Two Drugs Already On the Market Show Promise Against Tuberculosis

A two-drug combination is one of the most promising advances in decades for the treatment of tuberculosis (TB) -- a disease that kills 2 million people annually -- a scientist reported March 26 at the 243rd National Meeting & Exposition of the American Chemical Society (ACS). The treatment, which combines two medications already approved by the U.S. Food and Drug Administration (FDA), delivers a knockout punch to forms of TB that shrug off other antibiotics.

John Blanchard, Ph.D., pointed out that TB is fostering a global public health crisis. Up to one-third of the world's population is infected with Mycobacterium tuberculosis (Mtb), the bacterium that causes TB. Mtb can be especially serious among the elderly, individuals infected with the AIDS virus and others with weakened immune systems. Of special concern is the emergence of drug-resistant forms of the TB microbe, including the so-called XDR and MDR strains that shrug off the most powerful antibiotics.

But treatment with the antibiotic meropenem plus another drug, clavulanate, offers new hope for dealing with the disease.

"We've tested this combination against laboratory strains of Mtb, XDR and MDR strains from patients," explained Blanchard, who is Professor of Biochemistry at the Albert Einstein School of Medicine of Yeshiva University in New York City. "In all cases, the combination doesn't just slow down growth -- it kills the bacterium in laboratory tests."

The standard TB treatment consists of a so-called "short-course" of four drugs that was developed in the 1960s and 1970s. Patients take isoniazid, rifampin, pyrazinamide and ethambutol for two months, and then isoniazid and rifampicin alone for an additional four months.

"As you can well imagine, after 40 or 45 years of people being treated with the same drugs, what's happening is that the bacterium is developing resistance to those drugs," said Blanchard. "Some forms, or strains, are resistant to many drugs (MDR, or multidrug-resistant), and some are resistant to almost all known antibiotics (XDR, or extensively drug-resistant). A physician I know in India just reported a strain of TB that is totally drug-resistant. There's nothing currently available that he can use to treat these patients."

But now, there's hope. Blanchard and colleagues at Einstein and the National Institutes of Health found the potent two-drug combination that knocks out regular, MDR and XDR strains of Mtb. Discovery of the drug combo's effectiveness emerged from a study by Blanchard's team. Mtb microbes have an enzyme, beta-lactamase, that destroys many types of antibiotics, even meropenem and others in its medicinal family, which is called the "beta-lactams" or "carbapenems." These antibiotics were specifically developed with a molecular architecture to withstand the effects of the beta-lactamase enzyme. The increase in antibiotic resistance, however, reduced the effectiveness of these medications, and drug companies began marketing combinations of antibiotics and clavulanate. Those medications now are the last resort for treating certain drug-resistant infections.

Blanchard and colleagues found that clavulanate could stop this enzyme in TB microbes from destroying antibiotics. In doing so, it clears the way for antibiotics to do their job. The best combination in their research was clavulanate and meropenem, an ultra-broad spectrum antibiotic given by injection.

The two-drug combination also cuts in half the number of drugs that a patient would have to take compared with the current standard treatment regime, which would make it easier for a patient to stick with the treatment. Meropenem is expensive, but its cost is expected to decline later this year when it goes off-patent, and generic drug companies can begin producing low-cost versions of it.

Clinical trials testing safety and effectiveness of the two-drug treatment in people have not yet been done. However, a physician in Brussels, Dr. Marie-Christine Payen, has reported using the drugs to treat a young patient with severe TB. "Clinical validation of our biochemical studies has come with the recent publication of this case study in which a 14 year-old girl was cured after eight months of treatment," said Blanchard.

Einstein has filed a patent application on the two-drug combination to encourage drug companies to get involved with clinical trial development and improvements to the treatment, he noted.

The scientists acknowledged funding from the National Institutes of Health (NIH; AI33696 to J.S.B.) and in part by the Intramural Research Program of the NIH, National Institute of Allergy and Infectious Diseases.

Story Source:

The above story is reprinted from materials provided by American Chemical Society (ACS), via Newswise. 

Courtesy: ScienceDaily

Single Antibody Shrinks Variety of Human Tumors Transplanted Into Mice, Study Shows

Human tumors transplanted into laboratory mice disappeared or shrank when scientists treated the animals with a single antibody, according to a new study from the Stanford University School of Medicine. The antibody works by masking a protein flag on cancer cells that protects them from macrophages and other cells in the immune system. The scientists achieved the findings with human breast, ovarian, colon, bladder, brain, liver and prostate cancer samples.

It is the first antibody treatment shown to be broadly effective against a variety of human solid tumors, and the dramatic response -- including some overt cures in the laboratory animals -- has the investigators eager to begin phase-1 and -2 human clinical trials within the next two years.

"Blocking this 'don't-eat-me' signal inhibits the growth in mice of nearly every human cancer we tested, with minimal toxicity," said professor of pathology Irving Weissman, MD, who directs Stanford's Institute of Stem Cell Biology and Regenerative Medicine and the Ludwig Center for Cancer Stem Cell Research and Medicine at Stanford. "This shows conclusively that this protein, CD47, is a legitimate and promising target for human cancer therapy."

The antibody treatment also significantly inhibited the ability of the tumors to metastasize throughout the animals' bodies.

"This is exciting work and will surely trigger a worldwide wave of research designed to convert this strategy into useful therapies," said Robert Weinberg, PhD, a professor of biology at the Whitehead Institute for Biomedical Research in Massachusetts who was not involved in the research. "Mobilizing the immune system to attack solid tumors has been a longstanding goal of many cancer researchers for decades."

The research was published online March 26 in the Proceedings of the National Academy of Sciences. Weissman, who is the Virginia & D.K. Ludwig Professor for Clinical Investigation in Cancer Research at Stanford and a member of the Stanford Cancer Institute, is the senior author of the research. Postdoctoral scholars Stephen Willingham, PhD, and Jens-Peter Volkmer, MD, are the co-first authors of the study.

Previous work in Weissman's lab has shown that CD47 is normally expressed on the surfaces of circulating blood stem cells to protect them from immune cells called macrophages. Macrophages patrol the body looking for signs of trouble in the form of invaders or rogue cells, but they sometimes latch onto the wrong targets. CD47 prompts them to release cells they've grabbed by mistake.

Weissman and his colleagues also showed previously that some types of cancer cells -- particularly those of blood cancers such as leukemia and lymphoma -- have figured out a way to game the system and use this "don't-eat-me signal" to their advantage by expressing CD47 on their own surfaces. In 2010, they found that blocking CD47 with a specific antibody (plus adding another to further stimulate the macrophages' killing instinct) can cure some cases of human non-Hodgkin's lymphoma in mice. But it wasn't known until now how widespread or clinically important the phenomenon would be in human solid tumors.

In the current study, Willingham and Volkmer collected surgical samples of a variety of human tumors, including ovarian, breast, colon, bladder, brain, liver and prostate. To do so, they enlisted the help of clinical experts from across the School of Medicine, including those specializing in oncology, urology, obstetrics and gynecology, radiation oncology, neurosurgery, hematology, pathology, otolaryngology and hepatology.

They showed that nearly every human cancer cell they examined expressed CD47 -- usually at higher levels (on average, about three times more) than did non-cancerous cells. Furthermore, people whose cancer cells express a lot of CD47 tend to have shorter life spans than people with similar cancers that express less CD47. This suggests that an analysis of the levels of CD47 expression in some types of tumors could be a valuable prognostic tool for patients and their doctors.

Willingham and Volkmer then implanted the different human tumor cells into matching locations in the bodies of mice -- breast cancer tumors into the mammary fat pads, and ovarian cancer tumors into the abdomen, for example. Once the tumors were well-established (after two weeks or more), they treated the animals with the anti-CD47 antibody.

The researchers saw that most of the established tumors begin to shrink and even, in some cases, disappear within weeks of treatment with the antibody. In one case, antibody treatment cured five mice injected with the same human breast cancer cells. When the tumor was gone, the treatment was discontinued; the mice were monitored for four months with no signs of recurrence.

"These results indicate that anti-CD47 antibodies can dramatically inhibit the growth of human solid tumors by blocking the ability of CD47 to transmit the 'don't-eat-me' signal to macrophages," concluded the authors.

"If the tumor was highly aggressive," said Weissman, "the antibody also blocked metastasis. It's becoming very clear that, in order for a cancer to survive in the body, it has to find some way to evade the cells of the innate immune system." The innate immune system is the body's first line of defense against pathogens like bacteria and viruses. Unlike the adaptive immunity conferred by antibodies and T cells that recognize and battle specific molecules, cells of the innate immune system, like macrophages, respond non-specifically to a variety of threats.

The researchers' approach didn't work in every animal, though. A set of mice with breast cancer cells from a one human patient experienced no benefit from antibody treatment. "There's certainly more to learn," said Weissman. "We need to learn more about the relationship between macrophages and tumor cells, and how to draw more macrophages to the tumors." He suggested that reducing the size of a tumor with surgery or radiotherapy before antibody treatment could make the treatment more effective. Another option, he added, would be to use a second antibody in addition to CD47 that would further stimulate the ability of the macrophages or other immune cells to kill the cancer cells.

While treatment modifications may be beneficial, the findings about the effect of the single antibody are promising in their own right and set the stage for advancing the research. "We believe these results show that we should move forward quickly but cautiously into human clinical trials for many types of solid tumors," Weissman said.

Journal Reference:

1. Badreddin Edris, Kipp Weiskopf, Anne K. Volkmer, Jens-Peter Volkmer, Stephen B. Willingham, Humberto Contreras-Trujillo, Jie Liu, Ravindra Majeti, Robert B. West, Jonathan A. Fletcher, Andrew H. Beck, Irving L. Weissman, and Matt van de Rijn. Antibody therapy targeting the CD47 protein is effective in a model of aggressive metastatic leiomyosarcoma. Proceedings of the National Academy of Sciences, March 26, 2012 DOI: 10.1073/pnas.1121629109

Courtesy: ScienceDaily

Regular Chocolate Eaters Are Thinner, Evidence Suggests

 Katherine Hepburn famously said of her slim physique: "What you see before you is the result of a lifetime of chocolate." New evidence suggests she may have been right.

Beatrice Golomb, MD, PhD, associate professor in the Department of Medicine at the University of California, San Diego, and colleagues present new findings that may overturn the major objection to regular chocolate consumption: that it makes people fat. The study, showing that adults who eat chocolate on a regular basis are actually thinner that those who don't, will be published online in the Archives of Internal Medicine on March 26.

The authors dared to hypothesize that modest, regular chocolate consumption might be calorie-neutral -in other words, that the metabolic benefits of eating modest amounts of chocolate might lead to reduced fat deposition per calorie and approximately offset the added calories (thus rendering frequent, though modest, chocolate consumption neutral with regard to weight). To assess this hypothesis, the researchers examined dietary and other information provided by approximately 1000 adult men and women from San Diego, for whom weight and height had been measured.

The UC San Diego findings were even more favorable than the researchers conjectured. They found that adults who ate chocolate on more days a week were actually thinner -- i.e. had a lower body mass index -- than those who ate chocolate less often. The size of the effect was modest but the effect was "significant" -larger than could be explained by chance. This was despite the fact that those who ate chocolate more often did not eat fewer calories (they ate more), nor did they exercise more. Indeed, no differences in behaviors were identified that might explain the finding as a difference in calories taken in versus calories expended.

"Our findings appear to add to a body of information suggesting that the composition of calories, not just the number of them, matters for determining their ultimate impact on weight," said Golomb. "In the case of chocolate, this is good news -both for those who have a regular chocolate habit, and those who may wish to start one."

Additional contributors to the study include Sabrina Koperski and Halbert L. White, PhD, of UC San Diego.

Funding for this study was provided by the National Institutes of Health.

Journal Reference:

1. B. A. Golomb, S. Koperski, H. L. White. Association Between More Frequent Chocolate Consumption and Lower Body Mass Index. Archives of Internal Medicine, 2012; 172 (6): 519 DOI: 10.1001/archinternmed.2011.2100

Courtesy: ScienceDaily

Cell-Signaling Pathway Has Key Role in Development of Gestational Diabetes

Researchers at the University of Pittsburgh School of Medicine have identified a cell-signaling pathway that plays a key role in increasing insulin secretion during pregnancy and, when blocked, leads to the development of gestational diabetes. Their findings are available online March 16 in Diabetes, one of the journals of the American Diabetes Association.

During pregnancy, pancreatic beta cells should expand and produce more insulin to adapt to the needs of the growing baby, explained senior investigator Adolfo Garcia-Ocana, Ph.D., associate professor of medicine, Division of Endocrinology and Metabolism, Pitt School of Medicine. Newborns can suffer complications if the mother's blood glucose is abnormally high during pregnancy, a condition known as gestational diabetes.

"Not much was known about the maternal mechanisms that lead to increased beta cell number and function during pregnancy," Dr. Garcia-Ocana said. "But research has shown that high blood glucose in pregnancy can have long-term health consequences for the child, as well as a greater risk of hypertension, type 2 diabetes, and high cholesterol for the mother."

His team began studying a protein called hepatocyte growth factor (HGF), which was discovered by George K. Michalopoulos, M.D., Ph.D., professor and chair, Department of Pathology, Pitt School of Medicine, in 1990. Blood levels of HGF are markedly increased in pregnancy. The protein interacts with a cell surface receptor called c-MET.

The researchers engineered mice that lacked the c-MET receptor in pancreatic cells and found that their beta cells functioned correctly, keeping blood glucose within normal parameters in adult mice. But when the mice got pregnant, they took on the features of gestational diabetes.

"Mice that didn't have the c-MET receptor in their pancreas had lower plasma insulin levels, higher blood glucose and impaired ability to regulate glucose levels," Dr. Garcia-Ocana said. "Without the receptor, they couldn't respond to HGF." Also, unlike normal healthy pregnant females, these mice didn't produce more beta cells, had more beta cell death and so had reduced beta cell mass.

"These findings provide the first direct evidence that HGF/C-MET signaling pathway has an important role in maternal beta cell adaptation during pregnancy," Dr. Garcia-Ocana noted. "Perhaps women who have a variation in the HGF gene or in the c-MET receptor are predisposed to developing gestational diabetes because they cannot adequately compensate for the increased insulin demands of pregnancy."

In future work, he and his team will explore HGF signaling in pregnant women, which could one day provide a new means of diagnosing, treating or preventing gestational diabetes.

Co-authors include Cem Demirci, M.D., of the Department of Pediatrics, Pitt School of Medicine; and Sara Ernst, Ph.D., Juan C. Alvarez-Perez, Ph.D., Taylor Rosa, B.S., Shelley Valle, B.S.,Varsha Shridhar, Ph.D., Gabriella P. Casinelli, B.S., Laura C. Alonso, M.D., and Rupangi C. Vasavada, Ph.D., all of the Division of Endocrinology, Pitt School of Medicine.

The project was funded by grants DK067351, DK077096, DK072264, and T32DK07052-32 from the National Institutes of Health, as well as the American Diabetes Association and the Lawson Wilkins Pediatric Endocrine Society.

Journal Reference:

1. C. Demirci, S. Ernst, J. C. Alvarez-Perez, T. Rosa, S. Valle, V. Shridhar, G. P. Casinelli, L. C. Alonso, R. C. Vasavada, A. Garcia-Ocana. Loss of HGF/c-Met Signaling in Pancreatic   Cells Leads to Incomplete Maternal  -Cell Adaptation and Gestational Diabetes Mellitus. Diabetes, 2012; DOI: 10.2337/db11-1154

Courtesy: ScienceDaily

Common Virus Can Lead to Life-Threatening Conditions in Children

Respiratory Syncytial Virus (RSV) is a common virus that infects the lungs and breathing passage ways. Though it may only produce minor cold symptoms in adults, it can lead to serious illness in young children and those with compromised immune systems.

"This is an extremely contagious virus, so it can easily be spread from one child to another in a school or home setting. We continue to see a large amount of kids being admitted to the hospital this year due to RSV. Though it often peaks in winter, the virus may continue to affect communities through early spring," said Rahul Bhatia, MD, pediatric intensive care unit physician at Loyola University Health System and assistant professor of pediatrics at Loyola University Chicago Stritch School of Medicine.

According to the Centers for Disease Control, RSV is the leading cause of bronchiolitis, an inflammation of the small airways in the lung, in infants under the age of 1. Most children will have been exposed to RSV by their second birthday.

"Though younger children have a greater chance of being hospitalized due to the virus, any age group can be affected," Bhatia said.

Unfortunately, there is no vaccine to protect children against this virus. In fact, the best way to prevent the spread is good, old-fashioned hand washing.

"RSV is easily spread by touching infected people and surfaces, so washing your child's and your own hands often is the best way to prevent it from being spread," Bhatia said.

According to Bhatia, symptoms typically peak around 5-7 days into the illness and can continue to provide problems for 10-15 days. People with RSV are usually contagious for 3-8 days, but those with a weaken immune system can be contagious for up to four weeks.

"If your school-age child has cold symptoms, it may be best to try to keep them away from younger brothers or sisters to avoid transmission," Bhatia said. RSV symptoms vary with age and can be similar to that of a cold. Bhatia suggests calling your doctor if your child has the following symptoms: 1. It has become increasingly more difficult for your child to breathe 2. Your child has nasal flaring 3. A decreased appetite 4. Your child is not breathing properly 5. Your child has decreased urine output

Bhatia suggests going to the emergency room if your child: 1. Quits breathing 2. Is a dusky color 3. Is having problems breathing

"There are numerous viruses that can cause respiratory infections. The only way to know if it is RSV is to have testing done," Bhatia said. "RSV has been around for a while. It's nothing new, just every once in a while we see a spike in cases and this happens to be one of those years."

Story Source:

The above story is reprinted from materials provided by Loyola University Health System, via Newswise. 

Courtesy: ScienceDaily

White Rice Increases Risk of Type 2 Diabetes, Study Claims

The risk of type 2 diabetes is significantly increased if white rice is eaten regularly, claims a study published today on bmj.com.

 The authors from the Harvard School of Public Health look at previous studies and evidence of the association between eating white rice and the risk of type 2 diabetes. Their study seeks to determine whether this risk is dependent on the amount of rice consumed and if the association is stronger for the Asian population, who tend to eat more white rice than the Western world.

The authors analysed the results of four studies: two in Asian countries (China and Japan) and two in Western countries (USA and Australia). All participants were diabetes free at study baseline.

White rice is the predominant type of rice eaten worldwide and has high GI values. High GI diets are associated with an increased risk of developing type 2 diabetes. The average amount of rice eaten varies widely between Western and Asian countries, with the Chinese population eating an average of four portions a day while those in the Western world eat less than five portions a week.

A significant trend was found in both Asian and Western countries with a stronger association found amongst women than men. The results also show that the more white rice eaten, the higher the risk of type 2 diabetes: the authors estimate that the risk of type 2 diabetes is increased by 10% with each increased serving of white rice (assuming 158g per serving).

White rice has a lower content of nutrients than brown rice including fibre, magnesium and vitamins, some of which are associated with a lower risk of type 2 diabetes. The authors report, therefore, that a high consumption of white rice may lead to increased risk because of the low intake of these nutrients.

In conclusion, the authors state that "higher white rice intake is associated with a significantly elevated risk of type 2 diabetes." This applies for both Asian and Western cultures, although due to findings suggesting that the more rice eaten the higher the risk, it is thought that Asian countries are at a higher risk. The authors recommend eating whole grains instead of refined carbohydrates such as white rice, which they hope will help slow down the global diabetes epidemic.

In an accompanying editorial, Dr Bruce Neal from the University of Sydney suggests that more, bigger studies are needed to substantiate the research hypothesis that white rice increases the chances of getting type 2 diabetes.

Journal References:

1. E. A. Hu, A. Pan, V. Malik, Q. Sun. White rice consumption and risk of type 2 diabetes: meta-analysis and systematic review. BMJ, 2012; 344 (mar15 3): e1454 DOI: 10.1136/bmj.e1454
2. B. Neal. White rice and risk of type 2 diabetes. BMJ, 2012; 344 (mar15 3): e2021 DOI: 10.1136/bmj.e2021 

 Courtesy: ScienceDaily

Powerful Tool to Measure Metabolites in Living Cells

By engineering cells to express a modified RNA called "Spinach," researchers have imaged small-molecule metabolites in living cells and observed how their levels change over time. Metabolites are the products of individual cell metabolism. The ability to measure their rate of production could be used to recognize a cell gone metabolically awry, as in cancer, or identify the drug that can restore the cell's metabolites to normal.

Researchers at Weill Cornell Medical College say the advance, described in the March 9 issue of Science, has the potential to revolutionize the understanding of the metabolome, the thousands of metabolites that provide chemical fingerprints of dynamic activity within cells.
"The ability to see metabolites in action will offer us new and powerful clues into how they are altered in disease and help us find treatments that can restore their levels to normal," says Dr. Samie R. Jaffrey, an associate professor of pharmacology at Weill Cornell Medical College. Dr. Jaffrey led the study, which included three other Weill Cornell investigators.
"Metabolite levels in cells control so many aspects of their function, and because of this, they provide a powerful snapshot of what is going on inside a cell at a particular time," he says.
For example, biologists know that metabolism in cancer cells is abnormal; these cells alter their use of glucose for energy and produce unique breakdown products such as lactic acid, thus producing a distinct metabolic profile. "The ability to see these metabolic abnormalities can tell you how the cancer might develop," Dr. Jaffrey says. "But up until now, measuring metabolites has been very difficult in living cells."
In the Science study, Dr. Jaffrey and his team demonstrated that specific RNA sequences can be used to sense levels of metabolites in cells. These RNAs are based on the Spinach RNA, which emits a greenish glow in cells. Dr. Jaffrey's team modified Spinach RNAs so they are turned off until they encounter the metabolite they are specifically designed to bind to, causing the fluorescence of Spinach to be switched on. They designed RNA sequences to trace the levels of five different metabolites in cells, including ADP, the product of ATP, the cell's energy molecule, and SAM (S-Adenosyl methionine), which is involved in methylation that regulates gene activity. "Before this, no one has been able to watch how the levels of these metabolites change in real time in cells," he says.
Delivering the RNA sensors into living cells allows researchers to measure levels of a target metabolite in a single cell as it changes over time. "You could see how these levels change dynamically in response to signaling pathways or genetic changes. And you can screen drugs that normalize those genetic abnormalities," Dr. Jaffrey says. "A major goal is to identify drugs that normalize cellular metabolism."
This strategy overcomes drawbacks of the prevailing method of sensing molecules in living cells using green fluorescent protein (GFP). GFP and other proteins can be used to sense metabolites if they are fused to naturally occurring proteins that bind the metabolite. In some cases, metabolite binding can twist the proteins in a way that affects their fluorescence. However, for most metabolites, there are no proteins available that can be fused to GFP to make sensors.
By using RNAs as metabolite sensors, this problem is overcome. "The amazing thing about RNA is that you can make RNA sequences that bind to essentially any small molecule you want. They can be made in a couple of weeks," Dr. Jaffrey says. These artificial sequences are then fused to Spinach and expressed as a single strand of RNA in cells.
"This approach would potentially allow you to take any small molecule metabolite you want to study and see it inside cells," Dr. Jaffrey says. He and his colleagues have expanded the technology to detect proteins and other molecules inside living cells.
He adds that uses of the technology to understand human biology can be applied to many diseases. "We are very interested in seeing how metabolic changes within brain neurons contribute to developmental disorders such as autism," Dr. Jaffrey says. "There are a lot of opportunities, as far as this new tool is concerned."
Co-authors of the study include Dr. Jeremy S. Paige, Mr. Thinh Nguyen Duc, and Dr. Wenjiao Song from the Department of Pharmacology at Weill Cornell Medical College.
The study was funded by the National Institute of Biomedical Imaging and Bioengineering of the NIH, and the McKnight Foundation. The Cornell Center for Technology Enterprise and Commercialization (CCTEC), on behalf of Cornell University, has filed has filed for patent protection on this technology. Dr. Samie Jaffrey is the founder and scientific advisor to Lucerna Technologies, and holds equity interests in this company. In addition, Lucerna Technologies has a license that is related to technology described here.

Journal Reference:

1. J. S. Paige, T. Nguyen-Duc, W. Song, S. R. Jaffrey. Fluorescence Imaging of Cellular Metabolites with RNA. Science, 2012; 335 (6073): 1194 DOI: 10.1126/science.1218298

Courtesy: ScienceDaily

Drug Helps Purge Hidden HIV

A team of researchers at the University of North Carolina at Chapel Hill has successfully flushed latent HIV infection from hiding, with a drug used to treat certain types of lymphoma. Tackling latent HIV in the immune system is critical to finding a cure for AIDS.

The results were presented March 8 at the 19th Conference on Retroviruses and Opportunistic Infections in Seattle, Washington.

While current antiretroviral therapies can very effectively control virus levels, they can never fully eliminate the virus from the cells and tissues it has infected.

"Lifelong use of antiretroviral therapy is problematic for many reasons, not least among them are drug resistance, side effects, and cost," said David Margolis, MD, professor of medicine, microbiology and immunology, and epidemiology at the University of North Carolina at Chapel Hill. "We need to employ better long-term strategies, including a cure."

Margolis' new study is the first to demonstrate that the biological mechanism that keeps HIV hidden and unreachable by current antiviral therapies can be targeted and interrupted in humans, providing new hope for a strategy to eradicate HIV completely.

In a clinical trial, six HIV-infected men who were medically stable on anti-AIDS drugs, received vorinostat, an oncology drug. Recent studies by Margolis and others have shown that vorinostat also attacks the enzymes that keep HIV hiding in certain CD4+ T cells, specialized immune system cells that the virus uses to replicate. Within hours of receiving the vorinostat, all six patients had a significant increase in HIV RNA in these cells, evidence that the virus was being forced out of its hiding place.

"This proves for the first time that there are ways to specifically treat viral latency, the first step towards curing HIV infection," said Margolis, who led the study. "It shows that this class of drugs, HDAC inhibitors, can attack persistent virus. Vorinostat may not be the magic bullet, but this success shows us a new way to test drugs to target latency, and suggests that we can build a path that may lead to a cure."

The research conducted is part of a UNC-led consortium, the Collaboratory of AIDS Researchers for Eradication (CARE), funded by the National Institute of Allergy and Infectious Diseases. The consortium is administered by the North Carolina Translational and Clinical Sciences (NC TraCS) Institute at UNC, one of 60 medical research institutions in the US working to improve biomedical research through the NIH Clinical and Translational Science Awards (CTSA) program.

Other UNC authors on the paper include Nanci Archin, PhD, Shailesh Choudary, PhD, Joann Kuruc, MSN, and Joseph Eron, MD of the medical school; Angela Kashuba, PharmD of the Eshelman School of Pharmacy; and Michael Hudgens, PhD, of the Gillings School of Global Public Health.

Funding for this research was provided by the National Institutes of Health, Merck & Co., and the James B. Pendleton Charitable Trust.

Story Source:

The above story is reprinted from materials provided by University of North Carolina at Chapel Hill School of Medicine, via Newswise. 

Courtesy: ScienceDaily

Nanoparticles Affect Nutrient Absorption, Study SuggestsNanoparticles are everywhere. From cosmetics and clothes, to soda and snacks. But as versatile as they are, nanoparticles also have a downside, say researchers at Binghamton University and Cornell University in a recent paper published in the journal Nature Nanotechnology. These tiny particles, even in low doses, could have a big impact on our long-term health.

Nanoparticles are everywhere. From cosmetics and clothes, to soda and snacks. But as versatile as they are, nanoparticles also have a downside, say researchers at Binghamton University and Cornell University in a recent paper published in the journal Nature Nanotechnology. These tiny particles, even in low doses, could have a big impact on our long-term health.

According to lead author of the article, Gretchen Mahler, assistant professor of bioengineering at Binghamton University, much of the existing research on the safety of nanoparticles has been on the direct health effects. But what Mahler, Michael L. Shuler of Cornell University and a team of researchers really wanted to know was what happens when someone gets constant exposure in small doses -- the kind you'd get if you were taken a drug or supplement that included nanoparticles in some form.

"We thought that the best way to measure the more subtle effects of this kind of intake was to monitor the reaction of intestinal cells," said Mahler. "And we did this in two ways: in vitro, through human intestinal-lining cells that we had cultured in the lab; and in vivo, through the intestinal linings of live chickens. Both sets of results pointed to the same thing -- that exposure to nanoparticles influences the absorption of nutrients into the bloodstream."

The uptake of iron, an essential nutrient, was of particular interest due to the way it is absorbed and processed through the intestines. The way Mahler and the team tested this was to use polystyrene nanoparticles because of its easily traceable fluorescent properties.

"What we found was that for brief exposures, iron absorption dropped by about 50 percent," said Mahler. "But when we extended that period of time, absorption actually increased by about 200 percent. It was very clear -- nanoparticles definitely affects iron uptake and transport."

While acute oral exposure caused disruptions to intestinal iron transport, chronic exposure caused a remodeling of the intestinal villi -- the tiny, finger-like projections that are vital to the intestine's ability to absorb nutrients -- making them larger and broader, thus allowing iron to enter the bloodstream much faster.

"The intestinal cells are a gateway that ingested nanoparticles must go through to get to the body," said Mahler. "We monitored iron absorption both in vivo and in vitro and found that the polystyrene nanoparticles affected the absorption process and caused a physiological response."

The next step for Mahler and the team is to take a look at whether similar disruptions in nutrient absorption could be possible in other inorganic elements such as calcium, copper and zinc. Also on the research agenda is the reaction of other nutrients such as fat-soluble vitamins A, D, E and K. And chickens and their intestines will definitely be part of this next phase of the study.

"The gastrointestinal tract of a chicken has very similar features to that of a human," said Mahler. "We can learn a great deal from the way chicken tissue works which means we can make better predictions about how humans will react."

And humans certainly consume enough nanoparticles -- about 100 trillion of them every day. Their ultra-small size and amazing qualities makes them increasingly common in food and pharmaceutical products. Although the impact of chronic exposure remains somewhat unknown, the ingestion of dietary particles is thought to promote a range of diseases, including Crohn's disease. With so many nanomaterials under development and with so much yet to be learned about nanoparticle toxicity and potential human tissue reactivity, Mahler and the team are hoping that their work, particularly the in vitro model, will provide an effective low-cost screening tool.

Journal Reference:

1. Gretchen J. Mahler, Mandy B. Esch, Elad Tako, Teresa L. Southard, Shivaun D. Archer, Raymond P. Glahn, Michael L. Shuler. Oral exposure to polystyrene nanoparticles affects iron absorption. Nature Nanotechnology, 2012; DOI: 10.1038/nnano.2012.3

Courtesy: ScienceDaily

Heart Attacks Rise Following Daylight Saving Time

Daylight-saving time this year begins March 11, and while we all might look forward to another hour of sunshine a University of Alabama at Birmingham expert says the time change is not necessarily good for your health.

"The Monday and Tuesday after moving the clocks ahead one hour in March is associated with a 10 percent increase in the risk of having a heart attack," says UAB Associate Professor Martin Young, Ph.D., in the Division of Cardiovascular Disease. "The opposite is true when falling back in October. This risk decreases by about 10 percent."

The Sunday morning of the time change doesn't require an abrupt schedule change, but, Young says, heart-attack risk peaks on Monday when most people rise earlier to go to work.

"Exactly why this happens is not known but there are several theories," Young says. "Sleep deprivation, the body's circadian clock and immune responses all can come into play when considering reasons that changing the time by an hour can be detrimental to someone's health."

Why is daylight-saving time tied to these? Young says:

• Sleep deprivation

"Individuals who are sleep-deprived weigh more and are at an increased risk of developing diabetes or heart disease. Sleep deprivation also can alter other body processes, including inflammatory response, which can contribute to a heart attack. And, your reaction to sleep deprivation and the time change also depends on whether you are a morning person or night owl. Night owls have a much more difficult time with springing forward."

• Circadian clock

"Every cell in the body has its own clock that allows it to anticipate when something is going to happen and prepare for it. When there is a shift in one's environment, such as springing forward, it takes a while for the cells to readjust. It's comparable to knowing that you have a meeting at 2 p.m. and having time to prepare your presentation instead of being told at the last minute and not being able to prepare. The internal clocks in each cell can prepare it for stress or a stimulus. When time moves forward, cell clocks are anticipating another hour to sleep that they won't get, and the negative impact of the stress worsens; it has a much more detrimental effect on the body."

• Immune function

"Immune cells have a clock, and the immune response depends greatly on the time of day. In animal studies, when a mouse is given a sub-lethal dose of LPS, an endotoxin that elicits strong immune responses in animals, the mouse's survival depends upon the time of day they were given this endotoxin. Mice that were put through a phased advance much like Daylight Savings Time, and then had a challenge to their immune system, died, whereas the control animals that were not subjected to a phased advance survive when given the same dose of LPS, showing how an acute time change can be detrimental to the immune system response."

Luckily, the body's clock eventually synchs with the environment, Young says. While some researchers are examining strategies to help the body resynch to time changes more rapidly, including pharmaceuticals to cure states like jet lag, he advocates a natural approach that eases your body into the adjustment.

Young suggests:

Wake up 30 minutes earlier on Saturday and Sunday than you need to in preparation for the early start on Monday Eat a decent-sized breakfast Go outside in the sunlight in the early morning Exercise in the mornings over the weekend (as long as you do not have pre-existing heart disease)

"Doing all of this will help reset both the central, or master, clock in the brain that reacts to changes in light/dark cycles, and the peripheral clocks -- the ones everywhere else including the one in the heart -- that react to food intake and physical activity. This will enable your body to naturally synch with the change in the environment, which may lessen your chance of adverse health issues on Monday."

He added that while melatonin can certainly influence sleep/wake cycles, and some people respond well to it and use it for jet lag, it does not necessarily work for everyone.

"For this one-hour time shift, I prefer the natural solution when possible."

Story Source:
The above story is reprinted from materials provided by University of Alabama at Birmingham, via Newswise. The original article was written by Jennifer Lollar.

Courtesy: ScienceDaily