Epigenetic breakthrough bolsters understanding of Alzheimer's disease

Diagram of the brain of a person with Alzheimer's Disease. Credit: Wikipedia/public domain.

18 aug 2014--A team led by researchers at the University of Exeter Medical School and King's College London has uncovered some of the strongest evidence yet that epigenetic changes in the brain play a role in Alzheimer's disease.

Epigenetic changes affect the expression or activity of genes without changing the underlying DNA sequence and are believed to be one mechanism by which the environment can interact with the genome. Importantly, epigenetic changes are potentially reversible and may therefore provide targets for the development of new therapies.

Globally, more than 26 million people are currently affected by Alzheimer's Disease. As this number grows in line with an increasingly aging population, the need to identify new disease mechanisms is more important than ever. Post-mortem examinations have revealed much about how Alzheimer's damages the brain, with some regions, such as the entorhinal cortex, being particularly susceptible, while others, such as the cerebellum, remain virtually unscathed. However, little is yet known about how and why the disease develops in specific brain regions.

The current study found that chemical modifications to DNA within the ANK1 gene are strongly associated with measures of neuropathology in the brain. The study, published in Nature Neuroscience, found that people with more Alzheimer's disease-related neuropathology in their brains had higher levels of DNA modifications within the ANK1 gene. The finding was particularly strong in the entorhinal cortex, and also detected in other cortical regions affected by the disease. In contrast, no significant changes were observed in less affected brain regions or blood.

Professor Jonathan Mill, of the University of Exeter Medical School and King's College London, who headed the study, said: "This is the strongest evidence yet to suggest that epigenetic changes in the brain occur in Alzheimer's disease, and offers potential hope for understanding the mechanisms involved in the onset of dementia. We don't yet know why these changes occur – it's possible that they are involved in disease onset, but they may also reflect changes induced by the disease itself."

Dr Katie Lunnon, first author on the study, from the University of Exeter Medical School, added: "It's intriguing that we find changes specifically in the regions of the brain involved in Alzheimer's disease. Future studies will focus on isolating different cell-types from the brain to see whether these changes are neuron-specific."

Dr Simon Ridley, Head of Research at Alzheimer's Research UK, the UK's leading dementia research charity, who also provided funding for the study said:

"We know that changes to the DNA code of certain genes are associated with an increased risk of developing Alzheimer's disease. Investigating how epigenetic changes influence genes in Alzheimer's is still a relatively new area of study. The importance of understanding this area of research is highlighted by the fact that epigenetic changes have been associated with development of other diseases, including cancer.

"This innovative research has discovered a potential new mechanism involved in Alzheimer's by linking the ANK1 gene to the disease. We will be interested to see further research into the role of ANK1 in Alzheimer's and whether other epigenetic changes may be involved in the disease."

"Alzheimer's affects millions of people worldwide and we need pioneering research to understand exactly why the disease occurs. Alzheimer's Research UK is helping to fund research which will take us a step closer to understanding and defeating this devastating disease."

More information: Paper: dx.doi.org/10.1038/nn.3782
Related paper: dx.doi.org/10.1038/nn.3786

Provided by University of Exeter

Low vitamin D levels linked to increased risks after noncardiac surgery

Patients with low blood levels of vitamin D are at increased risk of death and serious complications after noncardiac surgery, suggests a study in Anesthesia & Analgesia.

17 aug 2014--"Vitamin D concentrations were associated with a composite of in-hospital death, serious infections, and serious cardiovascular events," according to the new research by Dr Alparslan Turan and colleagues of the Cleveland Clinic. They believe their results warrant further study to see if giving vitamin D supplementation before surgery can reduce the risk of these adverse outcomes.

Lower Vitamin D Levels Linked to Higher Surgical Risk

The researchers analyzed the relationship between vitamin D level and surgical outcomes in approximately 3,500 patients who underwent operations other than heart surgery between 2005 and 2011. Only patients who had available data on vitamin D levels around the time of surgery—from three months before to one month afterward—were included in the study.

The concentration of vitamin D (specifically, 25-hydroxyvitamin D) in blood samples was analyzed as a risk factor for death, cardiovascular events, or serious infections while in the hospital. The analysis included adjustment for other factors such as demographic characteristics, medical conditions, and type and duration of surgery.

Most patients did not meet the recommended 25-hydroxyvitamin D concentration of greater than 30 nanograms per milliliter (ng/mL). The median vitamin D level was 23.5 ng/mL—more than 60 percent of patients were in the range of vitamin D insufficiency (10 to 30 ng/mL). Nearly 20 percent had vitamin D deficiency (less than 10 ng/mL).

"Higher vitamin D concentrations were associated with decreased odds of in-hospital mortality/morbidity," the researchers write. For each 5 ng/mL increase in 25-hydroxyvitamin D level, the combined risk of death, cardiovascular events, or serious infections decreased by seven percent.

Patients at the lowest level of 25-hydroxyvitamin D (less than 13 ng/mL) were at highest risk of death or serious complications. Those with higher vitamin D levels (up to 44 ng/mL) had about half the risk as those in the lowest group. The association with low vitamin D was statistically significant only for cardiovascular complications, although there were "strong trends" for mortality and infections.

Further Study Needed to Determine Cause and Effect

"Vitamin D deficiency is a global health problem," according to Dr Turan and coauthors. In addition to protective cardiovascular and neurological effects, vitamin D plays an important role in the immune system.

The high rates of vitamin D insufficiency and deficiency in the surgical patients studied are consistent with previous findings in the general population. In recent years, studies have suggested that vitamin D levels may affect a wide range of health outcomes.

Patients undergoing surgery are at risk of cardiovascular and infectious complications, both of which may be aggravated by vitamin D deficiency. Previous studies found no increased risk of adverse outcomes related to vitamin D levels in patients undergoing cardiac surgery. It may be that the tissue injury and inflammation associated with heart surgery overwhelms any potential protective effect of vitamin D.

However, Dr Turan and colleagues note that their study had some important limitations of their study—especially the fact that it included only patients who had recent measurements of vitamin D levels. They may represent a less-healthy group, introducing a potential source of selection bias.

The study can't determine whether there is any cause-and-effect relationship between vitamin D levels and the risk of adverse outcomes. Dr Turan and colleagues suggest a formal randomized trial to evaluate whether preoperative vitamin D supplementation can reduce the risk of serious complications and death after surgery.

More information: Anesthesia & Analgesia. journals.lww.com/anesthesia-an… entration.98423.aspx

Provided by Wolters Kluwer Health

Decline in daily functioning related to decreased brain activity in Alzheimer's

Diagram of the brain of a person with Alzheimer's Disease. Credit: Wikipedia/public domain.

16 aug 2014--Decline in daily functioning associated with Alzheimer's disease is related to alterations in activity in certain regions of the brain, according to a study published in the August 2014 issue of the Journal of Alzheimer's Disease.

Impairment in instrumental activities of daily living—or an inability to perform high-level daily activities such as calculating finances, remembering appointments and medications, and driving—is first seen when a person has mild cognitive impairment, which can later progress to dementia due to Alzheimer's disease. Deterioration in the ability to carry out daily activities has been associated with changes in brain activity measured as use of energy (or metabolism of sugar) with a nuclear medicine scan called 18F-Flourodeoxy glucose (FDG) positron emission tomography (PET).

To further investigate the relationship between instrumental activities of daily living and brain activity (FDG metabolism), a team led by researchers from Brigham and Women's Hospital (BWH) analyzed data from the Alzheimer's Disease Neuroimaging Initiative database, a multi-center study that BWH has been a part of for nearly 10 years.

They looked at data from 104 clinically normal elderly participants, 203 participants with mild cognitive impairment, and 95 participants with mild dementia due to Alzheimer's disease. The participants had a baseline PET scan to determine brain activity and underwent clinical assessments every 6 to 12 months for up to three years. The participants' study partners (family members or friends who knew them well) also completed questionnaires about the participants' daily living activities.

The researchers found that decreased activity in frontal areas of the brain, which are responsible for cognitive processing and decision making, and deep temporal and parietal (back) areas of the brain, which are associated with memory, were associated with greater impairment of instrumental activities of daily living initially and over time.

"Impairment in activities of daily living is a major source of burden for Alzheimer's disease patients and caregivers alike," said Gad Marshall, MD, BWH Center for Alzheimer Research and Treatment, assistant professor of Neurology at Harvard Medical School, senior study author. "Therefore, detecting these important deficits early on prior to the dementia stage, along with a better understanding of how they relate to changes in the brain, can lead to more effective design of clinical trials that focus on vital patient-centered outcomes. This in turn will ultimately lead to better treatments prescribed to patients at the early stages of Alzheimer's disease before they are robbed of their faculties and autonomy."

According to the National Institute on Aging, National Institutes of Health, as many as five million people age 65 and older in the United States have dementia due to Alzheimer's disease. As the rapid growth of the aging population continues, the number of those developing the disease is expected to increase significantly, with the number of people with dementia due to Alzheimer's disease doubling for every five-year interval beyond age 65.

Provided by Brigham and Women's Hospital

Global public health objectives need to address substance abuse in developing countries

Substance addiction is a large and growing problem for developing societies. A new study that surveyed reports on modalities for treating addiction and their effectiveness in the developing world calls on policymakers to use this information to support the design of programs that meet known population needs. The study also encourages looking at ways to adapt the Alcoholics Anonymous (AA) model to fit different cultural norms. The findings are published in the Annals of Global Health.

15 aug 2014--The World Health Organization has indicated that alcohol and illicit drugs pose multifaceted dangers to millions of people, from the psychological damage of addiction to a range of physical health problems. A recent report highlights the need to address a broad spectrum of mental health issues, including substance use disorder (SUD), in order to achieve global public health objectives. This led to a call by policymakers to improve access to treatment for SUD in developing nations. Resources to address SUD in the developing world are severely limited, however, and some 34% of low- and middle-income nations have not yet developed a substance use policy.

"It is difficult to assess the extent of SUD. This is, in part, because of the limited capacity of these countries' governments to conduct national surveys, but it is also due to underinvestment in mental health care in these countries and to underutilization of mental health services in resource-poor settings," says Craig L. Katz, MD, of the Departments of Psychiatry and Medical Education, Icahn School of Medicine at Mount Sinai, New York. "The poorest nations allocate the smallest portion of their already strained public budgets to mental health."

These challenges provided the impetus for a review of the current literature on SUD treatment in the developing world, with the aim of informing future program development and research. Investigator Jasleen Salwan, MD-MPH Candidate, Icahn School of Medicine at Mount Sinai, identified 30 relevant studies published in 1994 or later. The treatment methods included pharmacological approaches, intervention studies to prevent, detect, and reduce harm, the AA-style or Minnesota/Therapeutic Community Model, and multimodal approaches. Two studies compared treatment approaches between two different countries: China with Germany, and El Salvador with Puerto Rico. Other studies looked at access to treatment and resources for providers.

"An important finding is that what works well in one setting may not work well in another," notes Salwan. "Existing research highlights the need to provide secular alternatives to the dominant faith-based treatment approach in El Salvador, to improve access to harm reduction programs for crack cocaine users in Brazil, and to ensure the availability of safe havens for recovering addicts in China to avoid being treated as criminals."

Although comprehensive overviews of treatment models were markedly absent from the literature surveyed, the studies highlight specific areas of need within developing countries, building on existing awareness of general barriers to treatment in those countries. "Policymakers can use this information to design programs that meet known population needs and avoid providing extraneous services," adds Katz.

The investigators recommend that future research should blend inquiry with practice. "Although further investigation is clearly needed in order to better understand the specific needs of developing world populations, assisting those populations should be a primary goal of all endeavors. Conversely, service-oriented planning for addressing SUD in the developing world should be done with a mandate to study the effect of interventions in order to establish program efficacy," comments Katz.

Finally, the authors suggest further evaluation of the AA model. There were mixed results in the literature regarding implementation of the AA model in developing countries that invite further exploration, ideally in more systematic and comprehensive ways.

"Although there is reason to question whether a model that relies so heavily on self-revelation and sharing will work in all places due to cultural and privacy concerns, the AA model has great appeal for developing countries that lack financial resources to create more comprehensive substance use treatment programs. Finding successful ways to adapt the AA model in different settings therefore may not only be a cost-effective way to scale up services, but also help foster a culture of awareness of substance use issues that can in turn spark greater investment in medicalized resources beyond what AA can offer," Katz concludes.

More information: "A Review of Substance Use Disorder Treatment in Developing World Communities," by Jasleen Salwan, MD-MPH Candidate, and Craig L. Katz, MD, DOI: dx.doi.org/10.1016/j.aogh.2014.04.010, Annals of Global Health, Volume 80, Issue 2 (2014)

Provided by Elsevier

Verbal abuse of older adults: A disturbing influence on quality of life

Newly published research from Journal of Elder Abuse & Neglect (Routledge) has determined that verbal mistreatment is a highly prevalent concern among older adults in primary care clinics because of its relation to negative mental health outcomes including poor social functioning and major depression. Verbal Mistreatment of the Elderly, conducted by a research team from Northeastern University, is now available online with Free Access.

14 aug 2014--"Our work demonstrates that words can hurt and older adults who suffer from verbal mistreatment have serious sequela," said Terry Fulmer, a member of the research team. "All of us have a responsibility to better understand verbal mistreatment and develop interventions to help stop these unwanted behaviors. Further, we need to develop strategies that help older adults cope with verbal mistreatment."

A diverse sample of 142 older adults aged 65 and older were surveyed regarding verbal mistreatment, quality of life, and depressive symptoms. 38 percent of the sample reported having experienced at least one instance of verbal mistreatment from their primary caregiver. No significant differences were found among factors like age, gender, ethnicity, or marital status. Verbal mistreatment was not strongly associated with physical health, but showed significant detrimental effects on social functioning and mental health. In addition, respondents subjected to verbal mistreatment were three times more likely to report role limitations due to emotional problems.

The research team does offer future directions to alleviate this issue. "Future research should be directed at determining the best methods of intervening for patients who have reported verbal mistreatment. Sensitive and valid screening methods should also be developed to identify the patients who may be at risk for verbal mistreatment and identify patients that are currently experiencing some form of verbal mistreatment," as explained in the conclusion. "Screening methods are important in light of research that has suggested elder mistreatment is grossly under-reported."

More information: www.tandfonline.com/doi/full/1… 08946566.2013.801817

Provided by Taylor & Francis

Digital literacy reduces cognitive decline in older adults, experts finds

Researchers have found a link between digital literacy and a reduction in cognitive decline, according to a study published in The Journals of Gerontology, Series A: Medical Sciences on July 8th.

13 aug 2014--Led by Andre Junqueira Xavier at the Universidade do Sul de Santa Catarina, this is the first major study to show that digital literacy, or the ability to engage, plan and execute digital actions such as web browsing and exchanging emails, can improve memory. Drawn from the English Longitudinal Study of Ageing, the study followed 6442 participants in the UK between the ages of 50 and 89 for 8 years.

The data measures delayed recall from a 10-word-list learning task across 5 separate measurement points. Higher wealth, education and digital literacy improved delayed recall, while people with functional impairment, diabetes, cardiovascular diseases, depressive symptoms or no digital literacy showed decline.

The researchers' findings suggest that "digital literacy increases brain and cognitive reserve or leads to the employment of more efficient cognitive networks to delay cognitive decline." The authors write, "countries where policy interventions regarding improvement in DL are implemented may expect lower incidence rates for dementia over the coming decades."

More information: The paper, "English Longitidunal Study of Ageing (ELSA): Can internet/email use reduce cognitive decline?," can be accessed here: www.oxfordjournals.org/page/5759/14

Provided by Oxford University Press

Bisphosphonates for osteoporosis not associated with reduced breast cancer risk

An analysis of data from two randomized clinical trials finds that three to four years of treatment with bisphosphonates to improve bone density is not linked to reduced risk of invasive postmenopausal breast cancer.

12 aug 2014--The authors are Trisha F. Hue, Ph.D., M.P.H., of the University of California, San Francisco, and colleagues.

Some studies have suggested that bisphosphonates, which are commonly used to treat osteoporosis, may have antitumor and antimetastatic properties. Some observational studies have suggested bisphosphonates may protect women from breast cancer.

The authors analyzed the relationship of postmenopausal breast cancer and bisphosphonate use by examining data from two randomized, double-blind, placebo-controlled trials. The Fracture Intervention Trial (FIT) randomly assigned 6,459 women (ages 55 to 81 years) to alendronate or placebo with an average follow-up of 3.8 years. The Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly-Pivotal Fracture Trial (HORIZON-PFT) randomly assigned 7,765 women (ages 65 to 89 years) to annual intravenous zoledronic acid or placebo with an average follow-up of 2.8 years. The authors compared rates of breast cancer in the bisphosphonate treatment groups to the placebo groups.

There was no significant difference in breast cancer rates between the bisphosphonate and placebo groups. In FIT, the breast cancer rate was 1.5 percent in the placebo group and 1.8 percent in the alendronate group. In HORIZON-PFT the rate was 0.8 percent in the placebo group and 0.9 percent in the zoledronic acid group. There also was no significant difference when data from the two trials were combined.

"These data provide evidence that three to four years of treatment with bisphosphonate, alendronate or zoledronic acid, therapy does not reduce the risk of incident breast cancer in postmenopausal women. The discrepancy between our results and the reports of associations in observational studies may be an example of indication bias and illustrates the limitation and hazard of drawing conclusions about treatment effects from observational studies (even those that are very well done) and emphasizes the value of confirming such associations in randomized trials. The effect of bisphosphonate treatment on breast cancer risk in nonosteoporotic populations should be investigated in other randomized trials."

In a related editor's note, Joseph S. Ross, M.D., M.H.S., a JAMA Internal Medicine associate editor, writes: "Whereas these findings highlight why it is so important for new therapies to be evaluated using RCTs (randomized clinical trials), they also reinforce the importance of assessing the methodological rigor of observational studies before interpreting real-world effects."

"Just as we closely scrutinize RCT design, so must we understand the quality and statistical power of the data used for observational studies, how participants were identified, the duration of follow-up, the end points examined, and the analytical strategy used. Observational studies are particularly valuable for clinical situations unlikely to be tested using RCTs, and many provide valid and reliable real-world evidence," Ross continues.

"Thus, whereas we all can remember examples of when RCTs and observational studies differed, less memorable are the even more numerous examples in which results were consistent. In the end, we should be open to all types of evidence and rely on rigorous clinical science to guide practice," Ross concludes.

More information: JAMA Intern Med. Published online August 11, 2014. DOI: 10.1001/jamainternmed.2014.3634

Provided by The JAMA Network Journals

Digoxin tied to increased risk of death in patients with atrial fibrillation

In An Account of the Foxglove and Some of its Medical Uses, published in 1785, Sir William Withering cautioned readers that extracts from the plant foxglove, also called digitalis, was not a perfect drug. "Time will fix the real value upon this discovery," he wrote.

12 aug 2014--Now, more than 200 years later, researchers at the Stanford University School of Medicine have validated Withering's warning with the discovery that patients with atrial fibrillation—a rapid and irregular heart rhythm—who are treated with the digitalis-derivative digoxin are more likely to die than similar patients who received different treatments.

"The take-home point is to question whether people should really be on this drug," said the study's lead author, Mintu Turakhia, MD, assistant professor of cardiology at Stanford and director of cardiac electrophysiology at the Veterans Affairs Palo Alto Health Care System. "These data challenge the current guidelines."

The study will be published online Aug. 11 in the Journal of the American College of Cardiology, and will appear in the Aug. 19 print issue of the journal.

Turakhia and his team analyzed records from 122,465 patients who received a new diagnosis of atrial fibrillation from the U.S. Department of Veterans Affairs health-care system between 2003 and 2008. Doctors prescribed digoxin to 23 percent of the patients, and 70 percent of those patients were still on the drug one year later. Patients treated with digoxin were 1.2 times more likely to die than comparable patients prescribed other therapies. Patients receiving digoxin were more likely to die regardless of age; use of other drugs such as beta-blockers, amiodarone or warfarin; or the presence of other factors such as kidney disease, heart attack or heart failure, the study found.

"This is going to be as close to proof positive as we get because we may never have a randomized trial of this drug," Turakhia said. Pharmaceutical companies lack the incentive to finance studies on a long-accepted, generic drug.

Although recent studies showed mixed results, doctors and patients trusted digoxin because of its historic status, Turakhia said.

"There's an evidence gap," he said, adding that he launched the investigation because digoxin hasn't been rigorously tested like the many other atrial fibrillation treatment options.

The VA patient pool was predominantly male—only 1,980, or 1.6 percent, were female—and Turakhia has called for additional studies to establish whether the results are applicable to women as well.

Turakhia said many other drugs with better safety results are available to treat atrial fibrillation. Digoxin slows the heart rate but does not correct it to a normal rhythm. "We are not asserting this drug should never be used," he said. "However, in light of the many other drugs that can be used to slow down the heart rate in atrial fibrillation, patients and providers need to ask whether digoxin should be the treatment of choice when there are other, safer drugs. "

Provided by Stanford University Medical Center

Dementia risk quadrupled in people with mild cognitive impairment

In a long-term, large-scale population-based study of individuals aged 55 years or older in the general population researchers found that those diagnosed with mild cognitive impairment (MCI) had a four-fold increased risk of developing dementia or Alzheimer's disease (AD) compared to cognitively healthy individuals. Several risk factors including older age, positive APOE-ɛ4 status, low total cholesterol levels, and stroke, as well as specific MRI findings were associated with an increased risk of developing MCI. The results are published in a supplement to the Journal of Alzheimer's Disease.

11 aug 2014--"Mild cognitive impairment has been identified as the transitional stage between normal aging and dementia," comments M. Arfan Ikram, MD, PhD, a neuroepidemiologist at Erasmus MC University Medical Center (Rotterdam). "Identifying persons at a higher risk of dementia could postpone or even prevent dementia by timely targeting modifiable risk factors."

Unlike a clinical trial, the Rotterdam study is an observational cohort study focusing on the general population, instead of persons referred to a memory clinic. The Rotterdam study began in 1990, when almost 8,000 inhabitants of Rotterdam aged 55 years or older agreed to participate in the study. Ten years later, another 3,000 individuals were added. Participants undergo home interviews and examinations every four years.

"This important prospective study adds to the accumulating evidence that strokes, presumably related to so called 'vascular' risk factors, also contribute to the appearance of dementia in Alzheimer's disease. This leads to the conclusion that starting at midlife people should minimize those risk factors. The recent results of the Finish FINGER study corroborate this idea. It should be remembered that delaying the onset of dementia by five years will reduce the prevalence of the disease by half. And of course, since there is no cure for AD, prevention is the best approach at present," explains Professor Emeritus Amos D Korczyn, Tel Aviv University, Ramat Aviv, Israel, and Guest Editor of the Supplement.

To be diagnosed with MCI in the study, individuals were required to meet three criteria: a self-reported awareness of having problems with memory or everyday functioning; deficits detected on a battery of cognitive tests; and no evidence of dementia. They were categorized into those with memory problems (amnestic MCI) and those with normal memory (non-amnestic MCI).

Of 4,198 persons found to be eligible for the study, almost 10% were diagnosed with MCI. Of these, 163 had amnestic MCI and 254 had non-amnestic MCI.

The risk of dementia was especially high for people with amnestic MCI. Similar results were observed regarding the risk for Alzheimer's disease. Those with MCI also faced a somewhat higher risk of death.

The research team investigated possible determinants of MCI, considering factors such as age, APOE-ɛ status, waist circumference, hypertension, diabetes mellitus, total and HDL-cholesterol levels, smoking, and stroke. Only older age, being an APOE-ɛ4 carrier, low total cholesterol levels, and stroke at baseline were associated with developing MCI. Having the APOE-ɛ4 genotype and smoking were related only to amnestic MCI.

When the investigators analysed MRI studies of the brain, they found that participants with MCI, particularly those with non-amnestic MCI, had larger white matter lesion volumes and worse microstructural integrity of normal-appearing white matter compared to controls. They were also three-times more likely than controls to have lacunes (3 to 15 mm cerebrospinal fluid (CSF)-filled cavities in the basal ganglia or white matter, frequently observed when imaging older people). MCI was not associated with total brain volume, hippocampal volume, or cerebral microbleeds.

"Our results suggest that accumulating vascular damage plays a role in both amnestic and non-amnestic MCI," says Dr. Ikram. "We propose that timely targeting of modifiable vascular risk factors might contribute to the prevention of MCI anddementia."

Provided by IOS Press

Mammography benefits women over 75

This bar graph shows the change in detection method over time (1990-2011) for breast cancer cases in patients aged 75 years and older (n = 1162). Pt/PhysD = detection by patient or physician. Credit: Radiological Society of North America

10 aug 2014--Mammography-detected breast cancer is associated with a shift to earlier stage diagnosis in older women, subsequently reducing the rate of more advanced, difficult-to-treat cases, according to a new study published online in the journal Radiology. Researchers said the findings lend support to regular mammography screening in women ages 75 and older.

The value of mammography screening in older women has been subject to much debate in recent years. The American Cancer Society recommends annual mammograms for women age 75 and older as long as they are in good health, while the U.S. Preventive Services Task Force (USPSTF) does not recommend mammography screening in this age group, citing insufficient evidence to evaluate benefits and harms.

A lack of research is chiefly responsible for the divergent recommendations, according to Judith A. Malmgren, Ph.D., affiliate assistant professor at the University of Washington's School of Public Health and Community Medicine in Seattle.

"There are no studies on women age 75 and older, despite the fact that they are at the highest risk for breast cancer," she said.

Dr. Malmgren and her research partner, Henry Kaplan, M.D., from the Swedish Cancer Institute in Seattle, recently looked at the impact of mammography detection on older women by studying data from an institutional registry that includes more than 14,000 breast cancer cases with 1,600 patients over age 75.

This graph shows the change in stage over time (1990-2011) for breast cancer cases in patients aged 75 years and older (n = 1162). Credit: Radiological Society of North America

The majority of mammography-detected cases were early stage, while physician- and patient-detected cancers were more likely to be advanced stage disease. Mammography-detected invasive breast cancer patients were more often treated with lumpectomy and radiation and had fewer mastectomies and less chemotherapy than patient- or physician-detected cases.

Mammography detection was associated with a 97 percent five-year disease-specific invasive cancer survival rate, compared with 87 percent for patient- or physician-detected invasive cancers.

"Mammography enables detection when breast cancer is at an early stage and is easier to treat with more tolerable options," Dr. Malmgren said. "In this study, older women with mammography-detected invasive cancer had a 10 percent reduction in breast cancer disease-specific mortality after five years."

The early detection provided by mammography is particularly important in older women, Dr. Malmgren noted, because they cannot easily tolerate the chemotherapy that is commonly used to treat more advanced breast cancers.

"Longer life expectancies for women also increase the importance of early detection," Dr. Malmgren said. "A 75-year-old woman today has a 13-year life expectancy. You only need five years of life expectancy to make mammography screening worthwhile."

Dr. Malmgren acknowledged that the potential costs of mammography, such as those associated with false-positive results, are an important consideration when weighing screening benefits. However, she said that false-positive findings are less common in older women.

"It's easy to detect a cancer earlier in older women because breast density is not an issue," Dr. Malmgren said. "And mammography is not expensive, so doing it every other year would not add a lot of cost to healthcare."

The researchers hope that the study results help women and their physicians make better informed decisions about mammography, ultimately leading to lower mortality rates.

"Breast cancer survival in younger women has improved dramatically over last 20 years, but that improvement has not been seen in older women," Dr. Malmgren said.

More information: "Improved Prognosis of Women Aged 75 and Older with Mammography-detected Breast Cancer." Radiology, 2014.

Provided by Radiological Society of North America

Loss of sensation in the feet of diabetes patients linked to cardiovascular disease, say researchers

Experts have discovered that loss of sensation in the feet, a result of diabetes, may be a predictor of cardiovascular events such as heart attack and strokes.

09 aug 2014--Diabetes, which affects 3.7million people in the UK, can cause damage to a person's blood vessels and nerves, especially if their blood sugar is poorly controlled, leading to poor circulation and loss of sensation in the feet, known as peripheral neuropathy.

The damage to vessels and nerves may be associated with the development of foot ulcers and, in extreme cases, can lead to foot or leg amputation.

The new research, carried out using information on over 13,000 patients, with type 2 diabetes in England, shows that lack of sensation in feet, which can be easily identified by a patient's GP, may also indicate future heart and circulation problems.

The new study suggests that testing for peripheral neuropathy, which is offered on an annual basis to all patients with diabetes, may provide a simple clinical way to identify those higher-risk individuals with diabetes who may need more intensive monitoring or treatment.

Jack Brownrigg, a PhD student at St George's, University of London, who conducted the research at St George's Vascular Institute, said: "While the risk of cardiovascular disease is known to be higher in patients with diabetes, predicting which patients may be at greatest risk is often difficult.

"We looked at data on individuals with no history of cardiovascular disease and found that those with peripheral neuropathy were more likely to develop cardiovascular disease."

Robert Hinchliffe, Senior Lecturer and Consultant in Vascular Surgery at St George's who co-led the study with Professor Kausik Ray, said: "While loss of sensation in the feet is known to be a key risk factor for foot ulcers, it may also provide additional useful information to guide patient management. This is the first study to show that it can also indicate an increased risk of cardiovascular problems like heart attacks or strokes.

"The good news is that peripheral neuropathy can be easily identified by simple tests carried out in GP surgeries. The results of the study warrant further investigation as to whether even greater control of risk factors including blood pressure and blood sugar can prevent or delay the onset of cardiovascular disease.

"There is likely an unmet potential to reduce cardiovascular disease in this group of patients through greater monitoring and simple treatments".

The paper, "Peripheral Neuropathy and the Risk of Cardiovascular Events in Type 2 Diabetes Mellitus", is published in the leading UK cardiovascular journal Heart.

More information: "Peripheral neuropathy and the risk of cardiovascular events in type 2 diabetes mellitus." Jack R W Brownrigg, Simon de Lusignan, Andrew McGovern, Cian Hughes, Matthew M Thompson, Kausik K Ray, Robert J Hinchliffe.Heart heartjnl-2014-305657Published Online First: 5 August 2014 DOI: 10.1136/heartjnl-2014-305657

Provided by St. George's University of London

Link between vitamin D and dementia risk confirmed

Vitamin D deficiency is associated with a substantially increased risk of dementia and Alzheimer's disease in older people, according to the most robust study of its kind ever conducted.

08 aug 2014--An international team, led by Dr David Llewellyn at the University of Exeter Medical School, found that study participants who were severely Vitamin D deficient were more than twice as likely to develop dementia and Alzheimer's disease.

The team studied elderly Americans who took part in the Cardiovascular Health Study. They discovered that adults in the study who were moderately deficient in vitamin D had a 53 per cent increased risk of developing dementia of any kind, and the risk increased to 125 per cent in those who were severely deficient.

Similar results were recorded for Alzheimer's disease, with the moderately deficient group 69 per cent more likely to develop this type of dementia, jumping to a 122 per cent increased risk for those severely deficient.

The study was part-funded by the Alzheimer's Association, and is published in August 6 2014 online issue of Neurology, the medical journal of the American Academy of Neurology. It looked at 1,658 adults aged 65 and over, who were able to walk unaided and were free from dementia, cardiovascular disease and stroke at the start of the study. The participants were then followed for six years to investigate who went on to develop Alzheimer's disease and other forms of dementia.

Dr Llewellyn said: "We expected to find an association between low Vitamin D levels and the risk of dementia and Alzheimer's disease, but the results were surprising – we actually found that the association was twice as strong as we anticipated.

"Clinical trials are now needed to establish whether eating foods such as oily fish or taking vitamin D supplements can delay or even prevent the onset of Alzheimer's disease and dementia. We need to be cautious at this early stage and our latest results do not demonstrate that low vitamin D levels cause dementia. That said, our findings are very encouraging, and even if a small number of people could benefit, this would have enormous public health implications given the devastating and costly nature of dementia."

Research collaborators included experts from Angers University Hospital, Florida International University, Columbia University, the University of Washington, the University of Pittsburg and the University of Michigan. The study was supported by the Alzheimer's Association, the Mary Kinross Charitable Trust, the James Tudor Foundation, the Halpin Trust, the Age Related Diseases and Health Trust, the Norman Family Charitable Trust, and the National Institute for Health Research Collaboration for Leadership in Applied Research and Care South West Peninsula (NIHR PenCLAHRC).

Dementia is one of the greatest challenges of our time, with 44 million cases worldwide – a number expected to triple by 2050 as a result of rapid population ageing. A billion people worldwide are thought to have low vitamin D levels and many older adults may experience poorer health as a result.

The research is the first large study to investigate the relationship between vitamin D and dementia risk where the diagnosis was made by an expert multidisciplinary team, using a wide range of information including neuroimaging. Previous research established that people with low vitamin D levels are more likely to go on to experience cognitive problems, but this study confirms that this translates into a substantial increase in the risk of Alzheimer's disease and dementia.

Vitamin D comes from three main sources – exposure of skin to sunlight, foods such as oily fish, and supplements. Older people's skin can be less efficient at converting sunlight into Vitamin D, making them more likely to be deficient and reliant on other sources. In many countries the amount of UVB radiation in winter is too low to allow vitamin D production.

The study also found evidence that there is a threshold level of Vitamin D circulating in the bloodstream below which the risk of developing dementia and Alzheimer's disease increases. The team had previously hypothesized that this might lie in the region of 25-50 nmol/L, and their new findings confirm that vitamin D levels above 50 nmol/L are most strongly associated with good brain health.

Commenting on the study, Dr Doug Brown, Director of Research and Development at Alzheimer's Society said: "Shedding light on risk factors for dementia is one of the most important tasks facing today's health researchers. While earlier studies have suggested that a lack of the sunshine vitamin is linked to an increased risk of Alzheimer's disease, this study found that people with very low vitamin D levels were more than twice as likely to develop any kind of dementia.

"During this hottest of summers, hitting the beach for just 15 minutes of sunshine is enough to boost your vitamin D levels. However, we're not quite ready to say that sunlight or vitamin D supplements will reduce your risk of dementia. Large scale clinical trials are needed to determine whether increasing vitamin D levels in those with deficiencies can help prevent the dementia from developing."

Provided by University of Exeter

New study finds shingles vaccine remains effective after chemotherapy

The herpes zoster vaccine continues to be effective in protecting older adults against shingles, even after they undergo chemotherapy, according to a Kaiser Permanente study published today in the journal Clinical Infectious Diseases.

07 aug 2014--Researchers examined the electronic health records of more than 21,000 Kaiser Permanente patients in Southern California who were 60 years of age and older and received chemotherapy between January 2007 and December 2012.

Researchers found that those patients who were previously vaccinated with zoster vaccine were 42 percent less likely to develop shingles following chemotherapy. In addition, no vaccinated patients underwent hospitalization for shingles, while six unvaccinated patients were hospitalized with the disease, according to the study.

"The zoster vaccine has been shown to be safe and effective in elderly adults with healthy immune systems but until now, there has been a lack of data on whether the vaccine remains safe and effective for individuals who might have compromised immune systems resulting from treatments like chemotherapy," said study lead author Hung Fu Tseng, PhD, MPH, of the Kaiser Permanente Southern California Department of Research & Evaluation. "Our study demonstrates that older patients who had previously been vaccinated against shingles have a lower chance of developing this painful and often debilitating disease after chemotherapy."

Shingles is caused by the varicella zoster virus and can affect anyone who has had chickenpox. Symptoms of shingles include a painful rash and blisters that develop on one side of the face or body as well as fever, headache and chills. According to the Centers for Disease Control and Prevention, before the zoster vaccine was available, almost one out of every three people in the United States would develop shingles at some point in their lifetime, which translated into more than 1 million cases of shingles expected each year in the U.S.

The risk of developing shingles also increases among those receiving treatments that weaken the immune system, such as chemotherapy for cancers. The lifetime risk of developing cancer is nearly 40 percent among 60-year-old adults, according to the National Cancer Institute. The CDC recommends that people aged 60 years and older get one dose of the zoster vaccine as this is the only way to reduce the risk of developing shingles and prevent long-term complications.

"Age is associated with increased risk of cancers and other medical conditions that may require immunocompromising treatments such as chemotherapy," said Tseng. "It is important that elderly patients get vaccinated when they are relatively healthy, or before starting immunocompromising treatments, because the vaccine isn't advised for those who have weakened immune systems."

Provided by Kaiser Permanente

Study examines midlife hypertension, cognitive change over 20-year period

Hypertension in middle age (48 to 67 years) was associated with a greater, although still a modest, decline in cognition over a 20-year period compared with individuals who had normal blood pressure.

06 aug 2014--Evidence suggests hypertension is a risk factor for cognitive change and dementia and midlife hypertension may be the stronger risk factor.

Authors used the Atherosclerosis Risk in Communities (ARIC) study to examine the effects of hypertension by analyzing the results of three cognitive tests over time. Data from 13,476 participants (3,229 of whom were African American) were used and the maximum follow up was 23.5 years.

The decline in global cognitive scores for participants with hypertension was 6.5 percent greater than for individuals with normal blood pressure. An average ARIC participant with normal blood pressure at baseline had a decline of 0.840 global cognitive z score points during the 20-year period compared with 0.880 points for participants with prehypertension and 0.896 points for patients with hypertension. Individuals with high blood pressure who used medication had less cognitive decline during the 20 period than participants with high blood pressure who were untreated. A greater decline in global cognition scores also was associated with higher midlife blood pressure in white participants than in African Americans.

"Although we note a relatively modest additional [cognitive] decline associated with hypertension, lower cognitive performance increases the risk for future dementia, and a shift in the distribution of cognitive scores, even to this degree, is enough to increase the public health burden of hypertension and prehypertension significantly. Initiating treatment in late life might be too late to prevent this important shift. Epidemiological data, including our own study, support midlife BP [blood pressure] as a more important predictor of – and possibly target for prevention of – late-life cognitive function than is later-life BP." Rebecca F. Gottesman, M.D., Ph.D., of the Johns Hopkins University School of Medicine, Baltimore, and colleagues said in their JAMA Neurology paper today.

In a related editorial, Philip B. Gorelick, M.D., M.P.H., of the Michigan State University College of Human Medicine, Grand Rapids, writes: "In this issue of JAMA Neurology, Gottesman and colleagues provide additional evidence to support the association between midlife hypertension and cognitive change. The study provides a unique opportunity to understand the role of raised BP on cognition during a 20-year period."

More information: JAMA Neurol. Published online August 4, 2014. DOI: 10.1001/.jamaneurol.2014.164

JAMA Neurol. Published online August 4, 2014. DOI: 10.1001/.jamaneurol.2014.2014

Provided by The JAMA Network Journals

A polypill strategy to improve global secondary cardiovascular prevention

This Central Illustration for the article shows adherence to the polypill compared to usual care with multiple pills extracted from published research studies, and identifies reasons patients fail to take medications prescribed for secondary prevention of heart disease. Credit:Journal of the American College of Cardiology. 2014;64(6):613-621

05 aug 2014--The polypill, a combination pill taken just once a day that includes key medications for secondary prevention of heart disease, may be an effective low-cost strategy to improve adherence to medication recommendations and reduce costs, according to researchers from Spain and New York, who reviewed research on the polypill.

The review article, A Polypill Strategy to Improve Global Secondary Cardiovascular Prevention, was published online today in the Journal of the American College of Cardiology and will appear in the August 12, 2014 print issue.

Cardiovascular disease is the leading global cause of death, accounting for 17.3 million deaths per year. As the population ages and patients with heart disease survive longer, a growing pool of patients could benefit from secondary prevention of heart disease.

Secondary prevention includes lifestyle changes and the use of medications—including statins, medications to reduce blood pressure, and antithrombotic agents. Use of these medications, which are generally low cost and safe, is thought to be responsible for half of the overall 50 percent reduction in mortality from heart disease in the past 20 years in some Western countries.

According to the researchers, there is room for improvement in secondary prevention, especially in nations with limited resources. The polypill, a combination pill taken just once a day that includes key medications for secondary prevention of heart disease, has been proposed as a low-cost strategy to improve adherence and reduce costs.

More information: Journal of the American College of Cardiology, dx.doi.org/10.1016/j.jacc.2014.06.009

Provided by American College of Cardiology

How is depression related to dementia?

A new study by neuropsychiatric researchers at Rush University Medical Center gives insight into the relationship between depression and dementia. The study is published in the July 30, 2014, online issue ofNeurology, the medical journal of the American Academy of Neurology.

04 aug 2014--"Studies have shown that people with symptoms of depression are more likely to develop dementia, but we haven't known how the relationship works," said study author Robert S. Wilson, PhD, neuropsychiatrist at the Rush Alzheimer's Disease Center and lead study investigator. "Is the depression a consequence of the dementia? Do both problems develop from the same underlying problems in the brain? Or does the relationship of depression with dementia have nothing to do with dementia-related pathology?"

The current study indicates that the association of depression with dementia is independent of dementia-related brain changes. "These findings are exciting because they suggest depression truly is a risk factor for dementia, and if we can target and prevent or treat depression and causes of stress we may have the potential to help people maintain their thinking and memory abilities into old age," Wilson said.

The study involved 1,764 people from the Religious Orders Study and the Rush Memory and Aging Project with an average age of 77 who had no thinking or memory problems at the start of the study. Participants were screened every year forsymptoms of depression, such as loneliness and lack of appetite, and took tests on their thinking and memory skills for an average of eight years. A total of 680 people died during the study, and autopsies were performed on 582 of them to look for the plaques and tangles in the brain that are the signs of dementia and other signs of damage in the brain.

During the study, 922 people, or 52 percent of the participants, developed mild cognitive impairment (MCI), or mild problems with memory and thinking abilities that is often a precursor to Alzheimer's disease. A total of 315 people, or 18 percent, developed dementia.

The researchers found no relationship between how much damage was found in the brain and the level of depression symptoms people had or in the change in depression symptoms over time.

People who developed mild cognitive impairment were more likely to have a higher level of symptoms of depression before they were diagnosed, but they were no more likely to have any change in symptoms of depression after the diagnosis than people without MCI. People with dementia were also more likely to have a higher level of depression symptoms before the dementia started, but they had a more rapid decrease in depression symptoms after dementia developed.

Having a higher level of depression symptoms was associated with more rapid decline in thinking and memory skills, accounting for 4.4 percent of the difference in decline that could not be attributed to the level of damage in the brain.

Provided by Rush University Medical Center

Common drugs adversely impair older adults' physical as well as cognitive functioning

A class of medications previously linked to cognitive impairment in older adults also appears to negatively affect their physical functioning according to investigators from the Regenstrief Institute, the Indiana University Center for Aging Research, the University of East Anglia and several other United Kingdom institutions.

03 aug 2014--In a systemic review of more than a decade of studies on the effects of drugs with anticholinergic properties, they report that these drugs have a significant adverse effect on both cognitive and physical functioning, including the ability to feed and dress oneself. Anticholinergic medications affect the brain by blocking acetylcholine, a nervous system neurotransmitter. They are sold over the counter as sleep aids and bladder leakage preventives and prescribed for many diseases including hypertension and congestive heart failure.

The review found that these 46 studies, which followed 60,944 patients, showed only limited evidence of a connection between anticholinergics and delirium, a short-term decline in cognition. Additionally the review indicated that the studies did not demonstrate a strong tie between medications with anticholinergic properties and death. According to Regenstrief Institute investigator Noll Campbell, Pharm.D., senior author of the review paper, this may be because most studies were insufficient in length to reveal a significant link between the medications and death.

This is the first systematic review to assess the effects of medications with anticholinergic properties on physical function and delirium. The authors say it also provides an important update on cognitive function and mortality.

"Anticholinergics, both over-the-counter and prescription medications, impact the lives of older adults in ways doctors, patients and their families may not realize," said Dr. Campbell, who is also a research assistant professor in the Purdue University College of Pharmacy. "I don't see use of these medications declining. Doctors and patients are familiar with these drugs and unfortunately are far less familiar with equally effective alternatives."

For example, Dr. Campbell advised, rather than taking sleeping pills with anticholinergic properties, one could refrain from napping, limit evening exercise and remove distractions from the bedroom. Institutions like hospitals and nursing homes could work to keep older adults awake and stimulated during the day, naturally encouraging nighttime slumber.

Dr. Campbell and colleagues from the Regenstrief Institute and the IU Center for Aging Research are working to identify diagnosis- and patient-dependent alternatives to exposure to anticholinergic medications as well as methods to inform physicians of their advisability via prompts within electronic medical record systems.

"Significant ongoing concerns remain about these medicines, and this review paper for the first time in one place has highlighted the impact on function as well as memory and death," said Chris Fox, M.D., of the University of East Anglia, the review paper's first author. Dr. Fox is a psychiatrist. In 2011, he and Regenstrief and IU Center for Aging Research collaborators published the results of a study of 13,000 men and women age 65 and older in which they found a link between anticholinergic medications and death.

Provided by Indiana University

First clinical data of therapeutic Parkinson's disease vaccine encourages continued development

02 aug 2014--AFFiRiS AG announced today at a press conference in New York results of AFF008, a Phase I clinical trial of PD01A, a vaccine against Parkinson's disease. PD01A is the first therapy against the protein alpha-synuclein, a promising Parkinson's drug target, to enter clinical testing.

The Michael J. Fox Foundation for Parkinson's Research (MJFF) supported the study with a $ 1.5 million grant, and presented at the press conference on the impact a disease-modifying therapy would have for patients. The Foundation will support a follow-up study testing a boost vaccination, the next step toward a Phase II trial.

"A treatment that could slow or stop Parkinson's progression would be a game changer for the five million worldwide living with this disease and the many more who will become at risk as our population ages", said MJFF CEO Todd Sherer, PhD. "The AFF008 trial is one of the most promising efforts toward that goal, and we're proud to support this work of AFFiRiS AG."

In this study, two different doses of PD01A were safe and well tolerated, meeting the primary endpoint of the trial. Secondary endpoints of the study included the induction of an alpha-synuclein-specific antibody response. A hallmark pathology of Parkinson's disease is aggregates of protein—chiefly alpha-synuclein—called Lewy bodies that accummulate in brain cells, leading to cell degeneration and cell death. Researchers hypothesize that reducing alpha-synuclein accumulation will be neuroprotective; AFFiRiS is using active immunotherapy to test that theory and develop a disease-modifying treatment.

PD01A was applied at two different doses (15 µg and 75 µg) to 12 patients per group. All received four vaccinations in monthly intervals, and all completed the study. Eight patients on best medical care, including standard symptomatic medication, served as a control group. Each patient was regularly seen and evaluated during a 12-month period.

Fifty percent of the vaccinated patients generated alpha-synuclein-specific antibodies as measured in serum samples. Additionally, vaccine-induced antibodies were detectable in cerebrospinal fluid. This induction of antibodies against alpha-synuclein is strong preliminary evidence in support of the principle of AFFiRiS' proprietary therapeutic vaccine.

Furthermore, analysis of clinical endpoints revealed a trend, consistent over all parameters, towards functional stabilization of the vaccinated groups as compared to non-vaccinated control patients. The pharmacodynamic profile of PD01A and its clinical effects will be the basis of later phase studies, should development continue.

"The safety and tolerability observed in this study, especially in a protein such as alpha-synuclein where we do not yet know its normal function, are encouraging," said Walter Schmidt, PhD, Co-founder and CEO of AFFiRiS AG. "We are grateful for the continued support of The Michael J. Fox Foundation as we progress in clinical development."

The next study will take place in Vienna, Austria and focus on assessing the immunological and clinical effects of a boost vaccination. Recruitment is expected to begin September.

Provided by AFFiRiS AG

80 percent of aortic stenosis patients are in the same/better health 1 year after treatment

A survey, published online in the European Journal of Cardio-Thoracic Surgery, of 13,860 patients who had undergone interventions for aortic valve disease in Germany has revealed that over 80% were in the same or a better state of health one year after the intervention, and was satisfied with the procedural outcome.

01 aug 2014--Aortic stenosis : the narrowing of the aortic valve in the heart – is the most frequent valvular heart disease in the aging Western population, and the prognosis of this disease in symptomatic patients with conservative therapy is poor. As a result, surgical aortic valve replacement (AVR) has become the therapeutic gold standard with well-documented benefits in terms of symptom relief and survival. During the past decade, transcatheter aortic valve replacement (TAVR) has emerged as a minimally invasive alternative for higher-risk patients, and the number of these procedures being carried out in Germany and Europe as a whole has increased in recent years.

Prof. Dr. Friedrich W. Mohr and colleagues used the German Aortic Valve Registry (GARY) to look at the 13,860 registered patients undergoing either AVR or TAVR procedures from 2011. Enrolment in the Registry was voluntary, and took place in 78 German centres. Baseline, procedural, and outcome data, including quality of life, were acquired up to one year post-intervention. Vital status at one year was known for just over 98% of patients.

One-year mortality was 6.7% (6,523) for conventional AVR patients and 11% (3,464) for patients who underwent AVR with coronary artery bypass grafting. One-year mortality 20.7% and 28% in transvascular TAVR and transapical TAVR procedures respectively. However, if patients were stratified into four risk groups, the highest-risk cohorts showed the same mortality at one year regardless of type of therapy.

Over 80% of patients in all groups were in the same or better state of health at one year post-intervention and were satisfied with the procedural outcome.

Prof. Dr. Mohr said: 'GARY is unique in that it includes all interventional and surgical treatment options for aortic valve disease that are currently available in Germany. Our aim was to obtain a comprehensive and contemporary picture of the current practice of aortic valve intervention therapy and to create an independent database that will allow for long-term follow-up of those patients.

'The acceptance of this voluntary registry is demonstrated by the fact that 55% of all aortic valve procedures performed in Germany in 2011 were included, with an increasing recruitment rate observed in 2012. In addition, a good follow-up rate of 98.5% with regards to vital status and 90% for clinical information was achieved.

'The one-year results of the German Aortic Valve Registry confirm in a large "real world", all-comer patient population that conventional surgery in operable patients yields excellent results in all risk groups. TAVR is being performed in a significant proportion of cases and is a good alternative for high-risk patients. Continuation of the registry and long-term follow-up will help to develop robust future risk models to predict patient outcomes for each treatment option in patients with aortic stenosis.'

Provided by Oxford University Press

Brazilian researchers identify RNA that regulates cell death

Researchers from the University of São Paulo (USP) have identified an RNA known as INXS that, although containing no instructions for the production of a protein, modulates the action of an important gene in the process of apoptosis, or programmed cell death.

31 july 2014--According to Sergio Verjovski-Almeida, professor at the USP Chemistry Institute and coordinator of a research funded by São Paulo Research Foundation (FAPESP), INXS expression is generally diminished in cancer cells, and methods that are capable of stimulating the production of this non-coding RNA can be used to treat tumors.

In experiments on mice, the USP scientists were able to effect a 10-fold reduction in the volume of subcutaneous malignant tumors by administering local injections of a plasmid – a circular DNA molecule – containing INXS. The findings were published in the most recent issue of the journal Nucleic Acids Research.

The group headed by Verjovski-Almeida at USP has devoted the past five years to investigating the regulatory role of so-called intronic non-protein-coding genes – those found in the same region of the genome as a coding gene but on the opposite DNA strand. INXS, for example, is an RNA expressed on the opposite strand of a gene coding for a protein known as BCL-X.

"We were studying several protein-coding genes involved in cell death in search of evidence that one of them was regulated by intronic non-coding RNA. That was when we found the gene for BCL-X, which is located on chromosome 20," he explained.

The researcher explained that BCL-X is present in cells in two different forms: one that inhibits apoptosis (BCL-XL) and one that induces the process of cell death (BCL-XS). The two isoforms act on the mitochondria but in opposite ways. The BCL-XS isoform is considered a tumor suppressor because it activates protein complexes known as caspases, which are required for the activation of other genes that cause cell death.

"In a healthy cell, there is a balance between the two BCL-X isoforms. Normally, there is already a smaller number of the pro-apoptotic form (BCL-XS). However, in comparing tumor cells to non-tumor cells, we observed that tumor cells contain even fewer of the pro-apoptotic form, as well as reduced levels of INXS. We suspect that one thing affects the other," the researcher said.

To confirm the hypothesis, the group silenced INXS expression in a normal cell lineage and the result, as expected, was an increase in the BCL-XL (anti-apoptotic) isoform. "The rate between the two – which was 0.25 – decreased to 0.15; in other words, the pro-apoptotic form that previously represented one fourth of the total began to represent only one sixth," Verjovski-Almeida explained.

The opposite occurred when the researchers artificially increased the amount of INXS using plasmid expression in a kidney cancer cell line, with the non-coding RNA being reduced. "The pro-apoptotic form increased, and the anti-apoptotic form decreased," the researcher noted.

The next step was to subject the cancer cell lineages to agents known to induce cell death, such as ultraviolet light and chemotherapy drugs, to see whether INXS expression increased.

The researchers repeated the experiment, but his time silenced the INXS gene. They then observed that, even in the presence of ultraviolet light, the pro-apoptotic isoform did not increase and the cells did not die.

The final stage of the study was to verify whether the increase in INXS expression is related to the death of cancer cells in vivo. To do this, the researchers subcutaneously implanted human kidney cancer cells in mice and waited 40 and 60 days for the tumor to reach a volume of 300 cubic millimeters (mm3) and become palpable.

The animals were then divided into two groups: one half began to receive injections of the plasmid containing INXS at the site of the tumor; the other half, which served as the control, received only the empty plasmid.

After 15 days of treatment, the tumors in the control group animals had grown to an average volume of 600 mm3. However, in the group treated with INXS, the average tumor volume measured 70 mm3 – nearly 10 times smaller.

According to the assessment of Verjovski-Almeida, it is possible to develop therapies to fight cancer that are able to increase the quantity of INXS in only the tumor cells, and the USP group plans to test some of these strategies in the future.

In a new thematic project, titled "Characterization of the mechanisms of action of long non-coding RNA involved in the programs of gene activation in human cells," recently approved by FAPESP, the group plans to further study the mechanisms through which INXS modulates the BCL-X gene to understand why this non-coding RNA is reduced in cancer cells.

Provided by Fundação de Amparo à Pesquisa do Estado de São Paulo