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Research Team Discovers Gene-Silencing Technology

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Genes that can cause certain diseases can be silenced by a new technology that could help prevent disease where gene dysfunction is involved. The research was led by Ming-Ming Zhou, Ph.D., Professor and Chairman of the Department of Structural and Chemical Biology at Mount Sinai School of Medicine.

“By being able to silence certain genes, we may be able to suppress genes that can cause diseases such as HIV/AIDS, cancer, inflammation and diseases of the central and peripheral nervous systems. We now know we can focus on these genes and potentially change the ultimate course of many diseases that have a major impact on people’s lives,” says Dr. Zhou.

Dr. Zhou, Shiraz Mujtaba, Ph.D., Assistant Professor of Structural and Chemical Biology at Mount Sinai and their colleagues found that Paramecium bursaria chlorella virus uses a viral protein to modify host DNA packing chromatin and switch host transcription machinery for viral replication. Using this information, the doctors developed a new technology capable of suppressing transcriptional expression of targeted genes in human cells, including genes that are linked to the onset of a number of diseases.

Source: Nature Cell Biology, September, 2008

Medicare Patches and Hotline Help Seniors Quit Smoking

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Seniors trying to quit smoking can be helped by Medicare-supplied nicotine patches and a Medicare hotline, according to new research conducted to estimate the cost of such a Medicare program. The study revealed that close to 20% of seniors who tried the program quit smoking for a year.

“From a public health perspective, it works,” said study lead author Geoffrey Joyce, a senior economist with RAND, which provides research services to the government. While most antismoking efforts focus on younger people, “Nobody has really paid attention to the elderly,” Joyce said.

Even inveterate smokers among seniors can benefit from quitting: a 1986 study showed that a senior who smokes 20 or more cigarettes a day and quits at age 65 could expect to add two to three years to his or her life.

The question being asked by Medicare meanwhile was—is it cost-effective to help seniors quit smoking? This new study was published in the current online issue of the journal Health Services Research.

7,354 seniors participated in the study, and all had enrolled in smoking cessation programs in 7 states between 2002 and 2003. The researchers divided the seniors into 4 groups—one group was given a brochure on smoking cessation; one group was paid for four counselling sessions with doctors; another group was given counseling and a nicotine patch, or the smoking-cessation drug bupropion. Thje last group used a nicotine patch and a hotline.

The one-year quit rates for the first three groups were 10%, 14% and 16%. For the last group the rate was 19%, and participants did not tuch cigarettes for the ensuing year.

Joyce said the difference between the 10 percent quit rate in the brochure group and the 19 percent quit rate in the hotline and patch group was significant: “You can double quit rates with a telephone quitline and a free patch.” Helen Ann Halpin, director of the Center for Health and Public Policy Studies at the University of California at Berkeley, said the study results suggest that “older smokers are motivated to quit and that quitlines and pharmacotherapy greatly increase the odds of successfully quitting.” She added that all 50 states now have a quitline for smokers of all ages.

As for Medicare’s need for cost-effective care, “what we don’t know is how much money this really saves if saving money is your goal,” Joyce said. Still, it seems clear that “if you just look at it from a strict budget perspective, it’s not going to save Medicare a lot one way or another.”

Source: Health Behavior News Service, August, 2008

The Dangers of Using Performance Enhancing Drugs

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More than 10,000 athletes from 205 countries will strive to win medals at the 2008 Summer Olympic Games in Beijing, just started. “The heavy preparation for the Olympics puts severe strain on an athlete’s musculoskeletal frame,” said Edward McDevitt, MD, spokesperson for the American Academy of Orthopaedic Surgeons (AAOS) and orthopaedic surgeon specializing in sports medicine.

The dream of every athlete is to win a medal for his or her country,” stated Dr. McDevitt. “This is a great attitude to have, but it can become problematic if the athlete develops the ‘stop-at- nothing mentality’ to win.”

Athletes prepared to go to any lengths to win are known to use PEDs, performance enhancing drugs, which include Human Growth Hormones (hGH or IGF-1), erythropoietin (EPO), and anabolic steroids. The danger of using PEDs is that athletes are only interested in the potential short-term benefits of these drugs and do not consider the important long-term consequences of using them.

The AAOS stresses that severe long-term musculoskeletal, psychological and physiological risks attach to using them, including stunted growth, diabetes, impaired reproductive functioning, the spread of cancerous tumors, early osteoarthritis and accelerated vascular heart disease, heart attack, and strokes. Increased aggressiveness and the possibility of anti-social behavior can also ensue from using these drugs.

Anabolic steroids, growth hormone and other PEDs are readily available through the Internet and local gyms, and Dr. McDevitt recommends that physicians, coaches, trainers and parents maintain constant contact with their athletes to advise on the effects of PEDs.

“All of us who care about the health of our athletes should be aware of the warning signs of PED use for all athletes, not just Olympians,” stated Dr. McDevitt. The following warning signs should be looked for: a sudden increase in am athlete’s height or weight, a shrinking of the male testicles, male-pattern hair loss in men and women, significant acne on the athlete’s back, problems with anger management and increased aggressiveness.

“With the easy availability of these drugs, some athletes are looking to get bigger and stronger as quickly as possible,” stated Dr. enhancing drugs today can lead to life-long medical and musculoskeletal problems down the road.”McDevitt. “It is our responsibility to educate and inform our athletes of all ages that use of performance.

Source: American Academy of Orthopaedic Surgeons (AAOS)

First Ever U.S. DuraHeart Patient Doing Well

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The DuraHeart, a new experimental, hi-tech heart-assist device, was implanted in Anthony Shannon July 30—a procedure which made history. A week later, the 62-year old Shannon was reported doing well after the operation performed by a team led by surgeon Francis Pagani, M.D., Ph.D. at the University of Michigan Cardiovascular Center. Shannon is the former director of homeland security and emergency management for Wayne County, Mich., and holds a Ph.D, in public administration.

The “maglev” or magnetic levitation technology used means that that a crucial, constantly revolving part within the hockey puck-sized implanted device never touches the walls of the pumping chamber. Instead, it levitates in the middle, suspended in a magnetic field and pushing blood along. The battery-powered device pushes blood from the heart to the body, taking over most of the function of the left side of a severely weakened heart. The advantage of this technology is that the risk of allowing blood clots to form is reduced, as is damage to blood cells, compared with devices using mechanical pumps. DuraHeart has been used for 70 European patients, and received commercial use approval after a 20-07 clinical trial.

A clinical trial for DuraHeart is being conducted by Drs. Pagani and Yoshifumi Naka, M.D.,Ph.D., from Columbia Presbyterian Hospital in New York, and heart failure patients at U-M and other U.S. centers will be invited to volunteer for it.

“The DuraHeart gives us a new, third-generation option for patients with advanced heart failure who need help to allow them to survive until they can receive a heart transplant,” says Pagani, who leads the U-M Center for Circulatory Support. He has led other national clinical trials of heart-assist devices, including the HeartMate II, which in April received approval from the U.S. Food and Drug Administration after a clinical trial. U-M now offers heart failure patients nearly a dozen different options to support their heart function, including heart transplants. U-M is the national training center for the trial, which is funded by Terumo Heart, and teams from Columbia and the University of Louisville have already traveled to Ann Arbor to learn how to implant the device.

“This trial will test the DuraHeart’s potential to overcome some of the issues that have been seen with other devices, including hemolysis caused by shear stress on red blood cells, and clotting risk caused by blood that does not circulate rapidly enough from all areas of the chamber,” Pagani explains. “It also remains to be seen if this device offers superior durability, which might make it useful as a destination therapy that could remove the need for a heart transplant.”

Some 5.3 Americans currently experience heart failure, and at any given time some 4,000 are on a waiting list for heart transplants. Because there is a shortage of suitable organ donors however, only 2,100 people in the U.S. receive new hearts, and hundreds of people die each year while waiting for a new heart. Most of the devices developed to help the heart pump over the past 20 years have been left-ventricular assist systems, known as LVADs or LVASs; others have assisted the right side or both, and all are known as VADs. Hospitals can apply for accreditation as a certified VAD center, and U-M recently became one ofmthe few such centers in the U.S.

The DuraHeart was invented and developed by a team led by Chisato Nojiri, M.D., Ph.D., the chief executive officer of Terumo Heart. More than a decade of research and development has led to this clinical trial and the trial in Europe, as well as a trial in Japan that may begin later this year. Pagani serves as an unpaid consultant to Terumo Heart.

To implant a DuraHeart device, the surgeon diverts blood flow from the ailing left ventricle of the heart into a titanium tube that leads into the pumping chamber. The magnetically levitating impeller, a flat magnetic disc, acts as a paddlewheel, turning constantly as it is magnetically attracted to the turning motor within the pump housing. This pushes blood into a flexible artificial blood vessel, which is connected to the large blood vessel called the ascending aorta.

By assisting the weak left ventricle, which is the heart chamber most commonly affected by heart failure, the DuraHeart allows the heart muscle to rest. It also provides better blood flow to the body, brain and organs than a weak heart ever could – which helps patients prepare for the arduous surgery of a heart transplant.

The DuraHeart is made by Terumo Heart, Inc. based in Ann Arbor, Michigan.

Source: University of Michigan, August, 2008

Eating Fish May Avert Memory Loss

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The risk of cognitive decline and stroke in older adults may be reduced by eating tuna and other kinds of fish, according to study by researchers in Finland.

The study used a sample of 3,660 men and women aged 65 or older and subjected them to brain scans to look for silent brain infarcts, stroke or dementia. 5 years later, 2,313 members of the sample were tested again with scans, and all participants were given questionnaires on fish in their diets.

Findings of the study showed that participants who ate broiled or baked tuna or other fish high in omega-3 fatty acids (DHA and EPA) three or more times a week were at a 26% lower risk of experiencing the silent brain lesions that cause dementia and stroke than people who were not regular fish eaters. Even one fish meal weekly reduced the risk by 13%, and the study found that regular consumption of these types of fish reduced the changes of white matter in the brains of fish eaters.

“While eating tuna and other types of fish seems to help protect against memory loss and stroke, these results were not found in people who regularly ate fried fish,” said Jyrki Virtanen, PhD, RD, with the University of Kuopio in Finland. “More research is needed as to why these types of fish may have protective effects, but the omega-3 fatty acids EPA and DHA would seem to have a major role.” Types of fish that contain high levels of DHA and EPA nutrients include salmon, mackerel, herring, sardines, and anchovies.

“Previous findings have shown that fish and fish oil can help prevent stroke, but this is one of the only studies that looks at fish’s effect on silent brain infarcts in healthy, older people,” said Virtanen. Research shows that silent brain infarcts, which are only detected by brain scans, are found in about 20 percent of otherwise healthy elderly people.

Source: Neurology, August 5, 2008

Researchers ID Genetic Variants Linked to Increased Risk of Metabolic Syndrome

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Nutrition researchers have identified five common genetic variations that increase the risk of metabolic syndrome, a group of factors linked to heart disease and diabetes. Another variant they found appeared to protect against the condition.

People with metabolic syndrome have at least three of the following symptoms: abdominal obesity, high blood triglyceride levels, lower good cholesterol (HDL), elevated blood pressure and elevated fasting blood glucose. They are four times as likely to develop heart disease and at least seven times more likely to develop diabetes as individuals without metabolic syndrome.

The investigators at Washington University School of Medicine in St. Louis looked for changes in the CD36 gene, which is located in a region of chromosome 7 that has been linked to metabolic syndrome in several genome-wide studies.

The researchers say linking changes in the CD36 gene to the risk for metabolic syndrome and abnormal levels of good cholesterol is important because as more people in the United States become obese, they also become susceptible to these problems. Better understanding of the relationships between obesity, the gene and disease risk may allow for earlier identification of individuals who are more susceptible to develop metabolic syndrome. Treatments such as medication or lifestyle changes could begin earlier, perhaps preventing or delaying future problems with diabetes or heart disease.

Senior investigator Nada A. Abumrad, Ph.D., the Dr. Robert C. Atkins Professor of Medicine and Obesity Research, first identified the CD36 protein in studies with mice. Her research has demonstrated that the protein facilitates the use of fatty acids for energy. CD36 is located on the surface of cells and distributed throughout many tissues, including fat cells, the digestive tract, heart and skeletal muscle.

The investigators focused on 36 small genetic variations, called single nucleotide polymorphisms (SNPs), in the CD36 gene. A SNP involves a single base-pair change in the DNA.

The team evaluated DNA taken from more than 2,000 African-Americans because variations in the gene are more common in individuals of African and Asian descent than in other racial groups. The researchers expect, however, that these findings also will be applicable in other populations.

“The idea was to look at the different variations in the gene and see whether they were more prevalent in people who also had elevated cholesterol, abnormal blood glucose or the other components of the metabolic syndrome,” says first author Latisha Love-Gregory, Ph.D., research instructor in the Division of Geriatrics and Nutritional Science.

Love-Gregory says the research team demonstrated an association between SNPs in the gene and metabolic syndrome.

“There is additional work to do to determine if the function of these genetic variants actually contributes to the development of type 2 diabetes or heart disease,” she explains. “We do expect that a number of different changes, in both CD36 and other genes, will be related to these diseases. What we’d like to learn, however, is whether the changes identified in the gene alter the CD36 protein in ways that change its function to make a person more vulnerable.”

The team determined that five of the SNPs they examined are more common in people who have symptoms of metabolic syndrome, but a sixth seemed to have a more favorable metabolic effect. The “protective” SNP makes people produce lower amounts of CD36 protein.

Humans have two copies of each chromosome. In this study, people who had the protective variant on only one of their copies of chromosome 7 were less susceptible to metabolic syndrome. But people with two copies of the variant, who were completely deficient in the CD36 protein, did not appear to be protected. They tended to have lower levels of HDL, the so-called good cholesterol.

“A bit less CD36 protein may improve your risk profile, but people need some CD36 function,” Abumrad says. “It’s like requiring a certain level of fat in the diet. Fatty acids are important for optimal function of many tissues — from pancreatic beta cells to skeletal muscle to the heart — but too much fat creates a problem.”

Love-Gregory and Abumrad found that many variants influenced blood levels of HDL cholesterol. Now they are taking a closer look at the relationship between CD36 and HDL cholesterol. Higher levels of HDL normally are considered positive, but because changes in the CD36 gene seem to influence HDL, the researchers want to make sure that the HDL molecule isn’t being altered in composition or function.

“We’re going to follow up on the HDL component of the study,” Love-Gregory says. “We’re also going to look for additional variants in the promoter region of the gene that controls how the gene is regulated. And we’re planning to look for evidence of these gene variants and their associations with HDL and the metabolic syndrome in other populations and ethnic groups.”

Source: Human Molecular Genetics, June, 2008

Differing Brain Connections May Cause Autism’s Social Impairment

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The brains of adults with autism may be "wired" differently from people without the disorder, and this abnormal pattern of connectivity may be responsible for the social impairments that are characteristic of autism.

Using functional magnetic resonance imaging, a team of researchers affiliated with the University of Washington’s Autism Center found that the most severely socially impaired subjects in the study exhibited the most abnormal pattern of connectivity among a network of brain regions involved in face processing.

"This study shows that these brain regions are failing to work together efficiently," said Natalia Kleinhans, a research assistant professor of radiology and lead author of the paper published in the journal Brain. "Our work seems to indicate that the brain pathways of people with autism are not completely disconnected, but they are not as strong as in people without autism."

The study is the first to look at brain connectivity and social impairment, and focused on how the brain processes information about faces. Deficits in face processing are one of the earliest characteristics to emerge in people with autism.

The research team led by Elizabeth Aylward, a UW professor of radiology, examined connectivity in the limbic system, or the network of brain regions that are involved with processing social and emotional information.

Participants in the study included 19 high-functioning adults with autism who had IQs of at least 85. They ranged in age from 18 to 44 and were compared with an age- and intelligence-matched sample of 21 typically developed adults.

The group with autism spectrum disorder included eight individuals diagnosed with autism, nine with Asperger’s syndrome and two diagnosed with pervasive developmental disorder not otherwise specified. The level of social impairment for each autistic participant was drawn from records of clinical observations and diagnoses that confirmed that each had autism.

Each participant had his or her brain scanned while looking at pictures of faces or houses. Participants were shown four series of 12 pictures of faces and a similar number of series showing houses. Each individual picture was seen for three seconds. Occasionally the same face or house picture was repeated, and participants were told to press a button when this occurred.

There was no significant difference on the two groups’ performance, because the task was so basic, said Todd Richards, a professor of radiology and co-author of the paper. "Differences might have shown up if they had been asked to do something more complicated."

However, the two groups exhibited different patterns of brain activity. The researchers focused on the fusiform face area of the brain, a region that is involved in face identification. Compared to the participants with autism, the typically developing adults showed significantly more connectivity between the fusiform face area and two other brain regions, the left amygdala and the posterior cingulate. In addition, autistic participants who had the largest social impairment showed the lowest level of connectivity between the right fusiform face area and the left amygdala and increased connectivity between the right fusiform face area and the right inferior frontal gyrus.

"This study shows that the brains of people with autism are not working as cohesively as those of people without autism when they are looking at faces and processing information about them," said Kleinhans.

Source: University of Washington, June 12, 2008

Regular Drinking May Reduce the Risk of Rheumatoid Arthritis

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Drinking alcohol regularly may reduce the risk of developing rheumatoid arthritis by up to 50%, according to recent research.

Scandinavian researchers conducted two studies, involving 2,750 people, assessing environmental and genetic risk factors for rheumatoid arthritis. 1,650 participants had the disease, and were questioned about their smoking and drinking habits, while blood samples were taken to check for genetic risk factors.

Findings showed that drinking alcohol was linked to a reduced risk of developing rheumatoid arthritis; in fact, the more the subject drank, the lower the risk of rheumatoid arthritis.

Among regular drinkers, the quartile drinking the most were up to 50% less likely to develop the disease than the half who drank the least. Findings were the same for both men and women. In addition, alcohol cut the risk most in smokers with genetic risk factors for rheumatoid arthritis.

The authors conclude that their research reinforces the importance of lifestyle factors in the development of the disease, and that giving up smoking remains the single most important preventive measure.

They point to recent experimental research by other authors, which shows that alcohol protects against the development and severity of rheumatoid arthritis, although it is not clear exactly how it does this. The study also draws parallels with the links between moderate alcohol consumption and a reduced risk of other inflammatory processes, such as cardiovascular disease.

The study was published in the Annals of the Rheumatic Diseases.

Source: First Ann Rheum Dis 10.1136/ard.2007.086314

Higher Fracture Risk for Diabetes Drugs Such as Pioglitazone and Rosiglitazone, Says Study

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Insulin-sensitizing thiazolidinediones, such as pioglitazone and rosiglitazone, appear to be associated with an increased risk of fractures, according to a recent report. These two drugs account for about 21% of oral diabetes medications prescribed in the United States, and 5% of those prescribed in Europe.

The class of drugs is a relatively new and effective class of oral antidiabetic agents that have gained wide use in clinical conditions characterized by insulin resistance, the study authors note. Other recent studies have suggested that these therapies may have unfavorable effects on bone, resulting in slower bone formation and faster bone loss.

According to the study, individuals who were currently taking rosiglitazone and pioglitazone had approximately 2x or 3x the likelihood of hip and other non-spine fractures than those who did not take these drugs. The odds for fracture were increased among patients who took the drugs for approximately 12 to 18 months and the risk was highest for those with two or more years of therapy.

Source: Archives of Internal Medicine, April 28, 2008

Research Shows Promise for Cystic Fibrosis and HIV Therapies

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Innovative therapies against cystic fibrosis have shown promise for increasing the effectiveness of antibiotics in the treatment of chronic and acute bacterial respiratory infections in cystic fibrosis patients, and may also provide a model for potential HIV therapies in the future.

A number of compounds that block a key protein (exoenzymeS or ExoS) have been identified by Professor Igor Stagljar of the University of Toronto, with one—exosin—inhibiting infections in mammalian cells.

Past studies have shown it is possible to prevent or delay the onset of certain chronic or deadly infections in cystic fibrosis patients with early antibiotic treatment. But the current availability of antibiotics against Pseudomonas aeruginosa, a pathogen that can cause urinary tract infections, respiratory system infections, dermatitis, soft tissue infections, bacteremia, bone and joint infections, gastrointestinal infections and a variety of systemic infections, is limited and the pathogen shows signs of drug resistance.

In an article published in the journal PLoS Genetics, a team of investigators identified several drugs that block a Pseudomonas aeruginosa toxin called ExoS.

"These studies created a road map to the rational design of more potent, highly selective inhibitors against other similar toxins using a totally novel yeast-based approach," says lead author Stagljar. "This innovative approach is an important advance, not only for the value it may have in cystic fibrosis treatment, but also because this technique could be used to design novel therapies for any bacterial pathogen as well as the HIV virus."

Staglar’s next step is to test the action of their inhibitors in an animal model of cystic fibrosis, which if successful may provide a way for the treatment ofthis debilitating disease.
In the next phase of their research, Stagljar and his colleagues plan to test the action of their inhibitors in an animal model of cystic fibrosis. If successful, the therapeutics may provide an avenue for the treatment of this debilitating disease.

Source: University of Toronto