Thursday, February 4, 2010

RESEARCH SUPPORTS THEORY THAT APPENDICITIS MAY BE RELATED TO VIRAL INFECTIONS

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Can you catch appendicitis? And if you do, is it necessarily an emergency that demands immediate surgery? Yes and no, according to a new study by UT Southwestern Medical Center surgeons and physicians.

The researchers evaluated data over a 36-year period from the National Hospital Discharge Survey and concluded in a paper appearing in the January issue of Archives of Surgery that appendicitis may be caused by undetermined viral infection or infections, said Dr. Edward Livingston, chief of GI/endocrine surgery at UT Southwestern and senior author of the report.

The review of hospital discharge data runs counter to traditional thought, suggesting that appendicitis doesn’t necessarily lead to a burst appendix if the organ is not removed quickly, Dr. Livingston said.

“Just as the traditional appendix scar across the abdomen is fast becoming history, thanks to new single-incision surgery techniques that hide a tiny scar in the bellybutton, so too may the conventional wisdom that patients with appendicitis need to be operated on as soon as they enter the hospital,” said Dr. Livingston. “Patients still need to be seen quickly by a physician, but emergency surgery is now in question.”

Appendicitis is the most common reason for emergency general surgery, leading to some 280,000 appendectomies being performed annually.

Appendicitis was first identified in 1886. Since then, doctors have presumed quick removal of the appendix was a necessity to avoid a subsequent bursting, which can be an emergency. Because removing the appendix solves the problems and is generally safe, removal became the standard medical practice in the early 20th century.

But this latest research studying appendicitis trends from 1970 to 2006 suggests immediate removal may not be necessary. Evidence from sailors at sea without access to immediate surgery and from some children’s hospitals, whose practice did not call for emergency surgery, hinted that non-perforated appendicitis may resolve without surgery, said Dr. Livingston.

In undertaking the study, the researchers screened the diagnosis codes for admissions for appendicitis, influenza, rotavirus and enteric infections. They found that seasonal variations and clustering of appendicitis cases support the theory that appendicitis may be a viral disease, like the flu, Dr. Livingston said.

Statistical data revealed peaks, which may be outbreaks of appendicitis, in the years 1977, 1981, 1984, 1987, 1994 and 1998. In addition, researchers uncovered some seasonal trends for appendicitis, documenting a slight increase in appendicitis cases during the summer.

“The peaks and valleys of appendicitis cases generally matched up over time, suggesting it is possible that these disorders share common etiologic determinates, pathogenetic mechanisms or environmental factors that similarly affect their incidence,” Dr. Livingston said.

Researchers have been able to rule out flu and several other common infections as a direct cause. They also were able to rule out several types of intestinal viruses.

Appendicitis afflicts about one in 10 people during their lifetime. The condition occurs when the appendix becomes obstructed, but doctors are unsure why. Dr. Livingston and other UT Southwestern researchers in 1995 identified an unexpected rise in appendicitis cases, reversing a downward trend throughout the previous 25 years.

“Though appendicitis is fairly common, it still remains a frustrating medical mystery,” Dr. Livingston said. “While we know surgical removal is an effective treatment, we still don’t know the purpose of the appendix, nor what causes it to become obstructed.”

Other UT Southwestern researchers involved in the Archives of Surgery paper were Dr. Robert W. Haley, chief of epidemiology, and Dr. Adam Alder, a resident and lead author. The team also collaborated with economists at Southern Methodist University on novel statistical methodologies to uncover the associations.

(Photo: UT Southwestern MC)

UT Southwestern

CARBON-CAPTURING ENZYME: MIT CHEMISTS LEARN FROM NATURE

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Each year, microorganisms containing a certain enzyme remove an estimated 100 million tons of the pollutant carbon monoxide (CO) from the environment. Now, MIT researchers have new insights into how they go about it—happy news for inorganic chemists who have long been trying to synthesize compounds that can do the same thing without the living creature.

“Microorganisms such as bacteria can do lots of chemistry that people would like to do,” says Catherine L. Drennan, professor of chemistry and a Howard Hughes Medical Institute investigator. “They can form and break carbon bonds, split nitrogen, and break apart hydrogen and oxygen—all things that we can’t do or can do only with great difficulty.”

Key to the microorganisms’ ability to perform such feats are large, powerful enzymes that catalyze (speed up) reactions. For many decades, researchers worldwide have been working to replicate that chemistry using smaller molecules in an artificial rather than natural setting. Success could mean the ability to make hydrogen for fuel cells, to remove the greenhouse gas carbon dioxide (CO2) from the atmosphere, to clean up CO in polluted urban areas, and more.

But the researchers’ best efforts are frequently unsuccessful—and Drennan is not surprised. “If we’re going to copy what microorganisms are doing, we need to have a clear understanding of how they do it—at the molecular level,” she says. She and her research group aim to develop that understanding by actually observing the physical structure of the key molecules involved and seeing how they change when a reaction takes place.

Recently, her work has focused on an enzyme that—depending on its change­able structure—can take up CO and release CO2, or take up CO2 and release CO, or use the CO to make a form of acetate that plays a key role in metabo­lism. “Unlike humans, these organisms are very flexible,” says Drennan. “They’ll take whatever is around them and find a way to live on it.”

To start, she has been investigating the reaction whereby CO is picked up by the enzyme, where it reacts with water to form CO2. That chemistry can be traced to a small section within the enzyme known as the C-cluster—an unusual and possibly quite ancient combination of metals and inorganic compounds including iron, nickel, and sulfur.

To help inorganic chemists replicate the abilities of the C-cluster, Drennan has been exploring its structural details. Using crystalline enzyme samples, she has looked at where the atoms are located, how they are oriented, and where empty sites are needed for other atoms to attach and catalyze chemical reactions.

Atoms are too small to see with an optical microscope, so Drennan turns to X-rays, which have a wavelength a thousand times shorter than that of visible light and comparable to the spacing of atoms in a crystal. The technique she uses, called X-ray crystallography, involves beaming X-rays through a crystal sample. Atoms in the sample diffract the X-rays, creating a diffraction pattern that a crystallographer—with the help of mathematical methods—converts into an electron density map and ultimately to an image, or “snapshot,” that shows where the atoms in the sample are located.

For these studies, Drennan receives samples of the enzyme from collabora­tor Stephen Ragsdale at the University of Michigan Medical School, who has a laboratory specially equipped to grow the microorganism of interest. The microorganisms grow rapidly at room temperature, and the enzyme is abun­dant and stable—except that the metal clusters are sensitive to oxygen, so all work takes place in chambers filled with argon or nitrogen.

Keeping their enzymes away from oxygen is a minor inconvenience compared with the challenges involved in using X-ray crystallography to study them. First, the researchers must get the enzyme to form a crystal—a task that Drennan deems the “hard part,” which can take many years of trying different materials and methods. In this case, her team uses salt at high concentrations to force the enzyme molecules out of solution and into a crystalline state. The individual enzymes line up in a regularly repeating pattern in a three-dimensional crystal, present­ing enough sample to be analyzed.

The next challenge is to stop the reaction just before it happens. “With X-ray crystallography you only get snapshots in time,” says Drennan. “If you give the enzyme everything it needs for the reaction, it’ll react—and your snapshot will show the end result but not how it happened.” Tests showed that providing the enzyme with cyanide (CN) rather than CO does the trick. CN is similar to CO in structure and will bind at the same site where the CO would bind—but it won’t react. The enzyme will be poised for action but frozen in time.

Their experiments worked well. They now have a clear image of the arrange­ment of the metal atoms in the C-cluster just prior to the reaction. They can see where the CO would bind, and they know the location of the nearby water molecule that participates in the reaction. From those observations, they can predict how the reaction would proceed.

The researchers’ results settled a long-standing debate about the pres­ence or absence of a single sulfur atom. Another group has argued that there is a sulfur atom at the site where the CN latched on. But Drennan’s results suggest that if a sulfur atom were there, it would block the CO from binding. Most experts in the field now agree that the “active” form of the C-cluster has no sulfur in that position—a finding significant for inorganic chemists as they manipulate materials to mimic the cluster’s CO-removal action.

Results from Holger Dobbek and his research group at the Max-Planck-Institut für Biochemie (Germany) both verify and supplement the MIT findings. That group produced an image of the C-cluster with a CO2 molecule in place—a structure that can be inter­preted as a post-reaction counterpart to Drennan’s pre-reaction images with CN (the stand-in for CO). Indeed, the structures from the two groups super­impose remarkably well, and in neither case is the disputed sulfur atom in evidence. “So at an atomic resolution, we have images that enable us to understand one of the important chemical reactions that happens on this metal site,” says Drennan. “It’s really very exciting.”

Drennan and her colleagues are now investigating other metal clusters in the same enzyme, in particular, one that controls the acetate-forming reactions. But, she warns, there is always the chance that—even getting the right structure—human-made copies of the metal clusters may not work. For example, it may be impossible to make a small version that is stable but still flexible enough to do chemistry. (In the CO reaction, for example, the carbon atom needs to rotate to react with the water.) Or the reaction may require other elements in the enzyme, not just the metals. As a result, it may be necessary to use the whole enzyme or perhaps even the whole microorganism to achieve the desired effect.

From a commercial perspective, this particular enzyme is attractive because it can be made in large quantities and at room temperature. The only down­side is having to keep it away from oxygen—a problem Drennan thinks she can fix. “I think I know the source of the problem with oxygen,” she says. “We may be able to redesign the enzyme to make it more stable in an oxygen environment.”

(Photo: Yan Kung, MIT)

MIT

PICTURE-DRIVEN COMPUTING

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Until the 1980s, using a computer program meant memorizing a lot of commands and typing them in a line at a time, only to get lines of text back. The graphical user interface, or GUI, changed that. By representing programs, program functions, and data as two-dimensional images — like icons, buttons and windows — the GUI made intuitive and spatial what had been memory intensive and laborious.

But while the GUI made things easier for computer users, it didn’t make them any easier for computer programmers. Underlying GUI components is a lot of computer code, and usually, building or customizing a program, or getting different programs to work together, still means manipulating that code. Researchers in MIT’s Computer Science and Artificial Intelligence Lab hope to change that, with a system that allows people to write programs using screen shots of GUIs. Ultimately, the system could allow casual computer users to create their own programs without having to master a programming language.

The system, designed by associate professor Rob Miller, grad student Tsung-Hsiang Chang, and the University of Maryland’s Tom Yeh, is called Sikuli, which means “God’s eye” in the language of Mexico’s Huichol Indians. In a paper that won the best-student-paper award at the Association for Computing Machinery’s User Interface Software and Technology conference last year, the researchers showed how Sikuli could aid in the construction of “scripts,” short programs that combine or extend the functionality of other programs. Using the system requires some familiarity with the common scripting language Python. But it requires no knowledge of the code underlying the programs whose functionality is being combined or extended. When the programmer wants to invoke the functionality of one of those programs, she simply draws a box around the associated GUI, clicks the mouse to capture a screen shot, and inserts the screen shot directly into a line of Python code.

Suppose, for instance, that a Python programmer wants to write a script that automatically sends a message to her cell phone when the bus she takes to work rounds a particular corner. If the transportation authority maintains a web site that depicts the bus’s progress as a moving pin on a Google map, the programmer can specify that the message should be sent when the pin enters a particular map region. Instead of using arcane terminology to describe the pin, or specifying the geographical coordinates of the map region’s boundaries, the programmer can simply plug screen shots into the script: when this (the pin) gets here (the corner), send me a text.

“When I saw that, I thought, ‘Oh my God, you can do that?’” says Allen Cypher, a researcher at IBM’s Almaden Research Center who specializes in human-computer interactions. “I certainly never thought that you could do anything like that. Not only do they do it; they do it well. It’s already practical. I want to use it right away to do things I couldn’t do before.”

In the same paper, the researchers also presented a Sikuli application aimed at a broader audience. A computer user hoping to learn how to use an obscure feature of a computer program could use a screen shot of a GUI — say, the button that depicts a lasso in Adobe Photoshop — to search for related content on the web. In an experiment that allowed people to use the system over the web, the researchers found that the visual approach cut in half the time it took for users to find useful content.

In the same way that a programmer using Sikuli doesn’t need to know anything about the code underlying a GUI, Sikuli doesn’t know anything about it, either. Instead, it uses computer vision algorithms to analyze what’s happening on-screen. “It’s a software agent that looks at the screen the way humans do,” Miller says. That means that without any additional modification, Sikuli can work with any program that has a graphical interface. It doesn’t have to translate between different file formats or computer languages because, like a human, it’s just looking at pixels on the screen.

In a new paper to be presented this spring at CHI, the premier conference on human-computer interactions, the researchers describe a new application of Sikuli, aimed at programmers working on large software development projects. On such projects, new code accumulates every day, and any line of it could cause a previously developed GUI to function improperly. Ideally, after a day’s work, testers would run through the entire application, clicking virtual buttons and making sure that the right windows or icons still pop up. Since that would be prohibitively time consuming, however, broken GUIs may not be detected until the application has begun the long and costly process of quality assurance testing.

The new Sikuli application, however, lets programmers create scripts that automatically test an application’s GUI components. Visually specifying both the GUI and the window it’s supposed to pull up makes writing the scripts much easier; and once written, they can be run every night without further modification.

But the new application has an added feature that’s particularly heartening to non-programmers. Like its predecessors, it allows users to write their scripts — in this case, GUI tests — in Python. But of course, writing scripts in Python still requires some knowledge of Python — at the very least, an understanding of how to use commands like “dragDrop” or “assertNotExist,” which describe how the GUI components should be handled.

The new application gives programmers the alternative of simply recording the series of keystrokes and mouse clicks that define the test procedure. For instance, instead of typing a line of code that includes the command “dragDrop,” the programmer can simply record the act of dragging a file. The system automatically generates the corresponding Python code, which will include a cropped screen shot of the sample file; but if she chooses, the programmer can reuse the code while plugging in screen shots of other GUIs. And that points toward a future version of Sikuli that would require knowledge neither of the code underlying particular applications nor of a scripting language like Python, giving ordinary computer users the ability to intuitively create programs that mediate between other applications.

(Photo: MIT)

MIT

GORILLAS CARRY MALIGNANT MALARIA PARASITE

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The parasite that causes malignant malaria in humans has been detected in gorillas, along with two new species of malaria parasites, reports a study co-authored by UC Irvine biologist Francisco Ayala.

The study also confirms a recent discovery by Ayala and colleagues that human malignant malaria, caused by Plasmodium falciparum, originated from a closely related parasite found in chimpanzees in equatorial Africa. P. falciparum is responsible for 85 percent of malignant malaria infections in humans and nearly all deaths from the disease.

The researchers cautioned that increased contact between primates and humans – mostly because of logging and deforestation – creates a greater risk of new parasites being transmitted to humans. It also could further jeopardize endangered ape populations by spreading diseases to them. Finding P. falciparum in gorillas also complicates the challenge of eradicating malaria.

“Hundreds of billions of dollars are spent each year toward ridding humans of malignant malaria. But success may be a pyrrhic victory, because we could be re-infected by gorillas – just as we were originally infected by chimps a few thousand years ago,” said Ayala, corresponding author of the study, published this week in the Proceedings of the National Academy of Sciences.

The researchers analyzed fecal samples from 125 wild chimpanzees and 84 gorillas in Cameroon and tested blood samples from three gorillas in Gabon. They identified two new closely related species of malaria parasites – Plasmodium GorA and Plasmodium GorB – that infect gorillas. The animals also were found to harbor P. falciparum, previously thought to only infect humans.

In August, Ayala and colleagues published a study reporting that P. falciparum had been transmitted to humans from chimpanzees perhaps as recently as 5,000 years ago – and possibly through a single mosquito. Before then, malaria’s origin had been unclear.
Chimpanzees were known to carry the parasite Plasmodium reichenowi, but most scientists assumed the two parasites had existed separately in humans and chimpanzees for the last 5 million years.

The discovery could aid the development of a vaccine for malaria, which each year causes 2 million infant deaths and sickens about 500 million people, mostly in sub-Saharan Africa. It also furthers understanding of how infectious diseases such as HIV, SARS, and avian and swine flu can be transmitted to humans from animals.

(Photo: Daniel A. Anderson / University Communications)

University of California, Irvine

GIANT INTERGALACTIC GAS STREAM LONGER THAN THOUGHT

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A giant stream of gas flowing from neighbor galaxies around our own Milky Way is much longer and older than previously thought, astronomers have discovered. The new revelations provide a fresh insight on what started the gaseous intergalactic streamer.

The astronomers used the National Science Foundation's Robert C. Byrd Green Bank Telescope (GBT) to fill important gaps in the picture of gas streaming outward from the Magellanic Clouds. The first evidence of such a flow, named the Magellanic Stream, was discovered more than 30 years ago, and subsequent observations added tantalizing suggestions that there was more. However, the earlier picture showed gaps that left unanswered whether this other gas was part of the same system.

"We now have answered that question. The stream is continuous," said David Nidever, of the University of Virginia. "We now have a much more complete map of the Magellanic Stream," he added. The astronomers presented their findings to the American Astronomical Society's meeting in Washington, DC.

The Magellanic Clouds are the Milky Way's two nearest neighbor galaxies, about 150,000 to 200,000 light-years distant from the Milky Way. Visible in the Southern Hemisphere, they are much smaller than our Galaxy and may have been distorted by its gravity.
Nidever and his colleagues observed the Magellanic Stream for more than 100 hours with the GBT. They then combined their GBT data with that from earlier studies with other radio telescopes, including the Arecibo telescope in Puerto Rico, the Parkes telescope in Australia, and the Westerbork telescope in the Netherlands. The result shows that the stream is more than 40 percent longer than previously known with certainty.

One consequence of the added length of the gas stream is that it must be older, the astronomers say. They now estimate the age of the stream at 2.5 billion years.

The revised size and age of the Magellanic Stream also provides a new potential explanation for how the flow got started.

"The new age of the stream puts its beginning at about the time when the two Magellanic Clouds may have passed close to each other, triggering massive bursts of star formation," Nidever explained. "The strong stellar winds and supernova explosions from that burst of star formation could have blown out the gas and started it flowing toward the Milky Way," he said.

"This fits nicely with some of our earlier work that showed evidence for just such blowouts in the Magellanic Clouds," said Steven Majewski, of the University of Virginia.

Earlier explanations for the stream's cause required the Magellanic Clouds to pass much closer to the Milky Way, but recent orbital simulations have cast doubt on such mechanisms.

(Photo: Nidever, et al., NRAO/AUI/NSF and Meilinger, Leiden-Argentine-Bonn Survey, Parkes Observatory, Westerbork Observatory, Arecibo Observatory)

The National Radio Astronomy Observatory

TYING LIGHT IN KNOTS

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The remarkable feat of tying light in knots has been achieved by a team of physicists working at the universities of Bristol, Glasgow and Southampton, reports a paper in Nature Physics.

Understanding how to control light in this way has important implications for laser technology used in wide a range of industries.

Dr Mark Dennis from the University of Bristol and lead author on the paper, explained: “In a light beam, the flow of light through space is similar to water flowing in a river. Although it often flows in a straight line – out of a torch, laser pointer, etc – light can also flow in whirls and eddies, forming lines in space called ‘optical vortices’.

“Along these lines, or optical vortices, the intensity of the light is zero (black). The light all around us is filled with these dark lines, even though we can’t see them”.

Optical vortices can be created with holograms which direct the flow of light. In this work, the team designed holograms using knot theory – a branch of abstract mathematics inspired by knots in everyday life, such as those that occur in shoelaces and rope. Using these specially designed holograms they were able to create knots in optical vortices.

This new research demonstrates a physical application for a branch of mathematics previously considered completely abstract.

Professor Miles Padgett from Glasgow University, who led the experiments, said: “The sophisticated hologram design required for the experimental demonstration of the knotted light shows advanced optical control, which undoubtedly can be used in future laser devices”.

“The study of knotted vortices was initiated by Lord Kelvin back in 1867 in his quest for an explanation of atoms”, adds Dennis, who began to study knotted optical vortices with Professor Sir Michael Berry at Bristol University in 2000. “This work opens a new chapter in that history.”

(Photo: Bristol U.)

Bristol University

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