Relative Abundance Of Common Microbes Living In The Gut May Contribute To Obesity

Science Daily — A link between obesity and the microbial communities living in our guts is suggested by new research at Washington University School of Medicine in St. Louis. The findings indicate that our gut microbes are biomarkers, mediators and potential therapeutic targets in the war against the worldwide obesity epide

A link between obesity and the microbial communities living in our guts is suggested by new research at Washington University School of Medicine in St. Louis. The findings indicate that our gut microbes are biomarkers, mediators and potential therapeutic targets in the war against the worldwide obesity epidemic.

In two studies published this week in the journal Nature, the scientists report that the relative abundance of two of the most common groups of gut bacteria is altered in both obese humans and mice. By sequencing the genes present in gut microbial communities of obese and lean mice, and by observing the effects of transplanting these communities into germ-free mice, the researchers showed that the obese microbial community has an increased capacity to harvest calories from the diet.

"The amount of calories you consume by eating, and the amount of calories you expend by exercising are key determinants of your tendency to be obese or lean," says lead investigator Jeffrey Gordon, M.D., director of the Center for Genome Sciences and the Dr. Robert J. Glaser Distinguished University Professor. "Our studies imply that differences in our gut microbial ecology may determine how many calories we are able to extract and absorb from our diet and deposit in our fat cells."

That is, not every bowl of cereal may yield the same number calories for each person. People could extract slightly more or slightly less energy from a serving depending upon their collection of gut microbes. "The differences don't have to be great, but over the course of a year the effects can add up," Gordon says.

Trillions of friendly microbes reside in the intestine, where they help to digest food that the body can't on its own, such as the complex sugars found in grains, fruits and vegetables. As part of the digestive process, the microbes break down nutrients to extract calories that can be stored as fat.

The researchers focused on two major groups of bacteria - the Bacteroidetes and the Firmicutes - that together make up more than 90 percent of microbes found in the intestines of mice and humans. In an earlier study, they compared genetically obese mice and their lean littermates. The obese mice had 50 percent fewer Bacteroidetes and proportionately more Firmicutes. Moreover, the differences were not due to a bloom of one species in the Firmicutes or a diminution of a single or a few species of Bacteroidetes: virtually all members of each group were altered.

In one of this week's Nature articles, Ruth Ley, Ph.D., a microbial ecologist in Gordon's group, reports on her investigation into whether these findings also held true among obese humans. She followed 12 obese patients at a Washington University weight loss clinic over a one-year period. Half the patients were on a low-calorie, low-fat diet and half were on a low-calorie, low carbohydrate diet.

At the outset of the study, the obese patients had the same type of depletion of Bacteroidetes and relative enhancement of Firmicutes as the obese mice. As the patients lost weight, the abundance of the Bacteroidetes increased and the abundance of Firmicutes decreased, irrespective of the diet they were on. Moreover, not one particular species of Bacteroidetes but the entire group increased as patients lost weight.

In a companion paper in the same journal, Peter Turnbaugh, a Ph.D. student in Gordon's lab, compared the genes present in the gut microbial communities of the obese and lean mice using the newest generation of massively parallel DNA sequencers.

The results of these so-called comparative metagenomic studies revealed that the obese animals' microbial community genome (microbiome) had a greater capacity to digest polysaccharides, or complex carbohydrates. By transferring the gut microbial communities of obese and lean mice to mice that had been raised in a sterile environment (germ-free animals), he confirmed that the obese microbial community prompted a significantly greater gain in fat in the recipients.

Gordon notes that these findings represent steps in a long journey designed to understand the contributions of our microbial self to our health. "Our microbial cells outnumber our human cells by as much as 10 fold and, and they may contain 100 times more genes than our own human genome," Gordon says.

These studies raise a number of questions, according to Gordon. "Are some adults predisposed to obesity because they 'start out' with fewer Bacteroidetes and more Firmicutes in their guts?" he asks. "Can features of a reduced Bacteroidetes-Firmicutes enriched microbial community become part of our definition of an obese state or a diagnostic marker for an increased risk for obesity? And can we intentionally manipulate our gut microbial communities in safe and beneficial ways to regulate energy balance?"

Turnbaugh PJ, Ley RE, Mahowald MA, Magrini V, Mardis ER, Gordon JI. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature, Dec. 21, 2006.

Ley RE, Turnbaugh PJ, Klein S, Gordon JI. Human gut microbes associated with obesity. Nature, Dec. 21, 2006.

Funding from the National Institutes of Health and the W.M. Keck Foundation supported this research.

Note: This story has been adapted from a news release issued by Washington University School of Medicine.

Source: Washington University School of Medicine

Drug Shown To Be Clinically Active Against Multiple Target Mutations In Two Types Of Leukemia And Myeloproliferative Disorders

Science Daily — Researchers at The University of Texas M. D. Anderson Cancer Center report that MK-0457 (VX-680), a novel multi-kinase inhibitor, is clinically active against multiple target mutations in two types of leukemia and myeloproliferative disorders, and produces few side effects for patients.

Francis J. Giles, M.D., professor in the Department of Leukemia at M. D. Anderson Cancer Center, presented the Phase I / II trial data at the annual meeting of the American Society of Hematology.

According to Giles, the study of 44 patients, conducted at M. D. Anderson Cancer Center and Duke University Medical Center, showed the first clinical activity of a kinase inhibitor against the T315I BCR-ABL mutation found in chronic myeloid leukemia (CML) and acute lymphocytic leukemia (ALL). In addition, the trial showed the first activity against the JAK-2 mutation found in myeloproliferative disorders (MPD), a group of blood diseases that can evolve into leukemia. MK-0457 has also been found in previous studies to inhibit Aurora kinases A, B, C and FLT3 in leukemias.

Giles reported that patients on the study experienced minimal side effects, such that no maximum tolerated dose was defined. Mild side effects included lowering of white blood cells, hair loss, nausea and inflammation of the mouth.

"MK-0457 is a drug that produces clinical and biologic activity where we have not seen it before - in T315I-positive CML and ALL and JAK-2-positive MPD. This is a very active biologic agent for patients with advanced leukemia, and has very few side effects, all of which are quite manageable," Giles said. "With the data from this trial, we have a strong rationale to take this agent forward to more definitive and larger studies."

Though CML, ALL and MPD are relatively rare cancers, they are very aggressive and often fatal after failing standard therapy, said Giles. For the subset of leukemia patients who have the T315I mutation or for MPD patients with the JAK-2 mutation - about 10 percent of patients with the respective diagnoses - there are no therapies available to specifically attack these key mutations.

"This is a relatively small population that can potentially benefit from the drug, but for those who have these mutations, this research opens the door to a tremendous option for them," said Giles. "At present, there is nothing to offer them."

According to the American Cancer Society, there are about 4,000 new cases of ALL, about 4,500 new cases of CML and about 10,000 new cases of MPD diagnosed each year.

The T315I mutation is known to be responsible for the aggressive biological growth cycle and resistance to imatinib (Gleevec), nilotinib (Tasigna) and dasatinib (Sprycel) in CML and ALL. These kinase inhibitors have been found to be effective treating patients with leukemias who carry different mutations.

According to the study, the 35 leukemia patients on the study had at least four prior types of therapy, many of who received at least one of the three standard chemotherapies. The nine MPD patients' treatments ranged from one to seven prior lines of therapy.

But because of the mutations associated with resistance to these treatments, the patients did not respond until they were given the intravenous MK-0457 for five consecutive days. Of the patients with the T315I mutation, eight of nine patients with CML responded as did both of the T315I-positive ALL patients who had a partial response after the second cycle and complete response after the third cycle of treatment respectively.

"While we went into this trial to determine the safety and dosage of the drug, it became apparent quite quickly that the drug was very well tolerated and showing clinical response not only in patients but in terms of pharmacodynamics," said Giles. "As a result, we ended the Phase I aspect of the trial earlier than anticipated and moved into Phase II with a range of different doses to safely prescribe, depending on the patient's condition and outlook. We are quite hopeful that this drug will be beneficial for this segment of patients, but additional research will be needed."

Giles and his team are planning to begin later this month an international Phase II study of MK-0457 in patients with the T315I mutation.

Merck and Co. is currently conducting clinical trials of MK-0457 in various cancer types as part of a collaboration with Vertex Pharmaceuticals Incorporated. Merck and Co. holds worldwide and commercialization rights to MK-0457. MK-0457 (VX-680) was discovered by Vertex Pharmaceuticals.

Note: This story has been adapted from a news release issued by University of Texas M. D. Anderson Cancer Center.

Source: University of Texas M. D. Anderson Cancer Center

Blame Our Evolutionary Risk Of Cancer On Body Mass

Science Daily — A key enzyme that cuts short our cellular lifespan in an effort to thwart cancer has now been linked to body mass
Until now, scientists believed that our relatively long lifespans controlled the expression of telomerase—an enzyme that can lengthen the lives of cells, but can also increase the rate of cancer.
Vera Gorbunova, assistant professor of biology at the University of Rochester, conducted a first-of-its-kind study to discover why some animals express telomerase while others, like humans, don't. The findings are reported in today's issue of Aging Cell.
"Mice express telomerase in all their cells, which helps them heal dramatically fast," says Gorbunova. "Skin lesions heal much faster in mice, and after surgery a mouse's recovery time is far shorter than a human's. It would be nice to have that healing power, but the flip side of it is runaway cell reproduction—cancer."
Up until now, scientists assumed that mice could afford to express telomerase, and thereby benefit from its curative powers, because their natural risk of developing cancer is low—they simply die before there's much likelihood of one of their cells becoming cancerous.
"Most people don't know that if you put mice in a cage so the cat can't eat them, 90 percent of them will die of cancer," says Gorbunova.
Evolution, it seems, has determined which species are allowed to express telomerase in their somatic cells in order to maintain a delicate balance between cells that live long, and cells that become cancerous. But while most scientists believed an organism's lifespan determined whether it was at a higher risk of cancer, Gorbunova has revealed evidence that it is not our long lifespan that puts us at risk, but our much-heavier-than-a-mouse body mass.
The tips of chromosomes, called telomeres, shorten every time a cell divides. After about 60 divisions, the telomeres are eroded away to the point that the cell stops dividing. Telomerase rebuilds those tips, so animals that express it, like mice, have cells that can reproduce more extensively and thus heal better.
Cancer cells, however, are those cells that constantly reproduce unchecked, and so evolution has shut off the expression of telomerase in human somatic cells, presumably because the threat of cancer outweighs the benefits of quick-healing.
But no one has looked into why mice express telomerase and humans don't. In fact, telomerase activity has been barely catalogued in the animal kingdom.
Gorbunova decided to take on the question by creating a unique test. She investigated 15 rodents from across the globe to determine what level of telomerase activity each species expressed, to see if there were some correlation she could find.
The species ranged from tiny field mice to the 100-pound capybara from Brazil. Lifespans ranged from three years for the mice, to 23 or more for common backyard squirrels.
Acquiring specimens of these animals from around the world proved to be an unusual task.
"At one point I was woken up at two in the morning by a guy on a cell phone hunting pest beavers in Montezuma," says Gorbunova. "I'm still trying to wake up and this voice says, 'I hear you're looking for beavers.' "
For over a year, Gorbunova collected deceased rodents from around the world and had them shipped to her lab in chilled containers. She analyzed their tissues to determine if the telomerase was fully active in them, as it was in mice, or suppressed, as it is in humans. Rodents are close to each other on the evolutionary tree and so if there were a pattern to the telomerase expression, she should be able to spot it there.
To her surprise, she found no correlation between telomerase and longevity. The great monkey wrench in that theory was the common gray squirrel, which lives an amazing two decades, yet also expresses telomerase in great quantity. Evolution clearly didn't see long life in a squirrel to be an increased risk for cancer.
Body mass, however, showed a clear correlation across the 15 species. The capybara, nearly the size of a grown human, was not expressing telomerase, suggesting evolution was willing to forgo the benefits in order to reign in cancer.
The results cannot be directly related to humans, but Gorbunova set up the study to produce very strong across-the-board indicators. It's clear that evolution has found that the length of time an organism is alive has little effect on how likely some of its cells might mutate into cancer. Instead, simply having more cells in your body does raise the specter of cancer—and does so enough that the benefits of telomerase expression, such as fast healing, weren't worth the cancer risk.
Gorbunova points out that these findings raise another, perhaps far more important question: What, then, does this mean for animals that are far larger than humans? If a 160-pound human must give up telomerase to thwart cancer, then what does a 250,000-pound whale have to do to keep its risk of cancer at bay?
"It may be that whales have a cancer suppressant that we've never considered," says Gorbunova. "I'd like to find out what kind of telomerase expression they have, and find out what else they use to combat cancer."
As for the tiny mice: "They don't have to worry about cancer," she says. "They're probably all praying for an anti-cat gene."
Note: This story has been adapted from a news release issued by University of Rochester.
Source:University of Rochester

Pioneers In Field Of Functional Genomics Work Toward Gene Therapy For Vision Defects

Science Daily — For millennia anglers have wondered how fish see colors, and the rainbow of lures in every bait shop reveal that we're still guessing. But, in fish, reptiles and birds, that's all we can do for now, according to husband and wife vision researchers, Drs. Jay and Maureen Neitz at the Medical College of Wisconsin in Milwaukee.
Primates and humans have three photoreceptors and can only see four basic colors, red, green, blue and yellow," says Jay Neitz, Ph.D. "Birds, fish and reptiles have four photoreceptors, allowing them to see things we cannot. They must see an entire dimension of color, including ultraviolet, infrared and all the combinations thereof, which we miss."
He is the R.D. and Linda Peters Professor in Ophthalmology at the Medical College. Maureen E. Neitz, Ph.D., is the Richard O. Schultz/Ruth Works Professor in Ophthalmology Research.
Two of the world's leading color vision researchers, the Neitzes are also pioneers in the field of functional genomics. Their studies of human color vision have not only identified the genes responsible for colorblindness, but also defined one of the first examples of a nervous system defect for which a person's DNA can predict both the occurrence and the severity of the disorder.
"This has been an important breakthrough, because as scientists strive to understand the genetic basis of human disease, more than merely revealing the presence of a genetic defect, it is also important to forecast the severity of the impairment," says Dr. Maureen Neitz.
They are currently studying gene therapy at the Froedtert & The Medical College of Wisconsin Eye Institute to evaluate the plasticity of the adult human visual system. Gene therapy has been demonstrated to correct deficits in the retina, but the major unanswered question is whether the brain can interpret new information it receives from the therapeutically-treated retina to restore vision. For humans to migrate around objects in their world requires that information about objects be transmitted from the retina to the brain, and that the brain recreate an image of the world.
Their color vision research has also provided them with unique opportunities to discover the steps in the causal chain from the gene, to protein function, to neural signal. They are applying these lessons to other genetic defects that cause visual impairment.
"We anticipate that our studies of the basic mechanisms controlling gene expression in the retina, and the structure/functional relationships among proteins involved in signal transduction, may lead to development of new methods for early diagnosis of retinal disorders, and ultimately extend our knowledge of the role genes play in construction of the nervous system," she says.
The Neitzes are currently conducting several research studies involving human subjects including a study of color vision and a study of how eye growth is controlled to cause nearsightedness. To learn more about these studies, interested participants can call (414) 456 2056.
Note: This story has been adapted from a news release issued by Medical College of Wisconsin.
Source:Medical College of Wisconsin

Bacterial infection ID method created

UPI-- US scientists say they've developed a method of identifying specific sites of localized bacterial infections in living animals.
Bradley Smith of the University of Notre Dame and colleagues previously developed fluorescent molecular probes containing zinc that could be used to discriminate between common pathogenic bacteria, such as E. coli and Staphylococcus aureus, and mammalian cells.
In the new study, the scientists used the probes to pinpoint the sites of staph infections in laboratory mice. The scientists say physicians might have difficulty distinguishing localized bacterial infections from sites of sterile inflammation.
"Bacterial imaging is an emerging technology that has many health and environmental applications," the researchers said. "For example, there is an obvious need to develop highly sensitive assays that can detect very small numbers of pathogenic bacterial cells in food, drinking water or biomedical samples. In other situations, the goal is to study, in vivo, the temporal and spatial distribution of bacteria in live animals."
The study is described in a report scheduled for the Jan. 10 issue of the Journal of the American Chemical Society.
Copyright 2006 by United Press International. All Rights Reserved.
via ScienceDaily

Testosterone Therapy May Prevent Alzheimer's Disease

Science Daily — Researchers at the University of Southern California have discovered a direct link between loss of testosterone and the development of an Alzheimer's-like disease in mice. They also discovered that testosterone treatment slows progression of the disease.
The study, published in the December 20 issue of The Journal of Neuroscience, predicts that testosterone-based hormone therapy may be useful in the treatment and prevention of Alzheimer's disease in aging men.
"We've known that low testosterone is a risk factor for Alzheimer's disease but now we know why," said Christian Pike, senior author and associate professor at the Leonard Davis School of Gerontology at USC. "The implication for humans is that testosterone therapy might one day be able to block the development of the disease."
In order to investigate testosterone's role in the development of Alzheimer's disease, the team took away the ability of male mice to produce testosterone. Some mice were then given a form of testosterone while others were given none.
The mice with lowered testosterone showed increases in levels of the protein beta-amyloid, which has been widely implicated as playing a role in the development of Alzheimer's disease. They also showed signs of behavioral impairment.
The mice that were given testosterone showed reduced accumulation of beta-amyloid and less behavioral impairment.
"These results are exciting because they tell us that we are on to something that is worth pursuing," said Pike. "The next step is to look at what the long term effects of testosterone therapy are in aging men."
This study adds valuable new information to understanding the role of hormones in aging and disease. Recent evidence has suggested that testosterone may be useful in other neurological conditions. In a presentation at the Society of Neuroscience's annual meeting this fall, Chien-Ping Ko, professor of biological sciences at USC reported that testosterone therapy improved muscle coordination in mice suffering from a form of Amyotrophic Lateral Sclerosis, Lou Gehrigs Disease.
Pike's co-authors on the Journal of Neuroscience study were Emily R. Rosario and Jenna Carroll of the USC Neuroscience Graduate Program and Salvatore Oddo and Frank M. LaFerla of the University of California, Irvine. The Alzheimer's Association and the National Institutes of Health provided funding.
Note: This story has been adapted from a news release issued by University of Southern California.
Source:
University of Southern California

Testosterone Therapy May Prevent Alzheimer's Disease

Researchers at the University of Southern California have discovered a direct link between loss of testosterone and the development of an Alzheimer's-like disease in mice. They also discovered that testosterone treatment slows progression of the disease.
The study, published in the December 20 issue of The Journal of Neuroscience, predicts that testosterone-based hormone therapy may be useful in the treatment and prevention of Alzheimer's disease in aging men.
"We've known that low testosterone is a risk factor for Alzheimer's disease but now we know why," said Christian Pike, senior author and associate professor at the Leonard Davis School of Gerontology at USC. "The implication for humans is that testosterone therapy might one day be able to block the development of the disease."
In order to investigate testosterone's role in the development of Alzheimer's disease, the team took away the ability of male mice to produce testosterone. Some mice were then given a form of testosterone while others were given none.
The mice with lowered testosterone showed increases in levels of the protein beta-amyloid, which has been widely implicated as playing a role in the development of Alzheimer's disease. They also showed signs of behavioral impairment.
The mice that were given testosterone showed reduced accumulation of beta-amyloid and less behavioral impairment.
"These results are exciting because they tell us that we are on to something that is worth pursuing," said Pike. "The next step is to look at what the long term effects of testosterone therapy are in aging men."
This study adds valuable new information to understanding the role of hormones in aging and disease. Recent evidence has suggested that testosterone may be useful in other neurological conditions. In a presentation at the Society of Neuroscience's annual meeting this fall, Chien-Ping Ko, professor of biological sciences at USC reported that testosterone therapy improved muscle coordination in mice suffering from a form of Amyotrophic Lateral Sclerosis, Lou Gehrigs Disease.
Pike's co-authors on the Journal of Neuroscience study were Emily R. Rosario and Jenna Carroll of the USC Neuroscience Graduate Program and Salvatore Oddo and Frank M. LaFerla of the University of California, Irvine. The Alzheimer's Association and the National Institutes of Health provided funding.
Note: This story has been adapted from a news release issued by University of Southern California.
Source:University of Southern California via Science Daily

Blood Transfusions Raise Heart Patients' Infection And Death Risk -- Especially Women

Science Daily — Blood transfusions save the lives of millions of heart surgery patients and others each year. But a new study suggests that patients who receive transfusions during heart bypass surgery have a higher risk of developing potentially dangerous infections, and dying, after their operation.
In fact, this increased risk may help explain a longstanding medical mystery: why women bypass patients are more likely than men to die in the first few months after surgery. Women are more likely to receive blood during heart bypass operations, which are performed on more than 465,000 Americans each year.
The findings, from the Patient Safety Enhancement Program (PSEP) at the University of Michigan Health System, are based on data from 9,218 Michigan bypass patients. After adjusting for factors such as the urgency of the operation, those who received blood transfusions from donors were five times more likely to die within 100 days of their operation than those who did not.
The paper is published in the December issue of the American Heart Journal. It builds on a previous U-M analysis that found that a difference in infection rates accounted for the difference in death risk between men and women bypass patients.
The U-M team, with the help of Neil Blumberg, M.D., of the University of Rochester Medical Center, focused on blood transfusions as a contributing factor. Prior research has shown that recipients of stored donor blood have more post-surgical infections, and that women receive more transfusions because they tend to have lower hemoglobin concentrations.
This new study connects the dots. "To the best of our knowledge, this is the first study to state that allogeneic transfusions may be the reason why women have a greater post-bypass surgery mortality risk than men," says author Mary A.M. Rogers, Ph.D., M.S., PSEP, research director and research assistant professor of internal medicine. Allogeneic is the term for blood from another person.
The authors strongly note that blood transfusions can be life-saving, and that the infections observed in this study are not likely due to contamination of the blood. Rather, they may be due to other factors, including the patient's immune response to substances such as white blood cells that are present in stored donor blood. These findings may help guide hospitals and blood banks in deciding whether to filter donated blood to reduce the levels of white blood cells. This practice is increasingly common, but not yet universal, in the United States.
The study is based on analysis of data from all Medicare beneficiaries ages 65 and older who had coronary artery bypass operations in Michigan in a single year.
The researchers performed statistical analyses that took into account the patients' blood transfusion status, their co-existing diseases, age, race, sex, and whether the bypass operation was done on an elective, urgent or emergency basis. They looked at infections and deaths that were reported during the 100 days after surgery.
In all, about 88 percent of women received an allogeneic blood transfusion during bypass surgery, compared with nearly 67 percent of men. When the researchers adjusted for other factors, women were 3.4 times as likely as men to receive blood. This gender difference was evident regardless of whether the operation was elective, urgent or emergency.
The odds of having an infection of any kind were about three times greater in patients who received allogeneic blood than in patients who did not. The more blood they received, the higher their infection risk. This "dose dependent" relationship strengthens the evidence that transfusions may be related to infections.
No single type of infection stood out as more common among blood recipients, which suggests a body-wide immune response issue rather than a problem, for example, at the site of the incision.
The analyses revealed that women were more likely to experience an infection than men after bypass surgery, which appeared to be due to the increased number of transfusions in women. This resulted in an increased mortality rate in women. Overall, 9 percent of women and 6 percent of the men died within 100 days of their operation.
For patients who had banked their own blood ahead of the operation and who received only their own blood, the infection risk was similar to that of patients who received no blood transfusions. Rogers notes that patients should ask their doctors regarding banking their own blood if possible, when scheduled for a bypass operation or other kind of surgery.
In addition, physicians are increasing their use of transfusion alternatives such as blood "expanders," blood substitutes and blood-conserving procedures during bypass surgeries.
The results also highlight the importance of the proper use of antibiotics and infection control practices in patients hospitalized for a surgical procedure, says Rogers.
The U-M team is investigating the issue further, including a new study funded by Blue Cross Blue Shield of Michigan Foundation to extend the research into elderly patients who recently underwent bypass surgeries in Michigan.
In addition to Rogers and Blumberg, the study authors included PSEP director Sanjay Saint, M.D., MPH; Catherine Kim, M.D., MPH; Brahmajee Nallamothu, M.D., MPH; and Kenneth Langa, M.D., Ph.D. It was funded by the Agency for Healthcare Research and Quality, the National Institutes of Health, the Department of Veterans Affairs, the John A. Hartford Foundation and a Paul B. Beeson Physician Faculty Scholars in Aging Research award.
Reference: American Heart Journal, Volume 152, Issue 6, Pages 1028-1034 (December 2006).
Note: This story has been adapted from a news release issued by University of Michigan Health System.
Source: University of Michigan Health System
via Sciencedaily

Study Explores Link Between Nanoparticles And Kidney Stones

Science Daily — Researchers at Mayo Clinic have successfully isolated nanoparticles from human kidney stones in cell cultures and have isolated proteins, RNA and DNA that appear to be associated with nanoparticles. The findings, which appear in the December issue of the Journal of Investigative Medicine, are significant because it is one step closer in solving the mystery of whether nanoparticles are viable living forms that can lead to disease -- in this case, kidney stones.
Kidney stones are associated with pathologic calcification, the process in which organs and blood vessels become clogged with calcium deposits that can damage major organs like the heart and kidneys. What causes calcium deposits to build up is not entirely known. Medical scientists at Mayo Clinic are studying calcification at the molecular level in an effort to determine how this phenomenon occurs.
There is a growing body of scientific evidence that links calcification to the presence of nanosized particles, particles so small that some scientists question whether a nanoparticle can live and if so, play a viable role in the development of kidney stones.
The presence of proteins, RNA and DNA does not prove that nanoparticles are viable living forms because a genetic signature has not been identified, says the study's author John Lieske, M.D., a nephrologist with Mayo Clinic. A genetic signature would prove that nanoparticles are indeed living forms that replicate and can cause disease.
"We are looking at how kidney stones start as very small calcifications inside the kidney and then eventually grow into stones," says Dr. Lieske. "In the laboratory, we have isolated nanoparticles from kidney tissue and kidney stones, and have successfully propagated them in culture. This does not clearly confirm the role of nanoparticles in the formation of kidney stones, but it offers insight not otherwise known."
Approximately 12 percent of men and 5 percent of women will develop kidney stones by the time they reach 70 years old. Some $5 billion is spent in the United States each year to treat patients with kidney stones, but exactly how kidney stones form is not known. Scientists theorize that if nanoparticles become localized in the kidney, they can become the focus of subsequent growth into larger stones over months to years. Other factors, such as physical chemistry and protein inhibitors of crystal growth, also play a role. But what scientists don't quite understand is why, where and how they start growing, Dr. Lieske says.
The study cites evidence that indicates the unlikelihood that events linked to the calcification process are driven solely by physical chemistry, but instead are influenced by specific proteins and cellular responses. Understanding these events will provide clues to develop new therapy to treat kidney stones, the authors say.
"There are at least two novel hypotheses here in terms of how stones might actually form. One: an infectious agent. If that was the case, that would point us in the direction of using different kinds of treatments specific to an infectious agent. Two: the idea that cells drive calcification. That would suggest other alternative therapies," according to Virginia Miller, Ph.D., a specialist in vascular research at Mayo Clinic and a study author.
In addition, researchers examined how urine proteins alter the way crystals and cells interact in binding to cells -- the way in which cells respond to the crystals and assume more of a bone-like morphology and drive calcification over time.
In a second study, due to appear in the December issue of the Journal of Investigative Medicine, Drs. Lieske, Miller, and Karim Benzerara, Ph.D., of the Institut de Physique du Globe de Paris, attempted to identify a DNA chemical marker in nanoparticles. The preliminary study suggests that nanoparticles from human samples share spectroscopic characteristics with calcified bacteria that exist in freshwater lakes. However, studies could not confirm whether the nanoparticles are calcified bacteria or hydroxyapatite crystals that precipitated upon proteins present in the culture medium used to replicate the nanoparticles. Researchers did, however, identify chemical bonds between proteins and calcium in nanoparticles that were similar to those found in the bacteria that calcified in the environment.
"Right now the results are inconclusive. In some of the segments we saw a characteristic signal that might suggest DNA, but in others we did not," Dr. Miller says.
This is a relatively new area of science, so the tools and processes used in this research have yet to be perfected. "Many of these tools haven't been applied to these systems in a consistent, rigorous way. So we are still in the learning process of how to handle the material. For example, what are the ideal conditions in the laboratory in which we should study nanoparticles?
"It was disappointing that we did not find any consistent DNA information. We think the findings were inconclusive, in part, because of the inability to apply these techniques in conditions suitable to nanoparticles," Dr. Miller says.
The Lieske study was supported by grants from the National Institutes of Health, the Ralph C. Wilson Sr. and Ralph C. Wilson Jr. Medical Research Foundation, the Oxalosis and Hyperoxaluria Foundation, and Mayo Clinic.
The Benzerara study was supported by a National Science Foundation grant, the Stanford Institute for the Environment, the France-Stanford Center for Interdisciplinary Studies, the U.S. Department of Energy at Lawrence Berkeley National Laboratory, the National Institutes of Health, the Ralph C. Wilson Sr. and Ralph C. Wilson Jr. Medical Research Foundation, and Mayo Clinic.
Note: This story has been adapted from a news release issued by Mayo Clinic.
Source:
Mayo Clinic
via Sciencedaily

New Technologies For Heart Disease: Are Drug-eluting Stents Worth The Cost?

Over the past 3 decades, percutaneous coronary intervention (PCI, or balloon angioplasty) has significantly changed the treatment of coronary artery disease (narrowing of the arteries supplying the heart muscle).
Unlike the more invasive coronary artery bypass graft (CABG) surgery, angioplasty is a nonsurgical procedure in which a tiny catheter with a balloon is inserted into the coronary artery. The balloon is then inflated to push aside the plaque causing the narrowing. Often a stent (wire mesh tube) is left in place to help keep the treated artery open; however, restenosis, or repeat narrowing, of the artery can occur over time.
Drug-eluting stents were recently introduced to lower this risk of restenosis and have become an attractive alternative to bare-metal stents. However, they are much more expensive than bare-metal stents, and studies have shown no significant differences in rates of death or heart attack between patient groups receiving either type of stent.
Two articles that will appear in the Jan. 16, 2007, issue of CMAJ provide new insights into the use of drug-eluting stents.
The first is a research article by Grilli and colleagues in which they compare the use of drug-eluting stents for PCI in public versus private sectors of the Italian medical community. They also evaluate the effect PCI with drug-eluting stents has had on the volume of cardiac surgery, including traditional CABG surgery. They found that drug-eluting stents were used more frequently in private hospitals, with public hospitals using them more sparingly and selectively in patients with high-risk coronary artery disease. Overall cardiac surgery volumes decreased significantly in the public hospitals but remained stable in the private hospitals.
The authors note that future assessments of the impact of drug-eluting stents need to consider the influence of system-wide financial and organizational incentives for adoption of their use.
In the second article, Ligthart and colleagues systematically review all published cost-effectiveness analyses comparing drug-eluting stents and bare-metal stents for PCI. They comment on how the conclusions of these analyses have differed despite using a relatively constant measure of the efficacy of drug-eluting stents. The factors they found to be associated with these different conclusions were study quality, funding source and country of origin.
In a related commentary, Knudtson examines the ongoing debates that surround the cost-effectiveness of drug-eluting stents and the clinical indications for their use. Knudtson notes that even the clinical indications for PCI have been questioned by the findings of a recent trial that has successfully challenged the long-held belief that an open artery is always worth striving for, even late in a heart attack.
Note: This story has been adapted from a news release issued by Canadian Medical Association Journal.
Source:Canadian Medical Association Journal
via Sciencedaily

Kidney Transplantation Linked With Increased Risk Of Various Cancers

Science Daily — Following kidney transplantation, some recipients may face a 3-fold increased risk of certain cancer types, according to a study in the December 20 issue of JAMA.
Immune suppression after organ transplantation is associated with a markedly increased risk of nonmelanoma skin cancer, non-Hodgkin lymphoma, and Kaposi sarcoma. Whether other cancers occur at increased rates is uncertain, because there have been few long-term population-based studies, according to background information in the article.
Claire M. Vajdic, Ph.D., of the University of New South Wales, Sydney, Australia, and colleagues compared the incidence of cancer in 28,855 patients with end-stage kidney disease (ESKD) who received renal (kidney) replacement therapy (RRT). Data were collected for three separate time periods: the 5 years before RRT, during dialysis, and after transplantation. New cancers (1982-2003) were determined by record linkage between the Australia and New Zealand Dialysis and Transplant Registry and the Australian National Cancer Statistics Clearing House.
The researchers found that the overall incidence of cancer, excluding nonmelanoma skin cancer and those cancers known to frequently cause end-stage kidney disease, was markedly increased (3.27 times) after transplantation. In contrast, cancer incidence was only slightly increased (1.35 times) during dialysis and before RRT (1.16 times). After transplantation, cancer occurred at significantly increased incidence at 25 sites, and risk exceeded 3-fold at 18 of these sites.
"Although the incidence of some cancers was increased during dialysis, and the incidence of a few was increased before RRT, the magnitude and breadth of the increased risk after transplantation suggests that immune suppression causes a substantial and broad-ranging increase in cancer risk," the authors write.
"After kidney transplantation, a wide variety of cancers across a number of organ systems occur with substantially increased incidence. Most, but not all, of these cancers are those with known or suspected viral causes. In contrast, cancer incidence was only slightly increased before kidney transplantation. Our findings point to an important role of the interaction between common viral infections and the immune system in the etiology [cause] of cancers at a broad range of sites," the researchers conclude.
Note: This story has been adapted from a news release issued by JAMA and Archives Journals.
Source:
JAMA and Archives Journals

Allergy Drug Slows Pancreatic Tumor Growth In Preclinical Studies

An anti-allergy drug in use for more than 40 years significantly reduced tumor growth in animal models of human pancreatic cancer and also increased the effectiveness of standard chemotherapy, say researchers at The University of Texas M. D. Anderson Cancer Center.
In the Dec. 20 issue of the Journal of the National Cancer Institute, the investigators report that combining the drug, cromolyn, with chemotherapy was nearly three times better at retarding growth of pancreatic tumors in mice compared to the chemotherapy agent gemcitabine alone.
The finding may lead to a treatment advance for patients with pancreatic cancer, believed to be the most lethal of all cancers. More than 95 percent of patients diagnosed with the disease die from it, and half of those deaths occur in the first six months after diagnosis.
"Our goal is to offer longer life to these patients, and the combination of these two agents may well do that," says the study's lead author, Craig Logsdon, Ph.D., a professor in the Department of Cancer Biology.
Logsdon is working with physicians at M. D. Anderson to prepare for a clinical trial. Although cromolyn is off patent and widely available, it has been used only as a topical agent (through an inhaler, nasal spray and eye drops), so the research team is studying how to deliver the drug internally.
"Cromolyn seems to reduce survival mechanisms in pancreatic cancer cells enough that when gemcitabine is added, the chemotherapy is more effective," Logsdon says. "This is good, because chemotherapy normally has very little effect in patients."
The JNCI study demonstrates in mouse models of human pancreatic cancer that the cromolyn-gemcitabine combination reduced cancer growth by 85 percent compared to control animals, Logsdon says. "Cromolyn used alone actually had a good effect on reduction of tumors compared to control animals, which surprised us," he adds. It reduced tumor growth by 70 percent, compared to growth reduction of 50 percent when gemcitabine was used as a single agent, compared to control animals.
No one knows exactly how cromolyn works to control allergies. However, Dr. Logsdon has found that cromolyn can bind a specific protein produced by cancer cells and block that protein's ability to interact with a receptor that stimulates cancer cell growth, survival, and spreading. The relationship between how the drug controls allergies and its anti-tumor effect in pancreatic cancer remains unclear. "It may be possible that cromolyn has more than one target that influences cancer," he says.
Logsdon discovered the cancer-stimulating protein, determined how it triggers tumor growth and spread, and identified cromolyn as an inhibitor. "Through serendipity and basic science sleuthing we may now have something that helps patients," he says.
The study culminates Logsdon's five-year search for an agent to treat pancreatic cancer.
Logsdon searched for genes that produced proteins secreted only by cancer cells, which would then loop around and act on the cancer cell through a receptor on the cell surface. "That way, we could have two potential drug targets - the secreted protein and the receptor," he said.
Out of a long list of such genes, Logsdon and his research team selected one called "S100P" because it is a member of the large S100 gene family, some of which produce secreted proteins and some of which are associated with other cancers. Further work showed that S100P over-expression was very specific to pancreatic cancer; the protein was not found in normal pancreatic cells. "It is important to embryonic development, but no one knows its physiological role in adult biology," he says.
By using gene-silencing techniques, Logsdon found that when the protein is disabled, cancer growth is slowed. "S100P plays a role in tumor development because it causes cancer cells to grow faster, survive better, and be more invasive," he says.
Logsdon found that S100P interacts with a receptor known as "RAGE" which also plays a role in diabetes, arthritis and Alzheimer's disease. If RAGE is blocked in pancreatic cancer cells, addition of synthetic S100P to the tumor does not accelerate growth.
While Logsdon was defining S100P in pancreatic cancer, a Japanese research team working on allergies ran an experiment to see which proteins "stuck" to anti-allergy drugs, including cromolyn. Several members of the S100 family did. Logsdon then discovered that the drug also bound to S100P. He applied cromolyn to laboratory pancreatic cancer cells, and found that tumor growth was slowed. A larger effect was seen when the chemotherapy agent gemcitabine was combined with cromolyn.
Logsdon suspects that cromolyn may have other anti-tumor effects, a theory which he is currently testing. "For me this is pretty thrilling," he says. "In a relatively short time, we have gone all the way from discovering a molecule to preparations for a clinical trial."
The study was funded by the Lockton Endowment and the M. D. Anderson Cancer Center Pancreatic SPORE grant from the National Cancer Institute. Working with Logsdon were M. D. Anderson researchers Thiruvengadam Arumugam Ph.D. and Vijaya Ramachandran, Ph.D.
Note: This story has been adapted from a news release issued by University of Texas M. D. Anderson Cancer Center.


Source:
University of Texas M. D. Anderson Cancer Center
via Sciendaily

High Levels Of Vitamin D In Body May Decrease Risk Of Multiple Sclerosis

The possibility that vitamin D could help protect people from developing multiple sclerosis (MS) has been posited by researchers in recent decades, but evidence to support that link has been scant. In the first large-scale, prospective study to investigate the relationship between vitamin D levels and MS, researchers at the Harvard School of Public Health (HSPH) have found an association between higher levels of vitamin D in the body and a lower risk of MS. The study appears in the December 20, 2006, issue of the Journal of the American Medical Association.

If confirmed, this finding suggests that many cases of MS could be prevented by increasing vitamin D levels. Although these levels could be increased by taking supplements, before any recommendation is made it is important to establish whether we are seeing a true causal association or whether vitamin D levels are only a marker of MS risk," said Alberto Ascherio, senior author of the study and associate professor of nutrition and epidemiology at HSPH.
MS is a chronic degenerative disease of the central nervous system. It affects some 350,000 people in the U.S. and 2 million worldwide, and occurs most commonly in young adults. Women, who are affected more than men, have a lifetime risk of about 1 in 200 in the U.S. Vitamin D is a hormone manufactured naturally in the body, and its levels can be increased with exposure to sunlight, consumption of foods rich in vitamin D, such as fatty fish, and by taking supplements.
The researchers, led by Ascherio, worked in collaboration with colleagues in the U.S. Army and Navy to determine whether vitamin D levels measured in healthy young adults predict their future risk of developing MS. The investigation relied on a study population of more than 7 million individuals, whose serum samples are stored in the Department of Defense Serum Repository. Between 1992 and 2004, 257 U.S. Army and Navy personnel with at least two serum samples stored in the repository were diagnosed with MS. A control group, consisting of participants who did not develop MS, was randomly selected from the study population. Serum samples were analyzed for levels of 25-hydroxyvitamin D, a good indicator of vitamin D availability to tissues, and individuals were divided into five groups of equal size according to their average levels. Because vitamin D levels are strongly influenced by skin color, separate analyses were conducted among whites, blacks, and Hispanics.
The results showed that, among whites, MS risk declined with increasing vitamin D levels--the risk was 62% lower among individuals in the top fifth of vitamin D concentration (corresponding approximately to levels above 100 nmol/L or 40 ng/mL) than among those in the bottom fifth (approximately below 63 nmol/L or 25 ng/mL). The association was strongest among individuals who were younger than 20 when they first entered the study. No significant association was found among blacks and Hispanics, possibly because of a smaller sample size and the lower levels of vitamin D found in those groups. The average age of onset of MS cases was 28.5 years old; there was no significant difference in the results between men and women.
"The results of this study converge with a growing body of experimental evidence supporting the importance of vitamin D in regulating the immune system and suppressing autoimmune reactions, which are thought by most experts to play a key role in the development of MS," said Ascherio. Kassandra Munger, first author and a doctoral candidate in nutrition at HSPH, added, "The amount of vitamin D that is needed to reach levels associated with MS protection is largely considered safe, and in fact higher vitamin D levels could be beneficial to prevent osteoporosis and other chronic diseases."
The researchers note that there could be other possible explanations for the protective role of vitamin D. For example, it's possible that exposure to UV light from the sun--the major determinant of serum levels of 25-hydroxyvitamin D--could protect people in other ways than increased vitamin D production.
The authors suggest further studies exploring how vitamin D may protect individuals from developing MS. "Although the results of this study are quite encouraging, reasonable certainty of a protective effect of vitamin D supplements requires direct experimental evidence in a large trial. Meanwhile, we are planning to expand our study to obtain more accurate data on the importance of age and of the vitamin D levels that need to be achieved for optimal protection," said Ascherio.
The work was supported by grants from the National Institute of Neurological Disease and Stroke and by a pilot grant from the National Multiple Sclerosis Society.
Note: This story has been adapted from a news release issued by Harvard School of Public Health.
Via: Sciencedaily