COLUMBUS, Ohio – New methods of studying avian influenza strains and visually mapping their movement around the world will help scientists more quickly learn the behavior of the pandemic H1N1 flu virus, Ohio State University researchers say.

The researchers linked many powerful computer systems together to analyze enormous amounts of genetic data collected from all publicly available isolated strains of the H5N1 virus – the cause of avian flu. They then developed a new Web-based application that will allow health officials and the public visualize how the virus moved across the globe using Google Earth.

The green lines on this interactive map represent how pandemic influenza (H1N1) has moved from points in the United States to geographic locations across the globe. Screenshot taken using Google Earth.

The resulting visualizations, based on results of the data analysis, represent the most comprehensive map to date of how avian flu has been transmitted among sites in Asia, Africa and Europe.

But underlying those findings is a new way of analyzing genetic data that generates more complete information about the flu’s spread. The method, combined with the increasing availability of sequenced genomes of isolated flu strains, is expected to help public health officials make more knowledgeable predictions about how the H1N1 flu pandemic will evolve.

“We are taking into account more data but at the same time, we’re making simpler visualizations, allowing users to choose what they want to see,” said Daniel Janies, associate professor of biomedical informatics at Ohio State and senior author of the study.

“We’ve created an environment where people can avail themselves of flu information specific to their region of the world or their area of interest. We waded through all of the complexities so people in the public health realm who want to determine how a flu virus got from point A to point B can find that out, and we’ll have better public health outcomes as a result.”

The visualizations and application are available online at http://routemap.osu.edu.

The research appears online in the journal Cladistics.

The research environment has changed dramatically since 1997, when an avian flu outbreak in Hong Kong alerted health officials to its dangers to humans, Janies noted. The technology behind the Human Genome Project has improved to enable the rapid sequencing of numerous genomes, and avian flu’s broad transmission has encouraged scientists to place viral sequence data into the public domain. At the same time, computational power has continued to expand.

Janies and colleagues obtained high-quality avian flu sequences contained in the repositories at the National Institutes of Health’s GenBank and the Global Initiative on Sharing Avian Influenza Data (GISAID). They then focused on studying two genes within the virus whose mutations are believed to have the most impact on H5N1 behavior: hemagglutinin, which produces the protein that recognizes the host cell receptor, and neuraminidase, an enzyme that helps the virus escape one cell so it can enter other cells.

The researchers used 1,646 sequences of hemagglutinin and 1,335 of neuraminidase in this study.

Biologists construct what are called phylogenetic trees to trace evolutionary relationships among species or strains believed to share a common ancestor. These trees’ branching diagrams can be designed to track similarities in physical characteristics, for example, in the study of dinosaurs, for which genetic data cannot be easily recovered. Or, in the study of influenza, the trees can show how viral strains are related based on shared mutations.

In the past, scientists – including Janies – have selected a single phylogenetic tree to represent related viruses that share mutations. But in this paper, the researchers used the power of supercomputers to generate millions of trees representing relationships among these thousands of viruses. They then picked a pool of thousands of high-quality trees based on a scoring system in the bioinformatics field to use in their analysis of disease transmission.

The scientists then asked of these trees – what are the geographic connections between the isolated viral strains?

These resulting diagrams were then used as the basis for an interactive map that traces the genetic, geographic and evolutionary history of avian influenza over 12 years. The highly pathogenic lineage of avian flu that crossed Asia and Africa can be traced to an isolate taken from a goose in 1996. Little genetic data is available for H5N1 viruses isolated before that.

To avoid creating a complex map that looks like “spaghetti thrown on the screen,” Janies and colleagues also simplified the map’s design. Green lines represent transmission pathways most strongly supported by the research findings. Yellow lines indicate less certainty. Lines also are colored differently depending on whether they indicate an incoming or outgoing virus from a specific location. And users can search for specific transmission routes rather than seeing all transmission events on the map at once.

The maps represent scientists’ best approximation of avian flu transmission based on the information available, Janies explained. Without access to every complete genome of every flu virus that ever infected a bird or human, researchers can never fully track evolutionary relationships, genetic histories and specific locations of each outgoing and incoming viral transmission.

Daniel Janies

“Collect and share as much data as possible and let the data tell the story,” he said. “We’re honest about the uncertainty our results may have – but even with partial data, we can infer much about a virus in an area based on its sources.”

The method has already been applied to studies of the H1N1 flu currently infecting millions of people in the United States. International cooperation spearheaded by the NIH, GISAID and the Centers for Disease Control and Prevention has resulted in ready availability of H1N1 sequences for study.

“With what we have so far, we can see the spread of H1N1 out of the United States and all over the world. There is a different dynamic, in that this is a virus carried by humans, who are cosmopolitan and moving both ways,” Janies said. “It’s also a virus that has been transmitted all over the world in a matter of months, and it’s still similar to its ancestors.”

H5N1, on the other hand, has been creeping across Asia and into Europe and Africa for more than a decade and picked up mutations along the way, he noted. While H1N1 has spread more quickly, it is far less deadly to humans than H5N1 – meaning it is still useful for the world to keep an eye on avian flu, Janies said.

His group’s visualizations will help make that possible.

The computing power used in this study was supplied by the Ohio Supercomputer Center and the Ohio State University Medical Center. The research is funded by the U.S. Army Research Laboratory and Office, Ohio State’s Department of Biomedical Informatics and the Mathematical Biosciences Institute (MBI) at Ohio State.

Janies conducted the work with Rasmus Hovmöller, Boyan Alexandrov and Jori Hardman of Ohio State’s Department of Biomedical Informatics. Hovmöller is also an investigator in the MBI.

Written by Emily Caldwell – Ohio State University

Researchers at Washington University School of Medicine in St. Louis have shed new light on a process that fixes breaks in the genetic material of the body’s cells. Their findings could lead to ways of enhancing chemotherapy drugs that destroy cancer cells by damaging their DNA.

An illustration of two proteins involved in DNA repair by artist Amy VanDonsel

Using yeast cells, the scientists studied protein molecules that have an important role in homologous recombination, which is one way that cells repair breaks in the DNA double helix. The process in yeast is similar to that in humans and other organisms.

Earlier research had established that a protein molecule named Srs2 regulates homologous recombination by counteracting the work of another protein, Rad51. Reporting in the July 10 issue of the journal Molecular Cell, the research team reveals the mechanism of how Srs2 removes Rad51 from DNA and thereby prevents it from making repairs to broken strands.

“Our findings may make it possible to uncover ways to augment the effect of DNA-damaging agents that are used for cancer chemotherapy,” says senior author Tom Ellenberger, D.V.M, Ph.D., the Raymond H. Wittcoff Professor and head of the Department of Biochemistry and Molecular Biophysics. “Many chemotherapeutic agents work by causing DNA damage in cancer cells, leading to their death, and tumors can become resistant to chemotherapy by using DNA repair mechanisms to keep the cells alive. Drugs that inhibit the DNA repair process could help increase the efficiency of chemotherapeutic agents.”

Ellenberger is also co-director of the Pharmacology Core at Siteman Cancer Center at Barnes-Jewish Hospital and Washington University. The facility aids in the development of anti-cancer agents.

Srs2 is a helicase molecule — a motor protein that’s able to walk or slide along a strand of DNA and remove other proteins from DNA or separate the two strands of the twisted double helix. For studies of Srs2, Ellenberger’s laboratory collaborated with Timothy Lohman, Ph.D., the Marvin A. Brennecke Professor of Biochemistry and Molecular Biophysics, a prominent expert in the biochemistry of motor proteins like Srs2.

Rad51’s job in the cell is to promote the exchange of sequences between two related DNA molecules, which can be used to repair breaks in DNA where both strands of the double helix are compromised. As a DNA matchmaker, Rad51 forms long filaments on DNA. Srs2 can remove these to prevent unwanted exchanges of DNA sequences. Without Srs2, cells lose their ability to maintain the normal structure of chromosomes, and DNA sequences become shuffled.

The biochemists found that Srs2 possesses a small arm that interacts with Rad51 and triggers a chemical reaction within the Rad51 protein causing it to fall off the DNA.

“Scientists had assumed that as Srs2 moved along the DNA strand, it just pushed off everything in its path,” says lead author Edwin Antony, Ph.D., a postdoctoral research associate in biochemistry and molecular biophysics. “This isn’t the case — we showed that Srs2 has a specialized structure that allows it to interact specifically with Rad51.”

This finding shows how a motor protein like Srs2 can perform the specialized task of remodeling a protein-DNA complex without interference by other similar helicases, he adds.

Because they now know more precisely the nature of this interaction between Srs2 and Rad51, the researchers can narrow their search for drugs that will block DNA repair by Rad51. This type of drug could make a lower dose of a DNA-damaging drug effective in treating cancer.

The research team is now trying to identify the Srs2 homologue in human cells and will study its structure in combination with Rad51. That will allow a more rational approach to understanding how cells cope with DNA damage and how some tumors evade cancer therapeutics, they say.

“In the long-term, my laboratory will look for drug-like molecules that influence this interaction,” Ellenberger says. “We are using the Chemical Genetics Screening Center here at the University (http://htc.wustl.edu). It has vast libraries of molecules that may have the activity we want. Edwin’s work on Srs2 and Rad51 will allow us to develop an assay to screen for agents that augment or supersede Srs2’s interference with DNA repair.”

Antony E, Tomko EJ, Xiao Q, Krejci L, Lohman TM, Ellenberger T. Srs2 disassembles Rad51 filaments by a protein-protein interaction triggering ATP turnover and dissociation of Rad51 from DNA. Molecular Cell. 2009;35(1):105-115.

Funding from the National Institutes of Health and the Young Scientist Program at Washington University supported this research.

Washington University School of Medicine’s 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked third in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare.

Siteman Cancer Center is the only federally designated Comprehensive Cancer Center within a 240-mile radius of St. Louis. Siteman Cancer Center is composed of the combined cancer research and treatment programs of Barnes-Jewish Hospital and Washington University School of Medicine. Siteman has satellite locations in West County and St. Peters, in addition to its full-service facility at Washington University Medical Center on South Kingshighway.

By Gwen Ericson – Washington University in St. Louis, School of Medicine

WEST LAFAYETTE, Ind. – A new prostate cancer “homing device” could improve detection and allow for the first targeted treatment of the disease.

A new prostate cancer “homing device” could improve detection and allow for the first targeted treatment of the disease.

This image depicts transporter molecules carrying therapeutic drugs to PSMA targets on a prostate cancer cell. A Purdue research team designed a molecule that finds and penetrates prostate cancer cells and can transport drugs or imaging agents into the cell. (Image courtesy of Low laboratory)

A team of Purdue University researchers has synthesized a molecule that finds and penetrates prostate cancer cells and has created imaging agents and therapeutic drugs that can link to the molecule and be carried with it as cargo.

A radioimaging application used for body scans is expected to enter clinical trials this fall, and an optical imaging application used to measure prostate cancer cells in blood samples is already in clinical trials.

Philip Low, the Ralph C. Corley Distinguished Professor of Biochemistry who led the team, said a targeted treatment could be much more effective in treating cancer and would greatly reduce the harmful side effects associated with current treatments.

“Currently none of the drugs available to treat prostate cancer are targeted, which means they go everywhere in the body as opposed to only the tumor, and so are quite toxic for the patient,” said Low, who is a member of the Purdue Cancer Center. “By being able to target only the cancer cells, we could eliminate toxic side effects of treatments. In addition, the ability to target only the cancer cells can greatly improve imaging of the cancer to diagnose the disease, determine if it has spread or is responding to treatment.”

Prostate cancer is the most common cancer, other than skin cancers, and is the second leading cause of cancer death in American men, according to the American Cancer Society. It is estimated that about 192,280 new cases will be diagnosed and 27,360 men will die of prostate cancer in the United States this year.

The molecule Low’s team created attaches to prostate-specific membrane antigen, or PSMA, a protein that is found on the membrane of more than 90 percent of all prostate cancers. It also is found on the blood vessels of most solid tumors and could provide a way to cut off the tumor blood supply, Low said.

“A lot of new drugs are being designed to destroy the vasculature of solid tumors, and, if they could be linked to this new targeting molecule, we could have a two-pronged attack for prostate cancer,” he said. “We could not only kill the prostate cancer cells directly, we could also destroy the vasculature that feeds the tumors.”

There also is potential for the targeting molecule to be used to attack the vasculature of solid tumors of other types of cancers, Low said.

Two papers detailing the work of the Purdue team were published in the June 1 issue of Molecular Pharmaceutics. Endocyte Inc. funded the work.

The team’s animal study data shows an ability to eliminate human prostate cancer cells in mice with no evidence of collateral toxicity in normal tissue.

Sumith Kularatne, a graduate student in Purdue’s chemistry department and first author of both papers, compared the targeting molecule to a homing device.

“The molecule acts like a homing device for prostate cancer,” he said. “PSMA, which is found only on prostate cancer cells and tumor blood vessels, acts as the homing signal that the molecule targets. The molecule and its cargo go only to cancerous tissue, leaving healthy tissue unharmed.”

Philip Low, the Ralph C. Corley Distinguished Professor of Biochemistry at Purdue, and graduate student Sumith Kularatne, in foreground, examine the uptake of an imaging agent in prostate cancer cells. Low led a research team that designed a molecule to find and penetrate prostate cancer cells and has created imaging agents and therapeutic drugs that can link to the molecule and be carried with it as cargo. (Purdue University photo/Andrew Hancock)

Once the molecule reaches the PSMA protein, it binds to it. The molecule is designed with a specific shape that fits with the protein like a key to a lock, Kularatne said. The molecule and its cargo are then carried inside the cell with the protein as it goes through its normal cycle.

In 1995 Low developed a similar method to infiltrate cancer cells by attaching treatments to the vitamin folate, which many cancers rapidly consume. This method provided a “Trojan Horse” entry of large treatment molecules that otherwise would not be able to enter cancer cells.

Low was inspired to find a similar way to target prostate cancer, which does not have the same appetite for folate, he said.

A clinical trial of the radioimaging application is expected to begin at the Indiana University Medical Center in the fall through a collaboration between the Purdue Cancer Center and the Indiana University Cancer Center with additional support from Endocyte Inc.

A radioimaging agent linked to the targeting molecule will be injected into prostate cancer patients and pictures will be taken using a special camera that detects radioactivity. The pictures show where the cancer is present to help doctors determine if it has metastasized, or spread, to any other areas of the body. It also will help doctors decide on the best course of treatment, Low said.

There is currently only one radioimaging agent for prostate cancer approved by the Food and Drug Administration.

“The current imaging capabilities available for prostate cancer are very poor,” Low said. “The existing imaging agent is limited because of its large size, which is difficult to get into a solid tumor. Also it seeks out a target located inside the cancer cell and is only able to mark injured cells that are falling apart as opposed to actively growing cancer cells.”

The targeting molecule and radioimaging agent combination designed by Low’s group is more than 150 times smaller than the existing agent and has much easier penetration through a solid tumor to reach all of the cells inside, he said. It also has the advantage of targeting an area of PSMA exposed on the outside of cancer cells.

Already in clinical trials is an optical imaging application that involves attaching a fluorescent dye to the targeting molecule and mixing it with a patient’s blood sample. Circulating prostate cancer cells in the sample fluoresce and are easily measured to help in diagnosing patients with prostate cancer. Researchers also are investigating whether this could be used to evaluate a patient’s response to therapy, Low said.

Low’s research group modeled the targeting molecule after a naturally occurring molecule that strongly binds to PSMA, called DUPA. Several alterations were necessary to create a molecule that fit the needs of a homing device and delivery vehicle, Kularatne said. The team created an area on the molecule that would link to various imaging or therapeutic agents to bring them along as cargo and created a spacer that would stretch the molecule so that its cargo would not keep it from properly fitting into the binding site. The spacer also was designed to improve binding of the targeting molecule to PSMA.

In addition to Low and Kularatne, co-authors of the papers include Endocyte researchers Kevin Wang and Hari-Krishna R. Santhapuram, graduate student in medicinal chemistry Zhigang Zhou, graduate student in chemistry Jun Yang, and professor of medicinal chemistry and molecular pharmacology Carol B. Post.

Low is the chief science officer for Endocyte, a Purdue Research Park-based company that develops receptor-targeted therapeutics for the treatment of cancer and autoimmune diseases. Endocyte holds the license to many of Low’s drug-targeting technologies.

Papers:

Prostate-Specific Membrane Antigen Targeted Imaging and Therapy of Prostate Cancer Using a PSMA Inhibitor as a Homing Ligand
Sumith A. Kularatne, Kevin Wang, Hari-Krishna R. Santhapuram, and Philip S. Low

Design, Synthesis, and Preclinical Evaluation of Prostate-Specific Membrane Antigen Targeted ^99mTc-Radioimaging Agents
Sumith A. Kularatne, Zhigang Zhou, Jun Yang, Carol B. Post, and Philip S. Low

By Elizabeth K. Gardner – Purdue University

CINCINNATI—Stereotactic radiosurgery for metastatic brain tumors can be accomplished safely and effectively without immobilizing a patient’s head with an invasive head frame, researchers at the Brain Tumor Center at the University of Cincinnati Neuroscience Institute have found.

Ronald Warnick, MD, and John Breneman, MD. (University of Cincinnati)

Their findings are published in two manuscripts in the July issue of the International Journal of Radiation Oncology, Biology, and Physics.

Stereotactic radiosurgery, often referred to as “surgery without the knife,” involves the destruction of cancerous tissue with precisely targeted beams of radiation. Since the advent of radiosurgery, and up until now at most radiosurgery centers, the standard of care has required the fixation of a rigid, invasive stereotactic head frame to the skull in order to immobilize the patient and provide a frame of reference for targeting the radiosurgery.

The head frame is attached to the skull with surgically implanted pins and can be associated with patient discomfort, anxiety and increased recovery time.

The UC Brain Tumor Center team found that treatment accuracy and success in eliminating brain metastases for patients fitted with a fabricated, noninvasive mask were comparable to those experienced by patients whose treatment involved an invasive head frame. The researchers also determined that the mask system was adequate for patient mobilization.

John Breneman, MD, professor of radiation oncology, was principal investigator of the team’s paper that detailed clinical outcomes; Michael Lamba, PhD, a UC physicist, was principal investigator of a paper that evaluated technical aspects of image-guided positioning of the fabricated mask. Co-investigators were Ronald Warnick, MD, director of the Brain Tumor Center and a neurosurgeon with the Mayfield Clinic; Ryan Steinmetz, MD, a radiation oncologist with Oncology Partners Network; and Aaron Smith, DO, a neurosurgeon from Columbus, Ohio.

Their studies involved patients who were treated at the Precision Radiotherapy Center of West Chester, Ohio. Precision Radiotherapy is a partnership of the Mayfield Clinic and UC Physicians.

The Precision Radiotherapy team began developing “frameless” radiosurgery in mid-2005 and initially used the technology for only those patients who had tumors in areas of the brain not associated with critical functions such as language and reasoning. Over the following two years the success of this approach allowed expansion of the indications for “frameless” radiosurgery to a point where the team now treats all of its radiosurgery patients with this method.

The frameless method involves fabricating a clamshell mask that precisely fits the patient and is equipped with infrared fiducial reflectors to help monitor the patient during treatment. In preparation for treatment, CT scans and contrast-enhanced MRI scans are taken of the patient with the mask in place. Immediately prior to treatment, with the patient again wearing the mask, additional X-rays are acquired. With the patient aligned on the treatment couch, radiation is delivered in arcs that rotate around the target.

In preclinical studies, using a phantom instead of a real patient, Lamba and the radiosurgery team confirmed that frameless targeting was as accurate as radiosurgery with the invasive, fixated frame. In the subsequent study of 49 patients treated with frameless radiosurgery for one or more brain metastases between August 2005 and October 2006, local control of the patients’ lesions and patient survival at one year compared favorably to studies of patients treated with frame-based techniques.

With the frameless method, local control of brain metastases was 80 percent at 12 months and 78 percent at both 18 months and 24 months. Patient survival was 44 percent at one year, 29 percent at 18 months and 16 percent at 24 months. These figures were equivalent to other patient series using frame-based techniques as well as the researchers’ own previously reported outcomes.

Breneman and Warnick point to several benefits of the frameless technique. “In the most obvious benefit, it has eliminated the discomfort and anxiety caused by the head ring,” Warnick said. “Patients who have undergone stereotactic radiosurgery both with a head ring and without clearly preferred the latter method.”

“The frameless technique also facilitates the implementation of fractionated radiosurgery, which our team is currently studying,” Breneman said. “Preliminary indications suggest that this technique—the delivery of lower doses of radiation over a period of days—can significantly reduce treatment complications in selected patients.”

Warnick added that the frameless technique has opened up radiosurgery “from a small select group to a greater universe of patients.” Where previously many patients were excluded, now virtually every patient with a brain metastasis can be treated painlessly with stereotactic radiosurgery. “For example, we can now treat patients with large numbers of metastases by enabling these patients to be treated in multiple sessions without the necessity of re-attaching a head ring,” Warnick said. “We have treated as many as 14 metastases in a single patient on three successive days.”

The Brain Tumor Center’s radiation oncology team used Novalis® technology, manufactured by BrainLAB AG, to perform their research. The Novalis® system is equipped with an image-guided technology and real-time infrared fiducial tracking. The research team received approximately $10,000 in the form of a nonrestricted educational grant from BrainLAB to support the development of their study of frameless radiosurgery. Warnick has received occasional honoraria from BrainLAB in the past as a member of its speakers bureau.

University of Cincinnati

HOUSTON – (June 22, 2009) – Researchers at The University of Texas School of Public Health have developed a game for HIV-positive youth, +CLICK, designed to reduce secondary transmission of the virus.

+CLICK. (The University of Texas School of Public Health)

+CLICK was developed by Christine Markham, Ph.D., and Ross Shegog, Ph.D., assistant professors of behavioral sciences. The game’s usability and credibility were assessed by HIV-positive (HIV+) youth at a Texas Children’s Hospital clinic. Results from the study were published in the May issue of AIDS Care.

According to the World Health Organization, adolescents and young adults ages 13-24 account for 40 percent of new HIV infections worldwide and almost half of all HIV infections in the United States. Many HIV+ youth engage in risky sexual behaviors, according to Markham.

“We wanted to create +CLICK so that we could help educate youth on the importance of making proper, healthy decisions to protect their relationships and themselves as well as help to reduce transmission of the HIV virus,” said Markham, lead investigator of the study.

The game was developed as an adjunct to the youths’ traditional clinic-based self-management education.

The small sample size of 32 study participants included 62.5 percent females and 37.5 percent males. Of those participants, 56.2 percent contracted the virus through birth and 43.8 percent became infected through sexual contact.

Markham and Shegog worked with Mary Paul, M.D., associate professor of pediatrics at Baylor College of Medicine, and Amy Leonard, M.P.H., research coordinator at Baylor College of Medicine, to develop the material presented in the interactive lessons.

Replicating a shopping mall, study participants travel through lessons on abstinence, condoms and contraception, and also watch video clips from experts and peers who are also HIV+. +CLICK is designed to target four behaviors: choosing not to have sex; disclosing HIV status to a potential partner; using condoms correctly and consistently; and using an effective method of birth control along with condoms.

Participants were able to play several of the game’s lessons in approximately 15 minutes during their regularly scheduled clinic visits. “Participants were very receptive and enthusiastic about playing the game,” said Leonard. “They also liked that they were able to ask the clinicians questions about what they learned on the lessons.” Credibility of the game was trusted by 93.8 percent of the participants and 84.4 percent of users found the game to be very easy to use and would tell others about +CLICK, according to the study.

A prototype of the game was used for the study. The game, which is in the last stages of development, is tentatively scheduled to be available to the public in approximately six months. In addition, the research team is working to create a similar web-based game that will focus on medication adherence for HIV+ youth.

This study was funded by the Baylor College of Medicine-University of Texas at Houston Center for AIDS Research.

The University of Texas
Health Science Center
At Houston

A discovery by a team of Canadian and American researchers could provide new ways to fight HIV-AIDS. According to a new study published in Nature Medicine, HIV-AIDS could be treated through a combination of targeted chemotherapy and current Highly Active Retroviral (HAART) treatments. This radical new therapy would make it possible to destroy both the viruses circulating in the body as well as those playing hide-and-seek in immune system cells.

(Université de Montréal)

The study was led by Dr. Rafick-Pierre Sékaly, of the Université de Montréal. Dr. Jean-Pierre Routy of the Research Institute of the McGill University Health Centre (RI-MUHC) and scientists from the National Institutes of Health (NIH) and the University of Minnesota in the United States also collaborated on the investigation. To date, anti-AIDS treatments have been stymied by “HIV reservoirs” – immune system cells where the virus hides and where existing HAART treatments cannot reach. The researchers successfully identified the cells where HIV hides and the “stealth” mechanisms that allow the virus to escape existing treatments. This breakthrough opens the way towards innovative therapies that are completely different from current approaches.

“Our results argue in favour of a strategy similar to the one used against leukemia, which is targeted chemotherapy, associated with a targeted immune treatment. This would make it possible to destroy the cells containing a virus, while giving the immune system time to regenerate with healthy cells,” says Dr. Rafick-Pierre Sékaly, a professor at the Université de Montréal, researcher at the Centre Hospitalier de Université de Montréal (CHUM), director of INSERM 743 and scientific director of the Vaccine and Gene Therapy Institute of Florida.

“For the first time, this study proves that the HIV reservoirs are not due to a lack of potency of the antiretroviral drugs, but to the virus hiding inside two different types of long life CD4 memory immune cells,” explains Dr. Jean-Pierre Routy, a hematologist with the MUHC, researcher in infection and immunity at the RI-MUHC and professor of hematology at McGill University. “There are several types of HIV reservoirs, each necessitating a different treatment to eliminate them.”

Nicolas Chomont and Rafick-Pierre Sékaly of the Université de Montréal with McGill University’s Jean-Pierre Routy. (Université de Montréal)

Indeed, once the virus is hidden in these reservoir cells, it becomes dependent on them: if the cell lives, the virus lives, but if the cell dies, so does the virus. As such, destroying these immune cells will allow for the elimination of the resilient or hidden parts of the virus. Existing HAART treatments destroy the viruses circulating in the body, yet cannot reach those hidden in reservoir cells.

“We now have brand-new options to fight HIV,” concludes Nicolas Chomont, a postdoctoral intern at the Université de Montréal’s Department of Microbiology and Immunology and one of the co-authors of this study. “The combination of fundamental and clinical approaches led to amazing results that allow us to elucidate another mystery of this virus of a thousand faces.”

These new therapeutic options will require many more years of research before they are validated and become a reality for patients. However, this study represents an invaluable work plan that will provide a map for many laboratories around the world.

Partners in research
This study was funded by the American Foundation for AIDS Research (amfAR), the National Institutes of Health, the Canadian Institutes of Health Research and the FRSQ-AIDS and Infectious Diseases Network.

About the study
The study, “HIV reservoir size and persistence are driven by T cell survival and homeostatic proliferation,” published in Nature Medicine, was coauthored by Rafick-Pierre Sékaly, Elias K. Haddad, Nicolas Chomont, Mohamed El Far, Petronela Ancuta, Lydie Trautmann, Francesco A. Procopio, Bader Yassine-Diab and Geneviève Boucher of the Université de Montréal and Centre Hospitalier de Université de Montréal (CHUM), Jean-Pierre Routy, Mohamed-Rachid Boulassel and Georges Ghattas of the McGill University Health Centre (MUHC) and McGill University, Brenna J. Hill, Daniel C. Douek and Jason M. Brenchley of the National Institutes of Health, U.S.A., and Timothy W. Schacker of the University of Minnesota, U.S.A.

On the web
About the Université de Montréal’s Faculty of Medicine
About the Research Centre of the Centre Hospitalier de Université de Montréal
About the Research Institute of the McGill University Health Centre
About McGill University
About INSERM
About Vaccine and Gene Therapy Institute of Florida

Université de Montréal

MANHATTAN — Owners of exotic animals like reptiles and birds need to be aware of illnesses that can affect both their pet and humans, according to a Kansas State University veterinarian.

Source: Kansas State University

Gary West, assistant professor of zoological medicine in K-State’s College of Veterinary Medicine, said exotic animals can make fun and interesting pets, but there are many health factors to consider before owning one.

West said common exotic pets are ferrets, rabbits, guinea pigs, reptiles and birds. He recommended several of these animals as good pets, including cockatiels, guinea pigs, rabbits, bearded dragons, corn snakes, blue-tongued skinks, some species of tarantulas, freshwater tropical fish and some tortoises.

Owning an exotic pet is different from owning pets like dogs and cats. Some exotic pets have specialized needs, such as lizards that require an ultraviolet light for basking, live insects for food or other whole prey items, West said.

“Many of our diets and health care are very advanced for dogs, which have been domesticated for a long time,” he said. “Many exotic pets are non-domestic, and although many advances have been made, there are still things we are learning about them.”

West said there are fad exotic animals every few years that can be challenging to own, such as a kinkajou. West said this South American animal is related to the raccoon and typically does not make a good pet because of special environmental requirements and that it can bite.

He said all exotic animals have specific needs and requirements, and it is important that the pet owner become educated about the animal before purchasing it. He said the best way to keep an exotic pet healthy is to know what it requires to stay healthy and thrive.

Exotic animals can carry diseases, West said. Reptiles are commonly known to be at risk of carrying salmonella, and there have been reports of other diseases, including chlamydia, in pet birds. Rabies also is a concern for mammals if they go outdoors.

However, unlike dogs and cats, exotic pets like reptiles can carry diseases like salmonella without getting sick — but that puts other animals and humans at risk.

West said after handling an exotic pet, people should wash their hands immediately. He also said reptiles should not be allowed to roam free, they should not be allowed in the kitchen or around people who are eating, and owners should disinfect surfaces where reptiles have been. Additionally, the U.S. Centers for Disease Control and Prevention recommends that reptiles not be kept in homes with children younger than 5 years or with immunocompromised people, he said.

Source: Kansas State University

West said typically there are no signs or symptoms to tell if an exotic animal is a carrier of salmonella or other diseases, though the animal could infect other pets. To keep other pets from getting the diseases, West said the same principles for humans apply. Other animals should not come into direct contact with the exotic pet, for mutual benefit, and the animals should keep away from each other’s food and water bowls.

Some exotic animals do not like much handling, noise or strangers, and agitating the animal puts the owner at risk for bites and scratches. Bite wounds can become infected with bacteria from the pet’s mouth and should be examined by a doctor. Additionally, injuries are fairly common in small pets, so owners should be careful when the animal is around larger animals like dogs or around young children, West said.

“We see many cases where the family cat or dog injures or bites the exotic pet, which are often can be life-threatening wounds,” he said.

He said owners should not impulse-buy pets, especially exotic animals. People also should buy from a good source who is knowledgeable about husbandry and care, and the source should also be able to recommend good products and guarantee that the animal is healthy.

West also said to see if the source is selling species that make good pets. He said there are many animals that should not be pets, such as monkeys. Primates make bad pets for several reasons, he said, including because they can carry diseases that are transmissible to humans.

“Wildlife do not make good pets, and it is illegal and irresponsible to take a baby animal from the wild and raise it or make a pet out of it,” West said. “You are not helping it.”

West said owning a pet can be good for children as a way to learn patience and responsibility, and all pets can be great companions and even stress relievers.

“Watching your fish or learning more about these fascinating creatures can be great hobbies for children and adults,” he said. “Observing and learning about their behavior can be very interesting and help foster an interest and love for animals and wildlife.”

By Kristin Hodges – Kansas State University

Sleep apnea can interrupt breathing and sleep all night, but daytime sleepiness may not be the most common consequence.

ANN ARBOR, Mich. — It may seem like common sense, but a good night’s sleep could be the answer to getting energy back, according to a study at the University of Michigan Sleep Disorders Center.

Source: University of Michigan Health System

Patients with complaints of fatigue, tiredness or lack of energy improved with nightly use of continuous positive airway pressure (CPAP) or related devices that are often prescribed for those with obstructive sleep apnea, according to the study published in this week’s issue of the Journal of Clinical Sleep Medicine.

Recent epidemiological studies have revealed an increase in the frequency of genital malformations in male newborns (e.g., un-descended testes) and a decrease in male fertility. The role played by the growing presence in our environment of contaminants that reduce male hormone action could explain this phenomenon.

Université de Montréal

It is known that the birth weight of males is higher than that of females due to the action of male hormones on the male fetus.If the exposure of pregnant women to environmental contaminants that diminish the action of male hormones has increased over the years, one would expect to see a decrease in the sex difference in birth weight.

This is exactly what a new study published in the July 2009 issue of Epidemiology shows. Investigators analyzed the Public Health Agency of Canada’s database on the birth weights of more than five million children born in Canada between 1981 and 2003.

Using statistical methods that control for changes over time of mother’s age and parity, the investigators effectively show a sustained decrease in birth weight differences between boys and girls, which supports the hypothesis of growing endocrine disruption related to environmental contaminants. Contaminants found in plastic materials represent plausible candidates, since they are known to diminish the action of male hormones.

“Our study underlines the importance of probing the impact of environmental contaminants on the health of mothers and fetuses and on the reproductive potential of future generations,” says lead researcher Dr. Guy Van Vliet, a pediatric endocrinologist and investigator at the Sainte-Justine University Hospital Research Center and a professor at the Department of Pediatrics of the Université de Montréal.

About the Study
The study Decreasing sex difference in birth weight, published in the journal Epidemiology, was authored by Dr. Guy Van Vliet, a pediatric endocrinologist and investigator at the Sainte-Justine University Hospital Research Center and a professor at the Department of Pediatrics of the Université de Montréal; Dr. Shiliang Liu, a perinatal epidemiologist at the Public Health Agency of Canada as well as with Dr. Michael S. Kramer, Scientific Director of the Institute of Human Development, Child and Youth Health of the Canadian Institutes for Health Research and a professor at the Departments of Pediatrics and Epidemiology, McGill University. The study was carried out under the auspices of the Canadian Perinatal Surveillance System (CPSS).

On the Web:
About the study cited in the journal Epidemiology
About the Sainte-Justine University Hospital Research Center
About the Université de Montréal
About McGill University
About the Canadian Institutes for Health Research

Université de Montréal

For the first time, researchers from Heidelberg prove the rapid, but reversible changes alcohol causes in human brain cells.

Caption: Tipsy in the “tube” – to test the effect of alcohol on brain tissue, subjects at the university hospital drank an unpleasant tasting alcoholic liquid from a 90 cm long straw. Photo: Heidelberg University Hospital.

Just one drink can quickly go to your head. Researchers in Heidelberg tested this well-known adage. Only six minutes after consuming an amount of alcohol equivalent to three glasses of beer or two glasses of wine, leading to a blood alcohol level of 0.05 to 0.06 percent, changes have already taken place in the brain cells, as the scientists in Heidelberg proved using magnetic resonance spectroscopy (MRS). Previously the only available data was from animal trials. The results of the study were published in the Journal of Cerebral Blood Flow and Metabolism.

Metabolism of brain cells affected

The brain reacts quickly to alcohol. “Our study provides evidence for alternative energy utilization upon alcohol ingestion, i.e. the brain uses an alcohol breakdown product instead of glucose for energy demands,” explains Dr. Armin Biller of the working group for cerebral metabolism at the Department of Neuroradiology at Heidelberg University Hospital (Medical Director: Prof. Dr. Martin Bendszus). The harmful effect also sets in quickly. During the experiment, the concentration of substances such as creatine (energy metabolism), which are attributed with protecting cells, decreases as the concentration of alcohol increases. Choline, a component of cell membranes, was also reduced. “That probably indicates that alcohol triggers changes in the composition of cell membranes,” says Dr. Armin Biller.

Is all consumption of alcohol harmful for the brain? “Our follow-ups on the next day showed that the shifts in brain metabolites after moderate consumption of alcohol by healthy persons are completely reversible,” says Dr. Armin Biller. “However, we assume that the brain’s ability to recover from the effect of alcohol decreases or is eliminated as the consumption of alcohol increases. The acute effects demonstrated in our study could possibly form the basis for the permanent brain damage that is known to occur in alcoholics. This should be clarified in future studies.”

Drinking for science / No differences between men and women

Eight male and seven female subjects participated in the alcohol experiment. While lying in the MRI scanner, they drank the specified amount of alcohol through a long straw. The goal was to reach a blood alcohol content of 0.05 to 0.06 percent – a level that impairs ability to drive, but does not induce severe intoxication. In the MRI scanner, the nuclei of atoms in brain tissue were stimulated by a high-frequency impulse and the signal transmitted during the return to the initial condition was received. The spectral properties of this signal can be analyzed, allowing conclusions to be made as to the contents of various products of metabolism in the tissue examined. This study found no differences between the results of male and female individuals – the brains of female and male subjects reacted to alcohol consumption the same way.

What substances cause a “hangover”?

In other studies, the researchers examined what a “hangover” does to the brain – magnetic resonance spectroscopy can possibly enable us to find out what substances in alcoholic beverages bring on the familiar “hangover”.

Reference:

Armin Biller, Andreas Bartsch, György Homola, Laszlo Solymosi, Martin Bendszus. The Effect of Ethanol on Human Brain Metabolites Longitudinally Characterized by Proton MR-Spectroscopy, Journal of Cerebral Blood Flow and Metabolism 2009, in press.

Information on the Internet: www.klinikum.uni-heidelberg.de/index.php?id=853&L=de

Heidelberg University Hospital