence that effective treatments modifying the course of some dementias may be in sight,” he said.
(Editing by Angus MacSwan)
Sep
10
NIH.gov, GoogleNews.com, September 9, 2010, ATLANTA (AP) – An apple a day? Apparently not in the United States.
A new government study says most Americans still don’t eat enough vegetables, and fruit consumption is actually dropping a little.
The Centers for Disease Control and Prevention found that last year about one-third of U.S. adults had two or more servings of fruit or fruit juice a day. That’s down slightly from more than 34 percent in 2000.
Only about 26 percent ate vegetables three or more times a day, the same as in 2000. The statistics come from a national telephone survey of hundreds of thousands of Americans.
Sep
10
MIT’s Self-Assembling Solar Cells Recycle Themselves Repeatedly, Just Like Plant Cells
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MIT’s Test Cell Credit: Patrick Gillooly, MIT
PopSci.com, September 9, 2010, by Clay Dillow – Plants are extremely efficient converters of light into energy, more or less setting the bar for researchers creating photovoltaic cells that convert sunlight into electricity. As such, researchers are constantly trying to mimic the tricks that millions of years of evolution and development have taught to plant biology. Now, a team of MIT scientists believe they’ve done it, creating a synthetic, self-assembling chloroplast that can be broken down and reassembled repeatedly, restoring solar cells that are damaged by the sun.
While the leaves on a tree appear to be as static as the PV cells on a solar panel, they’re not; sunlight is actually quite destructive, and to counter this effect leaves rapidly recycle their proteins as often as every 45 minutes when in direct summer sunlight. This rapid repair mechanism allows plants to take full advantage of the sun’s bountiful energy without losing efficiency over time.
To recreate this unique regenerative ability, the MIT team devised a novel set of self-assembling molecules that use photons to shake electrons loose in the form of electricity. The system contains seven different compounds, including carbon nanotubes that provide structure and a means to conduct the electricity away from the cells, synthetic phospholipids that form discs that also provide structural support, and other molecules that self-assemble into “reaction centers” that actually interact with the incoming photons to release electrons.
Under certain conditions, the compounds assemble themselves into uniform structures suitable for harvesting solar energy. But in the presence of a surfactant (similar to the stuff used to disperse oil during oil spills) the structures break down into a solution of nanotubes, phospholipids, and other constituent molecules. By pushing the solution through a membrane to remove the surfactant, the elements once again assemble into working, rejuvenated solar cells undamaged by their prior exposure to the sun.
The cells are work at 40 percent efficiency, and researchers think with some tweaks they could push that efficiency much higher. And because they don’t degrade over time – just give ‘em a quick shake with the surfactant and they’re essentially brand new – the tech could be the next big step forward for solar technology.
Sep
9
Finding The Best Blood Pressure Treatments
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FORBES.com, September 8, 2010 – A trio of studies published in the American Journal of Hypertension offers new insight into the field of personalized medicine, challenging conventional approaches to treating the hypertension suffered by one-in-three U.S. adults.
The studies show that some drug combinations work better than others among certain populations. This raises the possibility that measuring blood levels of renin, a hormone secreted by the kidneys, might help optimize the treatment of hypertension in some people.
Surprisingly, the research showed that taking a drug that’s a poor match to renin may not only fail to decrease a patient’s blood pressure, it might even raise it.
“The idea that one size fits all doesn’t make a lot of sense,” Dr. Michael Alderman of New York’s Albert Einstein College of Medicine told the Associated Press (AP).
Although Dr. Alderman supports the renin blood test approach, it is not likely such a test will become routine anytime soon.
Many physicians remain skeptical because previous research a few decades ago did not show a clear benefit to the test, hypertension specialist Dr. Ernesto Schiffrin of McGill University in Canada told AP.
“The reality is that trial and error is to some degree what has to be done because patients are different and some patients develop adverse effects with one agent and others don’t,” Schiffrin added.
However, given the reliability improvements in blood testing, some experts believe it is time for further studies to resolve the matter.
“The time for action is long overdue. We must redirect our efforts away from the strategy of treating hypertension as one condition (the way our colleagues treated fever centuries ago) toward building a treatment algorithm that incorporates the varying pathophysiologies of hypertension,” wrote Dr. Curt Furberg, a public health specialist with Wake Forest University, in an editorial accompanying the new research.
Cases of high blood pressure are on the rise in the U.S., as the population ages, becomes more sedentary and overweight. The condition is one of the leading causes of strokes, heart attacks and kidney failure.
Nevertheless, only about a half of all patients suffering from hypertension have their condition properly under control. Searching for the ideal combination of drug therapies to manage high blood pressure is among the reasons behind this figure.
Virtually everyone with hypertension begins treatment with a diuretic — a time-tested, low-cost class of drugs that reduces fluid in the body. Other medications that work in different ways are then added as needed to manage the condition.
Most patients ultimately end up taking two or more drugs.
But many doctors are hesitant to prescribe two- and three-drug combinations until they find the right mix of treatments.
Blood pressure is a balance between the amount of fluid in the arteries and how tight or relaxed those arteries are. The amount of renin in a person’s blood helps doctors determine whether their hypertension is related more to fluid volume or to constricted arteries, said Dr. Alderman.
The three studies examined differences in treatment outcomes given variations in renin blood levels, race and ethnicity.
In one study of 954 people prescribed a single drug, the researchers found that those with low levels of renin responded best to a diuretic. However, those with high renin levels responded better to medicines such as ACE inhibitors, which target an artery-narrowing substance triggered by the renin, Dr. Alderman said.
Roughly 8 percent of patients had an increase in blood pressure of at least 10 points after beginning medication, Dr. Alderman found. Those most at risk were participants with low renin levels but prescribed anti-renin drugs such as ACE inhibitors or beta-blockers.
When doctors observe that particular side effect, “we always assume it’s the patient’s fault” — that they did not take their pills or consumed too much salt, Dr. Alderman told AP.
“It may not be.”
In a different study, research conducted by Dr. Stephen Turner of the Mayo Clinic revealed that blood levels of renin after beginning an initial medication helped predict which additional drug was best to add for further treatment.
The scientists also found racial and ethnic variations in response to blood pressure treatments. For instance, black patients had a tendency toward lower renin levels than whites. Indeed, doctors have long known that blacks fare better that whites with a diuretic as an initial treatment than a beta-blocker.
A British study examined two-drug combinations and found blacks fared worse than whites when combining calcium channel blocker with an ACE inhibitor. However, that combination worked far better for south Asian patients, for reasons that are not yet clear.
Other experts believe that the best approach to treating hypertension is to initially have all patients begin a two-drug combination to target the condition from all directions.
A Canadian study conducted last year appears to support this approach, finding in favor of beginning treatment with a low-dose combination of diuretic plus an ACE inhibitor.
Dr. Turner said that while renin plays a small role in patient variability, he is still searching for underlying genetic variations that might one day offer a better guide to selecting optimal hypertension treatments.
The three studies were published in the American Journal of Hypertension.
http://www.nature.com/ajh/index.html
Am Journal of Hypertension
Sep
9
An array of 17 purpose-built oxygen-depleted titanium dioxide memristors built at HP Labs, imaged by an atomic force microscope. The wires are about 50 nm, or 150 atoms, wide. Electric current through the memristors shifts the oxygen vacancies, causing a gradual and persistent change in electrical resistance.
The New York Times, August/September 2010, by John Markoff — Scientists at Rice University and Hewlett-Packard are reporting this week that they can overcome a fundamental barrier to the continued rapid miniaturization of computer memory that has been the basis for the consumer electronics revolution.
In recent years the limits of physics and finance faced by chip makers had loomed so large that experts feared a slowdown in the pace of miniaturization that would act like a brake on the ability to pack ever more power into ever smaller devices like laptops, smartphones and digital cameras.
But the new announcements, along with competing technologies being pursued by companies like IBM and Intel, offer hope that the brake will not be applied any time soon.
In one of the two new developments, Rice researchers are reporting in Nano Letters, a journal of the American Chemical Society, that they have succeeded in building reliable small digital switches — an essential part of computer memory — that could shrink to a significantly smaller scale than is possible using conventional methods.
More important, the advance is based on silicon oxide, one of the basic building blocks of today’s chip industry, thus easing a move toward commercialization. The scientists said that PrivaTran, a Texas startup company, has made experimental chips using the technique that can store and retrieve information.
These chips store only 1,000 bits of data, but if the new technology fulfills the promise its inventors see, single chips that store as much as today’s highest capacity disk drives could be possible in five years. The new method involves filaments as thin as five nanometers in width — thinner than what the industry hopes to achieve by the end of the decade using standard techniques. The initial discovery was made by Jun Yao, a graduate researcher at Rice. Mr. Yao said he stumbled on the switch by accident.
Separately, H.P. is to announce on Tuesday that it will enter into a commercial partnership with a major semiconductor company to produce a related technology that also has the potential of pushing computer data storage to astronomical densities in the next decade. H.P. and the Rice scientists are making what are called memristors, or memory resistors, switches that retain information without a source of power.
“There are a lot of new technologies pawing for attention,” said Richard Doherty, president of the Envisioneering Group, a consumer electronics market research company in Seaford, N.Y. “When you get down to these scales, you’re talking about the ability to store hundreds of movies on a single chip.”
The announcements are significant in part because they indicate that the chip industry may find a way to preserve the validity of Moore’s Law. Formulated in 1965 by Gordon Moore, a co-founder of Intel, the law is an observation that the industry has the ability to roughly double the number of transistors that can be printed on a wafer of silicon every 18 months.
That has been the basis for vast improvements in technological and economic capacities in the past four and a half decades. But industry consensus had shifted in recent years to a widespread belief that the end of physical progress in shrinking the size modern semiconductors was imminent. Chip makers are now confronted by such severe physical and financial challenges that they are spending $4 billion or more for each new advanced chip-making factory.
I.B.M., Intel and other companies are already pursuing a competing technology called phase-change memory, which uses heat to transform a glassy material from an amorphous state to a crystalline one and back.
Phase-change memory has been the most promising technology for so-called flash chips, which retain information after power is switched off.
The flash memory industry has used a number of approaches to keep up with Moore’s law without having a new technology. But it is as if the industry has been speeding toward a wall, without a way to get over it.
To keep up speed on the way to the wall, the industry has begun building three-dimensional chips by stacking circuits on top of one another to increase densities. It has also found ways to get single transistors to store more information. But these methods would not be enough in the long run.
The new technology being pursued by H.P. and Rice is thought to be a dark horse by industry powerhouses like Intel, I.B.M., Numonyx and Samsung. Researchers at those competing companies said that the phenomenon exploited by the Rice scientists had been seen in the literature as early as the 1960s.
“This is something that I.B.M. studied before and which is still in the research stage,” said Charles Lam, an I.B.M. specialist in semiconductor memories.
H.P. has for several years been making claims that its memristor technology can compete with traditional transistors, but the company will report this week that it is now more confident that its technology can compete commercially in the future.
In contrast, the Rice advance must still be proved. Acknowledging that researchers must overcome skepticism because silicon oxide has been known as an insulator by the industry until now, Jim Tour, a nanomaterials specialist at Rice said he believed the industry would have to look seriously at the research team’s new approach.
“It’s a hard sell, because at first it’s obvious it won’t work,” he said. “But my hope is that this is so simple they will have to put it in their portfolio to explore.”
More chip news……….
A Computer Chip Based on Probability Not Binary (video)
Lyric’s tiny chip is full of possibilities.
SingularityHub.com, September 8, 2010, by Aaron Saenz — Traditional computer processing is based on 1 and 0, yes and no, but Lyric Semiconductor wants us to consider the power of ’maybe’. The Cambridge, Massachusetts startup recently came out of stealth to announce the development of their new computer chip that calculates using probabilities. Lyric has used $20 million in DARPA and venture funding to rethink the way we process problems, from the basic architecture of its circuits all the way up to its software language . Everything is grey, not black and white. This new approach to computing has led to a new kind of chip that can handle probability based decisions quicker, using less space, and less energy. Instead of just cramming more gates on an integrated circuit like other computer chip designers, Lyric may have found a way to make those elements work harder. Check out a brief example of the chip’s power in the video below.
Spam filtering, product suggestions, identity verification…a large portion of modern computer processing power is spent on problems that rely on computers to analyze the probability of a situation. The Lyric approach uses probability natively, allowing for a quicker solution to these problems. In the video below, a program attempts to determine how many users are typing on a keyboard, and in what order. Instead of trying to find the definite solution, it seeks the most likely solution…and ends up with the right answer. Pretty cool.
(wait for the delayed voice-over)
A big application for Lyric’s new technology will be error correction. 30 nm NAND flash memory will typically have 1 bit wrong per 1000. As we reach to build smaller and smaller chips, that error rate is likely to increase. Lyric Error Correction (LEC) uses their probability processing to counter for mistakes in memory processing. LEC gets the same results as traditional binary chips but in an area 30 times as small, and with only 10% of the power.
Lyric Error Correction cleans up mistakes in stored memory. LEC allows cheap flash drives (with higher error rates) to be used in small portable systems like phones.
While still built on silicon, Lyric’s probability chip uses a completely new architecture for gates. The chip doesn’t process a long series of opens and closed connections as ones and zeros. Instead, there’s a great connectivity between nodes, variables talk to each other, creating a highly parallel processing method. Instead of Boolean logic (And, Or, Not) the chip relies on Bayesian probability logic. At every step in the process, Lyric had to rethink how computer processing was done. That means their approach has the capability to produce a revolutionary advance in computing.
It also means that everything they do is relatively untested. What kind of artifacts does probability processing introduce into computing? Are there strange limits on power consumption, environmental sensitivities, or long term failure concerns? We don’t even know if they’ll be able to scale up production to meet demand. So while Lyric’s potential for more powerful processing has generated a lot of buzz, we need to be cautious in our expectations. It may take a long time before we know if this technology is truly viable.
That being said, I love to consider what probability based processing could mean. It could let us solve problems in a way akin to how the universe views the basic physical interactions between its smallest particles. Perhaps it will have an impact in how we model biological systems. Maybe it will affect how we simulate the brain. We’ll have to wait and see what Lyric can accomplish in the years ahead.
Personally, I’m hoping for an Infinite Improbability Drive.
Moore’s Law
Moore’s law describes a long-term trend in the history of computing hardware. The number of transistors that can be placed inexpensively on an integrated circuit has doubled approximately every two years. The trend has continued for more than half a century and is not expected to stop until 2015 or later.
The capabilities of many digital electronic devices are strongly linked to Moore’s law: processing speed, memory capacity, sensors and even the number and size of pixels in digital cameras. All of these are improving at (roughly) exponential rates as well. This has dramatically increased the usefulness of digital electronics in nearly every segment of the world economy. Moore’s law precisely describes a driving force of technological and social change in the late 20th and early 21st centuries.
The law is named after Intel co-founder Gordon E. Moore, who described the trend in his 1965 paper. The paper noted that number of components in integrated circuits had doubled every year from the invention of the integrated circuit in 1958 until 1965 and predicted that the trend would continue “for at least ten years”. His prediction has proved to be uncannily accurate, in part because the law is now used in the semiconductor industry to guide long-term planning and to set targets for research and development. This fact would support an alternative view that the “law” unfolds as a self-fulfilling prophecy, where the goal set by the prediction charts the course for realized capability.
The term “Moore’s law” was coined around 1970 by the Caltech professor, VLSI pioneer, and entrepreneur, Carver Mead. Predictions of similar increases in computer power had existed years prior. Alan Turing in a 1950 paper had predicted that by the turn of the millennium, computers would have a billion words of memory. Moore may have heard Douglas Engelbart, a co-inventor of today’s mechanical computer mouse, discuss the projected downscaling of integrated circuit size in a 1960 lecture. A New York Times article published August 31, 2009, credits Engelbart as having made the prediction in 1959.
Moore’s original statement that transistor counts had doubled every year can be found in his publication “Cramming more components onto integrated circuits“, Electronics Magazine 19 April 1965:
The complexity for minimum component costs has increased at a rate of roughly a factor of two per year… Certainly over the short term this rate can be expected to continue, if not to increase. Over the longer term, the rate of increase is a bit more uncertain, although there is no reason to believe it will not remain nearly constant for at least 10 years. That means by 1975, the number of components per integrated circuit for minimum cost will be 65,000. I believe that such a large circuit can be built on a single wafer.
Moore slightly altered the formulation of the law over time, in retrospect bolstering the perceived accuracy of his law . Most notably, in 1975, Moore altered his projection to a doubling every two years. Despite popular misconception, he is adamant that he did not predict a doubling “every 18 months”. However, David House, an Intel colleague, had factored in the increasing performance of transistors to conclude that integrated circuits would double in performance every 18 months.
In April 2005, Intel offered US$10,000 to purchase a copy of the original Electronics Magazine. David Clark, an engineer living in the United Kingdom, was the first to find a copy and offer it to Intel.
Future trends
Computer industry technology “road maps” predict (as of 2001) that Moore’s law will continue for several chip generations. Depending on and after the doubling time used in the calculations, this could mean up to a hundredfold increase in transistor count per chip within a decade. The semiconductor industry technology roadmap uses a three-year doubling time for microprocessors, leading to a tenfold increase in the next decade. Intel was reported in 2005 as stating that the downsizing of silicon chips with good economics can continue during the next decade and in 2008 as predicting the trend through 2029.
Some of the new directions in research that may allow Moore’s law to continue are:
- Researchers from IBM and Georgia Tech created a new speed record when they ran a silicon/germanium helium supercooled transistor at 500 gigahertz (GHz).The transistor operated above 500 GHz at 4.5 K (−451 °F/−268.65 °C) and simulations showed that it could likely run at 1 THz (1,000 GHz). However, this trial only tested a single transistor.
- In early 2006, IBM researchers announced that they had developed a technique to print circuitry only 29.9 nm wide using deep-ultraviolet (DUV, 193-nanometer) optical lithography. IBM claims that this technique may allow chipmakers to use then-current methods for seven more years while continuing to achieve results forecast by Moore’s law. New methods that can achieve smaller circuits are expected to be substantially more expensive.
- In April 2008, researchers at HP Labs announced the creation of a working “memristor“: a fourth basic passive circuit element whose existence had previously only been theorized. The memristor’s unique properties allow for the creation of smaller and better-performing electronic devices.[42] This memristor bears some resemblance to resistive memory (CBRAM or RRAM) developed independently and recently by other groups for non-volatile memory applications.
- In February 2010, Researchers at the Tyndall National Institute in Cork, Ireland announced a breakthrough in transistors with the design and fabrication of the world’s first junctionless transistor. The research led by Professor Jean-Pierre Colinge was published in Nature Nanotechnology and describes a control gate around a silicon nanowire that can tighten around the wire to the point of closing down the passage of electrons without the use of junctions or doping. The researchers claim that the new junctionless transistors can be produced at 10-nanometer scale using existing fabrication techniques.
The trend of scaling for NAND flash memory allows doubling of components manufactured in the same wafer area in less than 18 months.
Atomisic simulation result for formation of inversion channel (electron density) and attainment of threshold voltage (IV) in a nanowire MOSFET. Note that the threshold voltage for this device lies around 0.45 V. Nanowire MOSFETs lie towards the end of ITRS. roadmap for scaling devices below 10 nm gate lengths
On 13 April 2005, Gordon Moore stated in an interview that the law cannot be sustained indefinitely: “It can’t continue forever. The nature of exponentials is that you push them out and eventually disaster happens.” He also noted that transistors would eventually reach the limits of miniaturization at atomic levels:
In terms of size [of transistors] you can see that we’re approaching the size of atoms which is a fundamental barrier, but it’ll be two or three generations before we get that far—but that’s as far out as we’ve ever been able to see. We have another 10 to 20 years before we reach a fundamental limit. By then they’ll be able to make bigger chips and have transistor budgets in the billions.
In January 1995, the Digital Alpha 21164 microprocessor had 9.3 million transistors. This 64-bit processor was a technological spearhead at the time, even if the circuit’s market share remained average. Six years later, a state of the art microprocessor contained more than 40 million transistors. It is theorised that with further miniaturisation, by 2015 these processors should contain more than 15 billion transistors, and by 2020 will be in molecular scale production, where each molecule can be individually positioned.
In 2003 Intel predicted the end would come between 2013 and 2018 with 16 nanometer manufacturing processes and 5 nanometer gates, due to quantum tunnelling, although others suggested chips could just get bigger, or become layered. In 2008 it was noted that for the last 30 years it has been predicted that Moore’s law would last at least another decade.
Some see the limits of the law as being far in the distant future. Lawrence Krauss and Glenn D. Starkman announced an ultimate limit of around 600 years in their paper, based on rigorous estimation of total information-processing capacity of any system in the Universe.
Then again, the law has often met obstacles that first appeared insurmountable but were indeed surmounted before long. In that sense, Moore says he now sees his law as more beautiful than he had realized: “Moore’s law is a violation of Murphy’s law. Everything gets better and better.”
Futurists and Moore’s law
Kurzweil’s extension of Moore’s law from integrated circuits to earlier transistors, vacuum tubes, relays and electromechanical computers.
Futurists such as Ray Kurzweil, Bruce Sterling, and Vernor Vinge believe that the exponential improvement described by Moore’s law will ultimately lead to a technological singularity: a period where progress in technology occurs almost instantly.
Although Kurzweil agrees that by 2019 the current strategy of ever-finer photolithography will have run its course, he speculates that this does not mean the end of Moore’s law:
Moore’s law of Integrated Circuits was not the first, but the fifth paradigm to forecast accelerating price-performance ratios. Computing devices have been consistently multiplying in power (per unit of time) from the mechanical calculating devices used in the 1890 U.S. Census, to [Newman's] relay-based “[Heath] Robinson” machine that cracked the Lorenz cipher, to the CBS vacuum tube computer that predicted the election of Eisenhower, to the transistor-based machines used in the first space launches, to the integrated-circuit-based personal computer.
Kurzweil speculates that it is likely that some new type of technology (possibly optical or quantum computers) will replace current integrated-circuit technology, and that Moore’s Law will hold true long after 2020.
Lloyd shows how the potential computing capacity of a kilogram of matter equals pi times energy divided by Planck’s constant. Since the energy is such a large number and Plancks’s constant is so small, this equation generates an extremely large number: about 5.0 * 1050 operations per second.
He believes that the exponential growth of Moore’s law will continue beyond the use of integrated circuits into technologies that will lead to the technological singularity. The Law of Accelerating Returns described by Ray Kurzweil has in many ways altered the public’s perception of Moore’s Law. It is a common (but mistaken) belief that Moore’s Law makes predictions regarding all forms of technology, when it has only actually been demonstrated clearly for semiconductor circuits. However many people including Richard Dawkins have observed that Moore’s law will apply – at least by inference – to any problem that can be attacked by digital computers and is in it essence also a digital problem. Therefore progress in genetics where the coding is digital ‘the genetic coding of GATC’ may also advance at a Moore’s law rate. Many futurists still use the term “Moore’s law” in this broader sense to describe ideas like those put forth by Kurzweil but do not fully understand the difference between linear problems and digital problems.
Moore himself, who never intended his eponymous law to be interpreted so broadly, has quipped:
“Moore’s law has been the name given to everything that changes exponentially. I say, if Gore invented the Internet, I invented the exponential.”
Consequences and limitations
Transistor count versus computing performance
The exponential processor transistor growth predicted by Moore does not always translate into exponentially greater practical CPU performance. For example, the higher transistor density in multi-core CPUs doesn’t greatly increase speed on many consumer applications that are not parallelized. There are cases where a roughly 45% increase in processor transistors have translated to roughly 10–20% increase in processing power. Viewed even more broadly, the speed of a system is often limited by factors other than processor speed, such as internal bandwidth and storage speed, and one can judge a system’s overall performance based on factors other than speed, like cost efficiency or electrical efficiency.
Importance of non-CPU bottlenecks
As CPU speeds and memory capacities have increased, other aspects of performance like memory and disk access speeds have failed to keep up. As a result, those access latencies are more and more often a bottleneck in system performance, and high-performance hardware and software have to be designed to reduce their impact.
In processor design, out-of-order execution and on-chip caching and prefetching reduce the impact of memory latency at the cost of using more transistors and increasing processor complexity. In software, operating systems and databases have their own finely tuned caching and prefetching systems to minimize the number of disk seeks, including systems like ReadyBoost that use low-latency flash memory. Some databases can compress indexes and data, reducing the amount of data read from disk at the cost of using CPU time for compression and decompression. The increasing relative cost of disk seeks also makes the high access speeds provided by solid state disks more attractive for some applications.
Parallelism and Moore’s law
Parallel computation has recently become necessary to take full advantage of the gains allowed by Moore’s law. For years, processor makers consistently delivered increases in clock rates and instruction-level parallelism, so that single-threaded code executed faster on newer processors with no modification. Now, to manage CPU power dissipation, processor makers favor multi-core chip designs, and software has to be written in a multi-threaded or multi-process manner to take full advantage of the hardware.
Obsolescence
A negative implication of Moore’s Law is obsolescence, that is, as technologies continue to rapidly “improve”, these improvements can be significant enough to rapidly obsolete predecessor technologies. In situations in which security and survivability of hardware and/or data are paramount, or in which resources are limited, rapid obsolescence can pose obstacles to smooth or continued operations.
IBM Chip
The Distant Future
Josephson Junctions
In this close-up of a Josephson junction chip, the junctions themselves lie beneath the four circles in the brown regions. Ultrafast switches, they can be turned on in as little as six trillionths of a second and are made of lead or niobium – both semiconductors – separated by a thin layer of insulating oxide. The narrowest lines in this photo are about 0.00001 inches wide. Actual size of the portion show here: 0.001 x 0.00112 inches
Source: Stan Augarten – The National Museum of American History and the Smithsonian Institution
Computer scientists are obsessed with speed, their obsession motivated by the harsh economics of the computer business as much as by personal and financial ambition. Computer manufacturers are constantly striving to shave billionths of a second off the performance times of their products – long-term efforts that lead some companies to spend tens of millions of dollars. For the faster a computer, the more tasks it can execute in a given period, and the better it can earn its keep.
Of course, most computers are perfectly adequate for the vast majority of their users; it doesn’t matter to most personal computer owners whether their machines need two millionths of a second to multiply two numbers or only half that. But there’s a certain rarefied class of operators – NASA, the military, the National Weather Bureau – for whom no machine is ever fast enough. These are the people who buy supercomputers like the Cray-1, built by Cray Research Inc. of Minnesota, which can carry out more than a hundred million operations a second. Supercomputers are used for such highly complex chores as weather predictions and airplane air-flow analysis.
For all their phenomenal speed, supercomputers still require hours to perform some calculations, and it may be impossible to boost their speed significantly with conventional semiconductor technology. High-speed chips generate excessive amounts of heat, particularly if they’re packed closely together. Scientists at IBM have therefore been experimenting with an exotic class of ICs called Josephson junctions, which are designed to operate in tubs of liquid helium at temperatures only a few degrees above absolute zero.
As envisioned by IBM, a Josephson junction computer would consist of a central core of about fifty to a hundred chips, all packed tightly in a cube about two inches to a side and immersed in liquid helium. The entire apparatus, core and tub, would probably be about the size of a refrigerator. By cooling the circuitry to almost absolute zero (-459.7º F) and reducing the lengths of the connecting wires to a bare minimum, a Josephson junction computer might attain speeds of one billionth of a second per operation, or less, ten times faster than today’s quickest computers. A full-scale Josephson junction device has yet to be made, but IBM expects to have one by the early 1990s, if not sooner.
Sep
8
Scientists are seeking to uncover why the immune system attacks healthy cells in lupus. Antinuclear antibodies, like those shown here in lupus-prone mice, are a hallmark of the disease. Photo Courtesy Dr. Mark Shlomchik, Yale School of Medicine
The New York Times, by Andrea Peirce – Lupus, the autoimmune disease, can attack any organ or tissue, including the heart, brain, lungs, kidneys, blood and skin. It is likely that a combination of genes, environmental triggers and hormones set the stage for lupus. Scientists are focusing on new components of the immune system to halt damage from lupus.
Lupus is in many ways the most fundamental of betrayals. The body’s immune system, schooled to identify and purge outside invaders like bacteria and viruses, mistakenly turns its force instead on healthy organs. The result is inflammation and often lasting damage to the heart, lungs, joints, brain, kidneys, blood and skin.
Despite an urgent need to find effective ways to understand and manage lupus, the tool set for doing so has been sparse and simplistic. Nearly a half century has passed since the Food and Drug Administration approved a new lupus treatment. Powerful yet imprecise medicines to control symptoms and complications, like the immune-suppressing steroid prednisone, are all that doctors have had to offer. Medicines to treat lupus are often as damaging as the disease itself.
But in the last five years, the field of lupus investigation has started to percolate. Many experts now say there is realistic hope that techniques and medicines to better monitor and manage the illness will soon emerge.
“This is probably the most promising and exciting time in lupus research, as we tease out the controlling influences of this complex disease and identify the disease drivers that actually lead to abnormalities in the immune system,” said Dr. Lee S. Simon, a former F.D.A. division director and associate clinical professor of medicine at Harvard Medical School.
Much of the new optimism stems from enhanced understanding of how the immune system functions, in health and illness. “We are becoming so much more sophisticated about immunology in general,” said Dr. Betty A. Diamond, head of the Feinstein Institute’s Center for Autoimmune Diseases at the North Shore-Long Island Jewish Health System in New York. “We have identified so many more molecules and pathways leading to lupus, which means so many more pathways and targets for lupus treatments.”
A new array of molecular tools to explore the immune system are now in the hands of medical researchers. And unlike a decade ago, investigators have brought into focus specific immune system components they suspect are involved in the disease. These include the various T cells and antibody-producing B cells that fight invaders. Additional targets include specialized cells and proteins, like the toll-like receptors, interferons and dendritic cells that act as sentinels and goad the immune system into action.
The sequencing of the human genome and techniques that knock out single genes in laboratory animals have shifted interest to the role of genetics as well. Confidence is growing that researchers will identify inherited genes that confer susceptibility to lupus, though most agree that DNA alone is not enough to explain who gets the disease.
External factors almost certainly come into play. A trigger in the environment to jump-start or accelerate the disease process is likely. Under suspicion are elements like exposure to ultraviolet light, crystalline silica used in industry and the Epstein-Barr virus that causes mononucleosis. Since 9 out of 10 lupus patients are women, sex hormones almost certainly play a role.
Identification of early signals of disease flare-ups holds the promise of vastly clarifying what is going on inside the body of the individual with lupus. Researchers are on the hunt for useful markers in the blood or urine. Such biomarkers would be useful for monitoring the effectiveness of new or existing treatments.
Rendering all these discoveries relevant to the person with lupus, however, hinges on bridging the gap between basic science findings and a practical application in humans. We still have to determine the relative benefit to risk of these potentially exciting new therapies.
The F.D.A. has issued guidelines that spell out just what needs to be done to have a lupus medicine approved, a move that has spurred drug makers to step up pursuits of new products. The surge in clinical trials for lupus, from a handful a few years ago to dozens today, suggests that the attempt to translate findings into the tangible care of people with the illness may be close at hand.
Drug-Induced Lupus Erythematosus
Lupus, Discoid – View of Lesions on the Chest
Lupus, Discoid on a Child’s Face
Lupus, Discoid on the Face
Antibodies
The New York Times, by Andrea Peirce – Drug-induced lupus erythematosus is an autoimmune disorder that is brought on by a reaction to medication. New understanding of the immune system aims to halt damage by lupus to the skin, heart, lungs, brain and other organs.
Causes
Drug-induced lupus erythematosus resembles systemic lupus erythematosus (SLE). It results from a hypersensitivity reaction to a medication. The drug may react with cell materials, causing the body to form antibodies that attack the body’s own healthy cells.
Several medications are known to cause drug-induced lupus. They include:
- Chlorpromazine
- Hydralazine
- Isoniazid
- Methyldopa
- Penicillamine
- Procainamide
- Quinidine
- Sulfasalazine
Symptoms tend to occur after taking the drug for at least 3 to 6 months.
Persons with drug-induced lupus erythematosus may have symptoms that affect the joints (arthritis), heart, and lungs. Other symptoms associated with SLE, such as lupus nephritis and neurological disease, are rare.
Drug-induced lupus affects men and women equally.
Symptoms
- Blurred vision
- Fever
- General ill feeling (malaise)
- Joint pain
- Joint swelling
- Loss of appetite
- Pleuritic chest pain
- Skin rash
- Gets worse with sunlight
- “Butterfly” rash across bridge of nose and cheeks
- Weight loss
Exams and Tests
The doctor will listen to your chest with a stethoscope. A sound called a heart friction rub or pleural friction rub may be heard. Signs of pericarditis may be present.
A skin exam shows a characteristic skin rash.
The patient will have taken a medicine linked to drug-induced lupus.
Tests that may be done include:
- Antihistone antibody (often positive in drug-induced lupus)
- Antinuclear antibody (ANA) panel
- Lupus erythematosus cell test (rarely used)
A chest x-ray may show signs of pleuritis or pericarditis. An ECG may show heart involvement.
Treatment
Usually, symptoms go away within several days to weeks after stopping the medication that caused the symptoms.
Treatment may include:
- Nonsteroidal anti-inflammatory drugs (NSAIDs) to treat arthritis and pleurisy
- Corticosteroid creams to treat skin rashes
- Antimalarial drugs (hydroxychloroquine) to treat skin and arthritis symptoms
Occasionally, the steroid prednisone is used to treat more severe cases, especially if the heart is involved.
Very rarely, high doses of steroids and immune system suppressants, such as azathioprine or cyclophosphamide, are used to treat persons with severe drug-induced lupus that affects the heart, kidney, and neurological system.
Protective clothing, sunglasses, and sunscreen are recommended.
Outlook (Prognosis)
Drug-induced lupus erythematosus is usually not as severe as SLE. Usually, the symptoms go away within a few days to weeks after stopping the medication.
You should avoid the medication in the future, or symptoms usually return. Routine eye exams are recommended to detect eye complications early.
Possible Complications
- Infection
- Thrombocytopenia purpura — bleeding near the skin surface, resulting from a low number of platelets in the blood.
- Hemolytic anemia
- Myocarditis
- Pericarditis
When to Contact a Medical Professional
Call for an appointment with your health care provider if symptoms do not improve after discontinuing the medication that caused the symptoms. You should also call if new symptoms develop.
Prevention
Be aware of the risk when taking medications that are known to cause this reaction. If symptoms begin to appear, contact your doctor.
References:
Harris ED, Budd RC, Genovese MC, Firestein GS, Sargent JS, Sledge CB. Kelley’s Textbook of Rheumatology. 7th ed. St. Louis, Mo: WB Saunders; 2005:1183, 1598.
Noble J. Textbook of Primary Care Medicine. 3rd ed. St. Louis, Mo: Mosby. 2001:1270.
Sep
8
Oxidative and Nitrosative Stress Contribute to Lupus Disease Activity
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ScienceDaily.com — University of Texas Medical Branch researchers have uncovered an association between free radical-mediated reactions and the severity and progression of system lupus erythematosus (SLE). Higher levels of oxidative and nitrosative stress markers were found in SLE patients with greater disease activity suggesting a causal relationship.
Full findings of the study are available in the July issue of Arthritis & Rheumatism, a journal published by Wiley-Blackwell on behalf of the American College of Rheumatology.
Lupus, an autoimmune disease in which the body’s immune system produces antibodies against itself, causes inflammation, joint pain, fatigue, as well as tissue and organ damage. Approximately 1.5 million Americans and 5 million people worldwide have a form of lupus according to the Lupus Foundation of America with SLE accounting for 70% of all cases. Experts estimate that 70% to 90% of those with this chronic and potentially life-threatening disease are women.
While prior studies have suggested an association between oxidative and nitrosative stress and autoimmunity in mice, its relevance in SLE disease development and progression in humans is not fully understood. To explore the link between reactive oxygen and nitrogen species (RONS) and SLE, M. Firoze Khan, Ph.D., and colleagues used serum from 72 patients (62 female and 10 male) with SLE and 36 healthy control subjects (31 female and 5 male) in their study. The mean age was 47.2 years for the SLE group and 43.1 years in the control. Researchers used the SLE Disease Activity Index (SLEDAI) scores to measure disease activity which ranged from 0 to 38 (mean 10.7). SLE participants were divided into 2 groups — those with a low SLEDAI score of <6 and those with a higher score of ≥6.
Blood levels of oxidative and nitrosative stress markers, including antibodies to malondialdehyde (anti-MDA), 4-hydroxynonenal (anti-HNE), MDA/HNE protein adducts, superoxide dismutase (SOD), nitrotyrosine (NT), and inducible nitric oxide synthase (iNOS) were evaluated in each sample. “Our analysis showed significantly higher levels of anti-MDA and anti-HNE antibodies (biomarkers of oxidative stress) in SLE compared with healthy controls,” said Dr. Khan. Researchers also found that the levels of both these antibodies were significantly higher in lupus patients whose SLEDAI scores were greater than 6, suggesting that increased lipid peroxidation is associated with SLE disease progression.
“Our results clearly show significant increases in oxidative and nitrosative stress in lupus patients suggesting that there is an imbalance between RONS production and antioxidant defense mechanisms in SLE,” concluded Dr. Khan. “Longitudinal studies are needed to further establish how free radical-mediated reactions contribute to SLE development, and to determine the value of anti-MDA and anti-HNE antibodies in assessing the progression and severity of the disease.”
Journal Reference:
- 1. Gangduo Wang, Silvia S. Pierangeli, Elizabeth Papalardo, G.A.S. Ansari, M. Firoze Khan. Markers of oxidative and nitrosative stress in systemic lupus erythematosus: Correlation with disease activity. Arthritis & Rheumatism, 2010; DOI: 10.1002/art.27442
Sep
8
Antibodies Linked to Cardiovascular Disease Increase in Patients with Active Lupus
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ScienceDaily.com — A study by researchers in Australia and the United Kingdom suggests that autoantibodies to fat binding proteins significantly increase in systemic lupus erythematosus (SLE) patients with active disease. This increase in anti-apolipoprotein (anti-Apo A-I), anti-high-density lipoprotein (anti-HDL), and anti-C-reactive protein (anti-CRP) may contribute to the development of atherosclerosis in SLE patients, placing them at risk for cardiovascular disease (CVD). Complete findings of this study are available in the March issue of Arthritis & Rheumatism.
Lupus is a chronic autoimmune disease where the immune system creates antibodies that attack an individuals’ own cells, causing inflammation throughout the body. The inflammation leads to tissue and organ damage, affecting the heart, kidneys, lungs, brain, blood, skin and/or joints of those with SLE. According to a 2008 study for the National Arthritis Data Workgroup 322,000 Americans have a definite or probable SLE diagnosis. The Lupus Foundation of America’s figures are much higher, with up to 1.5 million in the U.S. and close to 5 million worldwide reported having form (SLE, discoid, sub-acute cutaneous, drug-induced, or neonatal) of lupus.
In the current study serum levels of anti-Apo A-I, anti-HDL, and anti-CRP were taken from participants that included 39 SLE patients with high disease activity over the previous 2-year period; 42 SLE patients with low disease activity over the previous 2 years; 16 patients newly diagnosed with lupus nephritis (inflammation of the kidney caused by SLE); 25 patients with samples obtained at the time of a SLE flare and during inactivity of the disease; 24 SLE patients who had prior CVD events; and 34 healthy subjects in the control.
Researchers found that antibodies above the upper limit of normal (ULN) were higher in patients in the high disease activity group compared with the low disease activity group: anti-Apo A-I were higher in 35.9% vs. 12% of subjects; anti-HDL levels at 44.7% vs. 30.9%; and anti-CRP at 26.3% vs. 12.8%. Results further indicate that in 55% of the subjects, anti-Apo A-I levels were higher at the time of a disease flare compared with only 34.5% in preflare samples. “The main finding in our study was that levels of anti-Apo A-I and anti-HDL were significantly higher in patients with greater disease activity than in those with less active disease over the same period,” said the authors.
In her editorial also published in Arthritis & Rheumatism, Bevra Hahn, M.D., from the David Geffen School of Medicine at the University of California Los Angeles, acknowledged that the study by O’Neill et al provided a novel method for studying association of autoantibodies with active disease by classifying SLE patients according to sustained chronic disease activity (or not) instead of the traditional approach of using a validated scoring system that identifies active disease at one point in time. “While this is an important step, measuring antibodies to Apo A-I, HDL or CRP in SLE patients has not yet reached the point where it can be used routinely to identify risk of accelerated atherosclerois,” commented Dr. Hahn. “As risk prediction models emerge over the next few years, these antibodies may be included along with other predisposing variables.”
Journal References:
- 1. Sean G. O’Neill, Ian Giles, Anastasia Lambrianides, Jessica Manson, David D’Cruz, Leslie Schrieber, Lyn M. March, David S. Latchman, David A. Isenberg,and Anisur Rahman. Antibodies to Apolipoprotein A-I, High-Density Lipoprotein, and C-Reactive Protein Are Associated With Disease Activity in Patients With Systemic Lupus Erythematosus. Arthritis & Rheumatism, Published Online: February 25, 2010; Print Issue Date: March 2010 DOI: 10.1002/art.27286
- 2. Bevra H. Hahn. Should Antibodies to High-Density Lipoprotein Cholesterol and Its Components Be Measured in All Systemic Lupus Erythematosus Patients to Predict Risk of Atherosclerosis? Arthritis & Rheumatism, February 25, 2010; Print Issue Date: March 2010 DOI: 10.1002/art.27298
Sep
8
Rescue NET for Lupus Patients
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These are white blood cells and NETs in a lupus patient. The DNA in NETs is shown in blue; the antibodies binding to the NET are shown in red (fluorescence microscopy). (Credit: Volker Brinkmann)
Max-Planck-Gesellschaft — Lupus is a disease where the immune system attacks healthy cells of the body. This leads to progressive damage of different tissues and organs. The classical characteristic of the disease is the so-called butterfly rash in the face. Many Lupus patients eventually die of kidney failure. Scientists at the Max Planck Institute for Infection Biology in Berlin together with medical scientists from the University of Erlangen succeeded in elucidating basic principles of the disease. This opens up new perspectives for methods that might enable early diagnosis and treatment of Lupus patients with a high risk at kidney failure.
Lupus is one of the most common autoimmune diseases. The symptoms vary from patient to patient and can include rashes, muscle and joint pain, fatigue, inflammation, and miscarriage. One third of the patients die of kidney failure. Little is known about the origin and the pathogenesis of this disease. Diagnosis is difficult because many symptoms are common with other diseases. The hallmark of Lupus is that the body produces antibodies against its own DNA, certain proteins of the nucleus and of white blood cells. The course of the disease is characterized by flares which are often triggered by infections. After a flare the health of the patient improves but often there are sequelae, resulting in a continuous exacerbation of the disease.
Scientists of the Max Planck Institute for Infection Biology suspected that an immune mechanism that was only recently discovered by them, plays a key role in Lupus: During an infection, white blood cells are stimulated and extrude nets in which they trap and kill pathogens. This NET (an acronym for Neutrophil Extracellular Traps) is composed of exactly those components against which a Lupus patient produces antibodies: DNA, as well as proteins of the nucleus and the white blood cells. In co-operation with clinical scientists from the University of Erlangen, the Max Planck scientists could show for the first time that, in contrast to healthy persons, a part of the Lupus patients could not degrade NETs after the infection.
The scientists also discovered that NETs are degraded by the enzyme DNase-1, a protein which normally is found in the blood. Lupus patients, however, either lack this enzyme or their DNase-1 is blocked. Further examination of this patient group revealed that the remains of NETs together with the auto-antibodies are deposited in the kidneys of SLE patients. Indeed, the scientists showed a strong correlation between the inability to degrade NETs in Lupus and a high risk of kidney failure. These results provide a starting point for the development of a test that might allow an early diagnosis and treatment of these high risk patients.
Journal Reference:
- 1. Abdul Hakkim, Barbara G. Fürnrohr, Kerstin Amann, Britta Laube, Ulrike Abu Abed, Volker Brinkmann, Martin Herrmann, Reinhard E. Voll, and Arturo Zychlinsky. Impairment of NET degradation is associated with Lupus nephritis. PNAS, May 3, 2010 DOI: 10.1073/pnas.0909927107