Risk Factors for Heart Attack Remain Low Seven Years After Gastric Bypass

Total cholesterol, triglycerides and C-reactive protein levels are among 11 risk factors for heart attack that remained greatly reduced up to seven years after gastric bypass surgery, according to a new Stanford University study* presented here at the 29th Annual Meeting of the American Society for Metabolic & Bariatric Surgery (ASMBS). Researchers say the study is the first to demonstrate a long-term and sustained cardiac benefit for patients after gastric bypass across so many risk factors.

"Patients significantly decreased their risk for having a heart attack within the first year of surgery and maintained that benefit over the long-term," said lead study author John Morton, MD, Associate Professor of Surgery and Director of Bariatric Surgery at Stanford Hospital & Clinics at Stanford University. Researchers also noted significant decreases in blood pressure and diabetes markers like fasting insulin and hemoglobin A1c.

Dr. Morton, a bariatric surgeon, and colleagues, studied 182 patients who had gastric bypass surgery and follow-up beyond three years at Stanford between 2003 and 2011. Patients were on average 44-years-old, and had an average body mass index (BMI) of 47.

Study investigators analyzed changes to 11 cardiac risk factors that have been shown to increase the likelihood of future heart attacks or coronary artery disease. These markers included lipid and cholesterol levels, metabolic syndrome, homocysteine (amino acid) levels, Framingham Risk Score and C-reactive protein levels, a measure of inflammation that Dr. Morton says may be the single most important predictor of future heart disease.

In up to seven years of follow-up, patients maintained a loss of about 56 percent of their excess weight, going from about 286 pounds, to about 205 pounds after surgery. Before surgery, nearly one-in-four patients were on statins, cholesterol lowering medications, which were discontinued shortly after surgery.

Patients saw a 40 percent increase in high-density lipoproteins ("good cholesterol"), a 66 percent drop in fasting insulin levels and sharp drops in triglycerides, which were reduced by 55 percent.

High sensitivity C-reactive protein fell by 80 percent (10.9 to 2.6 mg/dL). The Framingham Risk Score, a composite predictive tool for future cardiac events, also decreased by nearly 40 percent.

"An 80 percent reduction in the C-reactive protein level is an astounding drop," said Dr. Morton. "This is significantly better than what the best medical therapy has been shown to achieve and underscores the inflammatory nature of obesity, which can be reversed with surgical weight loss."

According to the Centers for Disease Control and Prevention (CDC) and American Heart Association, C-reactive protein levels greater than three indicate a higher risk for cardiovascular disease including heart attack and stroke.¹ Heart disease is the leading cause of death in the United States² and the main cause of heart attack,³ with obesity as a leading preventable risk factor.⁴

In addition to Dr. Morton, study co-authors include Nayna Lodhia, Leanne Almario, Adam Eltorai, Jaffer Kattan, Matthew Kerolus, and Margaret Nkansah -- all from Stanford University.

About Obesity and Metabolic and Bariatric Surgery

Obesity is one of the greatest public health and economic threats facing the United States.⁵ Approximately 72 million Americans are obese⁶ and, according to the ASMBS, about 18 million have morbid obesity. Obese individuals with a BMI greater than 30 have a 50 to 100 percent increased risk of premature death compared to healthy weight individuals as well as an increased risk of developing more than 40 obesity-related diseases and conditions including Type 2 diabetes, heart disease and cancer.^7,8 The federal government estimated that in 2008, annual obesity-related health spending reached $147 billion,⁹ double what it was a decade ago, and projects spending to rise to $344 billion each year by 2018.¹⁰

Metabolic/bariatric surgery has been shown to be the most effective and long lasting treatment for morbid obesity and many related conditions and results in significant weight loss.^11,12,13 In the United States, about 200,000 adults have metabolic/bariatric surgery each year.¹⁴ The Agency for Healthcare Research and Quality (AHRQ) reported significant improvements in the safety of metabolic/bariatric surgery due in large part to improved laparoscopic techniques.¹⁵ The risk of death is about 0.1 percent¹⁶ and the overall likelihood of major complications is about 4 percent.¹⁷ 

*PL-114: Long Term Improvement in Biochemical Cardiac Risk Factors Following Gastric Bypass Dr. John Morton; Nayna Lodhia; Leanne Almario; Adam Eltorai; Jaffer Kattan; Matthew Kerolus; Margaret Nkansah

REFERENCES

1. Ridker, P.M. (2003). Cardiology patient page -- C-reactive protien. American Heart Association -- Circulation. 107 pp. 499-511. Accessed May 2012 http://circ.ahajournals.org/content/108/12/e81.full

2. Centers for Disease Control and Prevention -- FastStats. (2012). Leading causes of death. Accessed May 2012 from http://www.cdc.gov/nchs/fastats/lcod.htm

3. Centers for Disease Control and Prevention -- Heart Disease. (2012). Heart attack. Accessed May 2012 from http://www.cdc.gov/heartdisease/heart_attack.htm

4. Centers for Disease Control and Prevention -- Heart Disease. (2012). Heart disease facts. Accessed May 2012 from http://www.cdc.gov/heartdisease/facts.htm

5. Flegal, K. M., Carroll, M. D., Ogden, C. L., et al. (2002). Prevalence and trends in obesity among US adults, 1999-2000. Journal of the American Medical Association. 288(14) pp. 1723-1727. Accessed March 2012 from http://aspe.hhs.gov/health/prevention/

6. Chronic Disease Prevention and Health Promotion -- Centers for Disease Control and Prevention. (2011). Obesity; halting the epidemic by making health easier at a glance 2011. Accessed February 2012 from http://www.cdc.gov/chronicdisease/resources/publications/AAG/obesity.htm

7. Office of the Surgeon General -- U.S. Department of Health and Human Services. Overweight and obesity: health consequences. Accessed March 2012 from http://www.surgeongeneral.gov/topics/obesity/calltoaction/fact_consequences.html

8. Kaplan, L. M. (2003). Body weight regulation and obesity. Journal of Gastrointestinal Surgery. 7(4) pp. 443-51. Doi:10.1016/S1091-255X(03)00047-7. Accessed March 2012 from http://edulife.com

9. Finkelstein, E. A., Trogdon, J. G., Cohen, J. W., et al. (2009). Annual medical spending attributable to obesity: payer- and service-specific estimates. Health Affairs. 28(5) pp. w822-w831. Accessed February 2012 from http://www.cdc.gov/obesity/causes/economics.html

10. Thorpe, K (2009). The future costs of obesity: national and state estimates of the impact of obesity on direct health care expenses. America's Health Rankings. Accessed June 2012 from http://www.fightchronicdisease.org/sites/fightchronicdisease.org/ files/docs/CostofObesityReport-FINAL.pdf

11. Weiner, R. A. (2010). Indications and principles of metabolic surgery. U.S. National Library of Medicine. 81(4) pp.379-394.

12. Chikunguw, S., Patricia, W., Dodson, J. G., et al. (2009). Durable resolution of diabetes after roux-en-y gastric bypass associated with maintenance of weight loss. Surgery for Obesity and Related Diseases. 5(3) p. S1

13. Torquati, A., Wright, K., Melvin, W., et al. (2007). Effect of gastric bypass operation on framingham and actual risk of cardiovascular events in class II to III obesity. Journal of the American College of Surgeons. 204(5) pp. 776-782. Accessed March 2012 from http://www.ncbi.nlm.nih.gov/pubmed/17481482

14. American Society for Metabolic & Bariatric Surgery. (2009). All estimates are based on surveys with ASMBS membership and bariatric surgery industry reports.

15. Poirier, P., Cornier, M. A., Mazzone, T., et al. (2011). Bariatric surgery and cardiovascular risk factors. Circulation: Journal of the American Heart Association. 123 pp. 1-19. Accessed March 2012 from http://circ.ahajournals.org/content/123/15/1683.full.pdf 16. Agency for Healthcare Research and Quality (AHRQ). Statistical Brief #23. Bariatric Surgery Utilization and Outcomes in 1998 and 2004. Jan. 2007.

17. Flum, D. R. et al. (2009). Perioperative safety in the longitudinal assessment of bariatric surgery. New England Journal of Medicine. 361 pp.445-454. Accessed June 2012 from http://content.nejm.org/cgi/content/full/361/5/445

Courtesy: ScienceDaily

Breast Cancer's Many Drivers

Breast cancer is not a single disease, but a collection of diseases with dozens of different mutations that crop up with varying frequency across different breast cancer subtypes. Deeper exploration of the genetic changes that drive breast cancer is revealing new complexity in the leading cause of cancer death in women worldwide.

In one of the largest breast cancer sequencing efforts to date, scientists from the Broad Institute, the National Institute of Genomic Medicine in Mexico City, Beth Israel Deaconess Medical Center, and Dana-Farber Cancer Institute have discovered surprising alterations in genes that were not previously associated with breast cancer. They report their results in the June 21 issue of Nature, which is publishing a series of papers characterizing the genomic landscape of breast cancer.

One of the team's new findings, a recurrent fusion of the genes MAGI3 and AKT3 in what is known as a translocation event, was observed in tumors from a rare but aggressive form of breast cancer known as triple-negative breast cancer. This cancer does not respond to conventional hormone therapy because its tumors lack three receptors that fuel most breast cancers: estrogen receptors, progesterone receptors, and human epidermal growth factor receptor 2 (known as HER2). But the biological pathway that is affected by the MAGI3-AKT3 reshuffling is already the target of experimental drugs.

The other new alteration reported by the team occurred in two transcription factor genes. Recurrent mutations were detected in the gene CBFB and deletions of its partner RUNX1. Cancer-causing rearrangements of these two genes are common in blood cancers, such as acute myeloid leukemia, but their discovery in breast cancer marks the first time they have been seen in a solid cancer.

"These genes wouldn't top the list of genes you think would be mutated in breast cancer," said Alfredo Hidalgo Miranda, co-senior author of the paper and head of the cancer genomics laboratory at the National Institute of Genomic Medicine, known by its Spanish acronym INMEGEN. "That's exactly the point of doing this type of analysis. It gives you the opportunity to find those genes that you never thought would be involved in the breast cancer process."

The scientists studied two kinds of samples. They sequenced the whole exomes -- the tiny fraction of the genome that encodes proteins -- of 103 breast cancer tumors and DNA from normal tissue from patients in Mexico and Vietnam. They also sequenced the entire genomes of 22 breast cancer tumors and matched normal tissue.

Their analysis confirmed the presence of previously known mutations, but it also turned up the unsuspected alterations.

"One of the lessons here is the real diversity of mutations in breast cancer. I think it's clear there are going to be roughly 50 or so different mutated genes in breast cancer," said Matthew Meyerson, co-senior author of the paper, Broad senior associate member, and professor of pathology at Dana-Farber Cancer Institute and Harvard Medical School. "There's a big diversity of driver genes in cancer. We don't understand what all of them are, but larger data sets will enable us to identify them."

The mutations in CBFB and RUNX1 point to the importance of understanding cell differentiation -- how cells become specialized -- and transcription factors that regulate that process of cell differentiation in epithelial tissue, which lines the inner and outer surfaces of the body. Further studies are needed to unravel that relationship, the authors concluded.

For the current study, inspecting the novel fusion gene MAGI1-AKT3 more closely showed not only that the translocation can transform normal cells into cancer cells, but also that the protein produced by the gene is insensitive to certain drugs now in clinical trials, yet sensitive to others.

In general, fusion genes are created within the same chromosome or across different chromosomes when parts of one gene join parts of another to become a novel gene that wouldn't normally exist. Like the CBFB and RUNX1 mutations, translocations are also more common in blood cancers but until now have rarely been detected in solid tumors, especially breast cancer.

This particular MAGI1-AKT3 fusion gene produces a fusion protein that acts in the PI 3-kinase pathway as an oncogene, or a gene that drives cancer, revealing a new target for potential therapy. The kinase pathway controls a multitude of cellular functions. When a gene is mutated in this pathway, the result is uncontrolled cell growth, a hallmark of cancer.

Other gene mutations in this pathway are well-known, but MAGI1-AKT3 is a first.

"This is the first translocation event resulting in an oncogenic fusion protein that has been identified in this pathway," said Alex Toker, a professor in the department of pathology at Beth Israel Deaconess and Harvard Medical School. "That's important because this is one of the most frequently mutated pathways in human cancer, especially in women's cancers such as breast, ovarian, and endometrial cancer."

The most frequently mutated pathway is also the most studied and, from a pharmaceutical perspective, among the most "druggable."

In laboratory dishes, tests confirmed that the novel structure of proteins encoded by the fusion gene provided no place for some drugs to bind but offered targets for other drugs.

"There are many additional studies that need to be performed using mouse models of disease that would recapitulate the expression of this protein in the mammary gland, in addition to the mechanism by which this protein promotes the effects associated with malignancy," Toker said. "These are all experiments that are under way."

Once the mechanism at work in triple-negative breast cancer is understood through animal models, the next step would be to test chemical compounds to see how effective they might be at targeting cells that harbor this fusion gene's protein.

Beyond these scientific findings, the study also represents a closer look at the Latino population, thanks to the collaboration between the Broad and INMEGEN forged through the Slim Initiative in Genomic Medicine.

"The Slim Initiative in Genomic Medicine aims to support the discovery of the genetic basis of diseases such as type 2 diabetes mellitus and several types of cancer which have a profound public health impact in Mexico and Latin America," said Roberto Tapia-Conyer, director general of the Carlos Slim Health Institute. "This novel bi-national scientific collaboration is contributing to put the Latin American genome on the map of the second generation worldwide genome studies."

INMEGEN scientists had previously built a large breast cancer study and then scientists at both the Broad and INMEGEN exchanged clinical, biological, and computational information.

"From the Mexican point of view, you can say the Latino population has not been extensively characterized using genomic methods," Hidalgo Miranda said. "This is a significant contribution to the knowledge of the architecture of breast tumors in this particular population."

The study represented a first opportunity to study the genetic basis of breast cancer in Mexico. Larger studies will be required to determine whether differences in the spectrum of mutations exist between different populations, but this was an important first step toward that goal.

Contributors to the work also include, from the Broad and its Harvard-affiliated hospitals: Shantanu Banerji (co-first author), Kristian Cibulskis (co-first author), Kristin K. Brown (co-first author), Scott L. Carter, Abbie M. Frederick, Michael S. Lawrence, Andrey Y. Sivachenko, Carrie Sougnez, Lihua Zou, Maria L. Cortes, Shouyong Peng, Kristin G. Ardlie, Daniel Auclair, Fujiko Duke, Joshua Francis, Joonil Jung, Robert C. Onofrio, Melissa Parkin, Nam H. Pho, Alex. H. Ramos, Steven E. Schumacher, Nicolas Stransky, Kristin M. Thompson, Jose Baselga, Rameen Beroukhim, Kornelia Polyak, Dennis C. Sgroi, Andrea L. Richardson, Eric S. Lander, Stacey B. Gabriel, Levi A. Garraway, Todd R. Golub, and Gad Getz (co-senior author). From Mexico: Claudia Rangel-Escareno (co-first author), Juan C. Fernandez-Lopez, Veronica Bautista-Pina, Antonio Maffuz-Aziz, Valeria Quintanar-Jurado, Rosa Rebollar-Vega, Sergio Rodriguez-Cuevas, Sandra L. Romero-Cordoba, Laura Uribe-Figueroa, Gerardo Jimenez-Sanchez, and Jorge Melendez-Zajgla.

The research was conducted as part of the Slim Initiative in Genomic Medicine, a project funded by the Carlos Slim Health Institute in Mexico. The work was also supported by grants from the National Institutes of Health and the National Cancer Institute.

Journal Reference:

1. Shantanu Banerji, Kristian Cibulskis, Claudia Rangel-Escareno, Kristin K. Brown, Scott L. Carter, Abbie M. Frederick, Michael S. Lawrence, Andrey Y. Sivachenko, Carrie Sougnez, Lihua Zou, Maria L. Cortes, Juan C. Fernandez-Lopez, Shouyong Peng, Kristin G. Ardlie, Daniel Auclair, Veronica Bautista-Piña, Fujiko Duke, Joshua Francis, Joonil Jung, Antonio Maffuz-Aziz, Robert C. Onofrio, Melissa Parkin, Nam H. Pho, Valeria Quintanar-Jurado, Alex H. Ramos, Rosa Rebollar-Vega, Sergio Rodriguez-Cuevas, Sandra L. Romero-Cordoba, Steven E. Schumacher, Nicolas Stransky, Kristin M. Thompson, Laura Uribe-Figueroa, Jose Baselga, Rameen Beroukhim, Kornelia Polyak, Dennis C. Sgroi, Andrea L. Richardson, Gerardo Jimenez-Sanchez, Eric S. Lander, Stacey B. Gabriel, Levi A. Garraway, Todd R. Golub, Jorge Melendez-Zajgla, Alex Toker, Gad Getz, Alfredo Hidalgo-Miranda, Matthew Meyerson. Sequence analysis of mutations and translocations across breast cancer subtypes. Nature, 2012; 486 (7403): 405 DOI: 10.1038/nature11154

Courtesy: ScienceDaily

Novel Animal Reservoir for Group of Tick-Borne Diseases Discovered -- And It Lives in Your Backyard

A team of scientists at Washington University in St. Louis has been keeping a wary eye on emerging tick-borne diseases in Missouri for the past dozen years, and they have just nailed down another part of the story.
They knew from earlier work that the animal reservoirs for the diseases included white-tailed deer, wild turkey and a species in the squirrel familiy, but the DNA assay they had used wasn't sensitive enough to identify the species.
Squirrels belong to a large family called the Sciuridae, which includes chipmunks, fox squirrels, red squirrels, flying squirrels, ground hogs and prairie dogs.
In the May issue of the Journal of Medical Entomology the scientists, led by Robert E. Thach, PhD, professor of biology in Arts & Sciences, report that a more sensitive assay has allowed them to identify the major species in question as the eastern gray squirrel.
Yes, the friendly neighborhood seed thief and dog tease is also a mobile tick blood supply and bacteria incubator.
The work is important because tick-borne diseases can be efficiently controlled only if all of the animal reservoirs that might contribute to transmission of the disease have been identified.
Not your New England tick
The most prevalent tick-borne disease in North America is Lyme disease, which is transmitted by the bite of an infected black-legged tick. In the southeastern United States, however, the most common diseases are ehrlichioses and STARI, which are transmitted by the bite of a different tick, the lone star tick.
Until 1986, ehrlichia bacteria were thought to cause disease only in animals. But in that year, a physician noticed mulberry-shaped aggregates characteristic of the bacteria in the blood of a gravely ill man.
The lone star tick, similarly, was thought to be merely a nuisance species until 1993, when the DNA of one of the ehrlichia species was found in lone star ticks collected in Missouri and several other states.
Ehrlichiosis typically begins with vague symptoms that mimic those of other bacterial illnesses. In a few patients, however, it progresses rapidly to affect the liver and other organs, and may cause death unless treated with antibiotics. STARI is similar to Lyme disease but seems to be less virulent.
The reservoirs
By 2010, with the pathogens and their vector identified, the WUSTL team was trying to find the animal reservoirs.
Looking for pathogens and host species, they ran two assays on the ground-up ticks: one to identify the DNA of pathogens and the other to identify the DNA of animals that had provided blood meals.
The blood meal assay on ticks carrying pathogens identified white-tailed deer blood and the blood of a species in the squirrel family, but it couldn't distinguish among 20 or so possible squirrel species.
So the team was very interested when they read a paper in the Journal of Medical Entomology about a new assay that could identify tick blood meals down to the species level.
The assay, developed by scientists at the University of Neuchatel in Neuchatel, Switzerland, used a segment of mitochondrial DNA instead of nuclear DNA as a species marker.
Mitochondria, organelles within the cells that convert energy into forms cells can use, have their own DNA, probably because they were once free-living bacteria.
For reasons that are not entirely clear, mitochondrial DNA mutates faster than DNA tucked away in the cell nucleus. It may be that the mitochondria simply have more primitive DNA repair mechanisms and so cannot fix mistakes if they occur.
In any case, the more mutations, the greater the difference between the DNA of two different species, and the greater the power of the assay to distinguish among species, Thach says.
To tailor the assay for their purposes, the team retrieved the DNA sequences for possible North American host species from Genbank, an open-access sequence database. Sequences not available in the database were determined by the lab.
Lisa S. Goessling, now a research lab supervisor in the School of Medicine, used the sequences to make a palette of probes for 11 species and -- just to make sure the net was cast wide enough -- several higher taxonomic orders.
The scientist then re-ran old samples and newly collected ticks through the new assay. Spots on the assay where the tick blood and the gray squirrel probe overlapped lit up, signaling the presence of gray squirrel blood in the ticks.
Why not the others?
Lone star ticks are famously aggressive and indiscriminate biters, so why hadn't they attacked other animals? Is there something special about deer or gray squirrels that makes the ticks prefer them?
This isn't the kind of question the scientists can answer definitively, but Thach doesn't think so. He has a simpler answer.
"If you think of an inventory of the animals in the woods and the amount of blood in each, well, most of the available blood in the woods is in deer, and next to that in turkeys and squirrels, because turkeys are so big and there are so many squirrels. So I suspect it's mainly just a mass phenomenon," he says.
Neighborhood, neighborhood, neighborhood
Having found gray squirrel DNA in tick blood, the scientists attacked the problem from a different angle to see if they could confirm their results. They trapped gray squirrels rather than ticks.
Were the gray squirrels carrying tick-borne pathogens? The answer, it turned out, depends on where you are. Only 5 percent of the squirrels in a relatively urban suburb (University City, Mo.) were carrying a pathogen, but 25 percent of the squirrels in a wooded "garden suburb" (Kirkwood, Mo.) were infected.
Why the difference? Thach suspects it comes down to white-tailed deer. There are few, if any, in University City, but they cruise backyards in Kirkwood. Wherever deer go they shed ticks.
This also is the likely answer to another conundrum: the absence or near absence of]ticks in Forest Park, the 1,371-acre urban park that adjoins Washington University in St. Louis. Thach says an exhaustive search turned up only one tick.
Why so few ticks? Perhaps because the only deer in Forest Park are the ones in the Saint Louis Zoo.
Journal Reference:

1. Goessling, L.S., Allan, B.F., Mandelbaum,R.S., and Thach, R.E. Development of a Mitochondrial 12S rDNA Analysis for Distinguishing Sciuridae Species 19 with Potential to Transmit Ehrlichia and Borrelia Species to Feeding Amblyomma 20 americanum (Acari: Ixodidae). Journal of Medical Entomology, 2012 (In press)

Courtesy: ScienceDaily

Natural Antioxidant Can Protect Against Cardiovascular Disease

 University of Minnesota Medical School researchers have collaborated with the School of Public Health and discovered an enzyme that, when found at high levels and alongside low levels of HDL (good cholesterol), can dramatically reduce the risk of cardiovascular disease.

The enzyme -- glutathione peroxidase, or GPx3 -- is a natural antioxidant that helps protect organisms from oxidant injury and helps the body naturally repair itself. Researchers have found that patients with high levels of good cholesterol, the GPx3 enzyme does not make a significant difference. However, those patients with low levels of good cholesterol, the GPx3 enzyme could potentially be a big benefit. The enzyme's link to cardiovascular disease may also help determine cardiovascular risk in patients with low levels of good cholesterol and low levels of the protective GPx3.

The new research, published June 16 by PLoS One, supports the view that natural antioxidants may offer the human body profound benefits.

"In our study, we found that people with high levels of the GPx3 enzyme and low levels of good cholesterol were six times less likely to develop cardiovascular disease than people with low levels of both," said lead author Jordan L. Holtzman, M.D., Ph.D., professor of pharmacology and medicine within the University of Minnesota Medical School. "This GPx3 enzyme gives us a good reason to believe that natural antioxidants like GPx3 are good for heart health."

The combination of low HDL and low GPx3 affects an estimated 50 million people -- one in four adults -- in the U.S. This condition can lead to fatal heart attacks and strokes. Researchers continue to look for new ways to better predict who is at risk for these diseases and how patients can limit the impact of the disease once it's diagnosed.

"It's important to point out that people should not rush out to their doctors and demand testing for the GPx3 enzyme," said Holtzman. "But in time, we hope that measuring this enzyme will be a common blood test when determining whether a patient is at risk for cardiovascular disease, including heart attacks and strokes."

To arrive at his results, Holtzman and his colleagues studied the three major risk factors for cardiovascular disease: hypertension, smoking and high cholesterol. Data suggests that those with low levels of HDL and GPx3 were six times more likely to die from cardiovascular disease, including heart attack or stroke, than those with low levels of HDL and high levels of GPx3.

The study examined 130 stored samples from the Minnesota Heart Survey from participants who died of cardiovascular disease after 5-12 years of follow-up care. The ages of patients studied ranged from 26-85 years old. Their data was compared to 240 control samples.

"This is an important enzyme for people with low HDL cholesterol," said Holtzman. "We think further research will be important in determining the future role of GPx3 and what drugs may serve to increase its activity in the blood."

The research reported in this publication was supported by the National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD (RO1-HL23727), the Mayo Chair Endowment, School of Public Health, University of Minnesota (DJ), and grant no. 2005R013 from the Netherlands Heart Foundation, Den Haag, the Netherlands (BB).

Journal Reference:

1. Brian Buijsse, Duk-Hee Lee, Lyn Steffen, Richard R. Erickson, Russell V. Luepker, David R. Jacobs, Jordan L. Holtzman. Low Serum Glutathione Peroxidase Activity Is Associated with Increased Cardiovascular Mortality in Individuals with Low HDLc’s. PLoS ONE, 2012; 7 (6): e38901 DOI: 10.1371/journal.pone.0038901

Courtesy: ScienceDaily

Breast Milk Kills HIV and Blocks Its Oral Transmission in Humanized Mouse

More than 15 percent of new HIV infections occur in children. Without treatment, only 65 percent of HIV-infected children will live until their first birthday, and fewer than half will make it to the age of two. Although breastfeeding is attributed to a significant number of these infections, most breastfed infants are not infected with HIV, despite prolonged and repeated exposure.

HIV researchers have been left with a conundrum: does breast milk transmit the virus or protect against it?

New research from the University of North Carolina School of Medicine explores this paradox in a humanized mouse model, demonstrating that breast milk has a strong virus killing effect and protects against oral transmission of HIV.

"This study provides significant insight into the amazing ability of breast milk to destroy HIV and prevent its transmission," said J. Victor Garcia, PhD, senior author on the study and professor of medicine in the UNC Center for Infectious Diseases and the UNC Center for AIDS Research. "It also provides new leads for the isolation of natural products that could be used to combat the virus."

Garcia and colleagues pioneered the humanized "BLT" mouse model, which is created by introducing human bone marrow, liver and thymus tissues into animals without an immune system of their own. Humanized BLT mice have a fully functioning human immune system and can be infected with HIV in the same manner as humans.

In the study, the researchers first determined that the oral cavity and upper digestive tract of BLT mice have the same cells that affect oral transmission of HIV in humans and then successfully transmitted the virus to the mice through these pathways. When the mice were given virus in whole breast milk from HIV-negative women, however, the virus could not be transmitted.

"These results are highly significant because they show that breast milk can completely block oral transmission of both forms of HIV that are found in the breast milk of HIV-infected mothers: virus particles and virus-infected cells," said Angela Wahl, PhD, a post-doctoral researcher in Garcia's lab and lead author on the paper. "This refutes the 'Trojan horse' hypothesis which says that HIV in cells is more stubborn against the body's own innate defenses than HIV in virus particles."

Finally, the researchers studied the effectiveness of pre-exposure prophylaxis (PrEP) with antiretroviral medication for oral transmission of HIV. Garcia and his team have previously shown that PrEP is effective against intravenous, vaginal and rectal transmission of HIV in humanized BLT mice. In this study, they gave the mice antiretroviral drugs for seven days (3 days before and 4 days after exposing them to the virus) and found 100 percent protection against virus transmission.

These latest findings provide important leads to alternative treatments that could be used to prevent transmission.

"No child should ever be infected with HIV because it is breastfed. Breastfeeding provides critical nutrition and protection from other infections, especially where clean water for infant formula is scarce," Garcia said. "Understanding how HIV is transmitted to infants and children despite the protective effects of milk will help us close this important door to the spread of AIDS."

The study appears in the June 14, 2012 issue of the online journal PLoS Pathogens.

The research was supported by funds from the National Institute of Allergy and Infectious Diseases of the National Institutes of Health and the UNC Center for AIDS Research.

Journal Reference:

1. Angela Wahl, Michael D. Swanson, Tomonori Nochi, Rikke Olesen, Paul W. Denton, Morgan Chateau, J. Victor Garcia. Human Breast Milk and Antiretrovirals Dramatically Reduce Oral HIV-1 Transmission in BLT Humanized Mice. PLoS Pathogens, 2012; 8 (6): e1002732 DOI: 10.1371/journal.ppat.1002732

Courtesy: ScienceDaily

Immune System May Protect Against Alzheimer's Changes in Humans

Recent work in mice suggested that the immune system is involved in removing beta-amyloid, the main Alzheimer's-causing substance in the brain. Researchers have now shown for the first time that this may apply in humans.

Researchers at the Peninsula College of Medicine and Dentistry, University of Exeter with colleagues in the National Institute on Aging in the USA and in Italy screened the expression levels of thousands of genes in blood samples from nearly 700 people. The telltale marker of immune system activity against beta-amyloid, a gene called CCR2, emerged as the top marker associated with memory in people.

The team used a common clinical measure called the Mini Mental State Examination to measure memory and other cognitive functions.

The previous work in mice showed that augmenting the CCR2-activated part of the immune system in the blood stream resulted in improved memory and functioning in mice susceptible to Alzheimer's disease.

Professor David Melzer, who led the work, commented: "This is a very exciting result. It may be that CCR2-associated immunity could be strengthened in humans to slow Alzheimer's disease, but much more work will be needed to ensure that this approach is safe and effective."

Dr Lorna Harries, co-author, commented: "Identification of a key player in the interface between immune function and cognitive ability may help us to gain a better understanding of the disease processes involved in Alzheimer's disease and related disorders."

Alzheimer's disease is the most common form of dementia and affects around 496,000 people in the UK.

Journal Reference:

1. Lorna W. Harries, Rachel M. Bradley-Smith, David J. Llewellyn, Luke C. Pilling, Alexander Fellows, William Henley, Dena Hernandez, Jack M. Guralnik, Stefania Bandinelli, Andrew Singleton, Luigi Ferrucci, David Melzer. LeukocyteCCR2Expression Is Associated with Mini-Mental State Examination Score in Older Adults. Rejuvenation Research, 2012; : 120518094735004 DOI: 10.1089/rej.2011.1302

Courtesy: ScienceDaily

Multi-Target Approach to Treating Tumors

Researchers from Mount Sinai School of Medicine developed a cancer model built in the fruit fly Drosophila, then used it to create a whole new approach to the discovery of cancer treatments. The result is an investigational compound AD80 that precisely targets multiple cancer genes. Tested in mouse models, the drug proved far more effective and less toxic than standard cancer drugs, which generally focus on a single target. This is the first time that whole-animal screening has been used in a rational, step-wise approach to polypharmacology.

The study appears online in the journal Nature.

Conventional drug design embraces the "one gene, one drug, one disease" philosophy. Polypharmacology focuses on multi-target drugs and has emerged as a new paradigm in drug discovery. The hope is that AD80 -- showing unparalleled effectiveness in fly and mouse models -- will be tested in Phase I clinical trials.

"We've come up with one drug that hits multiple targets through 'rational polypharmacology,' and our approach represents a new concept we believe will have great success in suppressing tumors," said Ross L. Cagan, Ph.D., Professor and Associate Dean at Mount Sinai School of Medicine, and senior author on the study. "Scientists are beginning to recognize that single-target drugs can be problematic. I believe that, within the next five years, we'll see more drugs entering clinical trials that use rational polypharmacology as the basis of drug discovery."

The study represented an unusual collaboration between fly geneticists and medicinal chemists. Typically, scientists use human tumor cell lines to screen for single target anti-cancer drugs. In this project, Dr. Cagan, along with co-authors Tirtha Das, Ph.D, from Mount Sinai and their collaborators Arvin Dar, PhD and Kevan Shokat, Ph.D. from the University of California, San Francisco, used their fly cancer models to screen a large chemical library for novel drug leads that shrunk the tumors. They then combined classical fly genetic tools with chemical modeling to develop second-generation drugs to better hit specific targets.

"Many successful drugs now in the marketplace have, by chance, wound up hitting several tumor targets, which is probably why they work," said Dr. Cagan. "The intention of our research was to hit multiple targets purposefully. By using fruit fly genetics we identified, step-by-step, the targets we needed. To my knowledge, this has never been done before. It's also a cost effective model and my prediction is there is going to be more emphasis on whole animal polypharmacology approaches in cancer drug research in the future."

For the study, investigators started out with Ret, the kinase that drives the growth of medullary thyroid tumors in people whose Ret has a cancer-activating mutation; a subset of lung cancer patients also have activated Ret. Researchers engineered a cancer form of Ret into fruit flies. The flies grew tumors wherever Ret was expressed. The investigators then tested dozens of drugs with the goal of curing the tumor.

One challenge is that Ret has many normal cellular roles and shutting it down everywhere in the body would lead to toxicity, a major problem with cancer drugs. "Our goal did not include the assumption that Ret needed to be shut down," said Dr. Cagan. "We wanted to see what worked on the tumors, and then figure out why it worked."

Researchers determined that their lead drug, AD57, suppressed several cancer signals emanating from Ret. These signals include some of the best-known cancer proteins such as Raf, Src, and Tor. Ret itself was not entirely shut down, which suggested to scientists that a patient would experience fewer side effects. The researchers then set out to improve AD57. They manipulated genes in the presence of the original drug hit, a process that had never been done before. As a result, they found that if they lowered the amount of Raf signaling in the presence of AD57, the drug would work even better.

Raf therefore was found to act as a desirable "target." Reducing Tor made AD57 more toxic, so researchers christened Tor an "anti-target," a new concept in drug discovery. Armed with an ideal target/anti-target profile, the Shokat laboratory then developed a derivative of AD57 called AD80.

"When we fed AD80 to the fruit flies, it was like a super drug," said Cagan. "It was remarkable how much AD80 you could give these flies and they didn't mind. This drug wiped the tumors out in a way AD57 or any other drug did not."

Tested in mice models with the same cancer, AD80 performed 500 times better on human cell lines, and far better in mice with very low toxicity, than a cancer drug that the FDA had recently approved for the same cancer type. That drug, vandetanib, is an orphan drug for patients with late-stage medullary thyroid cancer who are not eligible for surgery. Vandetanib was validated in similar fly models from the Cagan laboratory some years earlier.

"We hope that our research will influence the debate between those who favor pursuing drugs that address single vs. multiple tumor targets," said Cagan, who believes the rational polypharmacology model's success in identifying AD80 will prompt scientists and drug companies to pursue broader approaches to attack tumors.

Journal Reference:

1. Arvin C. Dar, Tirtha K. Das, Kevan M. Shokat, Ross L. Cagan. Chemical genetic discovery of targets and anti-targets for cancer polypharmacology. Nature, 2012; 486 (7401): 80 DOI: 10.1038/nature11127

Courtesy: ScienceDaily

Highly Contagious Honey Bee Virus Transmitted by Mites

Researchers at the University of Sheffield have discovered a parasitic mite has caused the deformed wing virus to proliferate in honey bee colonies.

This association is now thought to contribute to the world-wide spread and probable death of millions of honey bee colonies. The current monetary value of honey bees as commercial pollinators in the United States alone is estimated at about $15-$20 billion annually.

The research conducted in Hawaii by researchers from the University of Sheffield, the Marine Biological Association, the Food and Environment Research Agency and the University of Hawaii, and reported in the journal Science, showed how the Varroa mite caused deformed wing virus (DWV) -- a known viral pathogen -- to increase its frequency among honey bee colonies from 10 per cent to 100 per cent.

This change was accompanied by a million-fold increase in the number of virus particles infecting each honey bee and a massive reduction in viral strain diversity leading to the emergence of a single virulent DWV strain.

Dr Stephen Martin, of the University of Sheffield's Department of Animal and Plant Sciences said: "Just 2,000 mites can cause a colony containing 30,000 bees to die. The mite is the biggest problem worldwide for bee keepers; it's responsible for millions of colonies being killed.

"Understanding the changing viral landscape that honey bees and other pollinators face will help beekeepers and conservationists worldwide protect these important insects. We have discovered what happens at the start of an infection. The goal is to understand how the infection comes about so that we can control it.

"Deformed Wing Virus is naturally transmitted in bees through feeding or sex but the mites change the disease so it becomes more deadly, shortening the bees' lives."

As the mite and new virulent strain of the virus becomes established across the Hawaiian Islands the new emerging viral landscape will mirror that found across the rest of the world where the Varroa mite is now established.

This ability of a mite to permanently alter the honey bee viral landscape may by a key factor in the recent colony collapse disorder (CCD) and over-wintering colony losses (OCL) as the virulent pathogen strain remains even after the mites are removed.

Journal Reference:

1. S. J. Martin, A. C. Highfield, L. Brettell, E. M. Villalobos, G. E. Budge, M. Powell, S. Nikaido, D. C. Schroeder. Global Honey Bee Viral Landscape Altered by a Parasitic Mite. Science, 2012; 336 (6086): 1304 DOI: 10.1126/science.1220941

Courtesy: ScienceDaily

Mapping Genes: New Risk Factors for Neurodegenerative Diseases Found

Using a new and powerful approach to understand the origins of neurodegenerative disorders such as Alzheimer's disease, researchers at Mayo Clinic in Florida are building the case that these diseases are primarily caused by genes that are too active or not active enough, rather than by harmful gene mutations.

In the June 7 online issue of PLoS Genetics, they report that several hundred genes within almost 800 brain samples of patients with Alzheimer's disease or other disorders had altered expression levels that did not result from neurodegeneration. Many of those variants were likely the cause.

"We now understand that disease likely develops from gene variants that have modest effects on gene expression, and which are also found in healthy people. But some of the variants -- elevating expression of some genes, reducing levels of others -- combine to produce a perfect storm that leads to dysfunction," says lead investigator Nilufer Ertekin-Taner, M.D., Ph.D., a Mayo Clinic neurologist and neuroscientist.

"If we can identify the genes linked to a disease that are too active or too dormant, we might be able to define new drug targets and therapies," she says. "That could be the case for both neurodegenerative disease as well as disease in general."

Dr. Ertekin-Taner says no other lab has performed the extent of brain gene expression study conducted at Mayo Clinic's Florida campus. "The novelty, and the usefulness, of our study is the sheer number of brain samples that we looked at and the way in which we analyzed them. These results demonstrate the significant contribution of genetic factors that alter brain gene expression and increase risk of disease," she says.

This form of data analysis measures gene expression levels by quantifying the amount of RNA produced in tissue and scans the genome of patients to identify genetic variants that associate with these levels.

Mayo researchers measured the level of 24,526 transcripts (messenger RNA) for 18,401 genes using cerebellar autopsy tissue from 197 Alzheimer's disease patients and from 177 patients with other forms of neurodegeneration. The researchers then validated the results by examining the temporal cortex from 202 Alzheimer's disease patients and from 197 with other pathologies. The difference between these samples is that while the temporal cortex is affected by Alzheimer's disease, the cerebellum is relatively spared.

From these analyses, the researchers identified more than 2,000 markers of altered expression in both groups of patients that were common between the cerebellum and temporal cortex. Some of these markers also influenced risk of human diseases, suggesting their contribution to development of neurodegenerative and other diseases regardless of their location in the brain.

They identified novel expression "hits" for genetic risk markers of diseases that included progressive supranuclear palsy, Parkinson's disease, and Paget's disease, and confirmed other known associations for lupus, ulcerative colitis, and type 1 diabetes.

"Altered expression of brain genes can be linked to a number of diseases that affect the entire body," Dr. Ertekin-Taner says.

They then compared their eGWAS to GWAS data on Alzheimer's disease, conducted by the federally funded Alzheimer's Disease Genetics Consortium, to test whether some of the risk genes already identified promote disease through altered expression.

"We found that a number of genes already linked to Alzheimer's disease do, in fact, have altered gene expression, but we also discovered that many of the variants in what we call the gray zone of the GWAS -- genes whose contribution to Alzheimer's disease was uncertain -- were also influencing brain expression levels," Dr. Ertekin-Taner says. "That offers us new candidate risk genes to explore.

"This is a powerful approach to understanding disease," she says. "It can find new genes that contribute to risk, as well as new genetic pathways, and can also help us understand the function for a large number of genes and other molecular regulators in the genome that are implicated in very important diseases."

The study was funded in part by National Institutes of Health grants and the Mayo Alzheimer's Disease Research Center. The complete results are being made available to the scientific community.

Study co-authors include Fanggeng Zou, Ph.D., High Seng Chai, Curtis Younkin, Mariet Allen, Steven Younkin, M.D., Ph.D., and Minerva Carrasquillo, Ph.D., who also provided genotypes for the Mayo Alzheimer's disease GWAS; Dennis Dickson, M.D., Julia Crook, Ph.D., Shane Pankratz, Ph.D., Neill Graff-Radford, M.D., and Ronald Petersen, M.D., Ph.D.

Journal Reference:

1. Fanggeng Zou, High Seng Chai, Curtis S. Younkin, Mariet Allen, Julia Crook, V. Shane Pankratz, Minerva M. Carrasquillo, Christopher N. Rowley, Asha A. Nair, Sumit Middha, Sooraj Maharjan, Thuy Nguyen, Li Ma, Kimberly G. Malphrus, Ryan Palusak, Sarah Lincoln, Gina Bisceglio, Constantin Georgescu, Naomi Kouri, Christopher P. Kolbert, Jin Jen, Jonathan L. Haines, Richard Mayeux, Margaret A. Pericak-Vance, Lindsay A. Farrer, Gerard D. Schellenberg, Ronald C. Petersen, Neill R. Graff-Radford, Dennis W. Dickson, Steven G. Younkin, Nilüfer Ertekin-Taner. Brain Expression Genome-Wide Association Study (eGWAS) Identifies Human Disease-Associated Variants. PLoS Genetics, 2012; 8 (6): e1002707 DOI: 10.1371/journal.pgen.1002707

Courtesy: ScienceDaily