New biochemical discoveries into developing disease

Researchers have undertaken the most comprehensive investigation of genetic variance in human metabolism and discovered new insights into a range of common diseases. Their work has revealed 37 new variants that are associated with concentrations of metabolites in the blood. Many of these match variants associated with diseases such as chronic kidney disease, type 2 diabetes and blood clotting.

The team conducted the largest ever study of the human genome for genetic variants associated with metabolites - the biochemical compounds representing the start or end of metabolic reactions - using genome wide association analysis. They were searching for genetic influences on levels of more than 250 compounds in people's blood, including lipids, sugars, vitamins, amino acids and many others. They discovered variants that have a significant effect on the levels of these compounds, and hence on the underlying biological and disease processes.

"Our findings provide new insights for many disease-related associations that have been reported in previous studies, including cardiovascular and kidney disorders, type 2 diabetes, cancer, gout, thrombosis and Crohn's disease," says Dr Nicole Soranzo, one of the study's researchers from the Wellcome Trust Sanger Institute. "Often the effects of variants discovered in genome wide association analyses are modest and we perhaps have a poor understanding of the biologic mechanism behind the association. Our approach can overcome these problems and possibly inform individualized therapy/treatment."

In previous studies, scientists have looked at the levels of one or a few metabolic traits; for example, cholesterol levels, or sugar in the blood, that is investigated in the doctor's surgery to help to diagnose disease. The new approach in this work was to assay a much wider range of smaller biochemical compounds, to give as complete a picture as possible of the molecules that are symptoms of disease and those that might contribute to disease.
The hope was that this more complete picture would allow researchers to better understand the function of genetic variants responsible for driving disease. This was the case.

Among the discoveries made by the team was a previously unknown association of mannose, a natural sugar, with diabetes-associated variants; this link suggests a new line of research to examine the role of mannose in diabetes, both as a diagnostic and as part of the disease process.
They also identified a possible mechanism to detoxify substances, which could affect the risk of developing kidney disease. This followed the discovery of a highly significant association with the NAT8 gene.

"These are remarkable findings powered by our method that enables researchers to identify new and potentially relevant metabolic processes and pathways," says Professor Karsten Suhre. Dr Christian Gieger adds: "To improve effectively treatment through biomedicine, we need to put genetics into its biological context. In trying to do this in our study, we have identified new molecules of interest that could be clinically significant." Both are the lead authors from the Helmholtz Center Munich, German Research Centre for Environmental Health.

Their study also discovered variants associated with blood clotting and thrombosis.
"We were able to show that variants in or near three genes are associated with a biochemical modification to peptides, a small protein that controls blood clotting. These same variants are variously associated with an increased risk for heart disease, thrombosis and other similar conditions," says Professor Tim Spector, Director of the TwinsUK twin cohort at the Department of Twin Research and Genetic Epidemiology, King's College London, which provided one of the two study samples. "We speculate that this is a new example of a mechanism that alters blood clotting. This discovery could one day lead to improved treatments."

Additionally, the researchers investigated the association of metabolite levels with drug response and treatment, including statins and thalidomide. They showed that in one case, a variant in a gene called ACE, associated with blood pressure control, could undermine treatment effects. The novel biochemical basis could help to identify possible side effects in drug trials and support development of new formulations to reduce side effects.
The data will be made publicly available as a knowledge-based resource on the internet to aid future studies, and biological, as well as clinical, interpretation of genome wide association studies.

More information: Suhre K, Shin S-Y, Petersen A-K et al. (2011) Human metabolic individuality in biomedical and pharmaceutical research. Nature Published online 31 August 2011. doi: 10.1038/Nature10354

Provided by Wellcome Trust Sanger Institute

How to tell when someone's lying

How to tell when someone's lying

May 10, 2011

The ability to effectively detect deception is crucial to public safety, particularly in the wake of renewed threats against the U.S. following the killing of Osama bin Laden.

UCLA professor of psychology R. Edward Geiselman has been studying these questions for years and has taught investigative interviewing techniques to detectives and intelligence officers from the FBI, the Department of Homeland Security, the Marines, the Los Angeles police and sheriff's departments, and numerous international agencies.

He and three former UCLA undergraduates — Sandra Elmgren, Chris Green and Ida Rystad —analyzed some 60 studies on detecting deception and have conducted original research on the subject. They present their findings and their guidance for how to conduct effective training programs for detecting deception in the current (April) issue of the American Journal of Forensic Psychiatry, which is published this week.

Geiselman and his colleagues have identified several indicators that a person is being deceptive. The more reliable red flags that indicate deceit, Geiselman said, include:

• When questioned, deceptive people generally want to say as little as possible. Geiselman initially thought they would tell an elaborate story, but the vast majority give only the bare-bones. Studies with college students, as well as prisoners, show this. Geiselman's investigative interviewing techniques are designed to get people to talk.

• Although deceptive people do not say much, they tend to spontaneously give a justification for what little they are saying, without being prompted.

• They tend to repeat questions before answering them, perhaps to give themselves time to concoct an answer.

• They often monitor the listener's reaction to what they are saying. "They try to read you to see if you are buying their story," Geiselman said.

• They often initially slow down their speech because they have to create their story and monitor your reaction, and when they have it straight "will spew it out faster," Geiselman said. Truthful people are not bothered if they speak slowly, but deceptive people often think slowing their speech down may look suspicious. "Truthful people will not dramatically alter their speech rate within a single sentence," he said.

• They tend to use sentence fragments more frequently than truthful people; often, they will start an answer, back up and not complete the sentence.

• They are more likely to press their lips when asked a sensitive question and are more likely to play with their hair or engage in other "grooming" behaviors. Gesturing toward one's self with the hands tends to be a sign of deception; gesturing outwardly is not.

• Truthful people, if challenged about details, will often deny that they are lying and explain even more, while deceptive people generally will not provide more specifics.

• When asked a difficult question, truthful people will often look away because the question requires concentration, while dishonest people will look away only briefly, if at all, unless it is a question that should require intense concentration.

If dishonest people try to mask these normal reactions to lying, they would be even more obvious, Geiselman said. Among the techniques he teaches to enable detectives to tell the truth from lies are:

• Have people tell their story backwards, starting at the end and systematically working their way back. Instruct them to be as complete and detailed as they can. This technique, part of a "cognitive interview" Geiselman co-developed with Ronald Fisher, a former UCLA psychologist now at Florida International University, "increases the cognitive load to push them over the edge." A deceptive person, even a "professional liar," is "under a heavy cognitive load" as he tries to stick to his story while monitoring your reaction.

• Ask open-ended questions to get them to provide as many details and as much complete information as possible ("Can you tell me more about...?" "Tell me exactly..."). First ask general questions, and only then get more specific.

• Don't interrupt, let them talk and use silent pauses to encourage them to talk.

If someone in an airport or other public space is behaving suspiciously and when approached exhibits a majority of the more reliable red flags, Geiselman recommends pulling him or her aside for more questioning. If there are only one or two red flags, he would probably let them go.

Geiselman tested techniques for telling the truth from deception with hundreds of UCLA students, and the studies he and his co-authors analyzed involved thousands of people.

Detecting deception is difficult, Geiselman said, but training programs can be effective. Programs must be extensive, with an education phase followed by numerous video examples, and a phase in which those being trained judge video clips and simulate real-world interviewing. Training should be conducted on multiple days over a period of a week or two.

"People can learn to perform better at detecting deception," Geiselman said. "However, police departments usually do not provide more than a day of training for their detectives, if that, and the available research shows that you can't improve much in just a day."

When Geiselman conducted training with Marine intelligence officers, he found that they were impressively accurate in detecting deception even before the training began. In contrast, the average college student is only 53 percent accurate without training, and with abbreviated training, "we often make them worse," he said.

"Without training, many people think they can detect deception, but their perceptions are unrelated to their actual ability. Quick, inadequate training sessions lead people to over-analyze and to do worse than if they go with their gut reactions."

Geiselman is currently developing a training program that he hopes will effectively compress the learning curve and thus will serve to replicate years of experience.

The cognitive interview that Geiselman and Fisher developed works well with both criminal suspects and eyewitnesses of crimes. Geiselman thinks these techniques are likely to work in non-crime settings as well, but said additional research should be done in this area.

In the next year, Geiselman plans to teach police detectives techniques for investigative interviewing and spotting deception through the U.S. Department of Homeland Security's Rural Policing Institute for underserved police departments. He says this will be a perfect fit for him because he comes from Culver, Ind., a small town that has fewer residents than UCLA has psychology majors.

Later this month, Geiselman will travel to Hong Kong to provide training in investigative interviewing to the Independent Commission Against Corruption.

An instructional course Geiselman taught on investigative interviewing before the second Iraq war resulted in cognitive interviewing techniques that were used to interdict some insurgent activity in Iraq, perhaps saving many lives, he was later informed.

Geiselman also has worked with the Los Angeles County Sheriff's Department on effective techniques for interviewing children who may have been molested and has interviewed crime victims for police departments around the country in murder cases gone cold. His research has been funded by the U.S. Department of Justice and the U.S. Department of Homeland Security.

Provided by University of California - Los Angeles

Muscle Building

New Discovery Leads to Shocking Muscle Gains

A safe alternative to steroids is changing the way pro athletes and bodybuilders stay in shape.

Adam Hillbrand is a veteran Health Headlines writer specializing in sports nutrition. His professional interests include writing about healthy living, marketing strategy, consumer psychology, and technology. He lives in the Boston area with his wife and is an avid Boston sports fan. In his spare time, he loves to cook and travel. He also enjoys working out and spending as much time as possible outside.

With the recent media coverage exposing steroid use in professional sports, many everyday people are looking for an extra edge to build muscle, get stronger, and look better.

Steroids, although effective, are unhealthy and illegal to use without a prescription. Millions of dollars have been spent in sports medicine research to find a completely safe, natural alternative that produces the same results.

After years of research scientists now agree that nitric oxide supplements are a safe way to maximize your muscle gains.

UFC Champion BJ Penn started using a nitric oxide supplement called Force Factor last year. Penn recently told us, "Force Factor is the absolute best product to hit the market in years."

Other athletes like basketball Rookie of the Year Derrick Rose and professional football player Vernon Davis are just now discovering the dramatic benefits of using a nitric oxide supplement. Vernon has been an advocate of Force Factor since first taking it, telling his teammates in San Francisco, "Force Factor has proven results. I believe in results."

The Science Behind Nitric Oxide

Your body naturally produces nitric oxide to move oxygen into your muscles while you exercise. This burst of oxygen keeps your muscles functioning while lifting weights or through your cardio session.

Unfortunately, your body can only generate a limited amount of nitric oxide. When the nitric oxide runs out your muscles can no longer power through the exercise no matter how much mental determination you have.

Taking a nitric oxide supplement 30 minutes before your workout could be the push your body needs to add weight to your bench press or run that extra mile. This increased stamina results in longer, harder workouts and a better body in less time.

The Benefits of Nitric Oxide Supplements

· Drastic Muscle Gains

· Increased Blood Flow and Oxygen Delivery to Muscles

· Transform Your Body

· Boosted Strength, Endurance and Power

· Supports Your Immune System

· Immediate Results

Source: Health Headlines

SNP resides outside of genes

Epigenomic findings illuminate veiled variants

March 26th, 2011

Genes make up only a tiny percentage of the human genome. The rest, which has remained measurable but mysterious, may hold vital clues about the genetic origins of disease. Using a new mapping strategy, a collaborative team led by researchers at the Broad Institute of MIT and Harvard, Massachusetts General Hospital (MGH), and MIT has begun to assign meaning to the regions beyond our genes and has revealed how minute changes in these regions might be connected to common diseases. The researchers' findings appear in the March 23 advance online issue of Nature. The results have implications for interpreting genome-wide association studies - large-scale studies of hundreds or thousands of people in which scientists look across the genome for single "letter" changes or SNPs (single nucleotide polymorphisms) that influence the risk of developing a particular disease. The majority of SNPs associated with disease reside outside of genes and until now, very little was known about the functions of most of them. "Our ultimate goal is to figure out how our genome dictates our biology," said co-senior author Manolis Kellis, a Broad associate member and associate professor of computer science at MIT. "But 98.5 percent of the genome is non-protein coding, and those non-coding regions are generally devoid of annotation." The term "epigenome" refers to a layer of chemical information on top of the genetic code, which helps determine when and where (and in what types of cells) genes will be active. This layer of information consists of chemical modifications, or "chromatin marks," that appear across the genetic landscape of every cell, and can differ dramatically between cell types. In a previous study, the authors showed that specific combinations of these chromatin marks (known as "chromatin states") can be used to annotate parts of the genome - namely to attach biological meaning to the stretches of As, Cs, Ts, and Gs that compose our DNA. However, many questions remained about how these annotations differ between cell types, and what these differences can reveal about human biology. In the current study, the researchers mapped chromatin marks in nine different kinds of cells, including blood cells, liver cancer cells, skin cells, and embryonic cells. By looking at the chemical marks, the researchers were able to create maps showing the locations of key control elements in each cell type. The researchers then asked how chromatin marks change across cell types, and looked for matching patterns of activity between controlling elements and the expression of neighboring genes. "We first annotated the elements and figured out which cell types they are active in," said co-senior author Bradley Bernstein, a Broad senior associate member and Harvard Medical School (HMS) associate professor at Massachusetts General Hospital (MGH). "We could then begin to link the elements and put together a regulatory network." Having pieced together these networks connecting non-coding regions of the genome to the genes they control, the researchers could begin to interpret data from disease studies. The team studied a large compendium of genome-wide association studies (GWAS), looking to characterize non-coding SNPs associated with control regions in specific cell types. "Across 10 association studies of various human diseases, we found a striking overlap between previously uncharacterized SNPs and the control region annotations in specific cell types," said Kellis. "This suggests that these DNA changes are disrupting important regulatory elements and thus play a role in disease biology." The researchers confirmed the reliability of their approach by showing that SNPs were associated with the appropriate cell types. For example, SNPs from autoimmune diseases such as rheumatoid arthritis and lupus sit in regions that are only active in immune cells, and SNPs associated with cholesterol and metabolic disease sit in regions active in liver cells. While more in-depth, follow-up studies will be needed to confirm the biological significance of these connections, the current study can help guide the direction of these investigations. "GWAS has identified hundreds of non-coding regions of the genome that influence human disease, but a major barrier to progress is that we remain quite ignorant of the functions of these non-coding regions," said David Altshuler, deputy director at the Broad and an HMS professor at MGH, who was not involved in the study. "This remarkable and much-needed resource is a major step forward in helping researchers address that challenge." SNPs in the non-coding regions of the genome may have subtler biological effects than their counterparts that arise in genes because they can influence how much protein is produced. The researchers mainly focused on SNPs in enhancer regions, which help boost a gene's expression, and their network connections to regulators that control them and genes that they target. Follow-up efforts can then focus on specific pieces of this network that could be targeted with drugs. The team involved in this study hopes to expand its analysis to include many other cell types and map additional marks to expand their networks beyond enhancer regions. In the meantime, researchers involved in genome-wide association studies will be able to use the maps from this project to analyze non-coding SNPs in a new light. Source: Broad Institute

Will we hear the light?

Will we hear the light? Surprising discovery that infrared can activate heart and ear cells

March 28, 2011

University of Utah scientists used invisible infrared light to make rat heart cells contract and toadfish inner-ear cells send signals to the brain. The discovery someday might improve cochlear implants for deafness and lead to devices to restore vision, maintain balance and treat movement disorders like Parkinson's.

"We're going to talk to the brain with optical infrared pulses instead of electrical pulses," which now are used in cochlear implants to provide deaf people with limited hearing, says Richard Rabbitt, a professor of bioengineering and senior author of the heart-cell and inner-ear-cell studies published this month in TheJournal of Physiology.

The studies – funded by the National Institutes of Health – also raise the possibility of developing cardiac pacemakers that use optical signals rather than electrical signals to stimulate heart cells. But Rabbitt says that because electronic pacemakers work well, "I don't see a market for an optical pacemaker at the present time."

The scientific significance of the studies is the discovery that optical signals – short pulses of an invisible wavelength of infrared laser light delivered via a thin, glass optical fiber – can activate heart cells and inner-ear cells related to balance and hearing.

In addition, the research showed infrared activates the heart cells, called cardiomyocytes, by triggering the movement of calcium ions in and out of mitochondria, the organelles or components within cells that convert sugar into usable energy. The same process appears to occur when infrared light stimulates inner-ear cells.

Infrared light can be felt as heat, raising the possibility the heart and ear cells were activated by heat rather than the infrared radiation itself. But Rabbitt and colleagues did "elegant experiments" to show the cells indeed were activated by the infrared radiation, says a commentary in the journal by Ian Curthoys of the University of Sydney, Australia.

Curthoys writes that the research provides "stunningly bright insight" into events within inner-ear cells and "has great potential for future clinical application."

Shedding Infrared Light on Inner-Ear Cells and Heart Cells

The low-power infrared light pulses in the study were generated by a diode – "the same thing that's in a laser pointer, just a different wavelength," Rabbitt says.

The scientists exposed the cells to infrared light in the laboratory. The heart cells in the study were newborn rat heart muscle cells called cardiomyocytes, which make the heart pump. The inner-ear cells are hair cells, and came from the inner-ear organ that senses motion of the head. The hair cells came from oyster toadfish, which are well-establish models for comparison with human inner ears and the sense of balance.

Inner-ear hair cells "convert the mechanical vibration from sound, gravity or motion into the signal that goes to the brain" via adjacent nerve cells, says Rabbitt.

Using infrared radiation, "we were stimulating the hair cells, and they dumped neurotransmitter onto the neurons that sent signals to the brain," Rabbitt says.

He believes the inner-ear hair cells are activated by infrared radiation because "they are full of mitochondria, which are a primary target of this wavelength."

The infrared radiation affects the flow of calcium ions in and out of mitochondria – something shown by the companion study in neonatal rat heart cells.

That is important because for "excitable" nerve and muscle cells, "calcium is like the trigger for making these cells contract or release neurotransmitter," says Rabbitt.

The heart cell study found that an infrared pulse lasting a mere one-5,000th of a second made mitochondria rapidly suck up calcium ions within a cell, then slowly release them back into the cell – a cycle that makes the cell contract.

"Calcium does that normally," says Rabbitt. "But it's normally controlled by the cell, not by us. So the infrared radiation gives us a tool to control the cell. In the case of the [inner-ear] neurons, you are controlling signals going to the brain. In the case of the heart, you are pacing contraction."

New Possibilities for Optical versus Electrical Cochlear Implants

Rabbitt believes the research – including a related study of the cochlea last year – could lead to better cochlear implants that would use optical rather than electrical signals.

Existing cochlear implants convert sound into electrical signals, which typically are transmitted to eight electrodes in the cochlea, a part of the inner ear where sound vibrations are converted to nerve signals to the brain. Eight electrodes can deliver only eight frequencies of sound, Rabbitt says.

"A healthy adult can hear more than 3,000 different frequencies. With optical stimulation, there's a possibility of hearing hundreds or thousands of frequencies instead of eight. Perhaps someday an optical cochlear implant will allow deaf people to once again enjoy music and hear all the nuances in sound that a hearing person would enjoy."

Unlike electrical current, which spreads through tissue and cannot be focused to a point, infrared light can be focused, so numerous wavelengths (corresponding to numerous frequencies of sound) could be aimed at different cells in the inner ear.

Nerve cells that send sound signals from the ears to the brain can fire more than 300 times per second, so ideally, a cochlear implant using infrared light would be able to perform as well. In the Utah experiments, the researchers were able to apply laser pulses to hair cells to make adjacent nerve cells fire up to 100 times per second. For a cochlear implant, the nerve cells would be activated within infrared light instead of the hair cells.

Rabbitt cautioned it may be five to 10 years before the development of cochlear implants that run optically. To be practical, they need a smaller power supply and light source, and must be more power efficient to run on small batteries like a hearing aid.

Optical Prosthetics for Movement, Balance and Vision Disorders

Electrical deep-brain stimulation now is used to treat movement disorders such as Parkinson's disease and "essential tremor, which causes rhythmic movement of the limbs so it becomes difficult to walk, function and eat," says Rabbitt.

He is investigating whether optical rather than electrical deep-brain stimulation might increase how long the treatment is effective.

Rabbitt also sees potential for optical implants to treat balance disorders.

"When we get old, we shuffle and walk carefully, not because our muscles don't work but because we have trouble with balance," he says. "This technology has potential for restoring balance by restoring the signals that the healthy ear sends to the brain about how your body is moving in space."

Optical stimulation also might provide artificial vision in people with retinitis pigmentosa or other loss of retinal cells – the eye cells that detect light and color – but who still have the next level of cells, known as ganglia, Rabbitt says.

"You would wear glasses with a camera [mounted on the frames] and there would be electronics that would convert signals from the camera into pulses of infrared radiation that would be patterned onto the diseased retina that normally does not respond to light but would respond to the pulsed infrared radiation" to create images, he says.

Hearing and vision implants that use optical rather than electrical signals do not have to penetrate the brain or other nerve tissue because infrared light can penetrate "quite a bit of tissue," so devices emitting the light "have potential for excellent biocompatibility," Rabbitt says. "You will be able to implant optical devices and leave them there for life."

Provided by University of Utah

URINE TEST FOR DIABETES

Home Urine Test Measures Insulin Production in Diabetes

February 24th, 2011

A simple home urine test has been developed which can measure if patients with Type 1 and Type 2 diabetes are producing their own insulin. The urine test, from Professor Andrew Hattersley's Exeter-based team at the Peninsula Medical School, replaces multiple blood tests in hospital and can be sent by post as it is stable for up to three days at room temperature. Avoiding blood tests will be a particular advantage for children. The urine test measures if patients are still making their own insulin even if they take insulin injections. Researchers have shown that the test can be used to differentiate Type 1 diabetes from Type 2 diabetes and rare genetic forms of diabetes. Making the correct diagnosis can result in important changes in treatment and the discontinuation of insulin in some cases. Jillian, 35 has recently benefitted from the home urine test. She was diagnosed with diabetes aged 19 and put on insulin injections. The urine test identified that she is still making her own insulin 14 years after being diagnosed and a DNA test confirmed that she has a genetic type of diabetes. After 14 years of insulin treatment, Jillian is now off her insulin injections. "Being told I don't have to take insulin injections any more has changed my life", she said. The key studies, led by Dr Rachel Besser and Dr Angus Jones and were funded by Diabetes UK and the National Institute of Health Research, are published in leading diabetes journals, Diabetes Care and Diabetic Medicine. Dr Rachel Besser, who has led the studies on over 300 patients, commented: "The urine test offers a practical alternative to blood testing. As the urine test can be done in the patients own home we hope that it will be taken up more readily, and more patients can be correctly diagnosed and be offered the correct treatment". Dr. Iain Frame, Director of Research at leading health charity Diabetes UK, said: "Dr. Besser's research is an excellent example of Diabetes UK's commitment to fund scientists at the beginning of their careers in diabetes research. With growing numbers of people with diabetes, it's more important than ever to ensure that medically trained graduates are encouraged to enter the field of diabetes research to help improve the lives of people with the condition. Many aspects of diabetes, from diagnosis to treatment, are invasive. Therefore, we welcome Dr. Besser's research and look forward to further developments." Source: Peninsula College of Medicine & Dentistry

AFFECT OF CELL PHONE ON THE BRAIN

Cell phones show effect on brain activity most pronounced near the antenna

February 24th, 2011

In a study of the effects of cell phone usage on brain cell activity, NIH scientists and their colleagues at the U.S. Department of Energy's Brookhaven National Laboratory found that 50 minutes of cell phone usage (with the phone muted to avoid confounding effects from auditory stimulation) elevated brain glucose metabolism significantly in the parts of the brain closest to the phone's antenna. Elevations in glucose metabolism, a measure of brain cell activity, were correlated with the estimated strength of the electromagnetic field emitted by the phone in those regions. The findings are published in the in the February 22, 2011, issue of JAMA. Arrow in the left image shows the location in the orbitofrontal cortex in one subject where glucose metabolism was increased during cell phone use. Red and orange areas shows higher brain metabolic activity. On the right is a baseline image with the cell phone turned off, showing lower activity. "Although we cannot determine the clinical significance, our results give evidence that the human brain is sensitive to the effects of radiofrequency-electromagnetic fields from acute cell phone exposures," said Nora Volkow, the study's lead author. Discrepancies among studies on the effects of RF-electromagnetic fields (RF-EMF) from cell phones on the human brain highlight the need for additional research. Prior studies of the acute effects of cell phone use on human brain function, including measurements of cerebral blood flow monitored by positron emission tomography (PET), have yielded inconsistent results, which might have reflected, in part, the small sample sizes of such studies (the largest studies had 14 subjects). Arrow in the left image shows the location in the orbitofrontal cortex in one subject where glucose metabolism was increased during cell phone use. Red and orange areas shows higher brain metabolic activity. On the right is a baseline image with the cell phone turned off, showing lower activity. The current study, also using PET, provides a more direct measure of brain activity than cerebral blood flow. It uses a radioactively "tagged" form of glucose known as [18F]fluoro-deoxyglucose, or FDG, to measure glucose metabolism in specific regions of the brain. "FDG is a direct substitute for glucose, the brain's fuel. Measuring its concentration in the brain gives a highly specific measure of brain cell metabolism, which is a more direct measure of brain activity than measures of blood flow," Volkow said. Also, because brain glucose metabolic measures obtained with FDG reflect the averaged brain activity occurring over a 30-minute period, this method can assess the cumulative effects of cell phone exposure on resting brain metabolism, unlike blood flow measures, which isolate a more restricted point in time. Scientists conducted the study in 47 healthy individuals. All participants had two scans done on separate days. On both days, prior to the scans, two cell phones, one placed on the left and one on the right ear, were used so subjects wouldn't know which cell phone was active. For one of the days both cell phones were off. For the other day the right cell phone was on but muted while receiving a call from a recorded text. The order of conditions was randomly assigned, and participants did not know when an active phone was being tested. With the cell phones secured to their heads, the subjects sat in a quiet room, not speaking, with eyes open for 20 minutes prior to being injected with the FDG tracer, and then for 30 more minutes, for a total cell phone exposure time of 50 minutes . RF-EMF emissions were recorded once before the call (background) and every five minutes during the "on" phase to ensure that the call was not terminated. Using computational and photographic methods, the scientists were also able to calculate the relative amplitude of the cell phone's electric field at every position in the brain. After the exposure period, the phones were removed and the subjects were placed in the PET scanner for measurements of brain activity. There were no differences in overall brain metabolism between the on and off conditions, but during the on condition, the specific regions of the brain closest to the phone's antenna showed significant increases in brain glucose metabolism. The regions expected to have the greater absorption of RF-EMF from the cell phone exposure were the ones that showed the largest increases in glucose metabolism. "The linear association between cell phone-related increases in metabolism and electric field strength suggests that the metabolic increases are secondary to the absorption of RF-EMF from cell phone exposures," Volkow said. "Further studies are needed to assess if the effects we observed could have potential long-term consequences." This research was funded by the Intramural Research Program of the National Institutes of Health (NIH) using infrastructure supported at Brookhaven Lab by DOE's Office of Science. Source: Brookhaven National Lab

New insight on diabetes

Missing sugar molecule raises diabetes risk in humans

February 24th, 2011

Researchers at the University of California, San Diego School of Medicine and Rady Children's Hospital-San Diego say an evolutionary gene mutation that occurred in human millions of years ago and our subsequent inability to produce a specific kind of sugar molecule appears to make people more vulnerable to developing type 2 diabetes, especially if they're overweight. The findings are published in the Feb. 24 online edition of The FASEB Journal, a publication of the Federation of American Societies of Experimental Biology. Corresponding study author, Jane J. Kim is an assistant professor in the UCSD Department of Pediatrics and a member of the Pediatric Diabetes Research Center and Rady Children's Hospital-San Diego, a research and teaching affiliate of the UCSD School of Medicine. Kim said the findings represent the first documented evidence linking the sugar production to insulin and glucose metabolism problems associated with diabetes. "It opens up a new perspective in understanding the causes of diabetes," said Kim. "Given the global epidemic of obesity and diabetes, we think that these findings suggest that evolutionary changes may have influenced our metabolism and perhaps increased our risk of the disease." Type 2 diabetes is caused by both genetic and environmental factors, such as a fatty diet and lack of exercise, that result in progressively dysfunctional pancreatic beta cells, elevated blood sugar levels due to insulin resistance and eventual health complications, sometimes fatally so. Diabetes is an expanding problem, nationally and globally. In the United States, more than 25 million adults and children � almost nine percent of the population - have diabetes, according to the American Diabetes Association. Another 79 million Americans are estimated to be prediabetic. Worldwide, roughly 285 million people are believed to have the disease. Sialic acids are sugar molecules found on the surfaces of all animal cells, where they act as vital contact points for interaction with other cells and with their surrounding environment. Virtually all mammals produce two types: N-acetylneuraminic acid (Neu5Ac) and N-glycolylneuraminic acid (Neu5Gc). Humans are the exception. For reasons lost in the mists of evolution, a mutation in a gene called CMAH occurred 2 to 3 million years ago, inactivating an enzyme in humans that catalyzes production of Neu5Gc by adding a single oxygen atom to Neu5Ac. Researchers compared two groups of mice: one with a functional CMAH gene, the other with an altered CMAH gene similar to the human mutation. Both groups of mice were fed a high-fat diet. Mice in both groups became obese and developed insulin resistance. However, only mice with the CMAH gene mutation experienced pancreatic beta cell failure � the cells that make and release insulin, a hormone that controls blood sugar levels. Kim said the findings help refine understanding of why obese humans appear to be particularly vulnerable to type 2 diabetes, and also suggest that current animal models used to study diabetes may not accurately mirror the human condition. In clinical terms, she said further research to determine how sialic acid composition affects pancreatic beta cell function may reveal new strategies to preserve the cells, improve insulin production and prevent diabetes. Co-authors of the study are Sarah Kavaler and Alice Jih, UCSD Department of Pediatrics and Rady Children's Hospital-San Diego; Hidetaka Morinaga and WuQuiang Fan, UCSD Department of Medicine; Maria Hedlund and Ajit Varki, UCSD departments of Medicine, Cellular and Molecular Medicine and UCSD Glycobiology Research and Training Center. Funding support was provided by the National Institutes of Health Source: UC San Diego Credit: Eurekalert

BONES AND MALE FERTILITY

Skeleton regulates male fertility

February 17, 2011

Researchers at Columbia University Medical Center have discovered that the skeleton acts as a regulator of fertility in male mice through a hormone released by bone, known as osteocalcin.

The research, led by Gerard Karsenty, M.D., Ph.D., chair of the Department of Genetics and Development at Columbia University Medical Center, is slated to appear online on February 17 in Cell, ahead of the journal's print edition, scheduled for March 4.
Until now, interactions between bone and the reproductive system have focused only on the influence of gonads on the build-up of bone mass.
"Since communication between two organs in the body is rarely one-way, the fact that the gonads regulate bone really begs the question: Does bone regulate the gonads?" said Dr. Karsenty.
Dr. Karsenty and his team found their first clue to an answer in thereproductive success of their lab mice. Previously, the researchers had observed that males whose skeletons did not secrete a hormone called osteocalcin were poor breeders.
The investigators then did several experiments that show that osteocalcin enhances the production of testosterone, a sex steroid hormone controlling male fertility. As they added osteocalcin to cells that, when in our body produce testosterone, its synthesis increased. Similarly, when they injected osteocalcin into male mice, circulating levels of testosterone also went up.
Conversely, when osteocalcin is not present, testosterone levels drop, which causes a decline in sperm count, the researchers found. When osteocalcin-deficient male mice were bred with normal female mice, the pairs only produced half the number of litters as did pairs with normal males, along with a decrease in the number of pups per litter.
Though the findings have not yet been confirmed in humans, Dr. Karsenty expects to find similar characteristics in humans, based on other similarities between mouse and human hormones.
If osteocalcin also promotes testosterone production in men, low osteocalcin levels may be the reason why some infertile men have unexplained low levels of testosterone.
Skeleton Regulates Male Fertility, But Not Female
Remarkably, although the new findings stemmed from an observation about estrogen and bone mass, the researchers could not find any evidence that theskeleton influences female reproduction.
Estrogen is considered one of the most powerful hormones that control bone; when ovaries stop producing estrogen in women after menopause, bone mass rapidly declines and can lead to osteoporosis.
Sex hormones, namely estrogen in women and testosterone in men, have been known to affect skeletal growth, but until now, studies of the interaction between bone and the reproductive system have focused only on how sex hormones affect the skeleton.
"We do not know why the skeleton regulates male fertility, and not female. However, if you want to propagate the species, it's probably easier to do this by facilitating the reproductive ability of males," said Dr. Karsenty. "This is the only rationale I can think of to explain why osteocalcin regulates reproduction in male and not in female mice."
Other Novel Functions of Osteocalcin Reported Earlier
The unexpected connection between the skeleton and male fertility is one of a string of surprising findings in the past few years regarding the skeleton. In previous papers, Dr. Karsenty has found that osteocalcin helps control insulin secretion, glucose metabolism and body weight.
"What this work shows is that we know so little physiology, that by asking apparently naïve questions, we can make important discoveries," Dr. Karsenty says. "It also shows that bone exerts an important array of functions all affected during the aging process. As such, these findings suggest that bone is not just a victim of the aging process, but that it may be an active determinant of aging as well."
Next Steps and Potential Drug Development
Next, the researchers plan to determine the signaling pathways used by osteocalcin to enhance testosterone production.
And as for potential drug development, since the researchers have also identified a receptor of osteocalcin, more flexibility in designing a drug that mimics the effect of osteocalcin is expected.
Whether it's for glucose metabolism or fertility, says Dr. Karsenty, knowing the receptor will make it easier for chemists to develop a compound that will bind to it.
"This study expands the physiological repertoire of osteocalcin, and provides the first evidence that the skeleton is a regulator of reproduction," said Dr. Karsenty.

Provided by Columbia University Medical Center