Factfile: Health risks from radiation

Following is a primer on the health consequences of exposure to radiation:

RADIATION RISK

16 mar 2011--Three things, say experts, determine whether a blast of radiation will be harmless, debilitating or lethal: the intensity of exposure, its duration and access to treatment.

Radioactive fallout includes caesium 137, a long-term element, and iodine, which is a short-term element. Intensity of exposure is measured in a unit called millisieverts (mSv), while the absorbed dose in the body is measured in milligrays.

EXPOSURE

Small, controlled doses of exposure for medical applications cause no ill effects, doctors say. A brain scan, for example, generates 25 mSv, while a whole body scan puts out 150 mSv. A single dose of 1,000 mSv, though, can cause temporary radiation sickness, including nausea and vomiting.

About half of people exposed to a 5,000 mSv dose across the entire body would probably die, while 6,000 mSv would be fatal without immediate treatment.

Exposure to 10,000 mSv in a single dose would lead to death "within a few weeks," according to the World Nuclear Association (WNA), an industry group.

Japanese officials said radiation levels as of 10:20 a.m. (0122 GMT) Tuesday were 30 mSv between the No. 2 and No. 3 reactors, and 400 mSv near No. 3, and 100 mSv near No. 4.

During a severe nuclear accident, exposure can reach several thousand mSv near the reactor core.

RADIATION ILLNESS

The main health danger is cancer, especially leukaemia, along with lung, thyroid and colon cancer.

"The risk is proportional to the dose received," said Patrick Gourmelon, a top researcher at the French Institute for Radioprotection and Nuclear Safety (IRSN).

"Even for relatively small doses, the risk of developing cancers rises."

In cases of extreme irradiation, the body's bone marrow stops making red and white blood vessels, resulting in death. Cells inside the digestive tract are also especially vulnerable.

Over the long term, radiation can also damage DNA, leading to potential birth defects.

TREATMENT OPTIONS

Potassium iodine pills taken beforehand can help prevent radioactive iodine in the air from settling in the thyroid and causing cancer, especially in infants and children.

The tablets are preferably taken an hour before a known fallout incident.

Japanese guidelines say the pills should be distributed when the likely absorbed dose of radioactivity is 100 milligray, a unit named after a British physicist.

Once exposed, the best first step is to throw away contaminated clothes and wash one's hair and body.

Some drugs help boost white-blood cell production inside bone marrow, and build up the body's compromised immunity.

Vitamin D insufficiency high among patients with early Parkinson disease

Patients with a recent onset of Parkinson disease have a high prevalence of vitamin D insufficiency, but vitamin D concentrations do not appear to decline during the progression of the disease, according to a report in the March issue of Archives of Neurology, one of the JAMA/Archives journals.

15 mar 2011--Vitamin D is now considered a hormone that regulates a number of physiological processes. "Vitamin D insufficiency has been associated with a variety of clinical disorders and chronic diseases, including impaired balance, decreased muscle strength, mood and cognitive dysfunction, autoimmune disorders such as multiple sclerosis and diabetes (types 1 and 2), and certain forms of cancer," the authors write as background information in the article. "Vitamin D insufficiency has been reported to be more common in patients with Parkinson disease (PD) than in healthy control subjects, but it is not clear whether having a chronic disease causing reduced mobility contributes to this relatively high prevalence."

Marian L. Evatt, M.D., M.S., of Emory University School of Medicine and the Atlanta Veterans Affairs Medical Center, and colleagues examined the prevalence of vitamin D insufficiency in untreated patients with early PD, diagnosed within five years of entry into the study. They conducted a survey study of vitamin D status in stored blood samples from patients with PD who were enrolled in the placebo group of the Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism (DATATOP) trial.

The authors found a high prevalence of vitamin D insufficiency and deficiency in 157 study participants with early, untreated PD. At the baseline visit, most study participants (69.4 percent) had vitamin D insufficiency and more than a quarter (26.1 percent) had vitamin D deficiency. "At the end point/final visit, these percentages fell to 51.6 percent and 7 percent, respectively."

"Contrary to our expectation that vitamin D levels might decrease over time because of disease-related inactivity and reduced sun exposure, vitamin D levels increased over the study period," the authors write. "These findings are consistent with the possibility that long-term insufficiency is present before the clinical manifestations of PD and may play a role in the pathogenesis of PD."

Vitamin D insufficiency in patients with early PD was similar or higher than the prevalence reported in previous studies.

"We confirm a high prevalence of vitamin D insufficiency in patients with recent onset of PD, during the early clinical stages in which patients do not require symptomatic therapy," the authors conclude. "Furthermore, vitamin D concentrations did not decrease but instead increased slightly over the course of follow-up. This provides evidence that during early PD, vitamin D concentrations do not decrease with disease progression."

More information: Arch Neurol, 2011;68[3]:314-319.

CDC Study Shows Growing Number of Cancer Survivors

If it feels like you know more cancer survivors lately, don't worry about an increase in the dreaded disease. Blame it on a higher survival rate.

14 mar 2011--According to the Centers for Disease Control and Prevention, the number of cancer survivors is rapidly increasing as technology for early detection, public awareness and treatment options improve. The CDCP released a report Friday indicating that a mere 3 million Americans were cancer survivors in 1971; in 2007, the last year for which data is available, that number had increased to 11.7 million. That means there are almost as many cancer survivors in the United States as there are people in Illinois.

Increasing public awareness of cancer symptoms and the campaign to increase cancer screenings has helped to increase the number of survivors as have advances in cancer treatment. The majority of the cancer survivors alive when these numbers were developed had been treated for breast, prostate or colorectal cancers. Those three types of cancers accounted for more than half the survivors.

The report also pointed out that nearly two-thirds of patients diagnosed with cancer had lived at least five years after their diagnosis. The CDCP advised in the report that physicians and other medical professionals should become accustomed to treating cancer survivors and should learn to recognize the special health needs of those patients.

"Public health and health-care professionals should understand the potential long-term needs of cancer survivors, engage in health promotion (e.g., urging cancer screening and smoking cessation), and ensure coordination of follow-up care for this growing population," the report said.

This study excluded patients with in situ cancer and non-melanoma skin cancer in the developing of the statistics. Various types of cancer are considered more treatable than others and several, including breast cancer, are more often screened for, but the study indicates that on the whole, cancer is becoming more survivable.

Elderly Tend to Drive Slower to Make Up for Reaction Time

13 mar 2011-- One reason that elderly people tend to be slower drivers than younger people is because they have a narrower field of vision and have more difficulty seeing pedestrians, according to a new study.

Israeli researchers tested experienced elderly and non-elderly drivers, and compared the differences between them in reaction times and when pedestrians were perceived as hazards.

Driving simulator tests showed that the elderly drivers noticed pedestrians half as often as younger drivers and also took longer to respond to hazardous situations involving pedestrians.

The elderly drivers reduced their driving speed by almost 20 percent in order to give themselves more time to respond to hazards and dangers, said the team at Ben-Gurion University of the Negev.

The study was released online in advance of publication in an upcoming print issue of the journal Accident Analysis and Prevention.

"These findings strengthen the notion that elderly drivers, shown to have a narrower useful field of view, may also be limited in their ability to detect hazards, particularly when outside the center of their view," Tal Oron-Gilad, of the department of industrial engineering, said in a university news release.

She added that "authorities should be aware of these limitations and increase elderly drivers' awareness of pedestrians by posting traffic signs or dedicated lane marks that inform them of potential upcoming hazards."

More information

The U.S. Centers for Disease Control and Prevention

Keys to long life: Longevity study unearths surprising answers

Cheer up. Stop worrying. Don't work so hard. Good advice for a long life? As it turns out, no. In a groundbreaking study of personality as a predictor of longevity, University of California, Riverside researchers found just the opposite.

12 mar 2011--"It's surprising just how often common assumptions – by both scientists and the media – are wrong," said Howard S. Friedman, distinguished professor of psychology who led the 20-year study.

Friedman and Leslie R. Martin , a 1996 UCR alumna (Ph.D.) and staff researchers, have published those findings in "The Longevity Project: Surprising Discoveries for Health and Long Life from the Landmark Eight-Decade Study" (Hudson Street Press, March 2011).

Friedman and Martin examined, refined and supplemented data gathered by the late Stanford University psychologist Louis Terman and subsequent researchers on more than 1,500 bright children who were about 10 years old when they were first studied in 1921. "Probably our most amazing finding was that personality characteristics and social relations from childhood can predict one's risk of dying decades later," Friedman concluded.

The Longevity Project, as the study became known, followed the children through their lives, collecting information that included family histories and relationships, teacher and parent ratings of personality, hobbies, pet ownership, job success, education levels, military service and numerous other details.

"When we started, we were frustrated with the state of research about individual differences, stress, health and longevity," Friedman recalled. "It was clear that some people were more prone to disease, took longer to recover, or died sooner, while others of the same age were able to thrive. All sorts of explanations were being proposed – anxiety, lack of exercise, nerve-racking careers, risk-taking, lack of religion, unsociability, disintegrating social groups, pessimism, poor access to medical care, and Type A behavior patterns." But none were well-studied over the long term. That is, none followed people step-by-step throughout their lives.

When Friedman and Martin began their research in 1991, they planned to spend six months examining predictors of health and longevity among the Terman participants.

But the project continued over the next two decades – funded in part by the National Institute on Aging – and the team eventually involved more than 100 graduate and undergraduate students who tracked down death certificates, evaluated interviews, and analyzed tens of thousands of pages of information about the Terman participants through the years.

"We came to a new understanding about happiness and health," said Martin, now a psychology professor at La Sierra University in Riverside. "One of the findings that really astounds people, including us, is that the Longevity Project participants who were the most cheerful and had the best sense of humor as kids lived shorter lives, on average, than those who were less cheerful and joking. It was the most prudent and persistent individuals who stayed healthiest and lived the longest."

Part of the explanation lies in health behaviors – the cheerful, happy-go-lucky kids tended to take more risks with their health across the years, Friedman noted. While an optimistic approach can be helpful in a crisis, "we found that as a general life-orientation, too much of a sense that 'everything will be just fine' can be dangerous because it can lead one to be careless about things that are important to health and long life. Prudence and persistence, however, led to a lot of important benefits for many years. It turns out that happiness is not a root cause of good health. Instead, happiness and health go together because they have common roots."

Many of the UCR findings fly in the face of conventional wisdom. For example:

* Marriage may be good for men's health, but doesn't really matter for women. Steadily married men – those who remained in long-term marriages – were likely to live to age 70 and beyond; fewer than one-third of divorced men were likely to live to 70; and men who never married outlived those who remarried and significantly outlived those who divorced – but they did not live as long as married men.
* Being divorced is much less harmful to women's health. Women who divorced and did not remarry lived nearly as long as those who were steadily married.
* "Don't work too hard, don't stress," doesn't work as advice for good health and long life. Terman subjects who were the most involved and committed to their jobs did the best. Continually productive men and women lived much longer than their more laid-back comrades.
* Starting formal schooling too early – being in first grade before age 6 – is a risk factor for earlier mortality. Having sufficient playtime and being able to relate to classmates is very important for children.
* Playing with pets is not associated with longer life. Pets may sometimes improve well-being, but they are not a substitute for friends.
* Combat veterans are less likely to live long lives, but surprisingly the psychological stress of war itself is not necessarily a major health threat. Rather, it is a cascade of unhealthy patterns that sometimes follows. Those who find meaning in a traumatic experience and are able to reestablish a sense of security about the world are usually the ones who return to a healthy pathway.
* People who feel loved and cared for report a better sense of well-being, but it doesn't help them live longer. The clearest health benefit of social relationships comes from being involved with and helping others. The groups you associate with often determine the type of person you become – healthy or unhealthy.

It's never too late to choose a healthier path, Friedman and Martin said. The first step is to throw away the lists and stop worrying about worrying.

"Some of the minutiae of what people think will help us lead long, healthy lives, such as worrying about the ratio of omega-6 to omega-3 fatty acids in the foods we eat, actually are red herrings, distracting us from the major pathways," Friedman said. "When we recognize the long-term healthy and unhealthy patterns in ourselves, we can begin to maximize the healthy patterns."

"Thinking of making changes as taking 'steps' is a great strategy," Martin advised. "You can't change major things about yourself overnight. But making small changes, and repeating those steps, can eventually create that path to longer life."

Provided by University of California - Riverside

Aging with grace: In-home assessments lead to better care, lower health costs

The March 2011 issue of the journal Heath Affairs highlights an evidence-based model of geriatric care management developed, implemented and tested by researchers and clinicians from Indiana University, the Regenstrief Institute and Wishard Health Services.

11 mar 2011--Geriatric Resources for Assessment and Care of Elders (GRACE) optimizes the health and functional status of community dwelling lower income, older adults. GRACE is now in use by Wishard Health Services, the third-largest safety-net health organization in the United States; by HealthCare Partners Medical Group, a large managed care organization in Southern California and by a growing number of other organizations.

A previous clinical trial found that GRACE improves health and quality of life, decreases emergency department visits and lowers hospital admission rates in lower income older adults at high risk for hospital admission. The care delivery model focuses on the many issues faced by older adults -- access to needed services, medications, mobility, depression, transportation, nutrition, as well as other health issues of aging.

"Healthcare reform is calling out for ways to improve health and lower costs. We have found a strategy to do that for a very vulnerable growing population in a way that shows cost savings over time and has the added benefit of providing services that these seniors desperately need but can't get elsewhere," said Steven R. Counsell, M.D., Mary Elizabeth Mitchell Professor of Geriatrics at the IU School of Medicine, an IU Center for Aging Research center scientist, a geriatrician at Wishard, and an affiliated scientist of the Regenstrief Institute, the principal investigator of the GRACE clinical trial. He is currently leading GRACE dissemination initiatives while working to influence health policy to improve integration of medical and social care for vulnerable elders.

The key to GRACE is two teams. The support team, consisting of a nurse practitioner and a social worker, meet with each patient in the home to conduct an initial comprehensive geriatric assessment from the medicine cabinet to the kitchen cabinet. Based on the support team's findings, a larger interdisciplinary team (including a geriatrician, pharmacist, mental health social worker, and community-based services liaison) helps develop an individualized care plan.

Then the ball is back in the support team's court. The nurse practitioner and the social worker meet with the patient's primary care doctor to come up with a healthcare plan consistent with the patient's goals, such as maintaining the ability to participate in social and religious activities. The support team then works with the patient to implement the plan which contains strategies for medical issues of concern as well as elements related to maintaining quality of life. With the assistance of an electronic medical record and web-based tracking system, the GRACE support team provides ongoing comprehensive care management.

Because it improves health and quality of life, GRACE is cost effective. By the second year GRACE even saves money for the sickest (those with three to four chronic diseases). Results of the GRACE trial were published in the Dec. 12, 2007, issue of the Journal of American Medical Association (JAMA). The cost analysis of the GRACE model was published in the August 2009 issue of the Journal of the American Geriatrics Society.

"The GRACE model improves health and reduces healthcare costs by lowering hospitalization rates in high risk seniors. The GRACE intervention can be financed by a health plan under managed care Medicare using the savings from fewer hospitalizations to offset GRACE program expenses. Most seniors, however, are not enrolled in managed care Medicare plans, and most services provided by the GRACE program are not currently reimbursed by traditional fee-for-service Medicare. Thus, payment reform is needed for broad dissemination of the GRACE model to benefit seniors under traditional Medicare. We are pleased that the newly created U.S. government Center for Medicare and Medicaid Innovation is looking at GRACE and other novel ways of delivering medical care and paying healthcare providers that can improve health and also save money for Medicare and Medicaid," said Dr. Counsell.

Provided by Indiana University School of Medicine

Fast, accurate test for Alzheimer's

Scientists at the National Institute for Health Research’s (NIHR) Biomedical Research Centre for Mental Health at the King’s College London Institute of Psychiatry (IoP) and South London and Maudsley NHS Foundation Trust (SLaM) are the first to use an advanced computer program to accurately detect the early signs of Alzheimer's disease from a routine clinical brain scan. The new scan can return 85 per cent accurate diagnostic results in under 24 hours.

10 mar 2011--The 'Automated MRI' software automatically compares or benchmarks someone’s brain scan image against 1200 others, each showing varying stages of Alzheimer’s disease. This collection of images is thought to be the largest of its kind in the world.

Normally in routine clinical practice, brain scans are used to simply exclude diseases that can mimic Alzheimer’s disease, but here automated MRI software is being used for the first time in a NHS setting (Memory Clinics) to make an early and accurate diagnosis of the illness.

Early diagnosis

Early diagnosis of Alzheimer's is clinically difficult and patients with the early signs are frequently not treated until their symptoms become stronger. The new scan however can return 85 per cent accurate diagnostic results in under 24 hours.

An early diagnosis allows someone to plan their care before the condition worsens - helping to prevent institutionalisation, dramatically improving their quality of life. It is also a cost effective and efficient way to manage and organise treatment of the disease.

The scan has been developed by scientists at the IoP, together with colleagues from the Karolinska Hospital in Stockholm.

The system is being 'field tested' over the next 12 months with patients attending SLaM memory services in Croydon, Lambeth and Southwark. The ‘field test’ will also provide a supply of research grade images, which has important implications for the development of the next generation of drugs for dementia and individualised treatments.

There are 750,000 people with dementia in the UK. The financial cost of dementia to the UK is over £20 billion a year. According to the Alzheimer’s Society, in just 15 years a million people will be living with dementia. This will soar to 1.7 million people by 2051.

Provided by King's College London

Mediterranean diet: A heart-healthy plan for life

The Mediterranean diet has proven beneficial effects not only regarding metabolic syndrome, but also on its individual components including waist circumference, HDL-cholesterol levels, triglycerides levels, blood pressure levels and glucose metabolism, according to a new study published in the March 15, 2011, issue of the Journal of the American College of Cardiology. The study is a meta-analysis, including results of 50 studies on the Mediterranean diet, with an overall studied population of about half a million subjects.

09 mar 2011--"The prevalence of the metabolic syndrome is increasing rapidly throughout the world, in parallel with the increasing incidence of diabetes and obesity, and is now considered a major public health problem," said lead investigator Demosthenes Panagiotakos, Ph.D., associate professor in Biostatistics-Epidemiology of Nutrition, Department of Science of Dietetics - Nutrition, Harokopio University of Athens. "Additionally, the metabolic syndrome is one of the main causes of cardiovascular disease (directly or indirectly), associated with personal and socio-economic burdens. As a result, prevention of this condition is of considerable importance."

The Mediterranean diet is a dietary pattern characterized by high consumption of monounsaturated fatty acids, primarily from olives and olive oils; daily consumption of fruits, vegetables, whole grain cereals, and low-fat dairy products; weekly consumption of fish, poultry, tree nuts, and legumes; a relatively low consumption of red meat; and a moderate daily consumption of alcohol, normally with meals.

The Mediterranean diet, according to Dr. Panagiotakos and Christina-Maria Kastorini, MSc, Ph.D. cand., is one of the best-known and well-studied dietary patterns, which has been shown to be associated with decreased mortality from all causes, lower risk for cardiovascular disease, type 2 diabetes, obesity and some types of cancer. Additionally, it has a beneficial effect on abdominal obesity, lipids levels, glucose metabolism and blood pressure levels, which are also risk factors for the development of cardiovascular disease and diabetes. The antioxidant and anti-inflammatory effects of the Mediterranean diet as a whole, as well as the effects of the individual components of the diet, and especially olive oil, fruits and vegetables, whole grains and fish, also confer to the beneficial role of this pattern.

"To the best of our knowledge, our study is the first work that has systematically assessed, through a large meta-analysis, the role of the Mediterranean diet on metabolic syndrome and its components," he said. "Our results add to the existing knowledge, and further demonstrate the protective role and the significance that lifestyle factors, and mainly dietary habits, have when it comes to the development and progression of the metabolic syndrome."

Encouraging adherence to a healthy dietary pattern like the Mediterranean diet, as well as the adoption of an active lifestyle, seems to be a cornerstone in developing public health strategies for the prevention of the metabolic syndrome, Dr. Panagiotakos suggested. Taking into account the limited financial resources many countries face in the 21st century, better eating seems to be an effective and affordable means for preventing cardiovascular diseases, at the population level, he suggested. In addition to its various health benefits, this dietary pattern can be easily adopted by all populations and various cultures.

Provided by American College of Cardiology

Better than a BMI? New obesity scale proposed

Scientists have developed a new way to measure whether a person is too fat without having people step on the scale.

08 mar 2011--The new measure, called the Body Adiposity Index, or BAI, relies on height and hip measurements, and it is meant to offer a more flexible alternative to body mass index, or BMI, a ratio of height and weight, U.S. researchers said on Thursday.

BMI has been used to measure body fat for the past 200 years, but it is not without flaws, Richard Bergman of the University of Southern California, Los Angeles, and colleagues wrote in the journal Obesity.

While there are other, more complex ways to measure body fat beyond simply stepping on a scale, BMI is widely used both by researchers and doctors.

It is calculated by dividing weight in kilograms by height in meters squared. A person who is 5 feet 5 inches tall is classified as overweight at 150 pounds (68 kg) and obese at 180 pounds (82 kg).

But there is a lot of wiggle room in that calculation.

For example, women and men with the same BMI might have very different levels of extra flab. BMI numbers cannot be generalized across different ethnic groups or used with athletes, who have extra lean body mass.

The team made the index using data from a Mexican-American population study. They confirmed the scale's accuracy using an advanced device called a dual-energy X-ray absorption or DEXA scanner. Tests in a study of African Americans showed similar findings, suggesting BAI can be used across different racial groups.

BAI is a complex ratio of hip circumference to height that can be calculated by doctors or nurses with a computer or calculator.

The team says BAI still needs some fine tuning, and they still need to test it among whites and other ethnic groups, but they think it has promise as new tool, especially in remote settings with limited access to reliable scales.

"After further validation, this measure can be proposed as a useful measure of percent fat, which is very easy to obtain. However, it remains to be seen if the BAI is a more useful predictor of health outcome, in both males and females, than other indexes of body adiposity, including the BMI itself," the team wrote.

Obesity has become a global epidemic, with more than half a billion people, or one in 10 adults worldwide, considered to be obese -- more than double the number in 1980. Obesity-related diseases account for nearly 10 percent of U.S. medical spending, or an estimated $147 billion a year.

Social Activity in Older Adults May Prevent Disability

More socially active elderly are less likely to develop disabilities in basic activities

07 mar 2011-- The more socially active older people are, the less likely they are to become disabled, according to a study published online Feb. 7 in The Journals of Gerontology: Series A.

Bryan D. James, Ph.D., of Rush University Medical Center in Chicago, and colleagues investigated the association of incident disability and social activity among community-dwelling older adults. A total of 954 participants (mean age of 82 years) without clinical dementia, who reported independence in the functional areas assessed, were followed up for an average of 5.1 years. The participants' social activity was evaluated at baseline. An annual evaluation of disability in basic activities of daily living, mobility, and instrumental activities of daily living was carried out. The researchers adjusted for confounders, including depression, vascular disease and risk factors, body mass index, social networks, and self-reported physical activity.

The researchers found that social activity was associated with a decreased risk of incident disability. Each additional unit of social activity was correlated with a 43 percent reduction in the risk of developing a disability in activities of daily living. More socially active individuals were also significantly less likely to develop a disability in mobility (hazard ratio [HR], 0.69) and in instrumental activities of daily living (HR, 0.71).

"This study suggests that more socially active older persons are less likely to become disabled. Future research is needed to determine whether interventions aimed at increasing late-life social activity can play a part in delaying or preventing disability," the authors write.

Human stem cells transformed into key neurons lost in Alzheimer's

Northwestern Medicine researchers for the first time have transformed a human embryonic stem cell into a critical type of neuron that dies early in alzheimer's disease and is a major cause of memory loss.

06 mar 2011--This new ability to reprogram stem cells and grow a limitless supply of the human neurons will enable a rapid wave of drug testing for Alzheimer's disease, allow researchers to study why the neurons die and could potentially lead to transplanting the new neurons into people with Alzheimer's.

The paper is published March 4 in the journal Stem Cells.

These critical neurons, called basal forebrain cholinergic neurons, help the hippocampus retrieve memories in the brain. In early Alzheimer's, the ability to retrieve memories is lost, not the memories themselves. There is a relatively small population of these neurons in the brain, and their loss has a swift and devastating effect on the ability to remember.

"Now that we have learned how to make these cells, we can study them in a tissue culture dish and figure out what we can do to prevent them from dying," said senior study author Jack Kessler, M.D., chair of neurology and the Davee Professor of Stem Cell Biology at Northwestern University Feinberg School of Medicine and a physician at Northwestern Memorial Hospital.

The lead author of the paper is Christopher Bissonnette, a former doctoral student in neurology who labored for six years in Kessler's lab to crack the genetic code of the stem cells to produce the neurons. His research was motivated by his grandfather's death from Alzheimer's.

"This technique to produce the neurons allows for an almost infinite number of these cells to be grown in labs, allowing other scientists the ability to study why this one population of cells selectively dies in Alzheimer's disease," Bissonnette said.

The ability to make the cells also means researchers can quickly test thousands of different drugs to see which ones may keep the cells alive when they are in a challenging environment. This rapid testing technique is called high-throughput screening.

Kessler and Bissonnette demonstrated the newly produced neurons work just like the originals. They transplanted the new neurons into the hippocampus of mice and showed the neurons functioned normally. The neurons produced axons, or connecting fibers, to the hippocampus and pumped out acetylcholine, a chemical needed by the hippocampus to retrieve memories from other parts of the brain.

In new, unpublished research, Northwestern Medicine scientists also have discovered a second novel way to make the neurons. They made human embryonic stem cells (called induced pluripotent stem cells) from human skin cells and then transformed these into the neurons.

Scientists made these stem cells and neurons from skin cells of three groups of people: Alzheimer's patients, healthy patients with no family history of Alzheimer's, and healthy patients with an increased likelihood of developing the disease due to a family history of Alzheimer's because of genetic mutations or unknown reasons.

"This gives us a new way to study diseased human Alzheimer's cells," Kessler said. "These are real people with real disease. That's why it's exciting."

Researcher motivated by his grandfather's Alzheimer's disease

Bissonnette's persistence in the face of often frustrating research was fueled by the childhood memory of watching his grandfather die from Alzheimer's.

"I watched the disease slowly and relentlessly destroy his memory and individuality, and I was powerless to help him," Bissonnette recalled. "That drove me to become a scientist. I wanted to discover new treatments to reverse the damage caused by Alzheimer's disease."

"My goal was to make human stem cells become new healthy replacement cells so that they could one day be transplanted into a patient's brain, helping their memory function again," he said.

Bissonnette had to grow and test millions of cells to figure out how to turn on the exact sequence of genes to transform the stem cell into the cholinergic neuron.

"A stem cell has the potential to become virtually any cell in the body, from a heart cell to a layer of skin," he explained. "Its development is caused by a cascade of things that slowly bump it into a final cell type."

But it wasn't enough just to develop the neurons. Bissonnette then had to learn how to stabilize them so they lived for at least 20 days in order to prove they were the correct cells.

"Since this was brand new research, people didn't know what kind of tissue culture mature human neurons would like to live in," he said. "Once we figured it out, they could live indefinitely."

Provided by Northwestern University

Study: 50-year-old with diabetes dies 6 yrs sooner


A 50-year-old with diabetes dies six years sooner than someone without the disease, and not just from a heart attack or a stroke, new research suggests.

05 mar 2011--The large international effort to measure diabetes' toll found the disease also raises the risk of dying prematurely from a host of other ailments, even breast cancer and pneumonia.

"It's quite a wide sweep of conditions," said Dr. John Danesh of Cambridge University in Britain, who led the team of researchers. While most people think of heart problems, diabetes surprisingly "appears to be associated with a much broader range of health implications than previously suspected."

Putting the six years lost in context, he said, long-term smoking shortens life by 10 years.

The analysis used pooled medical information for 820,900 people from nearly 100 studies done mostly in Europe and North America. The results are published in Thursday's New England Journal of Medicine.

Diabetes, the seventh leading cause of death in the U.S., affects about 26 million Americans, or 8 percent, including 7 million who haven't been diagnosed. Most in the study were thought to have the most common kind - Type 2 - which occurs when the body makes too little insulin or cannot use what it does make to regulate blood sugar.

High blood sugar can damage nerves and blood vessels, and is a major cause of heart disease.

The new research didn't include those who had heart disease when they were first enrolled. Participants were followed on average for 13 1/2 years, and there more than 123,000 deaths. Overall, death rates from various causes were higher for those with diabetes than those without.

The researchers took into account other risk factors that could influence the results: age, gender, smoking and weight. Type 2 diabetes is tied to obesity. They found that those with diabetes had double the risk of dying from a heart attack or stroke, compared to those without the disorder. But they also found that diabetics had a 25 percent higher risk of dying from cancer and were more likely to die from a variety of illnesses including infections, lung and kidney disease as well as falls.


Exactly how diabetes raises those risks isn't clear, but in the case of infections, it could be that diabetes weakens the immune system, the researchers said. Diabetes can cause vision problems and loss of feeling in the legs, which may be the reason for falls, they said.

Danesh said one intriguing finding was a higher risk of suicide in those with diabetes. Other research has linked diabetes with depression, he noted.

The results are "another reason to try to normalize blood glucose in people who have diabetes," through diet, exercise and medication, said Dr. Alvin Powers, a diabetes specialist at Vanderbilt University. "There have been smaller studies that hinted at this but nothing where a study of this size looked at so many different outcomes."

Danesh and his colleagues also estimated diabetes' effect on life expectancy. They calculated that a 50-year-old diabetic without heart disease dies about six years earlier than someone without the disease, with 40 percent of the difference due to cancer and conditions other than heart disease.

"It underscores the need to prevent diabetes," Danesh said.

Previous studies have shown a possible link between diabetes and cancer. The new paper tied some, but not all, cancers; the increased risk ranged from 25 percent for breast cancer to double for liver cancer. Danesh said people with diabetes should get age-appropriate cancer screenings.

Last year, a joint report from the American Diabetes Association and the American Cancer Society looked at the issue and said that it wasn't clear whether any connection was direct, indirect or perhaps because the two disorders share common risk factors, like obesity.

The new research squares with that report's conclusion that "there's a lot more we need to understand about diabetes and the link to cancer," said one of the authors, Dr. Richard Bergenstal of the International Diabetes Center at Park Nicollet in Minneapolis. He a former president of the diabetes group.

While adding to the evidence, the study doesn't answer the question of why, he said.

"Diabetes is a serious condition. We often don't quite think about it quite that way," Bergenstal said.

More information:
Diabetes information: http://www.diabetes.org and http://diabetes.niddk.nih.gov/

New England Journal of Medicine: http://www.nejm.org

More evidence that Alzheimer's disease may be inherited from your mother

Results from a new study contribute to growing evidence that if one of your parents has Alzheimer's disease, the chances of inheriting it from your mother are higher than from your father. The study is published in the March 1, 2011, print issue of Neurology, the medical journal of the American Academy of Neurology.

04 mar 2011--"It is estimated that people who have first-degree relatives with Alzheimer's disease are four to 10 times more likely to develop the disease themselves compared to people with no family history," said study author Robyn Honea, DPhil, of the University of Kansas School of Medicine in Kansas City.

For the study, 53 dementia-free people age 60 and over were followed for two years. Eleven participants reported having a mother with Alzheimer's disease, 10 had a father with Alzheimer's disease and 32 had no history of the disease in their family. The groups were given brain scans and cognitive tests throughout the study.

The researchers found that people with a mother who had Alzheimer's disease had twice as much gray matter shrinkage as the groups who had a father or no parent with Alzheimer's disease. In addition, those who had a mother with Alzheimer's disease had about one and a half times more whole brain shrinkage per year compared to those who had a father with the disease. Shrinking of the brain, or brain atrophy, occurs in Alzheimer's disease.

"Using 3-D mapping methods, we were able to look at the different regions of the brain affected in people with maternal or paternal ties to Alzheimer's disease," said Honea. "In people with a maternal family history of the disease, we found differences in the break-down processes in specific areas of the brain that are also affected by Alzheimer's disease, leading to shrinkage. Understanding how the disease may be inherited could lead to better prevention and treatment strategies."

Provided by American Academy of Neurology

Ibuprofen may lower risk of Parkinson's disease

A new study by Harvard School of Public Health (HSPH) researchers shows that adults who regularly take ibuprofen, a non-steroidal anti-inflammatory drug (NSAID), have about one-third less risk of developing Parkinson's disease than non-users.

03 mar 2011--"There is no cure for Parkinson's disease, so the possibility that ibuprofen, an existing and relatively non-toxic drug, could help protect against the disease is captivating," said senior author Alberto Ascherio, professor of epidemiology and nutrition at HSPH.

The study will be published online March 2, 2011, in Neurology and is scheduled to appear in the March 8, 2011, print issue.

Parkinson's disease, a progressive nervous disease occurring generally after age 50, affects at least half a million Americans, according to the National Institute of Neurological Disorders and Stroke. About 50,000 new cases are reported each year, with the number expected to increase as the U.S. population ages. It is hypothesized that ibuprofen may reduce inflammation in the brain that may contribute to the disease.

Prior studies showed a reduced Parkinson's disease risk among NSAIDS users, but most did not differentiate between ibuprofen and other non-aspirin NSAIDs.

In the new study, Ascherio, lead author Xiang Gao, research scientist at HSPH and associate epidemiologist in the Channing Laboratory at Brigham and Women's Hospital, and colleagues analyzed data from nearly 99,000 women enrolled in the Brigham and Women's Hospital-based Nurses' Health Study and over 37,000 men in the Health Professionals Follow-Up Study. The researchers identified 291 cases (156 men and 135 women) of Parkinson's disease during their six-year follow-up study (1998-2004 in women; 2000-2006 in men). Based on questionnaires, the researchers analyzed the patients' use of ibuprofen (e.g. Advil, Motrin, Nuprin), aspirin or aspirin-containing products, other anti-inflammatory pain relievers (e.g., Aleve, Naprosyn), and acetaminophen (e.g., Tylenol). (Although not an NSAID, acetaminophen was included because it's similarly used to treat pain.) Age, smoking, diet, caffeine, and other variables also were considered.

"We observed that men and women who used ibuprofen two or more times per week were about 38% less likely to develop Parkinson's disease than those who regularly used aspirin, acetaminophen, or other NSAIDs," Gao said. "Our findings suggest that ibuprofen could be a potential neuroprotective agent against Parkinson's disease, however, the exact mechanism is unknown."

These findings raise hope that a readily available, inexpensive drug could help to treat Parkinson's disease. "Because the loss of brain cells that leads to Parkinson's disease occurs over a decade or more, a possible explanation of our findings is that use of ibuprofen protects these cells. If so, use of ibuprofen could help slow the disease's progression," Gao said.

The findings do not mean that people who already have Parkinson's disease should begin taking ibuprofen, Ascherio added. "Although generally perceived as safe, ibuprofen can have side effects, such as increased risk of gastrointestinal bleeding. Whether this risk is compensated by a slowing of the disease progression should be investigated under rigorous supervision in a randomized clinical trial," he said.

More information: "Use of Ibuprofen and Risk of Parkinson's Disease," Xiang Gao, Honglei Chen, Michael A. Schwarzschild, and Alberto Ascherio. Neurology, March 8, 2011. Online March 2, 2011.

Provided by Harvard School of Public Health

Sugar-sweetened drinks associated with higher blood pressure

Soda and other sugar-sweetened beverages such as fruit drinks are associated with higher blood pressure levels in adults, researchers report in Hypertension: Journal of the American Heart Association.

02 mar 2011--In the International Study of Macro/Micronutrients and Blood Pressure (INTERMAP), for every extra sugar-sweetened beverage drunk per day participants on average had significantly higher systolic blood pressure by 1.6 millimeters of mercury (mm Hg) and diastolic blood pressure higher by 0.8 mm Hg. This remained statistically significant even after adjusting for differences in body mass, researchers said.

Researchers found higher blood pressure levels in individuals who consumed more glucose and fructose, both sweeteners that are found in high-fructose corn syrup, the most common sugar sweetener used by the beverage industry.

Higher blood pressure was more pronounced in people who consumed high levels of both sugar and sodium. They found no consistent association between diet soda intake and blood pressure levels.

Those who drank diet soda had higher mean BMI than those who did not and lower levels of physical activity.

"This points to another possible intervention to lower blood pressure," said Paul Elliott, Ph.D., senior author and professor in the Department of Epidemiology and Biostatistics in the School of Public Health at Imperial College London. "These findings lend support for recommendations to reduce the intake of sugar-sweetened beverages, as well as added sugars and sodium in an effort to reduce blood pressure and improve cardiovascular health."

In INTERMAP, researchers analyzed consumption of sugar-sweetened drinks, sugars and diet beverages in 2,696 participants, 40- to 59-years-old, in eight areas of the United States and two areas of the United Kingdom. Participants reported what they ate and drank for four days via in depth interviews administered by trained observers, underwent two 24-hour urine collections, eight blood pressure readings and responded a detailed questionnaire on lifestyle, medical and social factors.

The researchers found that sugar intake in the form of glucose, fructose and sucrose was highest in those consuming more than one sugar-sweetened beverage daily.

They also found that individuals consuming more than one serving per day of sugar-sweetened beverages consumed more calories than those who didn't, with average energy intake of more than 397 calories per day.


Those who did not consume sugar-sweetened beverages had lower average body mass index (BMI) than those who consumed more than one of these drinks daily.

"People who drink a lot of sugar-sweetened beverages appear to have less healthy diets," said Ian Brown, Ph.D., research associate at Imperial College London. "They are consuming empty calories without the nutritional benefits of real food. They consume less potassium, magnesium and calcium.

"One possible mechanism for sugar-sweetened beverages and fructose increasing blood pressure levels is a resultant increase in the level of uric acid in the blood that may in turn lower the nitric oxide required to keep the blood vessels dilated.

Sugar consumption also has been linked to enhanced sympathetic nervous system activity and sodium retention."

The study's limitations include that it was cross-sectional and diet was self-reported.

"This is a population study. It's one piece of the evidence in a jigsaw puzzle that needs to be completed," Brown said. "In the meantime, people who want to drink sugar-sweetened beverages should do so only in moderation."

The American Heart Association recommends no more than half of the discretionary calorie allowance from added sugars, which for most American women is no more than 100 calories per day and for most American men no more than 150 calories per day. Discretionary calories are the remaining calories in a person's "energy allowance" after consuming the recommended types and amounts of foods to meet all daily nutrient requirements.

Provided by American Heart Association

Older patients confused about multiple drug dosing

Many older patients, who take an average of seven medicines a day, are so confused by the vague instructions on prescription bottles that they don't realize they can combine their medications to take them more efficiently. A new Northwestern Medicine study shows patients thought they had to take seven medicines at least seven and up to 14 separate times a day.

01 mar 2011--"A complex and confusing regimen means people are less likely to take their drugs properly, and that means they are not getting the full benefits of their medicine," said Michael Wolf, associate professor of medicine and of learning sciences at Northwestern University Feinberg School of Medicine. He is lead author of the study, funded by the National Institute on Aging, that will be published February 28 in Archives of Internal Medicine.

Wolf an colleagues have proposed a universal medication schedule that standardizes medicine prescriptions into doses at four clearly identified periods of day – morning, noon, evening and bedtime (instead of twice daily or every eight hours.)

"Standardizing the times to take medicine will help patients safely take their medicine, make their lives easier and improve their health outcomes," Wolf said. He was on the panel of the U.S. Pharmacopeia that recently released guidance for drug labeling praising the four daily doses approach.

For the study, Wolf and colleagues interviewed 464 patients, with an average age of 63, at an academic general medicine practice and three federally qualified health centers in Chicago to see how patients would schedule a typical seven-drug regimen. The majority of participants were well educated, but nearly half had low or marginal health literacy skills.

Wolf found people overcomplicate the dosing schedule of prescription drugs. Even if two drugs were prescribed in the same manner (one pill twice daily), nearly a third of patients (30.8 percent) would not take them together. When two drugs could have been taken together but doctor instructions were written differently (one pill twice daily versus one pill every 12 hours) 79 percent of patients would not consolidate these medicines and take them at the same time. If instructions for two drugs were the same with the only exception that one said "with food and water," half the patients would not take the two drugs at the same time.

Low health literacy was the greatest predictor of patients dosing their medications a greater number of times per day.

Provided by Northwestern University

New research suggests that obesity and diabetes are a downside of human evolution

As if the recent prediction that half of all Americans will have diabetes or pre-diabetes by the year 2020 isn't alarming enough, a new genetic discovery published online in the FASEB Journal (http://www.fasebj.org) provides a disturbing explanation as to why: we took an evolutionary "wrong turn." In the research report, scientists show that human evolution leading to the loss of function in a gene called "CMAH" may make humans more prone to obesity and diabetes than other mammals.

28 feb 2011--"Diabetes is estimated to affect over 25 million individuals in the U.S., and 285 million people worldwide," said Jane J. Kim, M.D., a researcher involved in the work from the Department of Pediatrics at the University of California, San Diego in La Jolla, CA. "Our study for the first time links human-specific sialic acid changes to insulin and glucose metabolism and therefore opens up a new perspective in understanding the causes of diabetes."

In this study, which is the first to examine the effect of a human-specific CMAH genetic mutation in obesity-related metabolism and diabetes, Kim and colleagues show that the loss of CMAH's function contributes to the failure of the insulin-producing pancreatic beta cells in overweight humans, which is known to be a key factor in the development of type 2 diabetes. This gene encodes for an enzyme present in all mammalian species except for humans and adds a single oxygen atom to sialic acids, which are sugars that coat the cell surface.

To make their discovery, the researchers used two groups of mice. The first group had the same mutant CMAH gene found in humans. These mice demonstrated that the CMAH enzyme was inactive and could not produce a sialic acid type called NeuSGc at the cell surface. The second group had a normal CMAH gene. When exposed to a high fat diet, both sets of mice developed insulin resistance as a result of their obesity. Pancreatic beta cell failure, however, occurred only in the CMAH mutant mice that lacked NeuSGc, resulting in a decreased insulin production, which then further impaired blood glucose level control. This discovery may enhance scientific understanding of why humans may be particularly prone to develop type 2 diabetes. Results may also suggest that conventional animal models may not accurately mirror the human situation.

"The diabetes discovery is an important advance in its own right. It tells us a lot about what goes wrong in diabetes, and where to aim with new treatments," said Gerald Weissmann, M.D., Editor-in-Chief of the FASEB Journal, "but its implications for human evolution are even greater. If this enzyme is unique to humans, it must also have given us a survival advantage over earlier species. Now the challenge is to find the function of CMAH in defending us against microbes or environmental stress or both. This evolutionary science explains how we can win some and lose some, to keep our species ahead of the extinction curve."

More information: Sarah Kavaler, Hidetaka Morinaga, Alice Jih, WuQiang Fan, Maria Hedlund, Ajit Varki, and Jane J. Kim. Pancreatic β-cell failure in obese mice with human-like CMP-Neu5Ac hydroxylase deficiency. FASEB J. fj.10-175281; doi:10.1096/fj.10-175281

Provided by Federation of American Societies for Experimental Biology

Elderly patients admitted with high glucose levels are more likely to die in hospital

A two-country hospital study of 808 elderly patients found a strong association between high, undiagnosed blood glucose in non-diabetic patients and increased hospital death rates, according to the March issue of IJCP, the International Journal of Clinical Practice.

27 feb 2011--Researchers are now calling for routine blood glucose testing of elderly patients when they are admitted to hospital. The Spanish team looked at 447 consecutive patients admitted to a geriatric unit, while the Italian team studied 361 patients over 60 admitted to an internal medicine department.

They found that, when they excluded the 206 patients already diagnosed with diabetes, 25% of the remaining 602 patients had a fasting glucose level of 126 mg/dl or more, which is the threshold used to diagnose the disease, with just under a fifth of those exceeding 180 mg/dl.

Mortality rates in patients with a fasting glucose level of less than 126 mg/dl was just over 8% for both the total sample and the patients admitted without a diagnosis of diabetes. But when the researchers looked at the undiagnosed patients whose fasting glucose levels were 126 mg/dl to 180mg/dl, the death rate rose to 18% and, in patients whose levels exceeded 180mg/dl, the rate increased to 31%.

These levels were much higher than the 14% and 23% recorded for diabetic patients with fasting glucose levels exceeding 126 mg/dl and 180 mg/dl respectively.

"This is the first multi-centre prospective study to assess the relationship between fasting serum glucose levels and in-hospital mortality in a large cohort of elderly patients" says lead author Dr Pedro Iglesias from the Department of Endocrinology at Hospital Ramon y Cajal in Madrid, Spain.

"Our findings clearly show that fasting glucose is a significant risk factor for death during hospitalisation, especially in patients who have not been diagnosed with diabetes."

Other key findings of the study included:

• The average age of the total cohort was 84 years and 57% were female, but the Spanish geriatric cohort was older than the Italian internal medicine cohort (86 versus 80 years), with a higher percentage of women (62% versus 50%).
  
• There was a higher incidence of high blood pressure, lower systolic and diastolic blood pressure, higher serum glucose and creatinine and lower total cholesterol concentrations in the Spanish cohort.
  
• The five most common reasons for hospital admission in the total cohort were: congestive heart failure (19%), respiratory tract infection (12.5%), acute cerebrovascular disease (12%), exacerbation of chronic obstructive pulmonary disease (9%) and cancer (8%). However, there were significant variations between the two cohorts.
  
• 25% of the total cohort had a pre-existing diagnosis of diabetes, with 2% more patients in the Spanish cohort than the Italian cohort having the disease.
  
• Median fasting glucose rates for the total cohort were more than 20% higher in patients who died (127 mg/dl) than those who survived (105 mg/dl).
  
• Hospital stays averaged 10.5 days for the total cohort and the average time from admission to death was 11.3 days. The Italian internal medicine cohort had a lower death rate (8% versus 14%) and lower average hospital stay (nine days versus 12 days) than the Spanish geriatric group, but the intervals from admission to death were similar in both groups.

"Our study shows a high mortality rate and short hospital survival in non-diabetic elderly patients with a high baseline fasting glucose level of more than 180 mg/dl" concludes co-author Professor Fabio Monzani from the Department of Internal Medicine at the University of Pisa, Italy.

"It underlines the importance of testing elderly patients for fasting glucose levels on admission to hospital for acute illnesses and suggests that a blood glucose level of 180 mg/dl or less might be an appropriate target in people who have not been diagnosed with diabetes.

"These findings should help us to identify those patients at high risk during hospitalisation, so that they can be offered intensive therapy to reduce their risk of death and improve their prognosis."

More information: Fasting hyperglycaemia and in-hospital mortality in elderly population. Iglesias et al. IJCP. 65.3, pp308-313. (March 2011). DOI: 10.1111/j.1742-1241.2010.02514.x

Using amphetamines may increase risk of Parkinson's disease

New research shows people who have used amphetamines such as benzedrine and dexedrine appear to be at an increased risk of developing Parkinson's disease, according to a study released today that will be presented at the American Academy of Neurology's 63rd Annual Meeting in Honolulu April 9 to April 16, 2011.

26 feb 2011--Benzedrine and Dexedrine are amphetamines often prescribed to increase wakefulness and focus for people with attention deficit hyperactivity disorder and narcolepsy, a disorder that can cause excessive daytime sleepiness and sudden attacks of sleep. They are also used to treat traumatic brain injuries.

The study involved 66,348 people in northern California who had participated in the Multiphasic Health Checkup Cohort Exam between 1964 and 1973 and were evaluated again in 1995. The average age of the participants at the start of the study was 36 years old. Of the participants, 1,154 people had been diagnosed with Parkinson's disease by the end of the study.

Exposure to amphetamines was determined by two questions: one on the use of drugs for weight loss and a second question on whether people often used Benzedrine or Dexedrine. Amphetamines were among the drugs commonly used for weight loss when this information was collected.

According to the study, those people who reported using Benzedrine or Dexedrine were nearly 60 percent more likely to develop Parkinson's than those people who didn't take the drugs. There was no increased risk found for those people who used drugs for weight loss.

"If further studies confirm these findings, the potential risk of developing Parkinson's disease from these types of amphetamines would need to be considered by doctors before prescribing these drugs as well as be incorporated into amphetamine abuse programs, including illicit use," said study author Stephen K. Van Den Eeden, PhD, with the Division of Research at Kaiser Permanente Northern California in Oakland, Calif.

Van Den Eeden explained that amphetamines affect the release and uptake of dopamine, the key neurotransmitter involved in Parkinson's disease. He explained that more research needs to be completed to confirm the association and learn more about possible mechanisms.

Provided by American Academy of Neurology

Aging, interrupted

The current pace of population aging is without parallel in human history but surprisingly little is known about the human aging process, because lifespans of eight decades or more make it difficult to study. Now, researchers at the Salk Institute for Biological Studies have replicated premature aging in the lab, allowing them to study aging-related disease in a dish.

25 feb2011--In the February 23, 2011 advance online edition of the journal Nature, Juan Carlos Izpisúa Belmonte, Ph.D. a professor in the Salk Institute's Gene Expression Laboratory, and his team report that they have successfully generated induced pluripotent stem (iPS) cells from skin cells obtained from patients with Hutchinson-Gilford Progeria Syndrome—who age eight to 10 times faster than the rest of us—and differentiated them into smooth muscle cells displaying the telltale signs of vascular aging.

"The slow progression and complexity of the aging process makes it very hard to study the pathogenesis of cardiovascular and other aging-related disorders," says Izpisúa Belmonte. "Having a human model of accelerated aging will facilitate the development of treatments and possibly a cure for Progeria and give us new insights into how we age. It may also help prevent or treat heart disease in the general aging population."

Progeria's striking features resemble the aging process put on fast-forward and afflicted people rarely live beyond 13 years. Almost all of the patients die from complications of arteriosclerosis—the clogging or hardening of arteries or blood vessels caused by plaques—which leads to heart attack and stroke.

Scientists are particularly interested in Progeria in the hopes that it might reveal clues to the normal human aging process. However, the disease is exceedingly rare and only 64 children living with progeria are known making access to patients very difficult.

Hutchinson-Gilford Progeria Syndrome is caused by a single point mutation in the gene encoding lamin A, which forms a protein scaffold on the inner edge of the nucleus that helps maintain chromatin structure and organize nuclear processes such as RNA and DNA synthesis. The mutation creates an alternative splice site that leads to the production of a truncated version of the protein known as progerin. Unlike the full-length protein, progerin does not properly integrate into the nuclear lamina, which disrupts the nuclear scaffold and causes a host of problems.

"There is also evidence that defective lamin A accumulates during the normal aging process via the sporadic use of the alternative splice site, " explains Izpisua Belmonte. "Therefore we are very keen on using our in vitro iPS cell-based model to identify new aging markers and explore other aspects of human premature and physiological aging."

Compared to normal skin fibroblasts, cells from Progeria patients have misshapen nuclei and a range of other nuclear defects, including a disorganized nuclear lamina, loss of super-condensed DNA, telomere shortening and genomic instability. Yet, despite their "old" appearance and characteristics, these cells could be readily converted into iPS cells.

"The reprogramming process erased all nuclear and epigenetic defects and the rejuvenated pluripotent cells looked and acted like perfectly normal healthy cells," says first author Guang-Hui Liu, Ph.D., a postdoctoral researcher in the Belmonte lab.

Since lamin A is only expressed in differentiated cells but is absent from embryonic stem cells, he wondered whether iPS cells produce lamin A and/or progerin, which should follow the same expression pattern as lamin A. In his experiments, he couldn't detect either one. "The biological clock is reset in these cells because lamin A is silenced," explains Liu.

As soon as the Salk researchers differentiated Progeria-derived iPS cells, progerin expression was reactivated. "This reversible suppression of progerin expression by reprogramming and subsequent reactivation during differentiation, provides a unique model system to study human premature aging pathologies," says Izpisúa Belmonte.

Progerin accumulates mainly in smooth muscle cells found within the walls of arterial blood vessels, and vascular smooth muscle cells degeneration is one of the hallmarks of Hutchinson-Gilford Progeria Syndrome-associated arteriosclerosis. In fact, vascular smooth muscle cell senescence also plays a role in advanced arteriosclerosis within the normal aging population.

Upon directed differentiation of Progeria-derived iPS cells into smooth muscle cells the premature aging phenotype, including misshapen nuclei, the loss of gene silencing marks and compromised proliferation, reappeared. Genetically modifying progeria-derived iPS cells to shut down the expression of progerin staved off the premature appearance of aging phenotypes after differentiation. "Transplantation of the progenitor cells derived from the "corrected" progeria iPS cells might hold the promise to treat these progeria children in the future." says Liu.

Provided by Salk Institute