Monday, May 16, 2011

Hospital-Acquired Infections: Beating Back the Bugs

It is the ultimate paradox of American health care: going to the hospital can kill you. Every year nearly two million hospital-acquired infections claim roughly 100,000 lives and add $45 billion in costs; that is as many lives and dollars as taken by AIDS, breast cancer and auto accidents combined. And with antibiotic resistance rising steadily, those numbers promise to climb even higher.

Even more staggering than the numbers is that most of these infections are preventable. The Institute of Medicine has long since determined that if hospital staff would make some minor adjustments to their routines—like washing their hands more—the problem could be significantly minimized.

Washington is now starting to crack down. On January 1 the Centers for Medicare & Medicaid Services (CMS) began requiring that all acute care facilities report the number of intensive care unit patients who develop bloodstream infections. Eventually the information will be made public, requirements will expand to include all types of hospital-acquired infections, and the level of Medicare reimbursement will be tied to how effective hospitals are at reducing infection rates.

Some medical centers have already taken the initiative and started making changes. A handful “have virtually eliminated some forms of infection that other hospitals still think are inevitable,” said Donald M. Berwick, who heads the CMS, in congressional testimony last year.

One of them is Claxton-Hepburn Medical Center, a rural hospital with a 10-bed intensive care unit in Ogdensburg, N.Y. It has nearly wiped out ventilator-associated pneumonia (VAP)—a hospital-acquired infection that occurs in 25 percent of all people who require mechanical ventilation—just by making a handful of changes to its protocol. Instead of laying patients flat, nurses keep them elevated at a 30-degree angle, which studies show is better for the lungs and does not, as previously thought, increase the risk of bedsores. Rather than leaving patients sedated, doctors now wean them from sedatives once a day to test their progress—another trick proved to reduce the length of stay. Nurses also take care to brush patients’ teeth every day and to clean their mouths and gums every few hours because oral infections often spread to the lungs. In the five years that followed the adoption of these practices, not a single case of VAP emerged.

Claxton-Hepburn is not the only hospital with success stories to share. In fact, dozens of New York–based hospitals—including ones much larger than Claxton-Hepburn—managed to cut their VAP rates in half by employing similar methods. And in Michigan 103 intensive care units eliminated catheter-related bloodstream infections during an 18-month study; hospital workers credited evidence-based practices and simple checklists. With solutions that cost less than the penalties, more hospitals are sure to follow Claxton-Hepburn’s lead.


New class of compounds offers great potential for research and drug development

Scientists from The Scripps Research Institute have identified a class of compounds that could be a boon to basic research and drug discovery.

In a new study, published online in on May 15, 2011, the researchers show the new compounds powerfully and selectively block the activity of a large and diverse group of enzymes known as "serine hydrolases." Previously discovered serine hydrolase-blocking compounds have been turned into drugs to treat obesity, diabetes, and Alzheimer's disease, and are currently in testing as treatments for pain, anxiety, and depression.

"There are more than 200 serine hydrolases in , but for most we've lacked chemical inhibitors of their activity," said team leader Benjamin F. Cravatt III, professor and chair of the Department of Chemical Physiology at Scripps Research and a member of its Skaggs Institute for Chemical Biology, "so we've had only a limited ability to study them in the lab or to block them to treat medical conditions. This new research allows us to greatly expand our list of these inhibitors."

A Scaffold on Which to Build

Hints from previous work by the Cravatt lab and other groups led the team to investigate a group of molecules known as ureas for their ability to inhibit serine hydrolase activity. In initial tests using recently advanced techniques for measuring enzyme-inhibition strength and specificity, the Scripps found that molecules known as 1,2,3-triazole ureas could powerfully inhibit some serine hydrolases without affecting other enzymes.

In the next set of tests, the team synthesized a basic "scaffold" of 1,2,3-triazole urea, and found that it inhibited many more serine hydrolases – still without affecting other enzyme classes – than did an existing broad inhibitor known as a carbamate. The team then began modifying the scaffold compound to refine its inhibitory activity to specific serine hydrolase targets. This chemical tweaking would once have been a lengthy and burdensome task, but in this case it was done using simple "click chemistry" techniques developed at Scripps Research by Nobel laureate Professor K. Barry Sharpless and his colleague Associate Professor Valery Fokin.

"We can make these modifications in just two chemical steps, which is a great advantage," said Alexander Adibekian, a postdoctoral fellow in the Cravatt lab and first author of the new paper. "And despite this technical simplicity, we were able to generate compounds that were extremely potent and selective."

From the 20 compounds the scientists generated this way, they found three with powerful and highly specific inhibitory effects on individual serine hydrolases with many unknown characteristics.

Most of the study's enzyme-inhibition tests were conducted in mouse cell cultures, a more realistic biochemical environment than traditional "test-tube" biochemical preparations; but for one of the group's inhibitor compounds, AA74-1, the scientists extended their inhibition-measurement techniques to animal models, showing that the compound potently blocked the activity of its target serine hydrolase, acyl-peptide hydrolase, or APEH, without significantly affecting other enzymes.

Not much had been known about APEH, but with its inhibitor AA74-1, the team was able to illuminate the enzyme's normal role in the chemical modification of proteins, showing the levels of more than two dozen proteins dropped sharply when APEH was inhibited.

"This was unexpected and unusual," said Adibekian. "But it's what one wants to see with these compounds—strong enzyme-inhibiting activity in different tissues, at a low dose. And it's the first time this kind of evaluation has been done in both cultured cells and animal tissues."

The Cravatt lab is now using the expanding number of inhibitors that team members have generated so far to study serine hydrolases with previously unknown or uncertain biological functions.

"We're also using the techniques described in this paper to try to systematically generate more of these inhibitor compounds," said Cravatt. "We see these as basic tools that enable us to determine the roles of serine hydrolases in health and disease. As we understand these roles better, we expect that some of their inhibitors could become the bases for medicines."

Provided by The Scripps Research Institute (news : web)

'Computer synapse' analyzed at the nanoscale

ScienceDaily (May 15, 2011) — Researchers at Hewlett Packard and the University of California, Santa Barbara, have analysed in unprecedented detail the physical and chemical properties of an electronic device that computer engineers hope will transform computing.

Memristors, short for memory resistors, are a newly understood circuit element for the development of electronics and have inspired experts to seek ways of mimicking the behaviour of our own brains' activity inside a computer.

Research, published in IOP Publishing's Nanotechnology, explains how the researchers have used highly focused x-rays to map out the nanoscale physical and chemical properties of these electronic devices.

It is thought memristors, with the ability to 'remember' the total electronic charge that passes through them, will be of greatest benefit when they can act like synapses within electronic circuits, mimicking the complex network of neurons present in the brain, enabling our own ability to perceive, think and remember.

Mimicking biological synapses -- the junctions between two neurons where information is transmitted in our brains -- could lead to a wide range of novel applications, including semi-autonomous robots, if complex networks of neurons can be reproduced in an artificial system.

In order for the huge potential of memristors to be utilised, researchers first need to understand the physical processes that occur within the memristors at a very small scale.

Memristors have a very simple structure -- often just a thin film made of titanium dioxide between two metal electrodes -- and have been extensively studied in terms of their electrical properties.

For the first time, researchers have been able to non-destructively study the physical properties of memristors allowing for a more detailed insight into the chemistry and structure changes that occur when the device is operating.

The researchers were able to study the exact channel where the resistance switching of memristors occurs by using a combination of techniques.

They used highly focused x-rays to locate and image the approximately one hundred nanometer wide channel where the switching of resistance takes place, which could then be fed into a mathematical model of how the memristor heats up.

John Paul Strachan of the nanoElectronics Research Group, Hewlett-Packard Labs, California, said: "One of the biggest hurdles in using these devices is understanding how they work: the microscopic picture for how they undergo such tremendous and reversible change in resistance.

"We now have a direct picture for the thermal profile that is highly localized around this channel during electrical operation, and is likely to play a large role in accelerating the physics driving the memristive behavior."

This research appears as part of a special issue on non-volatile memory based on nanostructures.

Story Source:

The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by Institute of Physics, via EurekAlert!, a service of AAAS.

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

Disclaimer: Views expressed in this article do not necessarily reflect those of ScienceDaily or its staff.

Scientists design new anti-flu virus proteins using computational methods

A research article May 12 in Science demonstrates the use of computational methods to design new antiviral proteins not found in nature, but capable of targeting specific surfaces of flu virus molecules.

One goal of such protein design would be to block involved in and virus reproduction.

Computationally designed, surface targeting, antiviral proteins might also have diagnostic and therapeutic potential in identifying and fighting viral infections.

The lead authors of the study are Sarel J. Fleishman and Timothy Whitehead of the University of Washington (UW) Department of Biochemistry, and Damian C. Ekiert from the Department of and the Skaggs Institute for at The Scripps Research Institute. The senior authors are Ian Wilson from Scripps and David Baker from the UW and the Howard Hughes Medical Institute.

The researchers note that additional studies are required to see if such designed proteins can help in diagnosing, preventing or treating viral illness. What the study does suggest is the feasibility of using computer design to create new proteins with antiviral properties.

"Influenza presents a serious public health challenge," the researchers noted, "and new therapies are needed to combat viruses that are resistant to existing anti-viral medications or that escape the body's defense systems."

They focused their attention on the section of the known as the hemagglutinin stem region. They concentrated on trying to disable this part because of its function in invading the cells of the human respiratory tract.

Their approach was somewhat similar to engineering a small space shuttle with the right configuration and construction, as well as recognizance and interlocking mechanisms, to dock with a troublesome space station and upset its mission. Only these scientists attempted their engineering feat at an atomic and molecular level.

Central to their approach is the ability of biological molecules to recognize certain other molecules or their working parts, and to have an affinity for binding to them at pre-determined locations. This recognition has both physical and chemical bases. Protein-protein interactions underlie many biological activities, including those that disarm and deactivate viruses.

In their report, the researchers described their general computational methods for designing new, tiny protein molecules that could bind to a certain spot on large protein molecules. They took apart some protein structures and watched how these disembodied sections interacted with a target surface. They analyzed particular high-affinity interactions, and used this information to further refine computer-generated designs for interfaces.

"Protein surfaces are never flat, but have many crevices and bulges at the atomic scale," lead author Sarel Fleishman explained. "The challenge is to identify amino acid side chains that would fit perfectly into these surfaces. The fit must be precise both in shape and in other chemical properties such as electrostatic charge. This geometrical and biophysical problem can be computationally solved, but requires large computational resources."

The researchers made use of a peer-to-peer computing platform called Rosetta@Home for going through the hundreds of millions of possible interactions of designed proteins and the surface of hemagglutinin to solve this challenge.

Following optimization, the designed proteins bound hemagglutinin very tightly.

Through this method, the researchers created two designs for new proteins that could bind to a surface patch on the stem of the influenza hemagglutinin from the 1918 H1N1 pandemic flu virus.

The shortcomings of the approach, due to approximations, meant that the researchers started out with 73 possibilities of which just two were successful.

One of the disease-causing characteristics of the influenza hemagglutinin stem is that it changes shape by refolding when in an acidic environment. This reconfiguration appears to allow the virus reproduce itself inside of cells.

In this study, one of the newly designed proteins was shown to block a conformational change, not only in H1 influenza hemagglutinin, but also in a similar component in H5 avian influenza.

"This finding suggests that this new protein design may have virus-neutralizing effects against multiple influenza subtypes," the researchers reported.

What was unusual about the workable designs was that they had helical binding modes, roughly shaped like a spiral staircase, rather than the loop binding that naturally occurring antibodies employ.

X-ray crystallography of the proteins complex showed that the actual orientation of the bound proteins was almost identical to the way the binding mode was designed. The modified surface of the main recognition helix on the designed protein was packed into a groove on the desired region of the virus protein.

"Overall, the crystal structure is in excellent agreement with the designed interface," the researchers noted, "with no significant deviations at any of the contact points." The design and the actual formation were nearly identical.

The scientists were encouraged by this finding. Despite their limitations, the design methods, the scientists believe, capture the essential features of the desired protein-protein interaction.

Provided by University of Washington (news : web)

U.S. Action to Combat Climate Change Remains Urgent

Climate change poses "significant risks" to society, the National Academy of Sciences said yesterday, warning that delaying cuts in greenhouse gas emissions will make dealing with the problem harder in the future.

"Each additional ton of greenhouse gases emitted commits us to further change and greater risks," an academy panel said in a new report, which calls for the federal government to take a lead role in combating climate change at home and abroad.

Such advice runs counter to the political mood on Capitol Hill, where Senate Democrats recently defeated a Republican-led attempt to strip U.S. EPA of its ability to regulate carbon dioxide. That measure originated in the GOP-controlled House, which has also pushed for -- and won -- bruising budget cuts at federal environment and science agencies.

But the science academy's plain-spoken analysis, prepared in response to Congress' request for "action-oriented advice," warns of a "pressing need for substantial action to limit the magnitude of climate change and to prepare to adapt to its impacts."

"The risks associated with doing business as usual are a much greater concern than the risks associated with engaging in strong response efforts," the report adds. "This is because many aspects of an 'overly ambitious' policy response could be reversed if needed, through subsequent policy change; whereas adverse changes in the climate system are much more difficult (indeed, on the timescale of our lifetimes, may be impossible) to 'undo.'"

The analysis, prepared by a team of scientists, economists and engineers, also weighs in on the state of climate science, which it deems sound -- though it says some degree of uncertainty about the rate and severity of future climate change is inevitable.

"Given the inherent complexities of the climate system, and the many social, economic, technological, and other factors that affect the climate system, we can expect always to be learning more and to be facing uncertainties regarding future risks," the report says. "This is not, however, a reason for inaction."

In fact, said NAS committee chairman Albert Carnesale, "Uncertainty may be more of a need for taking action," because climate forecasts can't rule out the prospect that some impacts of climate change will be more severe than scientists now anticipate.

Report calls Congress to action, but are battle lines too hardened?
The report notes that climate change is already evident in the United States, where the average air temperature has risen 2 degrees Fahrenheit over the past 50 years, sea levels are rising along much of the coasts, patterns of rainfall and drought are changing, and Alaska's permafrost is warming.

Carnesale, chancellor emeritus at the University of California, Los Angeles, said his panel sought to make "policy-relevant" recommendations but stopped short of prescribing specific actions.

Those recommendations include calling for the federal government to take the lead on efforts to combat climate change with emissions cuts and programs to adapt to effects of warming that can't be avoided. Although several states and cities have put in place their own efforts to fight warming, the NAS panel said those piecemeal efforts aren't enough by themselves.

Similarly, action by the United States is key to international efforts to cut humans' greenhouse gas output, the report says.

"U.S. emissions alone will not be adequate to avert dangerous climate change risks," it notes, "but strong U.S. emission reduction efforts will enhance our ability to influence other countries to do the same."

Reaction to the report on Capitol Hill fell predictably along party lines.

Senate Foreign Relations Committee Chairman John Kerry (D-Mass.) called the NAS report "the latest watertight finding on the pile of countless peer-reviewed scientific studies that underscore the risks if the United States doesn't address climate change now, not in 10 or 20 years."