Even light to moderate exercise is good

A new study by researchers from the London School of Hygiene and Tropical Medicine (LSHTM), Cambridge University and the Karolinska Institute in Sweden has found that even light or moderate intensity physical activity, such as walking or cycling, can substantially reduce the risk of early death.

The study, published online 14 July 2010 in the International Journal of Epidemiology, combined the results from the largest studies around the world on the health impact of light and moderate intensity physical activity. It showed that the largest health benefits from light or moderate activity (such as walking and cycling) were in people who do hardly any physical activity at all. Although more activity is better – the benefits of even a small amount of physical activity are very large in the least physically active.

The good news from this study is that you don't have to be an exercise freak to benefit from physical activity. Just achieving the recommended levels of physical activity (equivalent to 30 minutes daily of moderate intensity activity on 5 days a week) reduces the risk of death by 19% while 7 hours per week of moderate activity (compared with no activity) reduces the risk of death by 24%. ● Ref: doi:10.1093/ije/dyq104

Researchers show ADAM10 is key molecule in Alzheimers

Researchers from the German Centre for Neurodegenerative Diseases (DZNE) and the Ludwig-Maximilians-Universität (LMU) in Munich have shown that the ADAM10 protein can inhibit the formation of beta-amyloid, which is responsible for Alzheimer’s disease. ADAM10 acts like a pair of molecular scissors to cut the protein from which beta-amyloid is formed, effectively preventing the formation of beta-amyloid. This makes ADAM10 a key molecule in Alzheimer’s therapy. The research team has published their findings in the online edition of the EMBO Journal.

The brains of Alzheimer patients have high accumulations of the material betaamyloid, which appear in the form of plaques. The precursors of these plaques are believed to be the underlying cause of the nerve cell loss that leads to the disruptions in memory that characterise Alzheimer’s disease. The main aim of many Alzheimer therapies is therefore to inhibit the formation of beta-amyloid. Since beta-amyloid is cleaved from the socalled amyloid precursor protein (APP), scientists have focused on stopping the two enzymes that attack the precursor protein.

These act like molecular scissors and cut out the beta-amyloid fragment. Blocking these scissors precludes the formation of beta-amyloid. DZNE and LMU researchers have succeeded in identifying an enzyme known as alpha secretase, which cleaves the amyloid precursor protein (APP) without forming betaamyloid. Up to this point three different candidates for this function had been under consideration, but the research team has now been able to show that the enzyme ADAM10 alone is responsible for the specific cleavage. ● Reference: doi:10.1038/emboj.2010.167

Boston Scientific starts MultiSENSE clinical trial

Boston Scientific has enrolled the first patient in its MultiSENSE clinical trial. The trial is designed to evaluate multiple physiologic sensors in the Company’s COGNIS cardiac resynchronization therapy defibrillators (CRT-Ds). The company plans to use the trial data to help develop a clinical alert that identifies the early onset of worsening heart failure.

When combined with the company’s LATITUDE Patient Management System, CRT-D sensors would be able to monitor a patient outside of a clinical setting and permit the LATITUDE system to deliver early notification to the physician when the patient’s heart failure worsens. “Heart failure is a complex disease and physicians use a number of diagnostics to assess a patient’s condition and disease progression,” said John Boehmer, MD, Medical Director, Heart Failure Program and Professor of Medicine, Penn State Hershey Medical Center and Principal Investigator of the MultiSENSE trial. ”A multi-sensor design in an implantable device, with the predictive power of multiple data points, would enable physicians to take clinical action sooner to avoid hospitalisation due to heart failure.”

New biomarkers identified for postmenopausal
cardiovascular disease

Analysis of blood protein data from the Women’s Health Initiative (WHI) cohorts has revealed new biomarkers for stroke and coronary heart disease (CHD). Research published in BioMed Central’s open access journal Genome Medicine found that beta-2 microglobulin (B2M) levels were significantly elevated in postmenopausal women with CHD, and insulin-like growth factor binding protein 4 (IGFBP4) was strongly associated with stroke.

Ross Prentice, from the Fred Hutchinson Cancer Research Centre, Seattle, USA, worked with a team of researchers to carry out proteomic analyses on samples from 800 women who developed CHD, 800 who developed stroke and a group of matched controls. “We contrasted pools formed by equal plasma volumes from 100 cases or from 100 pair-matched controls, with eight such pool pairs for each of the study diseases. The two novel markers we identified, B2M and IGFBP4, have the potential to help elucidate hormone therapy effects on the cardiovascular diseases as observed in the WHI randomised controlled trials,” Prentice said.

B2M has previously been associated with CHD risk factors including age, blood pressure, and C-reactive protein, and has been reported to show an inverse association with high-density lipoprotein (HDL) cholesterol. “Our finding of B2M elevation in plasma obtained months or years prior to CHD diagnosis appears to be novel, however”, said Prentice. The identification of IGFBP4 as a risk marker for stroke in postmenopausal women also appears to be a novel finding.

Speaking about the results, Prentice said: “Blood protein concentrations provide a source for novel disease risk markers that may be modifiable by treatments or other exposures. As such, protein markers have potential to enhance the understanding of disease pathogenesis, and to elucidate biological processes whereby an exposure affects disease risk.”

New, cheaper, simpler eye test device looks promising
for developing world

A team at Massachusetts Institute of Technology’s (MIT) Media Lab has come up with a much quicker, simpler and cheaper way to do an eye sight test – compared to the large phoropter device or the expensive aberrometer. The device, set to undergo clinical trials, provides an eye test method that is especially suitable for remote, developing-world locations that lack these expensive systems. According to the World Health Organisation, uncorrected refractive errors are the world’s second-highest cause of blindness, affecting some 2% of the world’s population, and two billion people have refractive errors; all these people are potential beneficiaries of the new system. Preliminary testing with about 20 people, and objective tests using camera lenses, have shown that it can achieve results comparable to the standard aberrometer test.

The team has applied for a patent on the system, named NETRA (Near-Eye Tool for Refractive Assessment). In its simplest form, the test can be carried out using a small, plastic device clipped onto the front of a cellphone’s screen. The patient looks into a small lens, and presses the phone’s arrow keys until sets of parallel green and red lines just overlap. This is repeated eight times, with the lines at different angles, for each eye. The whole process takes less than two minutes, at which point software loaded onto the phone provides the prescription data.

The device is described in a paper by MIT Media Lab Associate Professor Ramesh Raskar, visiting professor Manuel Oliveira, and Media Lab student Vitor Pamplona (lead author of the paper) and postdoctoral research associate Ankit Mohan, that was due to be presented in late July at the annual computer-graphics conference SIGGRAPH. “Our device has the potential to make routine refractive eye exams simpler and cheaper, and, therefore, more accessible to millions of people in developing countries,” Oliveira says.

Mohan pointed out that the key difference with their device was that it did not require any moving parts. The technology takes advantage of the huge improvements over the last few years in the resolution of digital displays and their widespread proliferation on cellphones. Apart from the software to run on the phone, all that’s needed is the snap-on plastic device, which Mohan says could cost only a few cents when manufactured in large quantities.

Essentially, Raskar explains, the test works by transforming any blurriness produced by aberrations in the eye into an array of separate lines or dots instead of a fuzzy blob, which makes it easier for the user to identify the discrepancy clearly. Rather than estimating which of two views looks sharper, as in conventional eye tests, the user adjusts the display to make the separate lines or dots come together and overlap, which corresponds to bringing the view into sharp focus.

Dengue vaccine begins Phase 1 human trials

After more than a decade of development a vaccine to prevent infection by the mosquito-borne dengue virus has begun human clinical testing. The vaccine was developed by scientists at the US National Institute of Allergy and Infectious Diseases (NIAID) and is undergoing clinical study at the Johns Hopkins Bloomberg School of Public Health in Baltimore.

Dengue fever is caused by any of four related viruses – DENV-1, DENV-2, DENV-3 and DENV-4 – which are transmitted to humans by Aedes mosquitoes. Dengue virus is prevalent in the tropical and subtropical regions of the world and each year infects about 50 million to 100 million people. It accounts for 25,000 deaths annually; most of them in children. There is no vaccine to prevent dengue infection or drug treatment for those who become infected.

The new vaccine is tetravalent – designed to protect against all four dengue viruses or serotypes.

The candidate vaccines in this Phase 1 trial are live-attenuated, or created by making the live virus harmless or less virulent. To optimise the immune response to each dengue serotype, the researchers are testing three different candidate combinations of the vaccine.

Evaluation of the second candidate combination vaccine has been initiated at the University of Vermont in Burlington, and trials of the third candidate will begin shortly thereafter at Johns Hopkins. These early clinical trials are designed to test the vaccine’s safety and ability to stimulate immune responses in healthy adults ages 18 to 50. After determining which tetravalent vaccine is most promising, the researchers will test that candidate in a trial in a new group of volunteers in Brazil, where dengue has become highly prevalent.

The next stage of testing, a Phase II trial, will involve more participants and will test for differences in preliminary signs of effectiveness between people who have been exposed to dengue and those who have not, as well as the need for a booster shot within a few months of the initial vaccination. “If everything goes well after that stage, we hope to start the final phase of human testing in three to four years,” says Anna Durbin, MD, who is leading the study at Johns Hopkins.

Scientists uncover large set of genes underlying high cholesterol

Following the scanning of the genomes of more than 100,000 people from around the world, scientists report the largest set of genes discovered underlying high cholesterol and high triglycerides – the major risk factors for coronary heart disease. Previous gene-scanning approaches have turned up hints about the nature of inherited heart disease risk. The new results take science well beyond what was previously known, and pinpoint research directions to elucidate the molecular and cellular mechanisms by which genetic variants contribute to disease.

Taken together, the gene variants explain between a quarter and a third of the inherited portions of cholesterol and triglyceride measured in the blood. The research, representing scientists from 17 countries, appears in two papers in the 5 August 2010 issue of Nature. Genome-wide association studies, or GWAS, analyse DNA across populations to pinpoint hard-to-find genetic hotspots for common diseases that are thought to have many causes, both genetic and environmental.

“Genetic studies that survey a wide variety of human populations are a powerful tool for identifying hereditary factors in health and disease,” Francis S. Collins, MD, PhD, study co-author and US National Institutes of Health Director, said. “These results help refine our course for preventing and treating heart disease, a health problem that affects millions of people worldwide.”

The research team found 95 genetic variants which contribute to changes in blood cholesterol and triglyceride levels in women and men of many ethnic backgrounds. Abnormal levels of blood cholesterol and of triglycerides are powerful risk factors for heart disease. Because high blood cholesterol on its own does not cause symptoms, doctors routinely do blood tests to assess individual risk, but they do not know how much risk of developing cardiovascular disease is inherited. Of the genetic variants, 59 had not been known and thus provide new clues for developing effective medicines to combat heart disease.

A significant insight from this research is that many of the variants show up in the DNA of people of widely diverse backgrounds. That is because the scientists scoured the DNA from people participating in large, population-based heart disease studies, reflecting people of European, Eastern and Southern Asian, and African-American descent.

“The new findings point us to specific genetic signposts that allow us to understand more fully why many people from all walks of life have abnormal levels of cholesterol and other blood lipids that lead to heart disease,” said Christopher J. O'Donnell, MD, associate director of the Framingham Heart Study and senior advisor for genomics to Susan B. Shurin, MD, the US National Heart, Lung, and Blood Institute acting director. “What's really exciting about this work is that we are moving from discovery to understanding brand-new information about how genes alter the lipids that contribute to heart disease.”

New studies question vascular Multiple Sclerosis
hypothesis and treatment

Two important new studies challenge the controversial hypothesis put forward by Zamboni et al. that venous congestion – chronic cerebrospinal venous insufficiency (CCSVI) – contributes to the development of multiple sclerosis (MS). This theory has resulted in many MS patients receiving experimental endovascular angioplasty, a treatment for MS unproven by clinical trials. The studies refuting the CCSVI theory with the first negative medical evidence on the subject, are published online 11 June 2010 in Annals of Neurology. doi: 10.1002/ana.22085.

Zamboni’s work gained much attention in the press, especially their report that ultrasound diagnosis of CCSVI perfectly matched an MS diagnosis with 100% sensitivity and 100% specificity. Stephen L. Hauser, MD, the Robert A. Fishman Distinguished Professor and Chair of the Department of Neurology at the University of California, San Francisco, and editor-in-chief of the Annals of Neurology, pointed out: “These two papers should add a note of caution for MS patients and physicians who are contemplating interventions for possible venous abnormalities based on the findings of Zamboni. At this time, the theory must be considered unconfirmed and unproven. Such interventions carry risk, and several people have already been harmed by the inappropriate application of venous angioplasty and stenting for MS.”

In their research article, Florian Doepp, MD, and colleagues in Germany performed an extended extra- and transcranial colour-coded sonography study on 56 MS patients (36 female; 20 male) and 20 control subjects (12 female; 8 male). The analysis included extra-cranial venous blood volume flow (BVF), internal jugular vein (IJV) flow analysis during Valsalva maneuver (VM), as well as tests included in the CCSVI criteria.

Results showed that blood flow direction was normal in all participants, excluding one subject with relapsing-remitting MS. Furthermore, the research team noted that blood volume flow (BVF) in both groups were equal in the supine body position. In summary, the researchers determined that none of the study participants fulfilled more than one criterion for CCSVI.

New compound improves obesity related complications

An experimental compound appears to improve metabolic abnormalities associated with obesity, according to a preliminary study led by researchers at the US National Institutes of Health. A report of the study, which was conducted with obese mice, appeared online 26 July 2010 in the Journal of Clinical Investigation.

“This is a promising early step toward a treatment for some of the serious health consequences of obesity,” says Kenneth R. Warren, PhD, acting director of the National Institute on Alcohol Abuse and Alcoholism (NIAAA), part of the NIH. “Our results suggest that this compound could perhaps provide clinical benefits for obese individuals without the liabilities seen thus far with similar compounds,” adds senior author and NIAAA Scientific Director, George Kunos, MD, PhD.

Previous studies have shown that similar compounds block the activity of endocannabinoids, natural messengers in the body that are chemically similar to the active compound in marijuana, and help regulate many biological functions. These compounds can help promote weight loss and improve metabolic complications of obesity, such as diabetes and insulin resistance, changes in blood lipid composition, and fatty liver. However, the clinical advancement of such compounds has been stymied by behavioural side effects associated with their use, such as anxiety, depression and suicidal thoughts.

Dr Kunos and first author Joseph Tam, DDS, PhD, of the NIAAA Laboratory of Physiologic Studies, collaborated with a team of researchers to investigate a compound designed to avoid those side effects while preserving the beneficial effects of blocking endocannabinoid activity.

They developed such a compound, tested it in obese mice, and found that the mice showed improvements in glucose regulation, fatty liver, and plasma lipid profiles. They also found that the compound did not affect behavioural responses, such as cannabinoid-induced immobility and hypothermia, that are mediated by endocannabinoid receptors in the brain, and that it reduced weight in mice with diet-induced obesity by about 12%, but did not affect weight in mice with a genetic predisposition for obesity.

Not all sugars are the same

Contrary to popular belief that all sugars are the same, researchers have shown that cancer cells can distinguish between fructose and glucose sugars and use fructose to divide and proliferate.

“These findings show that cancer cells can readily metabolise fructose to increase proliferation. They have major significance for cancer patients, given dietary refined fructose consumption,” said the study’s senior author, Dr Anthony Heaney, an associate professor of medicine and neurosurgery and a Jonsson Cancer Center researcher.

Although it is widely known that cancers use glucose, a simple sugar, to fuel their growth, this is the first time a link has been shown between fructose and cancer proliferation, said Dr Heaney.

“The bottom line is the modern diet contains a lot of refined sugar including fructose, and it’s a hidden danger implicated in a lot of modern diseases, such as obesity, diabetes and fatty liver,” said Heaney, who also serves as co-director of the Pituitary Tumor and Neuroendocrine Program at University of California Los Angeles. “In this study, we show that cancers can use fructose just as readily as glucose to fuel their growth.” The study is published in the 1 August issue of the peer-reviewed journal Cancer Research.

Sources of fructose in the Western diet include cane sugar (sucrose) and high-fructose corn syrup (HFCS), a corn-based sweetener that has been on the market since about 1970. HFCS accounts for more than 40% of the caloric sweeteners added to foods and beverages, and it is by far the most frequently used sweetener in American soft drinks. Between 1970 and 1990, the consumption of HFCS in the US increased by more than 1,000%, according to an article in the April 2004 issue of the American Journal of Clinical Nutrition. Food companies use HFCS – a mixture of fructose and glucose – because it is inexpensive.

In his study, Heaney and his team took pancreatic tumours from patients and cultured and grew the malignant cells in Petri dishes. They then added glucose to one set of cells and fructose to another. Using mass spectrometry, they were able to follow the carbon-labeled sugars in the cells to determine what, exactly, they were being used for and how.

Heaney found that the pancreatic cancer cells could easily distinguish between glucose and fructose, which are very similar structurally, and contrary to conventional wisdom, the cancer cells metabolised the sugars in very different ways. In the case of fructose, the pancreatic cancer cells used the sugar in the transketolase-driven non-oxidative pentose phosphate pathway to generate nucleic acids, the building blocks of RNA and DNA, which the cancer cells need to divide and proliferate.

“Traditionally, glucose and fructose have been considered as interchangeable monosaccharide substrates that are similarly metabolised, and little attention has been given to sugars other than glucose,” the study states. “However, fructose intake has increased dramatically in recent decades and cellular uptake of glucose and fructose uses distinct transporters.” Heaney said that while this study was done in pancreatic cancer, these finding may not be unique to that cancer type.

Going forward, Heaney and his team are exploring whether it is possible to block the uptake of fructose in the cancer cells with a small molecule, taking away one of the fuels they need to grow. The work is being done in cell lines and in mice, Heaney said.

Obesity surgery for mother can lead to blindness in newborns

Biliopancreatic diversion surgery for morbid obesity is known to cause multiple vitamin deficiencies that may worsen during pregnancy. In the June issue of the Journal of AAPOS, the official publication of the American Association for Pediatric Ophthalmology and Strabismus, a group of Australian clinicians report a child who was born blind as a result of Vitamin A deficiency caused by his mother’s obesity surgery.

Lowering radiation dose in perfusion CT

Perfusion CT scanning, an emerging imaging technology, got a bad rap last year when a machine set to incorrect radiation levels overdosed hundreds of people in Los Angeles. In the wake of this incident, researchers at the Mayo Clinic, excited by the technology’s promise for diagnosing stroke, cancer, and possibly heart disease, have developed a way to reduce the amount of radiation involved in the procedure – which, when done properly, already involves very little risk.

“At the correct dose, there should be no injury,” said Cynthia McCollough. “We believe in the clinical value of perfusion CT, so we’re trying to lower the dose and reduce the stigma.”

McCollough and her colleagues created a new image-processing algorithm that can give radiologists all of the information they need using as up to 20 times less radiation, depending on the diagnostic application.

A typical CT perfusion procedure lasts about half a minute and scans the same tissue many times, each scan at a low dose. These scans both reveal the internal anatomy of the patient and show how levels of a contrast agent, such as iodine injected into the bloodstream, change of over time. Changing concentrations of iodine can be used to calculate blood volume and flow in order to detect injuries to blood vessels or tumor responses to treatment.

The new adaptive algorithm compares these 20-30 scans and can differentiate between anatomical regions that do not change from moment to moment and those regions that carry the contrast agent – effectively reducing image noise while preserving iodine signal. The quality of each scan improves through non-linear comparisons with scans acquired earlier and later in the exam.

Myocardial perfusion imaging accounts for 74% of radiation dose

A study published online in the Journal of the American College of Cardiology warns that cardiac imaging procedures account for a large amount of accumulated ionizing radiation exposure for individuals. Speaking to healthimaging.com Dr Jersey Chen, lead author of the study, said: “The main significance of the study is to bring to the attention of people who perform or refer patients for cardiac testing how much radiation the patients are getting.” In the study he notes that cardiac imaging procedures frequently expose patients to ionizing radiation, but their contribution to effective doses of radiation in the general population is unknown.

The researchers looked at administrative claims to identify cardiac imaging procedures performed from 2005 to 2007 in 952,420 adults in the US. A total of 90,121 (9.5%) individuals underwent at least 1 cardiac imaging procedure using radiation. Among patients who underwent at least one of more cardiac imaging procedures, the mean cumulative effective dose over 3 years was 16.4 mSv (range 1.5 to 189.5 mSv). Myocardial perfusion imaging accounted for 74% of the cumulative effective dose.

Overall, 47.8% of cardiac imaging procedures were performed in physician offices; this proportion was higher for myocardial perfusion imaging (74.8%) and cardiac computed tomography studies (76.5%). The annual population-based rate of receiving an effective dose of between 3 and 20 mSv/year was 89.0 per 1,000; and 3.3 per 1,000 for cumulative doses greater than 20 mSv/year. Annual effective doses increased with age and were generally higher among men.

He explained that the question of risks versus benefits should always be considered before cardiac imaging, and noted that the US National Academies’ Seventh Biologic Effects of Ionizing Radiation report, estimates that a 100 mSv radiation dose would lead to one additional cancer per 100 individuals over a lifetime. Therefore, there is a risk for lifetime cancer for about 10% of the population who get a cardiac imaging dose of 23 mSv. But since cardiovascular disease is the number one killer in America, in patients who have a high probability of having cardiac disease the benefits of imaging outweigh the risks, he said.

● Citation: Cumulative Exposure to Ionizing Radiation from Diagnostic and Therapeutic Cardiac Imaging Procedures, Chen j. et al. J Am Coll Cardiol, doi:10.1016/j.jacc.2010.05.014 http://content.onlinejacc.org/cgi/content/ abstract/j.jacc.2010.05.014

● Meanwhile, an editorial in the July 2010 issue of Journal of the American Medical Association is calling for the US government to regulate the use of CT which they say is largely responsible for the doubling of radiation dose in the US population over the past 30 years.

While acknowledging the benefits of CT and the small individual risks of radiation carcinogenesis, the authors called for an optimal public benefit/risk balance. “Regardless of the actual magnitude, these population risks would undoubtedly be reduced if radiation doses were optimised for each procedure and if medically unnecessary imaging were minimised,” they wrote.

When two hearts beat as one

It has always been claimed that there is an unbreakable bond between a mother and her child. Now scientists appear to have proved it. A recent study has shown that meditation, or rhythmic breathing, during pregnancy makes a mother and her child’s hearts beat in unison.

Scientists at the University of Aberdeen and Witten/Herdenke University in Germany have shown that the heartbeat of a foetus will synchronise with the heartbeat of a pregnant mother when she breathes rhythmically. Interestingly, this synchronization does not take place if the mother breathes normally. The previously unknown connection has paved the way for a new technique to detect development problems during pregnancy.

The findings show that synchronisation between the heartbeats of a mother and foetus only occurs when the mother breathes rhythmically. To ensure rythmic breathing volunteers in the study were asked to breathe in time with a computer-generated clock. They were asked to inhale and exhale in time with the ticks of the clock, which were set at specific speeds.

If this synchronisation does not occur, it signals that something may be wrong with the development of the foetus. This opens up the potential for early medical intervention to be taken whilst the child is still in the womb.

Cutting edge computing technology was then used to generate simulated heartbeats, which revealed the interaction. Dr Marco Thiel, one of a team of physicists from the University of Aberdeen who worked on the study, said: “Pregnant mothers often report an awareness of a bond with their child, but until now there has been no hard evidence to suggest this bond is reflected in the interaction of their heartbeats.

“Our findings reveal that synchronisation between the heartbeat of a mother and foetus does actually occur, but only when the mother is breathing in a rhythmical fashion.

“The foetus can sense the rhythmical shift in the mother’s heartbeat and adapts its own heartbeat accordingly. Importantly, the phenomenon does not occur when a mother is breathing normally.

The findings of the study are now being used in the treatment of pregnant women at the Grönemeyer Institute for Microtherapy, at Witten/Herdenke University.

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