Shawn's Health Blog: Feb 5, 2009

2/05/2009

Rabies vaccine may fight HIV

Rabies, a relentless, ancient scourge, may hold a key to defeating another implacable foe: HIV. Scientists at Jefferson Medical College in Philadelphia have used a drastically weakened rabies virus to ferry HIV-related proteins into animals, in essence, vaccinating them against an AIDS-like disease. The early evidence shows that the vaccine %26#8211; which doesn%26#8217;t protect against infection %26#8211; prevents development of disease.

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Reporting April 1, 2007 in the Journal of Infectious Diseases, the scientists showed that two years after the initial vaccination, four vaccinated non-human primates were protected from disease, even after being "challenged" with a dangerous animal-human virus. Two control animals developed an AIDS-like disease.

Matthias Schnell, Ph.D., professor of microbiology and immunology at Jefferson Medical College of Thomas Jefferson University, and his co-workers tested the effects of inserting two different viral proteins into the rabies virus genome, and using such viruses-based vaccines in preventing disease in rhesus macaques. One was a glycoprotein on the surface of HIV, while the other was an internal protein from simian immunodeficiency virus (SIV). They used the latter because HIV does not cause disease in monkeys.

The idea was that such rabies%26#8217; vehicles, or "vectors," would help attract a strong response from the animal%26#8217;s immune system, though the rabies virus used cannot cause disease. Such vectors are based on a type of rabies vaccine strain that has been used for more than 20 years in oral vaccines against rabies in wildlife in Europe. The study was aimed at studying the safety and effectiveness of the rabies vaccine approach against HIV and related diseases.

Four macaques were immunized with both vaccines, while two animals received only a weakened rabies virus. After they gave the animals an initial vaccination, they then tried two different immune system boosts, but didn%26#8217;t see enhanced immune responses. They then developed a new vector, a viral surface protein from another virus, vesicular stomatitis virus (VSV). Two years after the initial immunization, they gave a booster vaccine with the rabies-VSV vector, and saw SIV/HIV-specific immune responses.

The group then challenged the animals with SIV and measured various parameters of infection, such as immune system CD4 cell count, amount of virus in the bloodstream and immune system antibody response. They found that those animals that were given the test vaccine could control the infection. The control animals without the experimental vaccine had high levels of virus and a loss of CD4 cells.

"We still need a vaccine that protects from HIV infection, but protecting against developing disease can be a very important step," Dr. Schnell says, noting that he and his colleagues aren%26#8217;t sure how long the viral immunity will last.

According to Dr. Schnell, the study demonstrated a "proof of principle" %26#8211; that is, that the method used is technically possible. He says that the results indicate the need for future studies in larger groups of animals, and that these currently are underway. In addition, one key question remains unanswered: Is such a rabies-based vaccine feasible as an HIV vaccine in humans?

Source: Thomas Jefferson University

Need to balance out intake of omega-6 and omega-3 fatty acids or risk depression and inflammatory diseases

A new study suggests that people whose diets contain dramatically more of one kind of polyunsaturated fatty acid than another may be at greater risk for both clinical depression and certain inflammatory diseases.The report, published online this week in the journal Psychosomatic Medicine, suggests t...

The report, published online this week in the journal Psychosomatic Medicine, suggests that we need to balance out our intake of omega-6 and omega-3 fatty acids. The current typical American diet contains 20 times more omega-6 than omega-3, a ratio that researchers say should be lowered to 4-to-1, or even 2-to-1.

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This is the most recent in a long series of experiments Ohio State University researchers have conducted on the links between psychological stress and immunity. The addition of dietary questions to studies that have previously focused solely on emotional and biochemical markers may yield important new clues about the immune system.

"In this study, we're looking at the intersection of behavior, immune function and diet. In past experiments, we concentrated only on the first two," explained Jan Kiecolt-Glaser, professor of psychiatry and psychology at Ohio State and lead author on the paper.

"It now appears that diet is a very important variable in the equation as to how people respond to depression and stress."

The study, conducted in OSU's Institute for Behavioral Medicine Research, focused on a group of 43 middle-aged to elderly men and women, nearly half of which were the caregiver spouses of people with Alzheimer's or other dementias. By including caregivers who typically report greater stress and more depression than similar ad ults who are not caregiving, the researchers could look at how depression and diet might interact to affect inflammation.

Blood samples were drawn from each person in the study and tested for interleukin-6 (IL-6), tumor necrosis factor -alpha (TNF-alpha ) and the receptor molecule for IL-6. Participants also completed a survey questionnaire that gauged their level of depression.

The analysis showed that participants who had much more omega-6 -- compared to omega-3 -- fatty acids, and who also were reporting more symptoms of depression, had much higher levels of IL-6 and TNF-alpha, two cytokines which enhance inflammation.

"The data suggest that higher depression and a poorer diet in terms of omega-3 can work together to promote inflammation. Other researchers have shown that clinically depressed people -- those with more severe depression -- often have lower omega-3 levels in their blood, and several studies have shown that supplementing diets with omega-3 improves depression," Kiecolt-Glaser said, although the reason isn't clear.

"People who are depressed don't eat well, or it might be that there is something about depression that affects how well people process such foods."

In recent years, research has shown that an increase in omega-3 fatty acids in the diet has specific health benefits, especially in patients with depression, cardiovascular disease and inflammatory and autoimmune diseases.

Martha Belury, an associate professor of human nutrition, endocrinology, diabetes %26amp; metabolism at Ohio State and co-author of the study, said the design of the study was important.

"We looked at people who were experiencing real depression, not those whose depression arose as a part of some experiment, and we could clearly see a relationship between lower omega-3 fatty acids and certain markers of depression and inflammation."

Belury said that current recommendations allow up to two servings each week of cold-water fish %26#8211; the best source of omega-3 %26#8211; such as salmon or trout. This would not apply to pregnant women, she said, where concerns are greater about the heavy metal contamination such fish might contain. Omega-3 is also available as nutritional supplements

"This study has shown that even in people who did not take supplements, maybe just a little bit more omega-3, could help reduce their markers for both stress and depression," Belury said.

"The important message for consumers is that they don't have to take mega-doses of omega-3 to have some impact. It might not take a whole lot to have a significant clinical impact," Belury said.

The researchers are now starting a larger, more comprehensive randomized and controlled trial of omega-3 in adults between the ages of 50 and 80 in hopes of testing the questions raised in this pilot study.

Source: Ohio State University

A laser, white light, and reflective tube rapidly measure multiple chemicals in body fluids

University of Rochester researchers announce in the current issue of Applied Optics a technique that in 60 seconds or less measures multiple chemicals in body fluids, using a laser, white light, and a reflective tube. The technique tests urine and blood serum for common chemicals important to monitoring and treatment of diabetes and cardiovascular, kidney, urinary and other diseases, and lends itself to the development of fast batch testing in hospitals and other clinical settings.

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Co-researchers Andrew J. Berger, associate professor of optics, and Dahu Qi, doctoral candidate, used low-refractive-index tubes instead of cuvettes or other bulky containers for holding biological specimens. And, to get more information from the fluids, they used white light%26#8212;like that from an ordinary light bulb%26#8212;along with the laser. The tubes and light bulbs made all the difference.

In the laser technique called Raman spectroscopy, scientists shine laser light onto molecules and the light scatters off, gaining or losing energy. A spectrograph translates the changed energies into spectra. Each chemical presents a Raman spectrum that scientists recognize. The Raman approach is a favorite for finding chemicals that overlap and mix in fluid, much like musical instruments in an orchestra. But Raman spectroscopy comes with a problem.

Raman signal is notoriously weak. Using it to test biofluids, with their lighter chemical concentrations than in many fluids, is not a natural choice. Berger and Qi injected fluid samples into a thin transparent tube specially made to contain the light, and the tube's long path length of interaction let the scientists collect more Raman scattering. "The tubes have a refractive index lower than water, so the light bounces along inside the liquid core, just as in solid optical fibers for telecommunications," said Berger. "Other groups had used these fibers to strengthen their Raman signals, so we wanted to see if we could translate that advantage to use with biofluids."

They did get the stronger signal they were looking for, but the increase threw off measurements when samples of urine or blood serum varied in color.

In previous experiments, Berger and his team had explored how a concentration of each chemical relates to the strength of Raman signal. It turned out the relationship is not a simple linear one. They were able to use that information for dealing with differences in sample color.

"We can't neglect that body fluid samples absorb light," said Berger. "We'd have two different samples with the same amount of protein and not get the same strength of signal. If we had two samples of blood serum, maybe one sample would be a little pinker due to a few ruptured red blood cells. Then we wouldn't get the same signal strength."

The solution flashed like a light bulb. The scientists sent a beam of white light through each sample to see how much light was absorbed at various wavelengths, and then they calculated corrections. It was easy enough to inject the light by using the end of the tube opposite the laser. The resulting corrections made chemical predictions significantly more accurate.

The team measured 11 chemicals in blood serum, including total protein, cholesterol, LDL and HDL levels, glucose, triglyceride, albumin, bilirubin, blood urea nitrogen, globulin, and CO2. In urine, they identified urea nitrogen and creatinine. The technique does not measure ions such as calcium or sodium, or other chemicals present at concentrations below about 0.01 mg/mL.

Spectral tests use no chemical reagents and therefore offer the advantage of being nondestructive to fluid samples, unlike many lab tests. After analysis, practitioners could use undamaged samples for other kinds of tests.

"We squeeze a small amount of fluid into the tube," said Berger. "In 10 or 20 seconds, we have a chemical breakdown, and we can see the presence of a lot of chemicals all at once. There's no chemistry performed, and there's no touching of the fluid."

The tubing doesn't just help with the signal strength; it also makes it easy to move biofluids around. "We pump a sample into the tube, pass some light through it, and send it along its way%26#8212;and then we're all set to pump in the next one," said Berger.

Source: University of Rochester

New medical device may "sniff out" diseases such as Alzheimer’s and Parkinson’s

A new medical device in development by University of Cincinnati researchers may sniff out olfactory disorders that could be an early warning of Alzheimers disease, Parkinsons disease and other problems outside the typical sensory loss associated with aging. The Sniff Magnitude Test (SMT), an inventi...

A new medical device in development by University of Cincinnati researchers may sniff out olfactory disorders that could be an early warning of Alzheimer%26#8217;s disease, Parkinson%26#8217;s disease and other problems outside the typical sensory loss associated with aging. The Sniff Magnitude Test (SMT), an invention of UC Psychology Professor Robert Frank and Professor Emeritus Robert Gesteland of the UC Department of Cell Biology, is now under further development with the WR Medical Electronics Company in Stillwater, Minn. The company will manufacture and market the test.

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The Sniff Magnitude Test project, a creation that was seven years in the making, was awarded a total of $1,340,098 from the National Institutes of Health in developmental funding. UC Psychology Professor Robert Frank says that in the near future, UC researchers will begin testing five different prototypes of the SMT built by WR Medical Electronics. Currently, Frank says an earlier model of the SMT is being tested in a high-profile clinic in Germany as well as at the University of Pennsylvania. Frank says the SMT customer base would be primarily otolaryngologists and neurologists.

%26#8220;The whole test is based on the very simple observation that when you sniff and you detect a smell, you take a smaller sniff than if you inhaled and didn%26#8217;t detect a smell,%26#8221; Frank explains. %26#8220;For someone with normal sense of smell, the size of the sniff when detecting an odor is cut in half. For someone who cannot detect odor, the size of the sniff for just air and the size of the sniff for an odor are the same.%26#8221;

In humans, Frank says the sense of smell is one of our less robust senses. He says it%26#8217;s more susceptible to harm because there is less neurological machinery in the brain devoted to processing the sense of smell. %26#8220;So, that%26#8217;s the reason it might be acting a little bit like the canary in the mineshaft. Because it%26#8217;s more fragile, when you have insult to the brain, it may be sensitive to loss earlier in the disease process.%26#8221;

Frank adds that because smells don%26#8217;t have to be identified as part of the Sniff Magnitude Test, the test can be used on adults as well as children (who may be too young to link a smell with a name) and people representing international cultures (who are unfamiliar with some common odors in the U.S.). %26#8220;What%26#8217;s also unique about this test is that it does not require a good memory, which is an issue in testing people with Alzheimer%26#8217;s or some other dementia-related disease,%26#8221; Frank says. %26#8220;For instance, other tests ask, %26#8216;Does this smell like garlic?%26#8217; or, %26#8216;Does this smell like tar, or roses?%26#8217; Once there%26#8217;s a problem with memory, this kind of test would be difficult.%26#8221;

So what does it mean if a child, or someone unlikely to have an age-related disease, flunks the sniff test? %26#8220;If they fail our test, that%26#8217;s a pretty good indication that there%26#8217;s something wrong with their sense of smell. Maybe there%26#8217;s an obstruction %26#8211; a deviated septum or polyps,%26#8221; Frank says. %26#8220;Perhaps the olfactory nerve has been damaged due to a head injury or a viral infection.%26#8221;

For those who are proud of their keen sense of smell, this is not a test to tickle their senses. Because the really nasty smells worked best for the Sniff Magnitude Test, Frank says the test subjects get a whiff of three odors: a blend of ripe cheese and rancid meat, a fragrance that combines a burning smell with a skunk-like smell, and amyl acetate, which smells like banana. %26#8220;You have to get people to really suppress the sniff and that%26#8217;s why the bad odors work so well,%26#8221; explains Frank. %26#8220;To a certain extent, we put the banana smell in there to give them a little break.%26#8221;

Frank adds that his current research is exploring the patterns of loss of smell that could be an indicator of Alzheimer%26#8217;s. He says the Sniff Magnitude Test is also getting a look by researchers at the Rush University Medical Center in Chicago as part of a major epidemiological study on aging, Alzheimer%26#8217;s disease and sense of smell.

Source: University of Cincinnati

Studying the geometry of viruses will help develop new anti-viral strategies

A mathematician at the University of York has been awarded a Research Leadership Award of more than ��700,000 by the Leverhulme Trust to study the geometry of viruses.Dr Reidun Twarock, an Anniversary Reader in the Departments of Biology and Mathematics, will study the structure and assembly of virus...

A mathematician at the University of York has been awarded a Research Leadership Award of more than %26#163;700,000 by the Leverhulme Trust to study the geometry of viruses.

Dr Reidun Twarock, an Anniversary Reader in the Departments of Biology and Mathematics, will study the structure and assembly of viruses, which will help to develop new anti-viral strategies.

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Viruses have highly symmetrical external shells formed from proteins that encapsulate the viral genome. Dr Twarock has developed a method for encoding the structures of these protein shells that pinpoint the locations of the proteins and the bonds between them. With collaborators Professor Cristian Micheletti, from the International School for Advanced Studies (SISSA) in Trieste, Italy, and Professor Anne Taormina, from the University of Durham, she has used these results to model the assembly of viruses.

Subsequent work with collaborators Professor Peter Stockley, Dr Neil Ranson and their groups at the Astbury Centre for Structural Molecular Biology at the University of Leeds suggests that not only the geometry of the viral capsids themselves but also the full three-dimensional structures of the particles are constrained. The implications of this discovery on virus assembly are currently being investigated.

Dr Twarock said: "I would like to use the Leverhulme Trust Award to build up a group of mathematicians, computational biologists and biophysicists to address a portfolio of projects arising from these results."

Source: University of York

Rabies vaccine may fight HIV

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Source: Thomas Jefferson University

Protein discovery may help limit body's capacity to store fat

A new "platform" with a crucial role in the body's ability to process and take up fat from the diet has been found, according to a report in the April issue of the journal Cell Metabolism, published by Cell Press.Researchers discovered a protein that sits on the inner surfaces of capillaries, where ...

Researchers discovered a protein that sits on the inner surfaces of capillaries, where it delivers "packages" of dietary fat from the bloodstream to enzymes that prepare them for entry into cells of the body. Once inside cells, the fats are either burned as a rich source of energy or stored for later use.

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"We've found a new, very important partner in a process people thought they understood 20 years ago," said Anne Beigneux of the University of California, Los Angeles.

While it is too soon to say whether the finding will have clinical implications%26#8212;in efforts to limit the body's capacity to store fat, for instance%26#8212;one thing is for certain: "Soon, every biochemistry book will have to be revised," she said.

Dietary fats in mammals are packaged by the intestine into "chylomicrons," which are large triglyceride-rich lipoproteins, Beigneux explained. After reaching the bloodstream, the triglycerides within chylomicrons are broken down by an enzyme found along the surface of capillaries, mainly in the heart, skeletal muscle, and fat tissue. In those tissues, the so-called lipoprotein lipase enzyme is synthesized, secreted, and transported to the capillaries, where the packaged lipids are taken apart.

The fat "bundles" have to be broken down because the lipids are otherwise unable to get across cell membranes, Beigneux added.

The researchers "stumbled onto" a new player in the process after a team at Genentech found mutant mice with severe chylomicronemia, a condition in which the inability to properly process dietary fat leads to high levels of blood triglycerides.

The mice%26#8212;which lacked a gene called glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1, or Gpihbp1%26#8212;exhibited a striking accumulation of chylomicrons in the plasma, even on a low-fat diet, the researchers report. The animals' deficiency caused their blood plasma to become milky as their blood triglyceride levels skyrocketed. Normally, the lipoprotein-binding protein is found at high levels in heart and adipose tissue, the same tissues that express high levels of the enzyme that breaks chylomicrons down, they report.

The researchers conclude that GPIHBP1 is crucial for chylomicron processing. It is located on the inner surface of the capillary and binds both chylomicrons and the processing enzyme, likely forming a platform for lipid breakdown and playing an important role in the delivery of lipid nutrients to cells.

The findings might have direct implications for patients with chylomicronemia, Beigneux said. The disorder in humans has been linked only to defects in the genes encoding the lipid-degrading enzyme or its cofactor, she explained.

"Now, anybody who has chylomicronemia without one of those mutations should be looked at for a mutation in [this platform protein, GPIHBP1]," she said.

Source: Cell Press

Intensive psychotherapy helps treat bipolar disorder

New results from the largest federally funded bipolar study ever conducted show that patients who receive psychotherapy in addition to medication get better faster from bipolar disorder's debilitating depression and stay better longer, according to a University of Colorado at Boulder researcher invo...

Part of a $26.8 million effort, the study found that adding intensive psychotherapy to a bipolar patient's medication treatment made them one and a half times more likely to be clinically well during any month of the study year, compared with a group that didn't receive intensive therapy, according to CU-Boulder psychology Professor David Miklowitz, the principal author of the study.

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"The take home message here is that psychotherapy is a vital part of the effort to stabilize episodes of depression in people suffering from bipolar disorder," Miklowitz said. "If you get regular intensive therapy, the outcome for depression is going to be better than if you just take medications and have a couple of case management sessions."

The results of the study were published today in the April edition of the journal Archives of General Psychiatry.

Medication is the first line of defense against the disease, also called manic depression. Bipolar disorder is inherited and caused by a biochemical imbalance in the brain. It affects an estimated 5.7 million Americans, many of whom develop the disorder in their teens or as young adults.

While psychotherapy is routinely used to treat bipolar disorder, its effectiveness up until now has been unclear, according to Miklowitz. The seven-year study involved 293 people suffering from bipolar depression who were already taking medication. The participants, who were treated in 15 sites across the country, were randomly assigned to one of three types of standardized, intensive, nine-month psychotherapies, or to a control group that received a brief psychotherapy program that involved three sessions of education about the disorder.

The three types of intensive therapies included a family-focused therapy that involves participants' family members and focuses on family coping, communication and problem-solving; cognitive behavioral therapy that focuses on helping the patient understand and cope with distortions in thinking and activity; and interpersonal and social rhythm therapy that focuses on stabilizing daily and nightly routines and solving key relationship problems.

After one year, 64 percent of those in the intensive psychotherapy groups had recovered from the episode of depression that brought them into treatment, compared with 52 percent in the control group. Patients in intensive psychotherapy also recovered an average of 110 days faster than those in the control group. None of the three therapies appeared to be significantly more effective than the others, although rates of recovery from depression were highest among those in family-focused therapy, Miklowitz said.

While fully controlling the ups and downs of bipolar disorder is not possible, doctors can delay patients' relapses into debilitating periods of depression and manic behavior. Relapses of the disorder can split up marriages, cause job loss and even lead to suicide, according to Miklowitz.

"You need drugs like lithium as a first-line offense against depression, but then the question becomes 'What if the person is not responding right away?' " Miklowitz said. "That's when therapy may be the missing ingredient. We're not saying you should get therapy instead of medication. It's therapy on top of medication."

Getting the treatments into the community will be a challenging task. "There also has to be a consciousness among clinicians that bipolar people benefit most from learning skills to cope with the disorder, rather than just generic counseling," he said. "Teaching patients and family members how to immediately recognize and get treatment for emerging symptoms is essential."

Source: University of Colorado, Boulder

Genes may help people's ability to stop smoking

Scientists supported by the National Institute on Drug Abuse (NIDA), part of the National Institutes of Health, have for the first time identified genes that might increase a person%26#8217;s ability to abstain from smoking. The breakthrough research was conducted by Dr. George Uhl at NIDA%26#8217;s Intramural Research Program and a team led by Dr. Jed Rose at the Center for Nicotine and Smoking Cessation Research at Duke University Medical Center.

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The study, published in the journal BMC Genetics, available on line April 2, brings researchers a step closer toward tailoring individualized drug therapy for addiction based on an individual%26#8217;s unique genetic makeup.

%26#8220;This research marks the first time we%26#8217;ve been able to identify genes involved in the ability to quit smoking,%26#8221; says NIDA Director Dr. Nora D. Volkow. %26#8220;It marks a movement from identifying the genetics of addiction vulnerability to identifying the genetic basis of successful abstinence. This knowledge could impact the success rate of cessation programs by helping health care providers choose the most appropriate treatment based on individual differences.%26#8221;

Dr. Uhl and his colleagues performed a genome-wide analysis on the DNA of two types of nicotine-dependent individuals, one that was able to successfully quit the cigarette- smoking behavior and one that was not.

%26#8220;We identified 221 genes that distinguished successful quitters from those who were unsuccessful,%26#8221; says Dr. Uhl. %26#8220;We know the functions of about 187 of these genes, but 34 have functions that are unknown at present. We also found that at least 62 of the genes that we had previously identified as playing roles in dependence to other drugs also contribute to nicotine dependence.%26#8221;

Genes that harbor variants that contribute to both success in quitting smoking and in vulnerability to become dependent on multiple substances include cadherin 13 (a molecule involved in cell adhesion, which governs how cells recognize and connect to their neighbors) and a cyclic G-dependent protein kinase gene, which plays a key role in normal brain development. In addition to genes implicated in intracellular signaling and intercellular interactions, a number of genes involved in other processes have also been identified. While many of the genes identified through this effort make sense because of their role in supporting new neural connections in the brain, more research is now needed to understand the actual mechanisms through which they may increase or reduce the rates of successful quitting.

Dr. Uhl says he and his colleagues have replicated this research in another sample, as he reported at the February 2007 meeting of the Society for Research on Nicotine and Tobacco.

%26#8220;These findings provide ample justification for continuing the search for even more genetic variants associated with smoking cessation success,%26#8221; says Dr. Volkow. %26#8220;We soon may be able to make use of this information to match treatments with the smokers most likely to benefit from them.%26#8221;

Source: NIH

Researchers synthesize 10 different flavanones, a type of flavonoid

Flavonoids. Youve heard of them -- the good-for-your-health compounds found in plants that we enjoy in red wine, dark chocolate, green tea and citrus fruits. Mother Nature is an ace at making them, producing different ones by the thousands, but no chemist has figured out a good way to synthesize a s...

Flavonoids. You%26#8217;ve heard of them -- the good-for-your-health compounds found in plants that we enjoy in red wine, dark chocolate, green tea and citrus fruits. Mother Nature is an ace at making them, producing different ones by the thousands, but no chemist has figured out a good way to synthesize a special class of these chemicals in the laboratory. Until now.

Karl Scheidt, assistant professor of chemistry in the Weinberg College of Arts and Sciences at Northwestern University, and his research team have synthesized 10 different flavanones, a type of flavonoid, using a new general method they developed that takes advantage of one simple catalyst.

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The basic research gives chemists -- for the first time -- a method for making new molecules based on flavonoids, setting the stage for the development of new cancer therapeutics. The team%26#8217;s findings will be reported today in the April 4 issue of the Journal of the American Chemical Society.

Flavonoids, a broad family with more than 2,000 reported compounds, provides many different structures for chemists to investigate. In addition to those with anti-cancer activity, researchers could mimic flavonoids with beneficial properties such as anti-inflammatory, anti-viral or antibiotic.

The natural sources of the flavanones Scheidt chose to mimic? Milk thistle, soy, grapefruit and kosam, a root used in traditional Korean medicine, to name a few. All are known for their anti-cancer properties.

"I%26#8217;m using nature as an inspiration for the development of new anti-tumor products," said Scheidt, who now will focus on using his method to develop molecules that will be effective against prostate cancer. "We have developed an enabling technology that opens up a new opportunity to make these flavanone compounds from scratch and to design them to do many things, including fight cancer. A better understanding of the flavanones%26#8217; modes of action will help us improve their potential for use in medicine."

Scheidt says prostate cancer, second only to lung cancer as the leading cause of cancer-related deaths in men, is an important target. He is collaborating with Raymond Bergan, M.D., a clinical oncologist at Northwestern%26#8217;s Feinberg School of Medicine who often treats prostate cancer patients who have run out of therapeutic options. The two were brought together through their involvement with the University%26#8217;s Center for Drug Discovery and Chemical Biology.

"Our goal is to keep cancer cells local, and some of the new molecules Karl already has made inhibit the motility of prostate cancer cells -- they stop the cells dead in their tracks," said Bergan, associate professor of hematology and oncology. "It is important for us to understand how these synthetic flavanones work because combination therapies are going to be the future in cancer treatment, much like we see with HIV. We need multiple compounds with different modes of action: one that stops cells from moving, another that kills cells where they are and a third that lets the body%26#8217;s immune system do its work. Karl and his team have opened this door."

"We are really excited to work on flavonoids with anti-cancer properties so we can selectively modify these natural products," said Scheidt. "We want to get selectivity and specificity using chemistry. A naturally occurring flavonoid may not have all the characteristics you want -- it may not be potent enough, for example -- but with chemistry you can go in and modify that structure, imbuing the molecule with more desirable traits, such as binding more effectively to a protein of interest or being less toxic to normal cells."

The biosynthesis of flavanones is not well understood; for years organic chemists have struggled to find a good way to make them in the lab. The difficulty was figuring out how to produce a desired molecule in one-handed form, as is found in nature.

In attacking this age-old problem, Scheidt and his team discovered a simple chiral catalyst, which comes from quinine, that successfully controls the chemical outcome and produces a left-handed molecule or a right-handed molecule, not a one-to-one mixture of both.

"Flavanones are chiral molecules, which come in two %26#8216;flavors,%26#8217;" said Scheidt, who is left-handed and says he has been sensitive to handedness all his life. "We have a method to make just one %26#8216;flavor,%26#8217; which no one has done before. Chiral molecules come in mirror images of the other, or two different %26#8216;hands.%26#8217; Like your own hands, you can%26#8217;t superimpose one hand on the other. In both people and molecules, a left hand and a right hand are very similar but are not the same. In synthesizing flavonoids, you want to make one handedness over the other."

Most therapeutics used today are chiral molecules that are synthesized to be either right- or left-handed. Controlling this is very important, said Scheidt, because a one-to-one mixture of right- and left-handedness in a drug could pose a serious problem, as was discovered with the medication thalidomide in the 1950s. The left handed version of thalidomide helped pregnant women combat morning sickness, but the right handed compound was a teratogen, causing children to be born with malformations, such as missing limbs. (Ibuprofen also is a one-to-one mixture with one hand as the active ingredient; the mirror image does nothing.)

After much trial and error in the lab, Scheidt and his colleagues hit upon a catalyst that, when added to other simple materials, produced a complex one-handed molecule like the flavonoids found in nature, with the core structure intact. (They tested 30 to 40 catalysts in different conditions over a period of six months before discovering the right one.) The catalyst is an organic molecule that sparks this impressive transformation through hydrogen bonding, which is used frequently in nature.

"Nature is the ultimate synthetic chemist and pharmacist," said Scheidt, who looks forward to synthesizing and evaluating new compounds with Bergan. "We may not be quite as sophisticated as nature, but our catalyst works beautifully. Small molecules can do really big things."

Source: Northwestern University

Plant hormone research has important implications for treatment of human disease

For the first time, scientists from the University of Washington School of Medicine, Indiana University Bloomington and the University of Cambridge have determined how a plant hormone -- auxin -- interacts with its hormone receptor, called TIR1. Their report, on the cover of this week's issue of Nature, also may have important implications for the treatment of human disease, because TIR1 is similar to human enzymes that are known to be involved in cancer.

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"Learning that auxin regulates TIR1 is a huge advance for plant biology that will probably have important implications for agriculture in the future," said IU Bloomington plant biologist Mark Estelle. "It's a bonus for us that TIR1 is related to proteins in other organisms, including humans. Some of TIR1's human relatives play a role in different human cancers, and it is possible that our work on plants will eventually lead to new cancer drugs."

Until now it was believed enzymes like TIR1, called ubiquitin ligases, could only be controlled through protein-protein interactions. Ubiquitin ligases influence growth and light response in plants, poison mitigation in yeasts and also cancerous cell division in humans.

"Although ubiquitin ligases have long been recognized as potential drug targets for treating cancers and other human diseases, it's been a bumpy road for scientists to come up with a feasible approach," said University of Washington School of Medicine pharmacologist Ning Zheng, who led the research. "The mechanism by which auxin works points out a new direction for us to develop therapeutic compounds targeting ubiquitin ligases."

The scientists extracted and purified TIR1 from the common plant model Arabidopsis. By x-raying crystals of the protein, Zheng, Estelle and colleagues determined the enzyme's three-dimensional structure -- a first for plant hormone receptors. The scientists then soaked the crystal in a solution containing auxin and repeated the x-ray treatment to determine where the auxin had bound. Finally the scientists added a peptide that TIR1 is known to bind and modify.

The scientists learned that auxin is a sort of "molecular glue" that improves the ability of TIR1 to bind its peptide target. In the absence of auxin, TIR1 does not bind its target as tightly.

Because the architecture of TIR1 is highly conserved among other ubiquitin ligases, including those in human cells, the scientists expect other ubiquitin ligases may be affected by small molecules like auxin. Organic chemists could, hypothetically, synthesize such molecules as a new type of cancer drug.

"A number of human disorders including Parkinson's disease, and colon and breast cancers, are caused by defective interactions between ubiquitin ligases and their substrate polypeptides. What the plant hormone tells us is that it might be possible to rescue these interactions using small molecules," said Zheng.

Two teams of scientists reported in May 2005 (also in Nature) that TIR1 is, in fact, a receptor for auxin. Estelle led one of the two teams; Ottoline Leyser of the University of York led the other. The discovery put to end conjecture about how auxin initiates growth and light response in plants, but it also caught the attention of those studying the molecular biology and biochemistry of human ubiquitin ligases.

Source: Indiana University

Study - Dieting does not work

Will you lose weight and keep it off if you diet? No, probably not, UCLA researchers report in the April issue of American Psychologist, the journal of the American Psychological Association."You can initially lose 5 to 10 percent of your weight on any number of diets, but then the weight comes back...

Will you lose weight and keep it off if you diet? No, probably not, UCLA researchers report in the April issue of American Psychologist, the journal of the American Psychological Association.

"You can initially lose 5 to 10 percent of your weight on any number of diets, but then the weight comes back," said Traci Mann, UCLA associate professor of psychology and lead author of the study. "We found that the majority of people regained all the weight, plus more. Sustained weight loss was found only in a small minority of participants, while complete weight regain was found in the majority. Diets do not lead to sustained weight loss or health benefits for the majority of people."

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Mann and her co-authors conducted the most comprehensive and rigorous analysis of diet studies, analyzing 31 long-term studies.

"What happens to people on diets in the long run?" Mann asked. "Would they have been better off to not go on a diet at all? We decided to dig up and analyze every study that followed people on diets for two to five years. We concluded most of them would have been better off not going on the diet at all. Their weight would be pretty much the same, and their bodies would not suffer the wear and tear from losing weight and gaining it all back."

People on diets typically lose 5 to 10 percent of their starting weight in the first six months, the researchers found. However, at least one-third to two-thirds of people on diets regain more weight than they lost within four or five years, and the true number may well be significantly higher, they said.

"Although the findings reported give a bleak picture of the effectiveness of diets, there are reasons why the actual effectiveness of diets is even worse," Mann said.

Mann said that certain factors biased the diet studies to make them appear more effective than they really were. For one, many participants self-reported their weight by phone or mail rather than having their weight measured on a scale by an impartial source. Also, the studies have very low follow-up rates %26#8212; eight of the studies had follow-up rates lower than 50 percent, and those who responded may not have been representative of the entire group, since people who gain back large amounts of weight are generally unlikely to show up for follow-up tests, Mann said.

"Several studies indicate that dieting is actually a consistent predictor of future weight gain," said Janet Tomiyama, a UCLA graduate student of psychology and co-author of the study. One study found that both men and women who participated in formal weight-loss programs gained significantly more weight over a two-year period than those who had not participated in a weight-loss program, she said.

Another study, which examined a variety of lifestyle factors and their relationship to changes in weight in more than 19,000 healthy older men over a four-year period, found that "one of the best predictors of weight gain over the four years was having lost weight on a diet at some point during the years before the study started," Tomiyama said. In several studies, people in control groups who did not diet were not that much worse off %26#8212; and in many cases were better off %26#8212; than those who did diet, she said.

If dieting doesn't work, what does?

"Eating in moderation is a good idea for everybody, and so is regular exercise," Mann said. "That is not what we looked at in this study. Exercise may well be the key factor leading to sustained weight loss. Studies consistently find that people who reported the most exercise also had the most weight loss."

Diet studies of less than two years are too short to show whether dieters have regained the weight they lost, Mann said.

"Even when you follow dieters four years, they're still regaining weight," she said.

One study of dieting obese patients followed them for varying lengths of time. Among those who were followed for fewer than two years, 23 percent gained back more weight than they had lost, while of those who were followed for at least two years, 83 percent gained back more weight than they had lost, Mann said. One study found that 50 percent of dieters weighed more than 11 pounds over their starting weight five years after the diet, she said.

Evidence suggests that repeatedly losing and gaining weight is linked to cardiovascular disease, stroke, diabetes and altered immune function. Mann and Tomiyama recommend that more research be conducted on the health effects of losing and gaining weight, noting that scientists do not fully understand how such weight cycling leads to adverse health effects.

Mann notes that her mother has tried different diets, and has not succeeded in keeping the weight off. "My mother has been on diets and says what we are saying is obvious," she said.

While the researchers analyzed 31 dieting studies, they have not evaluated specific diets.

Medicare raised the issue of whether obesity is an illness, deleting the words "Obesity is not considered an illness" from its coverage regulations in 2004. The move may open the door for Medicare to consider funding treatments for obesity, Mann noted.

"Diets are not effective in treating obesity," said Mann. "We are recommending that Medicare should not fund weight-loss programs as a treatment for obesity. The benefits of

dieting are too small and the potential harm is too large for dieting to be recommended as a safe, effective treatment for obesity."

From 1980 to 2000, the percentage of Americans who were obese more than doubled, from 15 percent to 31 percent of the population, Mann noted.

A social psychologist, Mann, taught a UCLA graduate seminar on the psychology of eating four years ago. She and her students continued the research when the course ended. Mann's co-authors are Erika Westling, Ann-Marie Lew, Barbra Samuels and Jason Chatman.

"We asked what evidence is there that dieting works in the long term, and found that the evidence shows the opposite" Tomiyama said.

Source: University of California, Los Angeles

How the brain stops us from doing stupid things

As wise as the counsel to "finish what you've started" may be, it is also sometimes critically important to do just the opposite -- stop. And the ability to stop quickly, to either keep from gunning the gas when a pedestrian steps into your path or to bite your tongue mid-sentence when the subject o...

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Researchers led by cognitive neuroscientist Adam Aron, an assistant professor of psychology at the University of California, San Diego, have found white matter tracts -- bundles of neurons, or "cables," forming direct, high-speed connections, between distant regions of the brain -- that appear to play a significant role in the rapid control of behavior.

Published in the April 4 issue of the Journal of Neuroscience, the study is the first to identify these white matter tracts in humans, confirming similar findings in monkeys, and the first to relate them to the brain's activity while people voluntarily control their movements.

"Our results provide important information about the correspondence between the anatomy and the activity of control circuits in the brain," Aron said. "We've known for some time about key brain areas involved in controlling behavior and now we're learning how they're connected and how it is that the information can get from one place to the other really fast."

"The findings could be useful not only for understanding movement control," Aron said, "but also 'self-control' and how control functions are affected in a range of neuropsychiatric conditions such as addiction, Tourette's syndrome, stuttering and Attention Deficit Hyperactivity Disorder."

To reveal the network, Aron and researchers from UCLA, Oxford University and the University of Arizona performed two types of neuroimaging scan on healthy volunteers.

They used diffusion-weighted MRI, in 10 subjects, to demonstrate the "cables" between distant regions of the brain known to be important for control, and they used functional MRI, in 15 other subjects, to show that these same regions were activated when participants stopped their responses on a simple computerized "go-stop" task.

One of the connected regions was the subthalamic nucleus, within the deep-seated midbrain, which is an interface with the motor system and can be considered a "stop button" or the brake itself. A second region was in the right inferior frontal cortex, a region near the temple, where the control signal to put on the brakes probably comes from.

"This begs the profound question," Aron said, "of where and how the decision to execute control arises."

While this remains a mystery, Aron noted that an additional, intriguing finding of the study was that the third connected node in the network was the presupplementary motor area, which is at the top of the head, near the front. Prior research has implicated this area in sequencing and imagining movements, as well as monitoring for changes in the environment that might conflict with intended actions.

The braking network for movements may also be important for the control of our thoughts and emotions.

There is some evidence for this, Aron said, in the example of Parkinson's patients. In the advanced stages of disease, people can be completely frozen in their movements, because, it seems, their subthalamic nucleus, or stop button, is always "on." While electrode treatment of the area unfreezes the patients' motor system, it can also have the curious effect of disinhibiting them in other ways. In one case, an upstanding family man became manic and hypersexual, and suddenly began stealing money from his wife to pay for prostitutes.

Examples like these motivate Aron to investigate the generality of the braking mechanism.

"The study gives us new targets for studying how the brain relates to behavior, personality and genetics," Aron said. "Variability in the density and thickness of the 'cable' connections is probably influenced by genes, and it would be intriguing if these differences explained people's differing abilities not only to control the swing of a bat but also to control their temper."

Source: University of California, San Diego

New approach to studying how immune cells respond to pathogens

A Sandia National Laboratories research team led by Anup Singh is taking a new approach to studying how immune cells respond to pathogens in the first few minutes and hours of exposure. Their method looks at cells one at a time as they start trying to fight the invading pathogens.Called the Microsca...

Called the Microscale Immune Studies Laboratory (MISL) Grand Challenge, the work is in its second of three years of funding by the internal Laboratory Directed Research and Development (LDRD) program. Sandia is partnering on the project with the University of Texas Medical Branch at Galveston and the University of California, San Francisco (UCSF).

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Singh says the researchers are interested in studying the early events in immune response when a pathogen invades a body. Understanding the early steps could lead to better ways to diagnose and stop disease before there are symptoms and development of more effective therapeutics.

Most existing research into how immune cells respond has been done by looking at large cell populations. The Sandia researchers say information gathered from a large population of cells may mask underlying mechanisms at the individual cell level.

"Cells have different life cycles, just like any living being. And not all cells are exposed to the pathogen at the same time," Singh says. "We wanted to look at cells in the same life cycle and same infectious state. This can only be done cell by cell. We also want to study populations, but one cell at a time."

The research is possible because of advances in several Sandia-developed tools, including:

-- Microfluidics that allows researchers to do single-cell experiments

-- Advanced imaging that allows researchers to image individual cells with much higher information content than possible with current commercial imaging technologies

-- Powerful computational modeling that allows researchers to make sense of data obtained from microfluidic analysis and imaging

Real immune cells are short-lived outside of bodies. To do the type of experiments they wanted, the researchers needed cells that can stay alive more than a couple of hours, have the ability grow and represent a relevant model of human immune cells. They obtained "immortalized mouse immune cells" from a collaborator at UCSF that have the needed life span, and are accepted as a model system by the immunology research community.

"We're starting with robust and well-characterized cells, which really simplifies development of our new technologies and methods," Singh says. "We'll soon be working with other cell types, though, like white blood cells directly isolated from human patients. Our approach is designed to be flexible enough to handle many different cell types, and it also minimizes the number of cells needed for analysis, so it should enable us to do some unique studies on rare cell types."

Proteins in the cells of interest are tagged with fluorescent molecules, essentially colored dyes. The dyes range from green to red and give researchers the opportunity to track proteins and see, for example, the dynamic cellular production of proteins or protein-binding processes inside or on the surface of the cells.

The team is developing one platform with two complementary microfluidic modules -- one for trapping and imaging viable cells during stimulation with pathogens. The other combines cell preparation steps, cell selection and sorting followed by analysis of protein content in the selected cell subpopulations.

"In effect, we are taking many work-horse technologies such as confocal microscopy, flow cytometry and immunoassays and combining them into one compact, miniaturized platform using our unique microfluidic and imaging tools," Singh says.

Hyperspectral fluorescence imaging with multivariate curve resolution (MCR) is used to image the tagged proteins and provide quantitative measurements on multiple proteins simultaneously. The goal is to analyze as many as 10 to 40 proteins and cellular stains at a time in three dimensions.

The end results of the imaging and protein analysis are large amounts of data that must be categorized and understood. Computational modeling is then used to develop network models from experimental data and predictive modeling generates hypotheses to be tested next.

Singh says using an integrated microfluidic platform sets Sandia apart from the rest of the world. Sandia researchers have been working in the area of microfluidics -- the science of designing, manufacturing, and formulating devices and processes that deal with volumes of fluid on the order of nanoliters -- since the 1990s and have a good understanding about how to use microfluids to analyze cell activity. The microfluidic platform is fast and highly parallel and can perform hundreds of measurements 50 to 100 times faster than alternate methods.

Singh says the end goal is to make a benchtop miniaturized system expected in about two years. It would be placed in Biosafety Level 3 or 4 labs to study immune response to highly pathogenic organisms. He notes the integrated platform, biological reagents and computational models developed under this project have applicability beyond infectious disease research. These technologies can also be used for studying cellular signaling involved in diseases such as cancer or by pharmaceutical companies for biomarker discovery.

Source: Sandia National Laboratories

Less worrying = Longer life

As reported in the May issue of Psychological Science, men who increased over time in neuroticism died earlier, mostly from cancer and heart disease.There is broad consensus today that personality traits are best described by the "Big Five": Extraversion, agreeableness, conscientiousness, emotional ...

As reported in the May issue of Psychological Science, men who increased over time in neuroticism died earlier, mostly from cancer and heart disease.

There is broad consensus today that personality traits are best described by the "Big Five": Extraversion, agreeableness, conscientiousness, emotional stability, and openness to experience. Each of these broad measures can be broken down into smaller ones, but in general, this taxonomy appears to take in most of what we think of as personhood. When you think of someone as "steady" or "flaky" or "gloomy" or "daring," what you%26#8217;re really doing is unconsciously taking a measure of these five traits and crunching them together.

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So what makes a healthy personality? Psychologists have been studying this important question, and at least two of these five traits appear to be directly related to physical well being and longevity: Emotional stability and conscientiousness. More to the point, wellness is linked to changes in these traits over time.

Consider emotional stability. Or, rather, it%26#8217;s polar opposite, which psychologists call neuroticism. Neuroticism is the tendency toward hand wringing and negative thinking. People with a heavy dose of neuroticism do not handle stress well, and are often anxious and moody. Such negativity has been linked to increased mortality in a number of studies, but for Purdue University psychologist Daniel Mroczek this finding raised as many questions as it answered. Does it follow that this inherited trait is a death sentence? Or can people with this propensity change their destiny?

Mroczek decided to explore this idea. Using a standard measure of neuroticism, he tracked more than 1600 men over 12 years, recording not only how neurotic they were at the start but also whether they got more or less neurotic over time. He also looked at mortality risk for these same men over an 18-year span. As reported in the May issue of Psychological Science, those who increased over time in neuroticism was a ticket to an early grave. In other words, these men%26#8212;all middle age or older to begin with%26#8212;did not grow old gracefully. They likely got more and more stressed, worried or fretful, and this downward spiral increased their risk for dying, mostly from cancer and heart disease.

The good news is that men with a fretful temperament, if they managed for whatever reason to calm down a bit over time, had survival rates similar to those of emotionally stable men.

Source: Association for Psychological Science

Eating apples while pregnant protects baby from developing asthma later

Eating apples while pregnant may give new meaning to an apple a day keeping the doctor away. Compelling new research has concluded that mothers who eat apples during pregnancy may protect their children from developing asthma later in life. The study was published in Thorax online.This unique longit...

This unique longitudinal study tracked dietary intake by nearly 2000 pregnant women, then examined the effects of the maternal diet on airway development in more than 1200 of their children five years later. Among a wide variety of foods consumed and recorded by the pregnant women, the researchers concluded that the children of mothers who ate apples had a significantly reduced risk for the development of asthma and childhood wheezing.

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This study focuses on medical evaluations for asthma and related symptoms (i.e., wheezing) when the children were five years old. As a result of the evaluations cited in this research, other than apples, there were no consistent associations found between prenatal consumption of a range of healthful foods and asthma in the 1253 children who were evaluated.

Children of mothers who ate apples during pregnancy were much less likely to exhibit symptoms of asthma (including wheezing), say the researchers who hail from institutions in The Netherlands and Scotland. These same researchers previously reported positive associations between maternal consumption of vitamins A, E, D and zinc with reduced risk of asthma, wheeze and eczema in children.

The only other positive association found between prenatal food intake and risk reduction in the children was with fish, for which the researchers found that children of mothers who ate fish had a lowered incidence of doctor-confirmed eczema.

According to the research, "The present study suggests beneficial associations between maternal apple intake during pregnancy and wheeze and asthma at age five years." They add that their findings "suggest an apple specific effect, possibly because of its phytochemical content, such as flavonoids." The research paper cites other related studies on apples, including those which found that "intake of apples as a significant source of flavonoids and other polyphenols has been beneficially associated with asthma, bronchial hypersensitivity, and lung function in adults."

In 2004, the National Center for Health Statistics reported that nine million U.S. children have been diagnosed with asthma at one point in their lives and four million children suffered from asthma attacks that year. Others suffer from "hidden asthma" %26#8211; undetected or undiagnosed asthma, according the American Lung Association. The cost of this disease is great %26#8211; statistics show asthma to be the third-ranking cause of hospitalization among children under 15 and is among the leading causes of school absenteeism.

Source: Kellen Communications

Shawn's Health Blog

2/05/2009

Rabies vaccine may fight HIV

Need to balance out intake of omega-6 and omega-3 fatty acids or risk depression and inflammatory diseases

A laser, white light, and reflective tube rapidly measure multiple chemicals in body fluids

New medical device may "sniff out" diseases such as Alzheimer’s and Parkinson’s

Studying the geometry of viruses will help develop new anti-viral strategies

Rabies vaccine may fight HIV

Protein discovery may help limit body's capacity to store fat

Intensive psychotherapy helps treat bipolar disorder

Genes may help people's ability to stop smoking

Researchers synthesize 10 different flavanones, a type of flavonoid

Plant hormone research has important implications for treatment of human disease

Study - Dieting does not work

How the brain stops us from doing stupid things

New approach to studying how immune cells respond to pathogens

Less worrying = Longer life

Eating apples while pregnant protects baby from developing asthma later

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