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Hypertension, alcohol OK in small doses

A drink or two a day shouldn't increase the risk of heart attack for men with high blood pressure, U.S. and Dutch researchers said.
"We could not find any increased risk of heart disease or death due to heart disease for moderate drinkers. Moderate drinkers may even have a reduced risk for heart attack," Joline Beulens, University Medical Center Utrecht in the Netherlands.
Beulens said the study is the first to examine whether men who drink moderately and have high blood pressure are more prone to heart attacks than non-drinkers, USA Today reported.
Researchers analyzed data from 11,711 men with hypertension in the Health Professionals Study, begun in 1986. Participants completed surveys noting how often they consumed alcohol.
From 1986 to 2002, subjects reported 653 heart attacks, of which 279 were fatal, researchers said in the Annals of Internal Medicine. Men who drank up to two drinks a day reduced their heart attack risk by about a third.
"Moderate consumption of alcohol seems to be associated with a lower risk of heart attack, similar to the association seen in healthy men in general," says co-author Dr. Kenneth Mukamal, Beth Israel Deaconess Medical Center, Boston.
Copyright 2007 by United Press International. All Rights Reserved.
UTRECHT, Netherlands
via Sciencedaily

Newly Identified Strains Of Chlamydia Trachomatis Could Produce New Diseases

A new study led by a scientist at Children's Hospital Oakland Research Institute (CHORI) is the first to conclude that Chlamydia trachomatis is evolving at a rate faster than scientists first thought or imagined. Chlamydia trachomatis is a bacterium that is the leading cause of sexually transmitted diseases and the second leading cause of blindness worldwide. Scientists believe the bacterium is evolving through a process called recombination where genes from one or more strains combine to create new strains and -- theoretically -- new diseases. The study is featured in the November issue of Genome Research and was led by Dr. Deborah Dean MD, MPH, senior scientist at Children's Hospital Oakland Research Institute (CHORI). Her research suggests that since Chlamydia trachomatis evolves through recombination where one or more strains combine, the traditional method of studying a single gene to track the transmission of the bacterium is wrong. "What we found is an organism that not only evolves rapidly, but in ways that we thought were rare. We also discovered that this organism can customize its attack," said Dr. Dean. "Consequently, the constant flux of the bacterium could serve as a gateway for new emerging diseases, but more research needs to be conducted to understand if and how this is happening."
600 million people are infected across the globe with Chlamydia trachomatis and 8 million are already blind or severely visually impaired. In some parts of third-world countries, more than 90% of the population is infected. Chlamydia trachomatis has a variety of strains; different strains are responsible for different diseases. Some strains cause sexually transmitted diseases while others cause eye infections. Blinding trachoma is caused by repeated eye infections that cause scarring, which result in the eyelashes turning in-wards. Bacterial infection develops as the eyelashes scratch the surface of the eye, which eventually heals by scarring, resulting in blindness.
Previously, the organism was identified using a single gene, ompA, and the protein encoded by that gene, MOMP. In this study, the clinical strains, which are samples of Chlamydia trachomatis currently responsible for human disease today, were compared to standard reference strains that have been laboratory adapted over the last few decades. By studying multiple strains, the researchers discovered that the strains that were identified as the same strain were actually different.
The next step will be to study clinical strains in comparison with laboratory reference strains to decipher exactly how different strains cause disease and whether new diseases are emerging as a result of the emergence of new strains. "Large-scale comparative genomics will be necessary to understand the precise mechanisms underlying Chlamydia trachomatis recombination and how other species of chamydiae may evolve and transfer from animals to humans."

Note: This story has been adapted from a news release issued by Children's Hospital & Research Center at Oakland. via Science Daily

Regulatory Pathway In Brain Development Possible Basis For Malformations

Researchers at the University of California, San Diego (UCSD) School of Medicine have identified a genetic regulator of brain development that sheds new light on how immature neural cells choose between proliferation and differentiation. Defects in regulating this choice result in brain malformations. Their research will be published on line the week of December 4, in advance of publication in the Proceedings of the National Academy of Sciences (PNAS.)

Animals that lack the Zfp423 gene (right) have a malformed cerebellum (cbm), including a complete loss of the midline structure (vermis). This structure is important for postural control and coordinated movement. The protein encoded by Zfp423 regulates the expression of other genes and is required for normal levels of proliferation by neural precursor cells in the cerebellum. (Credit: UCSD Medical Center)

Bruce Hamilton, Ph.D., associate professor in the Department Medicine, and his colleagues have identified a genetic regulatory pathway that controls a neural precursor cell's decision to self-renew as a dividing precursor or differentiate into a non-dividing neuron. Cells that are unable to differentiate appropriately and continue to proliferate may give rise to brain cancers. On the other hand, cells that differentiate too soon or make too few cells can result in malformations of critical brain structures.
"Development of the brain requires intricate coordination to control the proliferation, differentiation, and connections among different groups of cells," said Hamilton. "We have found a gene in mice, mutated in one kind of malformation, which appears both to promote proliferation and to help coordinate differentiation of immature precursor cells."
The work in Hamilton's lab, led by UCSD Biomedical Sciences graduate students Wendy Alcaraz and David Gold, discovered a specific transcription factor called Zfp423. When Zfp423 is mutated in mice, developmental defects in the cerebellum occur that resemble Dandy-Walker malformations seen in human patients.
Dandy-Walker malformations occur in about one in 25,000 human births. Patients have a congenital malformation in the cerebellum, an area of the brain that controls movement, which can significantly slow motor development and cause progressive enlargement of the skull. Dandy-Walker malformation is frequently associated with disorders of other areas of the central nervous system and malformations of the heart, face, limbs, fingers and toes. Study of the Zfp423 mouse model in Hamilton's lab provides an important genetic clue in Dandy-Walker malformations, whose causes are not well understood.
"Loss of Zfp423 in mice results in diminished proliferation by precursor cells at a key time in the development of the cerebellum, resulting in its malformation," said Alcaraz.
The protein encoded by Zfp423 regulates the expression of other genes and is required for normal levels of proliferation by neural precursor cells in the cerebellum. This gene had previously been identified as a co-factor in two distinct signaling or regulatory pathways that mediate neuronal differentiation. The new work proposes that Zfp423 actually acts as a bridge between the two pathways.
"This means that external signals used in cell-cell communication could affect the developing neurons in ways we hadn't previously realized," Hamilton said. "In particular, cell lineage pathways that are often thought of as independent of signaling once they are initiated may really be under tight regulation by signaling-dependent pathways that compete with them for access to factors like Zfp423." He added that development of this mouse could lead to targeted therapies for some genetic brain disorders.
Additional contributors to this paper include Eric Raponi and Dorothy Concepcion of the UCSD Department of Medicine and Peter M. Gent, of the UCSD Biomedical Sciences Graduate Program. The research was funded in part by grants from the National Institutes of Health.
Note: This story has been adapted from a news release issued by University of California - San Diego. via Science Daily

How Bacteria Can Escape Destruction: Scientists Discover Mechanism Used To Pump Out Drugs

In a new study published online in the open access journal PLoS Biology, Gaby Sennhauser, Marcus Gruetter, and colleagues use structural biology techniques to probe the molecular mechanisms of the major drug efflux pump in E. coli AcrB.
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Bacterial resistance to antibiotics is a major challenge for the current treatment of infectious diseases. One way bacteria can escape destruction is by pumping out administered drugs through specific transporter proteins that span the cell membrane, such as AcrB.
Making use of designer proteins that bind to and stabilize proteins of interest, the researchers were able to obtain better resolution structural data for the AcrB complex. After selecting for designed ankyrin repeat proteins (DARPins) that inhibit this pump, Sennhauser and colleagues solved the crystal structure of the DARPin inhibitor in complex with AcrB. They were able to confirm that the AcrB pump is split into three subunits, each of which exhibit distinctly different conformations.
Each subunit has a differently shaped substrate transport channel; these variable channels provide unique snapshots of the different phases employed by AcrB during transport of a substrate. The structure also offers an explanation for how substrate export is structurally coupled to simultaneous proton import--thus significantly improving our understanding of the mechanism of AcrB. This is the first report of the selection and co-crystallization of a DARPin with a membrane protein, which demonstrates not only DARPins' potential as inhibitors, but also as tools for the structural investigation of integral membrane proteins.
Citation: Sennhauser G, Amstutz P, Briand C, Storchenegger O, Gruetter MG (2007) Drug export pathway of multidrug exporter AcrB revealed by DARPin inhibitors. PLoS Biol 5(1): e7. doi:10.1371/journal.pbio.0050007.
Note: This story has been adapted from a news release issued by Public Library of Science.
via Science Daily

Brain chemical linked to alcohol desire

Australian scientists have identified a brain system that could not only blunt an alcoholic's craving for booze, but also the addiction.

The BBC reported Monday researchers at Melbourne's Howard Florey Institute discovered how to block the action of the brain's orexin system, which can also stop the desire for alcohol in its tracks.

Orexin cells, also known as hypocretins, are a pair of highly excitatory neuropeptides found in the brain. The chemical is involved in the "high" felt after drinking alcohol or taking illicit drugs or even eating a great meal.

Dr. Andrew Lawrence used a drug that actually blocked orexin's euphoric effects in the brain. Test rats, in fact, turned their noses up when faced with the oportunity of swilling unlimited alcohol, even those that had gone through detox chose to not imbibe.

"Orexin reinforces the euphoria felt when drinking alcohol, so if a drug can be developed to block the orexin system in humans, we should be able to stop an alcoholic's craving for alcohol," Lawrence told the BBC.

Copyright 2006 by United Press International. All Rights Reserved. via ScienceDaily

Measuring Pandemic Preparedness: Vaccination Campaigns Need A Shot In The Arm

A federal plan to vaccinate hospital healthcare workers against a threat of smallpox fell short on several levels, according to the first metric analysis of the prophylactic health program. Results of the Temple University study raise troubling questions about future preparedness against possible outbreaks of avian flu or SARS.

The study, "Preparedness for a smallpox outbreak: comparing metrics for assessing levels of vaccination among health-care workers by state," has been published online ahead of print in the journal Epidemiology and Infection.

In 2003, the Centers for Disease Control and Prevention asked each state to vaccinate at least 50 to100 healthcare workers per hospital, a number the government considered large enough to respond to a possible smallpox outbreak. These workers could then vaccinate and treat others.

Doses of smallpox vaccine were distributed nationally based on each state's requests, with a goal of vaccinating 500,000 workers in 30 days. Yet by mid-2005, only about 39,000 -- or 17 percent of the requested dosages -- had been used.

"Some states requested thousands of vaccines, while others only a few hundred," said lead researcher Sarah Bass, Ph.D., MPH, assistant professor of public health in Temple University's College of Health Professions.

To critically examine how well the program worked, researchers analyzed vaccination patterns based on a series of metrics: the absolute numbers of health care workers vaccinated compared to the percentage of doses distributed to each state, the rate of vaccination per capita population, and the percentage of healthcare workers vaccinated compared to the number recommended by the CDC. States were then ranked into four quartiles.

"We had to do a very careful analysis because some states appeared to have a very high vaccination rate if you only looked at the number of absolute vaccinations as a percentage of the number of vaccines requested," Bass said.

Oklahoma, for example, vaccinated 376 people with the 700 doses requested -- slightly more than 50 percent. However, the state would have needed an estimated 9,675 doses to meet the CDC's recommendations, which leaves Oklahoma's true vaccination rate only at 3.9 percent of the goal set by the CDC.

Overall, researchers found a generally low compliance rate along with a great variability among states. States most affected by 9/11-- New York, Pennsylvania and Virginia -- ranked in the bottom quartiles of most metrics, while several states perceived to be at a lower terror risk, such as Nebraska, ranked at the top.

While the lack of an impending smallpox crisis may account for the differences in state response, both the federal and state governments could have done a better job, Bass said.

"Some felt the CDC or state health departments sent ambivalent messages about the importance of the program, and many states did not fully support the effort," Bass said. "The result was a very inconsistent uptake of the vaccination program by states, where some states had very coordinated efforts and others did not."

Adding to the variability were many healthcare workers who didn't believe that the benefits of the vaccine outweighed the personal risks.

"Workers worried that the vaccine, which had not been given to middle-aged or older adults in the past, might have unanticipated dangers. Others wondered if the vaccine might be effective against newer forms of weaponized smallpox," said Bass.

To uncover why healthcare workers did not accept vaccines, Bass, along with colleagues Tom Gordon and Sheryl Ruzek, is working on a new study that employs perceptual mapping to evaluate how healthcare workers balance risks and benefits in deciding whether or not to take part in a vaccination program.

"To be prepared, we need to have health workers protected," Bass said. "But as long as it's a decentralized program without an immediate outbreak, it will be difficult."

Note: This story has been adapted from a news release issued by Temple University. via Science Daily

Abnormal Proteins Linked To Schizophrenia Found In Body Tissue

A new study suggests biochemical changes associated with schizophrenia aren't limited to the central nervous system and that the disease could have more encompassing effects throughout the body than previously thought. The findings, scheduled for publication in the January 2007 issue of the American Chemical Society's Journal of Proteome Research, could lead to better diagnostic testing for the disease and could help explain why those afflicted with it are more prone to type II diabetes, cardiovascular diseases and other chronic health problems.

Researcher Sabine Bahn, M.D., Ph.D., and her colleagues at Cambridge University in England and the University of Cologne in Germany, detected abnormal proteins linked to schizophrenia in the liver and red blood cells of people who have the disorder. It is the first time the same altered proteins have been detected both within brain tissue as well as in non-brain tissue, according to Bahn.

In time, Bahn says, these protein "biomarkers" could be used to trace the progression of the disease throughout the body.

"If changes in the rest of the body can be observed, and if these changes reflect what is going wrong in the brain, we can use these (findings) to learn about the cellular dysfunction that causes schizophrenia and this will allow us to develop better drugs and diagnostics," Bahn says.

About 1 percent of the world's population -- including 2.4 million Americans -- has schizophrenia, a complex and puzzling mental illness that can lead to delusions, hallucinations and disordered thinking. It is one of the world's most common causes of psychosis, according to Bahn. Since it was first described more than 100 years ago, scientists have made little progress in unraveling the causes of the disease, and no definitive test is available to diagnosis it, she says.

"We desperately need a better understanding of this illness. It is, however, difficult to study the disease, as the brain can't easily be investigated. We can't take multiple biopsies from patients to look at the disease-related changes," Bahn says. "We need a new concept."

While most scientists investigating the disease believe it only affects the brain, Bahn notes that researchers have long known that people who have schizophrenia are at higher risk than the general population for a number of chronic diseases. Some evidence suggests these health problems might be somehow tied to schizophrenia, she adds, but most studies have been inconclusive. Bahn's latest discovery could help bridge this gap.

Recently, Bahn and her colleagues discovered a set of abnormal proteins in post-mortem brains of people who had schizophrenia. In this new study, they sought to detect similarly altered proteins in other organs and tissues of individuals living with the disease. After looking at thousands of proteins, they found that people with schizophrenia had 14 liver proteins and eight red blood cell proteins that were significantly altered compared to individuals who didn't have the disease. These altered proteins were strikingly like those found in the post-mortem brains.

Several of these abnormal proteins appear to promote oxidative stress and disrupt energy metabolism in cells, Bahn says. She theorizes that schizophrenia is caused, at least in part, by these two problems. In her earlier work, for instance, Bahn found evidence that schizophrenic brains might have difficulty producing or using energy properly and are more susceptible to cell-damaging free radicals than healthy brains. The new findings, she says, suggest that the same sort of energy starvation, increased free-radical damage cycle could be occurring in other tissue and, in addition to schizophrenia, possibly be contributing to the onset of other chronic diseases.

Note: This story has been adapted from a news release issued by American Chemical Society. via Science Daily

Five New Technologies That Promise To Transform Medicine

Fat zapping to shed excess weight, miniature telescopes to restore vision, and smart nappies to detect common childhood infections: these are some of the new technologies that promise to transform medicine, according to this week's Christmas issue of the British Medical Journal.

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The forecasts are made by Professor Donald Combs of the Eastern Virginia Medical School and are based on existing technologies that are in varying stages of development and on extensions of those technologies.

His vision for the future includes airport x-ray style devices that "fry" excess fat with a laser. An overweight patient simply walks through the device and emerges several pounds lighter. No side effects are seen apart from the resizing of his wardrobe.

Patients with chronic diseases who need regular medication will benefit from a miniature implant that monitors and transmits data on heart and breathing rates, blood pressure, and blood sugar levels. And further into the future are links smart pumps that, when signalled, instantly deliver the correct medication.

Another prediction is the use of miniature telescopes that restore vision for patients with degenerative eye disease. The telescopes are powered by sunlight passing through the pupils to microscopic solar battery panels attached to the retinas.

These scenarios illustrate potential clinical applications of technologies currently under development, says Professor Combs. For instance, devices that can sense and transmit heart and breathing rates already exist and implantable lenses are well-known.

Other emerging technologies include wave technology to isolate cancer cells, fabrication technology to manufacture customised body parts, and the use of miniature robots to track and destroy infections before they cause disease.

The individual and collective impact of these technologies is already present in some aspects of contemporary medicine and the rate of their impact is increasing, he concludes.

Note: This story has been adapted from a news release issued by BMJ-British Medical Journal. via Science Daily

New Neurons Could Act To Alleviate Epilepsy

cience Daily — The new neurons generated as a result of neural damage due to epilepsy show a reduced excitability that could alleviate the disorder, researchers have found. The researchers said their results suggest that therapies for epilepsy aimed at inducing neurogenesis could prove effective in alleviating the disorder.

In an article in the December 21, 2006, issue of the journal Neuron, published by Cell Press, Olle Lindvall and colleagues at Lund University Hospital and Stem Cell Center described studies in rats examining neurons generated after an epileptic event has been triggered in the animals.

In their experiments, the researchers compared the properties of new neurons generated in rats allowed to exercise by running on a wheel with those in rats in which epileptic seizures were induced by electrical brain stimulation. Specifically, the researchers analyzed the electrical properties of a type of new cells, called granule cells, in the structure called the dentate gyrus of the hippocampus. This structure is known to be a "gate" for propagation of seizures in the hippocampus, a center for learning and memory.

The scientists' analysis showed that the new neurons in both the runners and the epileptic animals had all the characteristics of mature dentate gyrus cells. However, they found that neurons born into an epileptic environment, compared to the physiological running environment, showed reduced excitatory connectivity to other neurons, as well as increased inhibitory connectivity. Such differences could mean the newly generated neurons "could have significant beneficial effect on the epileptic syndrome," concluded the researchers.

"Our study demonstrates that both a physiological stimulus and an insult to the adult brain trigger the formation of new dentate granule cells, which are functionally integrated into hippocampal neural circuitry," concluded Lindvall and colleagues. They wrote that "following insult, the functional connectivity of new neurons seems to develop in order to mitigate the dysfunction in the epileptic brain. These data provide further evidence for a therapeutic potential of endogenous neurogenesis."

The researchers include Katherine Jakubs, Avtandil Nanobashvili, Sara Bonde, Christine T. Ekdahl, Zaal Kokaia, Merab Kokaia, and Olle Lindvall of Lund University Hospital and Stem Cell Center in Lund, Sweden.

This work was supported by Swedish Research Council, EU project LSHBCT-2003-503005 (EUROSTEMCELL), and Söderberg, Crafoord, and Kock Foundations. Lund Stem Cell Center is supported by a Center of Excellence grant in Life Sciences from Swedish Foundation for Strategic Research.

Jakubs et al.: "Environment Matters: Synaptic Properties of Neurons Born in the Epileptic Adult Brain Develop to Reduce Excitability." Publishing in Neuron 52, 1047--1059, December 21, 2006 DOI 10.1016/j.neuron.2006.11.004. http://www.neuron.org

Note: This story has been adapted from a news release issued by Cell Press.

Blood test could show transplant rejection

A blood test may replace invasive biopsies that heart transplant patients in the United States and elsewhere undergo to check for rejection, heart experts say.

The international team evaluated the blood test that analyzes a patient's genes and said it can accurately detect the absence of heart transplant rejection, according to data reported in an editorial the team wrote. The editorial was posted in the online edition of the Journal of Heart and Lung Transplantation.

The genetic-expression profiling test not only is less invasive and less risky than a biopsy, "it also monitors the absence of organ rejection and raises suspicion of damage before any damage to the heart happens. Biopsy records damage that has already occurred," said senior author Mario Deng, director of cardiac transplantation research and associate professor of clinical medicine at Columbia University College of Physicians and Surgeons.

About 30 percent of heart transplant patients reject their new heart at least once in the first year post-transplant. When testing reveals rejection, a patient's immunosuppressive regimen is adjusted.

The new data, however, showed that in more than 99 percent of cases, the GEP test predicted heart muscle biopsies that showed an absence of acute cellular rejection.

Copyright 2006 by United Press International. All Rights Reserved.
via Science Daily

Protection Against Cancer May Begin During Pregnancy, Nursing

There may be another reason for pregnant and nursing women to eat a nutritious diet that includes generous amounts of cruciferous vegetables like broccoli and cabbage -- it could help protect their children from cancer, both as infants and later in life.

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A new study by scientists from the Linus Pauling Institute at Oregon State University, done with laboratory mice, found that supplements of a key phytochemical found in certain vegetables provided a very high level of protection against leukemia and lymphoma in young animals, and also significantly protected against lung cancer during the rodent's equivalent of middle age.

The research, published in the journal Carcinogenesis, is one of the first of its type to demonstrate that diet may play a protective role in a fight against cancer that may begin -- and could be won or lost -- well before a person is ever born. And some of the protective benefits may last into adulthood.

"Research of this type is still in its infancy, but it's pretty exciting," said David Williams, an LPI researcher and director of the Marine and Freshwater Biomedical Sciences Center at OSU.

"There's strong epidemiologic evidence that infant cancers can be caused by exposure of the fetus to carcinogens, either during pregnancy or by nursing," Williams said. "Among all childhood deaths in the U.S., cancer is second only to accidents as the leading cause, and the fetus and neonate are sensitive targets for toxic carcinogens. It would be important if we could affect this through maternal diet."

There are particular concerns about common environmental pollutants called polycyclic aromatic hydrocarbons, or PAHs, which can be produced by cigarette smoking or the combustion of organic materials such as wood, coal, cooking oil or diesel fuel. Exposure of a fetus to PAHs has been shown to cause DNA damage in newborns and is also associated with increased levels of childhood leukemia. It has also been shown that a significant portion of the total lifetime exposure to PAHs and other toxins, including PCBs and dioxins, is transmitted to the fetus across the placental barrier and during nursing.

In laboratory studies, researchers exposed pregnant mice to a single high dose of one PAH called dibenzopyrene, a potent carcinogen, and about 80 percent of their 100 offspring died early in life from an aggressive T-cell lymphoma. Of those that survived to the mouse-equivalent of middle age, 100 percent had lung tumors.

By comparison, in a group of pregnant mice given the same carcinogen but who also received the chemoprotective supplement Indole-3-carbinol, or I3C, deaths from lymphoma were cut in half, and the number of lung tumors later in life was significantly reduced.

"It's clear that in mice this supplement provided significant protection against lymphoma and, later on, lung cancer," Williams said. "It's also worth noting that none of the infant mice received the protective supplement later in their life, at any stage beyond breast feeding. The protective effect of the compound came solely from maternal intake during pregnancy and nursing, but lasted into the animal's middle age. This is somewhat remarkable."

Although lung cancer is the leading cause of cancer death in both men and women, it's also true that only about one smoker in 10 gets lung cancer. It's possible, researchers say, that dietary and other factors in addition to smoking may predispose some smokers to get cancer while others don't. That this process may begin with carcinogens crossing the placental boundary -- and might be affected by diet -- is an area that has not been adequately studied, Williams said. In this study, both the exposure to carcinogens and the levels of Indole-3-carbinol given to pregnant mice through supplements were higher than those that would ordinarily be found in the environment or a normal diet, researchers said.

The scientists do not recommend that pregnant women take supplements of this compound, which is available in health food stores, because there have been questions about its possible role in causing birth defects when ingested at high levels in the first trimester of pregnancy. That topic needs further study, they said.

However, the amounts of this and other valuable phytochemicals that could be obtained in any normal diet rich in cruciferous vegetables should be safe and useful, they said. These vegetables include broccoli, cabbage, cauliflower, kale, radishes, turnips and other types of greens and cabbages.

Indole-3-carbinol is also being studied by scientists in other U.S. research programs for chemoprotection of women against breast cancer.

Cancer chemoprotection is one of the main research areas at the Linus Pauling Institute, a world leader in the study of vitamins, phytochemicals and other nutrients that may help prevent disease or provide optimum health.

This research was funded by the National Institutes of Health.

Note: This story has been adapted from a news release issued by Oregon State University.
via Science Daily

Researchers Find Stem-cell Therapy Effective In Targeting Metastatic Cancer

Patients with advanced cancer that has spread to many different sites often do not have many treatment options, since they would be unable to tolerate the doses of treatment they would need to kill the tumors.

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Researchers at City of Hope and St. Jude Children's Research Hospital may have found a way to treat cancers that have spread throughout the body more effectively. They used modified neural stem cells to activate and concentrate chemotherapeutic drugs predominately at tumor sites, so that normal tissue surrounding the tumor and throughout the body remain relatively unharmed.

"This approach could significantly improve future treatme nt options for patients with metastatic cancer," said Karen Aboody, M.D., assistant professor of Hematology/Hematopoietic Cell Transplantation and Neurosciences at City of Hope. "It not only has the potential to destroy residual tumor cells, but it should also improve patients' quality of life by minimizing toxic side effects such as nausea, diarrhea or bone marrow suppression."

Aboody is the lead investigator of the study done in collaboration with senior investigator Mary Danks, Ph.D., associate member of Molecular Pharmacology at St. Jude Children's Research Hospital in Memphis, Tenn. The study will be published Dec. 20 in PLoS ONE. A second paper with extended results from the study has been accepted for publication in Cancer Research in January.

Most chemotherapy drugs affect both normal and cancerous tissue, which is why they also are toxic to naturally fast-growing cells in the body such as hair follicles and intestinal cells. Aboody and her colleagues have developed a two-part system to infiltrate metastatic tumor sites, and then activate a chemotherapeutic drug, thereby localizing the drug's effects to the tumor cells.

The technique takes advantage of the tendency for invasive tumors to attract neural stem cells. The researchers injected modified neural stem/progenitor cells into immunosuppressed mice that had been given neuroblastoma cells, which then formed tumors. After waiting a few days to allow the stem cells to migrate to the tumors, researchers administered a precursor-drug. When it reached the stem cells, the drug interacted with an enzyme the stem cells expressed, and was converted into an active drug that kills surrounding tumor cells. The precursor-drugs were administered for two weeks, then after a two-week break, a second round of stem/progenitor cells and drugs were administered.

One hundred percent of the neuroblastoma mice appe ared healthy and tumor-free at six months. Without treatment, all the neuroblastoma mice died within two-and-a-half months.

The results hold promise for treating solid tumors that metastasize including neuroblastoma, which represents 6 percent to 10 percent of all childhood cancers worldwide, with higher proportions in children under 2 years of age.

"The results are especially important in the case of high-risk neuroblastoma, because treatment-resistant cancer returns in as many as 80 percent of children, and the majority die of their disease," said co-principal investigator Danks.

Aboody and her colleagues had previously published the efficacy of this technique in primary and metastatic tumors in the brain. This is the first research to demonstrate that it is also effective in a metastatic cancer model, targeting multiple solid tumor sites spread throughout the body. They speculate that the technique could also be applie d to other malignant solid tumors, including colon, brain, prostate and breast cancer, and are planning future preclinical trials using those tumors as well.

Citation: Aboody KS, Bush RA, Garcia E, Metz MZ, Najbauer J, et al (2006) Development of a Tumor-Selective Approach to Treat Metastatic Cancer. PLoS ONE 1(1): e23. doi:10.1371/journal.pone.0000023 (http://dx.doi.org/10.1371/journal.pone.0000023)

Note: This story has been adapted from a news release issued by Public Library of Science.
via Science Daily

Study On Accidental Introduction Of Invasive Snails With Parasitic Flatworms May Help Mitigate Spread Of Disease

A paper that authors are calling a "home run" study on the spread of disease is published in this week's issue of the Proceedings of the National Academy of Sciences (PNAS).

The study traces -- through genetic analysis -- the accidental introduction of invasive snails with parasitic flatworms. The invaders were probably transported with Japanese seed oysters imported into the waters of the Pacific Northwest over a century ago. It is the first comprehensive genetic analysis of an invasive marine host and its parasites. The study points to broad implications for identifying and mitigating spreading disease in a globalized economy.

Understanding the invasion pathways of disease-causing organisms and their hosts is key in limiting future disease outbreaks -- in humans, in agriculture, and in wildlife.

Co-author Armand Kuris, professor of zoology in the Department of Ecology, Evolution and Marine Biology at the University of California, Santa Barbara, is one of a handful of experts who have been studying the ecology of parasites since the 1960s, an area of research that Kuris reports is understudied because parasites are so often invisible. He calls this PNAS paper a home run because it describes a complete picture of biological invasions. He explained that the imported snail has wiped out the native snails, changing the ecosystems of the Northwest.

"Little did the American oystermen of the early 1900s know that their activities could impact local fisheries one hundred years later," said Kuris. "Oyster aquaculture brought in many exotic species, including clams, worms, and snails. Importation was done in a crude and sloppy manner; there was little government regulation of these things at the time."

Invasive North American populations of Asian mud snails, Batillaria attramentaria, probably arrived with Pacific oysters, Crassostrea gigas, imported from northern Japan in the early 1900s, according to the scientists. Genetic research has now confirmed this. The team included first author Osamu Miura, a scientist with Tohoku University in Sendai, Japan; colleagues from the Smithsonian Tropical Research Institute in Panama (STRI); and, scientists from UC Santa Barbara.

"We saw a lot of genetic variation among snail populations in Japan but the North American snails are genetically most similar to those from northern Japan, the source of the imported oysters," Miura reports.

"Using genetics we have shown how the pest snail was introduced and that it came with a parasite that infects fishes and birds," said Mark Torchin, a biologist with STRI. Later, a second parasite came that was spread by migratory birds that ate the infected fish in Japan. The process shows that establishment of an invasive pest can lead to later establishment of disease organisms.

Ryan F. Hechinger, a doctoral student at UCSB, explained how the parasitic flatworm, or trematode, castrates the snail, replacing the gonads with its own mass. "The infected snail will never again make snail babies," said Hechinger. "It is now a parasite making machine. It's basically a robot driven by the parasite."

Hechinger explained that this is the first time that scientists have examined an invasion of a host and a parasite. Migrating birds are bringing one of the trematode parasites; they ingest them when they eat infected fish. The host is a particular snail --- only one species is vulnerable ---- and it is used as an intermediate host. The trematode moves on from the snail to burrow into fish. The trematode has permeated the ecosystem's fish.

Of the eight species of trematode parasites that plague the snails in Japan, only the most common, Cercaria batillariae, has arrived in America. Gene sequencing showed that this single species actually consisted of several cryptic, or similar looking but genetically distinct, species in its home range in Japan. In North America, they commonly found two of the species. One parasite shows much less genetic diversity in America than in Japan, whereas the other parasite is equally diverse in both regions.

"Genetic evidence suggests that while one cryptic parasite species experienced a bottleneck and probably came with the snails, the other was probably historically dispersed by migratory birds and could only establish in North America after the snail hosts arrived," added Torchin. "This is because these trematode parasites have complex life cycles, using snails as first intermediate hosts, fishes as second intermediate hosts and birds as final hosts. As we homogenize biotas as a result of repeated species invasions through global trade, we increase the chances of reuniting infectious agents with suitable hosts."

Parasites which may have historically gone unnoticed as "tourists" in some regions may become pervasive residents after invasion of their missing hosts.

Funding for this study was provided by the Japan Society for the Promotion of Science, the Ecology of Infectious Diseases program of the U.S. National Institutes of Health, and the National Science Foundation.

Note: This story has been adapted from a news release issued by University of California - Santa Barbara.
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Gene Chip Discovery May Lead To Individualized Treatment For 5 Hereditary Liver Diseases

Gene Chip Discovery May Lead To

Researchers at Cincinnati Children's Hospital Medical Center have developed the first gene chip to use in the early diagnosis of at least five hereditary liver diseases, to detect genetic causes of jaundice in children and adults, and potentially to lead to personalized treatment options.

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The chip, termed the "jaundice chip," is nearly 100 percent effective in the detection of the most common mutations in children with inherited causes of jaundice, according to a new Cincinnati Children's study in the January issue of the journal Gastroenterology.

"Other chips have been developed to assess drug metabolism," said Jorge Bezerra, MD, a pediatric gastroenterologist at Cincinnati Children's and the study's lead investigator. "This is the first chip in the world that has been customized to diagnose genetic mutations in patients with inherited types of liver diseases."

The chip uses a new technology that rapidly and accurately discloses the composition of several genes known to cause liver disease in children and adults. "The jaundice chip may also help us to discover whether subtle changes in these five genes that can cause devastating diseases in children may also modify the clinical course of other common liver diseases in adults,"said Mitchell Cohen, M.D., director of the division of gastroenterology hepatology and nutrition at Cincinnati Children's.

Jaundice is a yellowing of the eyes and skin caused by impairment in bile flow from the liver to the intestine. Impaired bile flow, or cholestasis, commonly known as jaundice, can lead to severe liver disease. In children, jaundice and cirrhosis are responsible for more than half of the need for liver transplantation.

Previous research on humans identified five genes responsible for inherited forms of jaundice, Until now, the broad array of causes of cholestasis including genetic, metabolic, inflammatory and drug- or toxin-induced disorders, created a challenge for physicians to diagnose a specific disease. Therefore, the treatment of affected children was not disease-specific and aimed at optimizing care to help reduce liver transplantation. With the jaundice chip, however, diagnosis can be simplified by surveying the genetic code for mutations in specific diseases.

The jaundice chip was designed as a "five-in-one" gene chip to screen mutations (a permanent change in the DNA sequence that makes up a gene) in five genes using only one milliliter, or less than a half of a teaspoon, of blood. Gene chips contain several thousand small fragments of DNA on a small piece of glass. Incubation of these chips with the patient's DNA sample produce chemical signals that "glow" and allow for the detection of the normal gene sequence, or of mutations if they are present in the patient.

"The jaundice chip is an extraordinary advance for our patients with liver diseases. It will improve diagnostic accuracy for perplexing diseases in infants and children, potentially decrease the need for invasive and costly studies, and allow us to develop specific treatment plans based on the correct genetic diagnosis," said Dr. Cohen.

"With further genetic testing of liver disease, there is the potential that medications can be tailored to meet the needs of individual patients taking into account the patient's genetic make-up," adds Dr. Bezerra. "For now, the use of the gene chip gives families piece of mind, knowing what their child is living with. The next focus of advances will be the development of medication that may block progression of their disease.

Today, detection of liver diseases with the jaundice chip is continuing, using samples from children worldwide through a research protocol in the division of gastroenterology, hepatology and nutrition at Cincinnati Children's. Once approved by the Food and Drug Administration, the potential for wider use is limitless, according to Dr. Bezerra.

The discovery of the jaundice chip was made possible through a grant from the Research Foundation at Cincinnati Children's with additional support by the National Institutes of Health (NIH).

Note: This story has been adapted from a news release issued by Cincinnati Children's Hospital Medical Center.

Treatments For Urinary Infections Leave Bacteria Bald, Happy And Vulnerable

A different approach to treating urinary tract infections (UTIs) could defeat the bacteria that cause the infections without directly killing them, a strategy that could help slow the growth of antibiotic-resistant infections.

Instead of trying to wipe out bacteria, researchers in the laboratory of Scott Hultgren, Ph.D., the Helen L. Stoever Professor of Molecular Microbiology at Washington University School of Medicine in St. Louis, have been working to create pharmaceuticals that essentially "defang" the bacteria by preventing them from assembling pili, microscopic hairs that both enable the invasion of host cells and allow the bacteria to mount a cooperative defense against the host's immune system.

"We're leaving the bacteria bald but healthy and happy," says Jerome S. Pinkner, lab manager for Hultgren. "Rather than trying to kill them, we're working to make them non-pathogenic, so that they will be unable to adhere to or invade the bladder tissues and are readily eliminated from the body."

Pinkner and his colleagues think the bacteria will find it harder to evolve resistance to a treatment that does not directly impact their survival. According to an April 2006 National Institute of Allergy and Infectious Diseases fact sheet, resistance to at least one antibiotic has been detected in more than 70 percent of the bacteria that cause hospital-acquired infections.

In a recent paper in the Proceedings of the National Academy of Sciences, the Hultgren group and its collaborators reported on the successful development of a second generation of anti-pilus treatments or pilicides. A third generation is already undergoing tests now, and researchers are hoping to begin tests of their most potent pilicides in animal models in about a year.

UTIs mainly occur in women and are one of the most common infections, causing around $1.6 billion in medical expenses every year in the United States. Scientists believe 90 percent of all UTIs, which have been linked to poor hygiene, sexual behavior, and migration of intestinal flora, are caused by the bacterium Escherichia coli (E. coli).

Half of all women will experience a UTI at some point in their lives, and additional recurrent UTIs will affect 20 to 40 percent of these patients. Scientists previously thought repeat infections were primarily attributable to new infections from the intestine, where E. coli normally resides. But Hultgren's lab produced evidence showing that E. coli can enter a dormant state in the bladder where it causes no symptoms and is invisible to the immune system. Months or years later, the same bacteria can reactivate and start a new infection.

Hultgren's lab characterized in great detail the process E. coli uses to assemble its pili, which are capped by an adhesive compound that lets them attach to and invade host cells.

"E. coli is a Gram-negative bacterium, so it has an inner and an outer membrane, and many of its most important tools for interacting with the outside world are assembled in the space between the membranes," Pinkner explains.

A molecule known as the chaperone protein takes the parts of the pili from the inner membrane to their assembly site on the outer membrane. Hultgren's group determined the crystal structure of this protein and analyzed it to learn which regions of the protein needed to be blocked off by a pharmaceutical to prevent the chaperone from doing its job.

To synthesize an appropriate drug, Hultgren has been collaborating with chemists including Fredrik Almqvist, Ph.D., associate professor of bioorganic chemistry at Umeå University in Sweden.

Scientists hope that the pilicide approach will significantly diminish the bacteria's ability to find ways of evading the new treatments.

"For bacteria to develop resistance to a new antibiotic, which by definition kills bacteria, all you need is for one bacterium among trillions to acquire a genetic mutation that allows it to survive," Pinkner explains. "We think that pilicides will greatly reduce the pressure to develop resistance and have already shown in the lab that they have no effect on E. coli's growth or metabolic state."

Pinkner notes that all Gram-negative bacteria, including Yersinia pesitis (plague), Salmonella, and Klebsiella pneumoniae (pneumonia and burn and urinary tract infections) make pili and may be susceptible to the same treatments. Keeping the target of the drug specifically aimed at a virulence factor not essential for growth reduces the chances for general resistance to spread, Pinkner asserts. He also notes that such drugs will have fewer effects on bacteria that benefit the host by contributing to healthy human physiology.

"For example, there are bacteria in the intestinal tract that aid in metabolism and the normal function of the intestine, which also helps prevent this niche from being occupied by pathogenic bacteria," he explains. "Given the rise in antibiotic resistance, it is critical to design antimicrobials for the future that target the bad bacteria but leave the good ones alone."

Pinkner JS, Remaut H, Buelens F, Miller E, Åberg V, Pemberton N, Hedenström M, Larsson A, Seed P, Waksman P, Hultgren SJ, Almqvist F. Rationally designed small compounds inhibit pilus biogenesis in uropathogenic bacteria. Proceedings of the National Academy of Sciences, 2006 Nov 21;103(47):17897-17902.

Funding from the National Institutes of Health, the Swedish Natural Science Research Council, the Knut and Alice Wallenberg Foundation and the Medical Research Council supported this research.

Note: This story has been adapted from a news release issued by Washington University School Of Medicine.
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Researchers Use Stem Cells To Regenerate Parts Of Teeth

A multi-national research team headed by USC School of Dentistry researcher Songtao Shi, DDS, PhD, has successfully regenerated tooth root and supporting periodontal ligaments to restore tooth function in an animal model. The breakthrough holds significant promise for clinical application in human patients.

The study appears December 20 in the inaugural issue of PLoS ONE.

Utilizing stem cells harvested from the extracted wisdom teeth of 18- to 20-year olds, Shi and colleagues have created sufficient root and ligament structure to support a crown restoration in their animal model. The resulting tooth restoration closely resembled the original tooth in function and strength.

The technique relies on stem cells harvested from the root apical papilla, which is responsible for the development of a tooth's root and periodontal ligament. Previous studies conducted by Shi and collaborator Stan Gronthos at the National Institutes of Health had utilized dental pulp stem cells. Shi found the new technique to be superior.

"The apical papilla provides better stem cells for root structure regeneration. With this technique, the strength of the tooth restoration is not quite as strong as the original tooth, but we believe it is sufficient to withstand normal wear and tear," says Shi.

He hopes to move the technique to clinical trials within the next several years, a potential boon for dental patients who are not appropriate candidates for dental implant therapy or would prefer living tissue derived from their own teeth.

"Implant patients must have sufficient bone in the jaw to support the implant. For those who don't, this therapy would be a great alternative," says Shi.

According to Shi, the not-so-distant future may be one in which not only wisdom teeth, but those baby teeth once left to the tooth fairy for a pittance, will become valuable therapeutic tools.

"We will be able to provide not only this technique, but other new therapies utilizing a patient's own stem cells harvested from their preserved teeth. This is a very exciting discovery and one that I hope to see in wide-spread clinical use in the near future," says Shi.

Funding for this study came from the National Natural Science Foundation of China, the Beijing Major Scientific Program grant and the National Institute of Dental and Craniofacial Research.

Mesenchymal Stem Cell-Mediated Functional Tooth Regeneration in Swine. Wataru Sonoyama, Yi Liu, Dianji Fang, Takayoshi Yamaza, Byoung-Moo Seo, Chunmei Zhang, Liu He, Stan Gronthos, Cun-Yu Wang, Songlin Wang, Songtao Shi. PLoS ONE, 10.1371/journal.pone.0000079, Dec. 20, 2006.

Note: This story has been adapted from a news release issued by University of Southern California. via Science Daily

Risk Of Spina Bifida Associated With Choline Metabolism Genes, But Unrelated To Choline Intake

A new study finds an association between two genes involved in choline metabolism and the risk of spina bifida. The study, published in the open access journal BMC Medicine, also shows that this association is independent of dietary choline intake by the mother during pregnancy.

Choline is a nutrient, essential for cardiovascular and brain function, and for cellular membrane composition and repair. Often taken as a lecithin supplement, choline is found in beef liver, egg yolk, peanuts, sunflower seeds, cauliflower and soy. Recent studies had suggested that choline intake during pregnancy might decrease the risk of spina bifida.

James Enaw, from the Texas A&M University System Health Science Center in Houston, Texas and colleagues from the California Birth Defects Monitoring Program, analyzed the presence of two specific variants of the genes encoding the enzymes human choline esterase A (CHKA) and CTP:Phosphocholine cytidylytransferase(PCYT1A) in 103 infants suffering from spina bifida and 338 unaffected infants, who served as controls.

Although the study had limited statistical power, Enaw et al.'s results show that one variant of CHKA is associated with a reduced risk of spina bifida and one variant of PCYTA1A is associated with a two-fold increased risk of spina bifida. Interestingly, these associations are not modified by intake of choline by the mother during pregnancy.

The authors conclude: "The results indicate that dietary choline and choline metabolism genes may affect the risk of spina bifida independently or through some other unknown mechanisms."

Note: This story has been adapted from a news release issued by BioMed Central.

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Structure Of Iron Regulatory Protein-RNA Complex Solved

The surprising structure and properties of a protein responsible for regulating the transport, storage and use of iron -- as it binds its target RNA -- are described by researchers from the University of Illinois at Chicago in the Dec. 22 issue of Science.

Iron is an essential nutrient, and defects in uptake and metabolism that result in either deficiencies or overload of iron cause a variety of diseases and disorders, including heart disease, arthritis and cancer.

The iron regulating protein, called IRP1, has two structural forms, each with important functions within the cell.

When serving as one of two regulators of cellular iron metabolism through its control of gene expression, the tightly coiled IRP1 opens up to expose sites that bind messenger RNA at sites on the RNA called iron responsive elements, or IREs, that are common in genes involved in iron metabolism.

In its alternate form, IRP1 binds a cluster of iron and sulfur atoms to act as an important metabolic enzyme called aconitase. The assembly and disassembly of the iron/sulfur cluster in the aconitase form appears to be an effective mechanism for regulating IRP1 activity.

"We found that when IRP1 releases the iron/sulfur cluster and opens up to bind RNA, it undergoes an extraordinary, unexpected rearrangement," said William Walden, professor of microbiology and immunology at UIC and lead author of the study.

"This is the crucial step in understanding the specialized cellular processes that have evolved to maintain internal iron concentrations at the appropriate safe and useful levels and is important to the future design of therapeutic targets," Walden said.

IRP1 is a very large protein, composed of about 900 amino acids arranged into four major domains.

"We expected that IRP1 would open up the two major domains facing each other along a hinge, rather like a clam shell, to accommodate the RNA binding," Walden said. "What we didn't expect was that that opening up would also involve extensive movement within the domains."

The researchers also found two widely separated contact sites between IRP1 and the iron responsive element, said Karl Volz, associate professor in of microbiology and immunology at UIC and principle investigator of the study.

"This is one of the highest affinity bindings we have ever seen. The effect of binding a single iron responsive element, through interactions at two separate binding sites, essentially eliminates the possibility of non-specific binding," Volz said.

According to coauthor Elizabeth Theil, senior scientist at the Children's Hospital Oakland Research Institute in Oakland, Calif., just as drugs targeted to the three-dimensional protein structure emerged in the last century, "knowing how the iron response element RNA is folded in the IRP1 complex is a gift to drug design targeted to 3-D RNA structure -- a developing goal in this century."

The researchers believe the details of the IRP1:IRE interaction are likely also to apply to the other important iron regulatory molecule, IRP2, they wrote in their conclusion. "What remains to be determined is the evolutionary origin and selective advantage of such dramatic conformational plasticity and dual functionality as found in IRP1."

Anna Selezneva, of UIC, and Jerome Dupuy, Anne Volbeda and Juan Fontecilla-Camps of the Université Joseph Fourier in Grenoble, France, also contributed to the study. The study was funded by grants for the National Institutes of Health, and data were collected at the Southeast Regional Collaborative Access Team (SER-CAT) at the Advanced Photon Source at the U.S. Department of Energy's Argonne National Laboratory.

Note: This story has been adapted from a news release issued by University of Illinois at Chicago.
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Buildup Of Damaged DNA In Cells Drives Aging

The accumulation of genetic damage in our cells is a major contributor to how we age, according to a study published in the journal Nature by an international group of researchers. The study found that mice completely lacking a critical gene for repairing damaged DNA grow old rapidly and have physical, genetic and hormonal profiles very similar to mice that grow old naturally. Furthermore, the premature aging symptoms of the mice led to the discovery of a new type of human progeria, a rare inherited disease in which affected individuals age rapidly and die prematurely.These progeroid mice, even though they do not live very long, have remarkably similar characteristics to normal old mice, from their physical symptoms, to their metabolic and hormonal changes and pathology, right down to the level of similar changes in gene expression," said corresponding author Jan Hoeijmakers, Ph.D., head of the department of genetics at the Erasmus Medical Center in Rotterdam, Netherlands. "This provides strong evidence that failure to repair DNA damage promotes aging-- a finding that was not entirely unexpected since DNA damage was already known to cause cancer. However, it shows how important it is to repair damage that is constantly inflicted upon our genes, even through the simple act of breathing."

The study found that a key similarity between the progeria-like, or progeroid, mice and naturally old mice is the suppression of genes that control metabolic pathways promoting growth, including those controlled by growth hormone. How growth hormone pathways are suppressed is not known, but this response appears to have evolved to protect against stress caused by DNA damage or the wear-and-tear of normal living. The authors speculate that this stress response allows each of us to live as long and as healthy a life as possible despite the accumulation of genetic damage as we age.

Findings from this study help to reconcile two conflicting hypotheses currently favored in the field of aging research about why we get old, according to the authors. The first is that our lifespan and how well we age is determined by the genes inherited from our parents. The second is that lifespan and fitness in old age is determined by how much damage we incur over our lifetime.

"Our study suggests that both of these hypotheses are correct. Damage, including DNA damage, drives the functional decline we all experience as we age. But how we respond to that damage is determined genetically, in particular by genes that regulate the growth hormone and insulin pathways," said Laura Niedernhofer, M.D., Ph.D., assistant professor of molecular genetics and biochemistry, University of Pittsburgh School of Medicine, and first author of the study.

How the researchers came to study the relationship between DNA damage and aging began almost serendipitously in the late 1990s while Dr. Niedernhofer was a post-doctoral fellow in Dr. Hoeijmakers' laboratory at Erasmus Medical Center, a well-known European center for medical genetics, including the diagnosis of people with unusual sensitivity to sunlight.

A German physician had contacted the center about a 15-year old Afghan boy who was highly sensitive to the sun and had other debilitating symptoms including weight loss, muscle wasting, hearing loss, visual impairment, anemia, hypertension and kidney failure. The boy's family had immigrated to Germany to seek better medical treatment for his condition.

Extreme sensitivity to ultraviolet (UV) radiation from sunlight is a hallmark of diseases caused by defective DNA repair--an important mechanism by which skin and other cell types normally cut out, or excise, damage to their DNA caused by UV light. Defects in one DNA repair mechanism, nucleotide excision repair (NER), causes xeroderma pigmentosum, a rare disease in which people have a 2,000-fold increased risk of skin cancer from sun exposure.

When the investigators obtained cells from the boy and tested them for NER activity, they found almost none. Further analysis of the boy's DNA revealed a mutation in a gene known as XPF, which codes for part of a key enzyme required for the removal of DNA damage. The XPF portion of the enzyme harbors the DNA-cutting activity; whereas a second portion, known as ERCC1, is essential for the enzyme to bind to the damaged DNA. Mutations in either XPF or ERCC1 lead to reduced activity of this key DNA repair enzyme.

"We were completely surprised by the finding that the patient had a mutation in XPF, because mutations in this gene typically cause xeroderma pigmentosum, which is a disease characterized primarily by skin and other cancers rather than accelerated aging," said Dr. Hoeijmakers. "This patient, therefore, has a unique disease, which we named XPF-ERCC1, or XFE-progeroid syndrome."

To understand why this XPF mutation caused accelerated aging, the investigators compared the expression pattern of all of the genes (approximately 30,000) in the liver of 15-day-old mice that had been generated in the laboratory to harbor a defect in their XPF-ERCC1 enzyme and that had symptoms of rapidly accelerated aging to the genes expressed by normal mice of the same age. This comparison revealed a profound suppression of genes in several important metabolic pathways in the progeroid mice. Most notably, the progeroid mice had a profoundly suppressed somatotroph (growth hormone) axis--a key pathway involved in the promotion of growth and development--compared to normal mice.

The investigators also found low levels of growth hormones in the progeroid mice and ruled out the possibility that this suppression was due to problems with their hypothalamus or pituitary glands, which regulate growth hormone secretion. Furthermore, they demonstrated that if normal adult mice were exposed to a drug that causes DNA damage, such as a cancer chemotherapy agent, the growth hormone axis was similarly suppressed. In other words, DNA damage somehow triggered hormonal changes that halted growth, while also boosting maintenance and repair.

Because growth hormone levels go down as we get older, contributing to loss of muscle mass and bone density, the investigators systematically compared the gene expression pattern of their progeroid mice to normal old mice to look for other similarities. What they found was a striking similarity pattern between the progeroid and normal-aged mice in several key pathways.

Indeed, for genes that influence the growth hormone pathway, there was a greater than 95 percent correlation in changes in gene expression between the DNA repair-deficient mice and old mice. And, remarkably, there was a near 90 percent correlation between all other pathways affected in the progeroid mice and the older mice.

"Because there were such high correlations between these pathways in progeroid and normal older mice, we are quite confident that DNA damage plays a significant role in promoting the aging process. The bottom line is that avoiding or reducing DNA damage caused by sources such as sunlight and cigarette smoke, as well as by our own metabolism, also could delay aging," explained Dr. Niedernhofer.

This research was supported by the National Institute of Aging, the National Institute of Environmental Health Sciences, the National Cancer Institute, the American Cancer Society, the Dutch Cancer Society, the Dutch Science Foundation and the Ellison Medical Foundation.

In addition to Drs. Hoeijmakers and Niedernhofer, others involved in this study include Andria Rasile Robinson and Anwaar Ahmad, University of Pittsburgh Cancer Institute; George Garinis, Anja Raams, Astrid Lalai, Esther Appeldoorn, Hanny Odijk, Roos Oostendorp, Arjan Theil, Wibeke van Leeuwen, Wim Kleijer, Wim Vermeulen, Bert van der Horst and Koos Jaspers, Erasmus Medical Center, Rotterdam, Netherlands; Peter Meinecke, Altonaer Kinder- Krankenhaus, Hamburg, Germany; and Jan Vijg, The Buck Institute for Aging Research, Novato, Ca.

Note: This story has been adapted from a news release issued by University of Pittsburgh Medical Center.

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