April 29 — Viscosity enhancers that thicken the blood are highly effective in treating severe bleeding, according to a study by University of California, San Diego, bioengineering researchers.

Currently, intravenous administration of isotonic fluids is the standard emergency treatment for patients with severe bleeding. Previous research has shown that intravenous fluids eight times saltier than normal saline may be beneficial. Building on that research, the UCSD team combined hypertonic saline with viscosity enhancers that thicken blood.

They found this approach resulted in dramatic increases in beneficial blood flow in the small blood vessels of hamsters who’d lost as much as half of their blood. The combined hypertonic saline and viscosity enhancement significantly improved the hamsters’ functional capillary density, a key measure of healthy blood flow through tissues and organs.

The findings were published online in the journal Resuscitation.

“Of course, trauma physicians want to get the blood flowing as soon as possible, and increasing the viscosity of blood may not make any sense to them,” team leader Marcos Intaglietta, a professor of bioengineering, said in a prepared statement.

“However, our results are highly suggestive that increasing viscosity and partially restoring blood volume is a better way to increase blood flow through tissues. These findings also are consistent with recent discoveries showing that higher shear forces of more viscous blood leads to dilation of small blood vessels,” Intaglietta said.

Severe blood loss can lead to a dangerous condition called hypovolemic shock, which is one of the main causes of death in trauma patients. Trauma is the leading cause of death among North Americans aged 1 to 44, according to background information in a news release about the study. A loss of 40 percent or more of a patient’s blood is immediately life-threatening, which means quick action has to be taken by emergency workers and physicians.

SOURCE: University of California, San Diego, news release, April 29, 2008

April 29 — Most drugs aimed at suppressing HIV target proteins lying on the virus itself, but new research suggests that focusing on the human host’s immune cells might work even better.

That’s because human cells mutate at much slower rates than does HIV, so the virus would have much less chance of mutating around the drug, scientists explained.

The research is still in its early stages, but it “provides a very nice model that you can inhibit a cellular protein and affect HIV replication,” explained co-senior author Dr. Pamela Schwartzberg, a senior investigator at the U.S. National Human Genome Research Institute.

Her team published the findings in this week’s edition of the Proceedings of the National Academy of Sciences.

Almost all antiretroviral drugs work by targeting a viral protein. But HIV replicates continually, raising the odds for drug-resistant mutations. For this reason, HIV-positive patients must often take two or three different medications, so that if one drug fails, the others will still fend off the virus.

But there’s another player in HIV infection: the human immune system T-cell, the virus’ preferred host. T-cells carry their own surface proteins, but because humans replicate much less often than HIV, the odds of developing drug-resistant genetic mutations are much lower.

“If you are looking to affect a human protein, it’s going to be much less susceptible to the process of developing resistance,” explained Rowena Johnston, vice president of research at The Foundation for AIDS Research in New York City.

In their research, Schwartzberg and co-senior author Andrew Henderson, of Boston University, decided to focus on a T-cell protein called interleukin-2-inducible T-cell kinase . ITK is a “signaling” protein that works in a variety of ways to activate T-cells.

An activated T-cell is the ideal host for HIV, Schwartzberg pointed out, and ITK appears to be crucial to HIV’s invasion and spread.

“We found that there were several cellular processes in T-cells that HIV needs to use and that ITK was important to,” she said. “In fact, it seems to affect three stages in the HIV life cycle. That was a real surprise to us.”

But would inhibiting ITK inhibit HIV? The researchers got help in answering that question from the pharmaceutical industry, which has been developing ITK inhibitor drugs as possible anti-asthma medications.

In laboratory experiments, Schwartzberg and Henderson used these experimental ITK inhibitors — as well as another technique, called RNA interference — to reduce ITK activity in HIV-infected T-cells.

“We could see rather dramatic effects on HIV replication in T-cells,” Schwartzberg said.

Without active ITK in host T-cells, HIV found it much harder to enter the cell and to transcribe its genetic material into new viral particles, the team found. “The effect was quite strong over the course of a week, which was the length of time that we looked at,” Schwartzberg said.

Of course, ITK is important to the proper function of immune T-cells, so questions remain as to whether its suppression might have unwanted side effects, such as a weakening of immune function. But experiments in mice suggest these effects might be minimal.

ITK-suppressed mice did have impaired immune function, but it was mostly confined to a specific type of response — the defense the body mounts against allergies and asthma, Schwartzberg said. In other respects, ITK-suppressed cells appeared to “function in many circumstances, and they can fight off many infections,” she noted.

Still, it’s a long way from research in the test tube and in mice to human clinical trials. But the promise of a human cell-based HIV medication that attacks the virus at three different spots in its life cycle is hugely attractive, Johnston said.

“The virus would have to mutate in three different ways at once to overcome this ITK effect,” she said. “It’s not impossible, the virus can do it, but it would take a very long time.”

Dampening down T-cell activity might not be such a bad idea, either, Johnston added, since HIV thrives on fully activated T-cells.

Schwartzberg said her team will continue to investigate the biological mechanisms underpinning the ITK-HIV relationship. In the meantime, she is optimistic that the drug industry will take up the gauntlet, in terms of clinical research.

“We hope that one of these companies that have developed ITK inhibitors will try and pursue this — that would be wonderful,” Schwartzberg said.

SOURCES: Pamela Schwartzberg, M.D., Ph.D., senior investigator, U.S. National Human Genome Research Institute, Bethesda, Md.; Rowena Johnston, Ph.D., vice president, research, The Foundation for AIDS Research, New York City; April 28-May 2, 2008, Proceedings of the National Academy of Sciences

April 29 — Screening for cervical cancer reduces the risk for all types of the disease in women of all ages, say Swedish researchers. They also concluded that better follow-up of women who have cervical cancer screening could lower rates of the disease.

The researchers reviewed data from the National Cervical Cancer Screening Registry on 1,230 cervical cancer patients diagnosed between 1999 and 2001, and 6,124 age-matched women who hadn’t been diagnosed with cervical cancer.

Women who hadn’t had a Pap smear screening test within the recommended three-year interval were 2.5 times more likely to be diagnosed with cervical cancer than women who had regular Pap tests. Women who didn’t have regular screening were also nearly five times more likely to be diagnosed with advanced cervical cancer than those were had regular screening.

Regular screening reduced the risk for all types of cervical cancer and reduced the risk of women between ages 23 and 30, which were new findings, according to the researchers.

They noted that screening didn’t completely protect women from cervical cancer. Women who were screened at the recommended interval and were found to have abnormal cells were 7.6 times more likely to develop cervical cancer than women who were screened and had normal results.

Women with abnormal Pap results accounted for 11.5 percent of all cervical cancer cases. This increased risk was not noted in women diagnosed with advanced cervical cancer.

The study was published online April 29 in the Journal of the National Cancer Institute.

The researchers said their findings show that irregular screening is the most important risk factor for incident cervical cancer and that abnormal smears, if not followed up by a biopsy, are also an important risk factor.

In an accompanying editorial, Jack Cuzick, of the Cancer Research UK Centre in London, emphasized the importance of systematic audits of cancer screening programs.

“Audits, such as the one described , need to become routine within screening programs if screening is to achieve its full potential,” Cuzick wrote. These reviews identify areas of screening programs that are ineffective and need to be restructured and improved.

SOURCE: Journal of the National Cancer Institute, news release, April 29, 2008

April 29 — The launch of the International Cancer Genome Consortium was announced Tuesday by research organizations from around the world.

The consortium was created to produce high-quality genomic data on up to 50 types of cancer.

Each consortium member plans to conduct a comprehensive, high-resolution analysis of the full range of genomic changes in at least one specific type or subtype of cancer. Each project is expected to involve specimens from at least 500 patients and to have an estimated cost of $20 million.

The consortium will make its data available for free to the global research community and invites organizations in all nations to participate.

“Cancer’s complexity poses an enormous challenge. NIH [National Institutes of Health] is highly encouraged that the worldwide scientific community is joining to meet this challenge, and we are pleased to be a member of this ambitious international endeavor,” NIH Director Dr. Elias A. Zerhouni said in a prepared statement.

“The consortium’s commitment to making its data rapidly available in public databases will serve to accelerate research into the causes and control of cancer in the United States and throughout the world,” Zerhouni said.

Worldwide, more than 7.5 million people die of cancer, and more than 12 million new cases of cancer were diagnosed in 2007. Unless more is done to understand and control cancer, it’s expected there will be 17.5 million deaths and 27 million new cases in 2050.

“Clearly, there is an urgent need to reduce cancer’s terrible toll. To help meet that need, the consortium will use new genome analysis technologies to produce comprehensive catalogs of the genetic mutations involved in the world’s major types of cancer,” Dr. Thomas Hudson, of the consortium Secretariat, which is based at the Ontario Institute for Cancer Research in Toronto, said in a prepared statement. “Such catalogs will be valuable resources for all researchers working to develop new and better ways of diagnosing, treating and preventing cancer.”

Cancer was once thought of as a single disease, but it’s now recognized as a large number of different conditions. However, in nearly all forms of cancer, the disease changes the genetic blueprint of cells and causes disruptions within normal biological pathways, resulting in uncontrolled cell growth. Mapping the genomic changes associated with each type of cancer could help lead to new therapies, diagnostics and prevention methods.

Current consortium members include organizations in Australia, Canada, China, Europe, India, Japan, Singapore and the United States.

SOURCE: U.S. National Institutes of Health, news release, April 29, 2008

April 25 — A new report finds that where protein-destroying machines reside in the brain’s nerve cells may help determine how memories are formed, a finding that may play a role in future treatments for Alzheimer’s and other brain diseases.

Wake Forest University School of Medicine researchers studying mice discovered that cylinder-shaped proteasomes, which help control protein levels, play different roles in controlling synapse strength depending on where they are in the nerve cells of the hippocampus, an area of the brain linked to memory.

When humans or animals learn and store information in their memory, these connections between cells become stronger or weaker, Ashok Hegde, associate professor of neurolobiology and anatomy at Wake Forest, said in a prepared statement. For example, if people learn to do something better, such as playing softball, the synapses that control hand-eye coordination will become stronger. If they learn to ignore something, such as the barking of a neighbor’s dog, then the synapses that control paying attention will become weaker.

The findings were published in the current issue of Learning & Memory.

It is known that the degradation of proteins, which are made by cells to control cell functions, plays an important role in memory function. The team found that proteasomes in the dendrites — the branched parts of a neuron that conduct electrical stimulation — limit the connection strength between cells. Proteasomes in the nucleus, which contains the cell’s genetic material, help maintain synapse strength for long periods of time.

The researchers are now trying to learn how to block proteasome activity specifically in the dendrites of mice to increase the strength of synapses and of memory. In their ongoing studies, the mice will be analyzed on how well they can learn to navigate a maze.

“If we see a memory enhancement when we block the proteasome in dendrites, we can use this strategy to treat memory loss,” Hegde said.

SOURCE: Wake Forest University Baptist Medical Center, news release, April 23, 2008

April 25 — Even when air pollution levels are within current air quality standards, inner-city children with asthma suffer, a new study finds.

The Inner City Asthma Study Group researchers, who looked at 861 children, ages 5 to 12, with persistent asthma, said their findings raise questions about current air quality standards in the United States. They suggest that asthma management plans for inner-city children may need to include reduced exposure to air pollutants.

For two years, the researchers monitored the asthma symptoms of children living in low-income inner-city sections of Boston, New York CIty, Chicago, Dallas, Seattle and Tucson.

These youngsters had significantly decreased lung function following exposure to higher concentrations of air pollutants such as sulfur dioxide, airborne fine particles, and nitrogen dioxide. The study also found that higher nitrogen dioxide levels and higher levels of fine particles were associated with asthma-related school absences, and that higher nitrogen dioxide levels were associated with an increase in asthma symptoms.

Since motor vehicle exhaust is the main source of nitrogen dioxide, the findings suggest that car emissions may be causing respiratory problems among inner-city children with asthma, the researchers said.

The study, supported by the U.S. National Institutes of Health and Environmental Protection Agency, was published in The Journal of Allergy and Clinical Immunology.

SOURCE: U.S. National Institute of Allergy and Infectious Diseases, news release, April 23, 2008