Study Examines Testing Model To Predict And Diagnose New Cases Of Dementia

A report published by researchers at Albert Einstein College of
Medicine of Yeshiva University in the August 20 issue of JAMA suggests that measuring how much an
individual’s performance varies across several neuropsychological tests enhances the accuracy of
predicting whether older adults will develop dementia.

Developing strategies to improve the prediction and diagnosis of dementia has critical therapeutic
and public health implications. “Typically, when neuropsychological tests are used for diagnostic
purposes, an individual’s level of performance on specific tests is measured against healthy individuals to
determine cognitive impairment,” says Dr. Roee Holtzer, assistant professor of neurology and psychology
at Einstein and lead author of the study. “However, this approach does not take into account intraindividual
variability in cognitive function.” Intra-individual variability refers to inconsistency in
performance measured in the same person.
Dr. Holtzer and Einstein colleagues evaluated 897 individuals, age 70 or older, who have taken
part in The Einstein Aging Study, a longitudinal study of aging and dementia in Bronx, New York.
Participants had follow-up visits every 12 to 18 months, during which they underwent detailed
neurological and neuropsychological evaluations. The researchers included tests for verbal IQ,
attention/executive function, and memory.

The study focused on whether within-person variability across several neuropsychological tests,
assessed at the initial study visit, predicted future dementia. “We know that level of performance on tests
of memory, attention and executive function predicts dementia. However, this study showed for the first
time that the degree of variability in performance across neuropsychological tests, measured within a
person, improved the prediction of dementia above and beyond one’s level of performance on each test
alone,” says Dr. Holtzer.

In the follow-up visits, participants underwent extensive neurological and neuropsychological testing
to determine whether individuals remained normal or became demented. “Of the 897 participants, there were
61 cases of dementia (6.8 percent) identified during the follow-up period, which, on average, was 3.3 years,”
says Dr. Holtzer. “This figure is in line with what we’d expect for the incidence of dementia in this
population.”
The study concluded that within-person variability across these tests predicted the development of
dementia independently of how people performed on the tests. The authors recommend that their findings be
replicated in different populations before they’re applied in a clinical setting.
Other Einstein researchers involved in this study were: Drs. Joe Verghese, Cuiling Wang, Charles B.
Hall, and Richard B. Lipton. The Einstein Aging Study is supported by a National Institute on Aging grant.
Dr. Holtzer is supported by the National Institute on Aging Paul B. Beeson Award. Co-author Dr. Verghese
is supported by a National Institute on Aging grant.

About Albert Einstein College of Medicine of Yeshiva University

The Albert Einstein College of Medicine of Yeshiva University is one of the nation’s premier centers for
research, medical education and clinical investigation. It is the home to some 2,000 faculty members, 750
M.D. students, 350 Ph.D. students (including 125 in combined M.D./Ph.D. programs) and 380 postdoctoral
investigators. Last year, Einstein received more than $150 million in grant funding from the National
Institutes of Health (NIH). In addition, the NIH funds major research centers at Einstein in diabetes, cancer,
liver disease, and AIDS. Other areas where the College of Medicine is concentrating its efforts include
developmental brain research, neuroscience, cardiac disease, and initiatives to reduce and eliminate ethnic
and racial health disparities. Through its extensive affiliation network involving five hospital centers in the
Bronx, Manhattan and Long Island – which includes Montefiore Medical Center, Einstein’s officially
designated University Hospital – the College runs one of the largest post-graduate medical training program
in the United States, offering approximately 150 residency programs to more than 2,500 physicians in
training.

[i] Skljarevski, V. et al. Evaluating the Maintenance of Effect of Duloxetine in Patients with Diabetic Peripheral Neuropathic Pain. Poster presented at the Annual World Congress of Pain. 19 August 2008

Albert Einstein College of Medicine of Yeshiva University

“Asthma Warning In Wake Of Bushfires”

There is a heightened risk of asthma across Victoria due to the devastation of the weekend’s bushfires and the impact of high winds.

People with asthma are being urged to ensure they are carrying their asthma reliever medication and remain on high alert.

“Smoke and increased air pollution from fires can trigger asthma symptoms, such as wheezing, coughing or chest tightness,” warned National Asthma Council Australia Chief Executive Officer, Kristine Whorlow.

“If you have asthma, or if you are responsible for a child or elderly person with asthma, be aware of the risk and the fact that these triggers can linger long after the actual bushfire threat has subsided.

“This is also critically important for the many hundreds of volunteers, emergency personnel and media representatives who are working directly within the fire zones. I commend them for their work and urge them to maintain their own health.”

People in areas not directly impacted by the bushfires, including built up areas, are also at risk as this week’s erratic winds carry smoke and ash particles long distances.

The National Asthma Council Australia is encouraging anyone with asthma to ensure they have appropriate medication readily available.

“In an emergency situation such as this, if you have evacuated and find yourself without your prescribed medication, I urge you to visit a pharmacist who will be able to help you,” Kristine Whorlow said.

“You need to be aware of your personal asthma triggers and follow your asthma action plan.”

The Pharmacy Guild of Australia has today confirmed that many pharmacies in and around fire zones are operational.

“Pharmacies are a pivotal part of the communities affected by this terrible disaster, and I know pharmacists and their staff stand ready to do everything possible to assist patients in this very stressful and tragic time,” said Guild President, Kos Sclavos.

“Community pharmacies are frontline health destinations ready to give advice and assistance to all in need.”

Bushfire smoke contains particles of different sizes, water vapour and gases, including carbon monoxide, carbon dioxide and nitrogen oxides.

Larger sized air-borne particles, containing burning debris, contribute to the visible haze when a fire is burning. They are generally too large to be breathed into the lungs, but they can cause irritation to the lungs, throat and nose.

Finer particles and gases, however, are small enough to be breathed into the lungs.

Research conducted on smoke and its effect on asthma in Darwin during the dry season of 2000 found a significant 140% increase in asthma presentations to the Royal Darwin Hospital on very hazy days.

“The concentration of fine particles in the atmosphere was shown to increase asthma exacerbations,” Kristine Whorlow explained. “And this is the same scenario that we are now facing in Victoria.”

Anyone seeking asthma advice can contact the Asthma Foundation on 1800 645 130 or asthma.au or visit the National Asthma Council Australia’s website: nationalasthma.au.

National Asthma Council Australia

Bali Bomb Lessons Helped Shape Mental Health Response To Terrorism And Trauma

Healthcare professionals were able to offer better mental health support to the victims of the 2005 Bali bombings, thanks to improved procedures and services introduced after the first explosions in 2002, according to the May issue of the UK-based Journal of Psychiatric and Mental Health Nursing.

Staff at the Royal Darwin Hospital who treated many of the casualties also received vital personal support from mental health nurses, especially as they waited anxiously for the first victims to arrive.

“The 2002 bombings were Australia’s first large-scale introduction to terrorist activity in the immediate geographical area and they initiated a new phase of trauma response for public health services in the country” says Anthony Guscott of Top End Mental Health Services, which provides in-patient and consultation liaison nursing services at the Royal Darwin Hospital.

“A national mental health response to mass trauma was established and this proved particularly useful to the Royal Darwin Hospital, which handled a large number of casualties from both bombings.”

The national group driving the national mental health guidance were also able to draw on their experiences of other traumatic events, including the Eyre Peninsula bushfires that killed nine people and injured 110 in South Australia in January 2005.

This national guidance was then used to shape more effective local front line mental health services to cover both day-to-day needs and cope with major incidents. For example, the Royal Darwin Hospital now has a round-the-clock mental health presence in the emergency department and other departments can call on out-of-hours’ support as needed.

Many of the bomb victims suffered profound mental health problems immediately after the bombings. In 2002 the mental health response was poorly planned, but the lessons learnt from the first incident meant that in 2005 patients’ physical and mental health needs were better co-ordinated by staff who had already recognised and established a stronger link between trauma and psychiatric support.

Just over 200 people were killed by the 2002 bombs, including 88 Australians, and hundreds more suffered burns and other injuries. Many of the victims injured in the suicide bombings at Paddy’s Bar and the Sari Club in Kuta were taken to the Royal Darwin Hospital to be stabilised before being moved to other hospitals. A high proportion had suffered chemical burns.

A senior psychiatrist and the director of mental health nursing were available to provide advice, but no psychiatric reviews were requested by staff who treated the victims or prepared them for transfer to hospitals in their home states.

The experience in 2005 was very different.

Twenty people were killed and 129 wounded in the bombings in October 2005 four Australians died and 19 were injured. On this occasion the majority of deaths and injuries were caused by shrapnel rather than burns.

Top End Mental Health Services’ staff were involved in the trauma planning sessions as soon as word of the bombings reached the hospital.

The experienced mental health nurses who had previously worked with people affected by the Eyre Peninsula bushfires provided a high profile presence in the emergency department, for patients and staff alike, from the moment casualties were admitted. And all patients underwent a mental health review before being moved to hospitals in their home states.

“Staff saw victims who had severe shrapnel wounds and were physically and emotionally affected by the bombings” says Guscott.

“They experienced depersonalisation, disassociation, disbelief and anger. Many described greater physical pain than their injuries would be expected to cause, together with a physical ache over their losses, thoughts of what could have been and the futility of the situation.

“All spoke in their own ways of how they felt their safety and personal space had been violated.”

And because the 2005 bombs were detonated at dinner time, some victims found it difficult to eat and became anxious at mealtimes.

The early intervention by mental health nurses proved invaluable for many of the patients.

In a short period many changed from providing limited verbal responses to starting to communicate more confidently.

The mental health nurses also provided vital, confidential support for other hospital healthcare staff while they were waiting for the victims to arrive and ongoing support while they treated them.

“Some staff described the eeriness of the ward waiting to receive incoming patients and other were anxious about what to expect having been involved in caring for bomb victims three years earlier” says Guscott. “And a number of general nurses and support staff also experienced disturbing phenomena such as the smell of burning flesh ??” a throwback to the chemical burn victims treated by the hospital in 2002.”

Following the 2005 incident hospital staff also took part in feedback sessions run by mental health staff so that their comments could be used to make any further improvements to the major incident plan and identify any ongoing staff support that was needed.

Guscott doubts whether the Royal Darwin would have handled the second bombing as effectively without the lessons learnt from the first.

“The fact that mental health nurses had become a recognised part of the hospital establishment between the two incidents meant that staff worked together in a much more co-ordinated way to help the victims of the second bombing” he says. “They also recognised that the mental health nurses could provide them with the support they needed to handle the trauma.”

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AANMA Welcomes New Redskins Linebacker And Asthma Activist Chris Draft

Allergy & Asthma Network Mothers of Asthmatics (AANMA), the nation’s only family-founded patient education nonprofit organization for people with asthma, allergies and related conditions, congratulates NFL linebacker Chris Draft on his recent signing to the Washington Redskins and welcomes him to the nation’s capital.

Draft partnered with AANMA last week to launch the Great American Asthma Challenge – the first-ever national grassroots movement to end asthma deaths and suffering in the United States. A dedicated community activist as well as accomplished athlete, Draft helped kick off the program at AANMA’s 13th annual Asthma Awareness Day Capitol Hill on May 5.

“Chris Draft brings authenticity and conviction to his off-the-field work for families and people with asthma,” said Nancy Sander, AANMA founder and president. “Now that he’ll be right in our back yard, we look forward to more opportunities to work with him on our mission to end asthma deaths and suffering in the U.S.”

The proactive approach of the Great American Asthma Challenge is a way of life for Draft, founder of The Chris Draft Family Foundation and The Asthma Team™. Draft was diagnosed with asthma while attending Stanford and playing for the university’s football team. Today he motivates children and adults with asthma to take charge of their health through his foundation. In his keynote speech at Asthma Awareness Day Capitol Hill he spoke about the importance of a team effort – among patients, their families, healthcare providers, lawmakers and the community – to tackle asthma.

The Great American Asthma Challenge

Every day 10 people die from asthma. Most healthcare providers agree that these deaths are preventable. Patient education, access to care and a healthy lifestyle are proven methods that lead to less severe asthma symptoms, fewer hospitalizations and emergency department visits, fewer missed days of school and work – and fewer deaths.

The Great American Asthma Challenge is a self-paced program through which participants weave tried-and-true resources and health guidance supported by the NIH Guidelines for the Diagnosis and Treatment of Asthma into their daily lives, connecting with a network of others working toward the goal of ending asthma deaths and suffering in the U.S.

Participants log into a new interactive website, take a quick survey to establish a baseline and set goals, then they’re off to complete Challenge activities targeted for three levels of users: families, healthcare providers and legislators. Throughout the Challenge, participants see survey results and share feedback. At the end of the Challenge, users take a survey to measure their progress. For more details and to take the Challenge today, go here.

About the Chris Draft Family Foundation

The mission of the Chris Draft Family Foundation is to strengthen communities by empowering families to live healthy lifestyles. The Foundation focuses on seven primary initiatives with overarching themes that stress the importance of education, healthy lifestyles, character development, personal responsibility, self-discipline and physical fitness. For more information, please visit here.

Source
Allergy & Asthma Network Mothers of Asthmatics

Statins may help treat Multiple Sclerosis, Alzheimer’s and Ostoeporosis

Statins, or cholesterol-lowering drugs, may be effective in treating MS (multiple sclerosis), Alzheimer’s and osteoporosis, say some experts. Many are calling statins the new ‘aspirin’, but without so many side-effects (aspirin, as well as being a pain-killer, has many other benefits).

The first clinical evidence has been produced by scientists at the Medical University of S Carolina, USA, that statins can be effective in the treatment of MS.

You can read about this new study in The Lancet (medical journal).

Thirty MS patients were given Zocor (simvastatin), 80 mg per day. Zocor is a statin. Researchers reported that the patients experienced a 44% drop in brain lesions within three months of starting treatment.

When areas of the brain experience inflammations they are called brain lesions. Lesions tell us how the MS is progressing (becoming more severe). The nerve cells of people with MS lose their insulating sheath. This leads to muscle weakness, tiredness, bladder incontinence and problems with their eyesight.

Currently, MS patients are given interferon injections. Interferon injections are only partially effective. For patients to be able to switch to swallowing statin pills, which are much cheaper and seemingly more effective would be great news for them.

A large-scale controlled trial is going to take place soon with some of the volunteers on statins and others on placebo. Professor Chris Polman, VU Medical Center, Amsterdam, Netherlands, said that the trial should take about two years to complete.

Timothy Vollmer and his team in South Carolina who carried out this new study said that they had been encouraged by previous studies which indicated that statins reversed paralysis in mice with MS.

Apart from being able to block an enzyme which helps the liver produce cholesterol, statins seem to undermine the inflammatory processes as well. Inflammations in the body are associated with higher risks of developing many chronic diseases.

Scientists and doctors still have a long way to go, the team said. They have to find out what the ideal dosage might be. They think the dosage for people with MS will probably have to be higher than for people with clogged arteries.

Professor Polman told existing MS patients not to switch to statins now and drop their existing treatment. He said the use of statins without knowing more about them could boomerang.

The temptation to go out and get statins in the UK will be higher. In the UK statins will soon be available over the counter, without the need for a prescription from a doctor.

WHAT IS MULTIPLE SCLEROSIS?

MS is thought to be an autoimmune disease that affects the central nervous system (CNS). The CNS consists of the brain, spinal cord, and the optic nerves. Surrounding and protecting the nerve fibers of the CNS is a fatty tissue called myelin, which helps nerve fibers conduct electrical impulses.

In MS, myelin is lost in multiple areas, leaving scar tissue called sclerosis. These damaged areas are also known as plaques or lesions. Sometimes the nerve fiber itself is damaged or broken.

Myelin not only protects nerve fibers, but makes their job possible. When myelin or the nerve fiber is destroyed or damaged, the ability of the nerves to conduct electrical impulses to and from the brain is disrupted, and this produces the various symptoms (nationalmssociety/symptoms.asp) of MS.

People with MS can expect one of four clinical courses of disease, each of which might be mild, moderate, or severe.

RELAPSING-REMITTING

Characteristics: People with this type of MS experience clearly defined flare-ups (also called relapses, attacks, or exacerbations). These are episodes of acute worsening of neurologic function. They are followed by partial or complete recovery periods (remissions) free of disease progression.
Frequency: Most common form of MS at time of initial diagnosis.
Approximately 85%.

PRIMARY-PROGRESSIVE

Characteristics: People with this type of MS experience a slow but nearly continuous worsening of their disease from the onset, with no distinct relapses or remissions. However, there are variations in rates of progression over time, occasional plateaus, and temporary minor improvements.
Frequency: Relatively rare. Approximately 10%.

SECONDARY-PROGRESSIVE

Characteristics: People with this type of MS experience an initial period of relapsing-remitting disease, followed by a steadily worsening disease course with or without occasional flare-ups, minor recoveries (remissions), or plateaus.
Frequency: 50% of people with relapsing-remitting MS developed this form of the disease within 10 years of their initial diagnosis, before introduction of the “disease-modifying” drugs. Long-term data are not yet available to demonstrate if this is significantly delayed by treatment.

PROGRESSIVE-RELAPSING

Characteristics: People with this type of MS experience a steadily worsening disease from the onset but also have clear acute flare-ups (attacks or relapses), with or without recovery. In contrast to relapsing-remitting MS, the periods between relapses are characterized by continuing disease progression.
Frequency: Relatively rare. Approximately 5%.

View drug information on Zocor.

Baird’s Bill To Raise Awareness Of Pulmonary Fibrosis Passes House, USA

Following the death of his colleague, Congressman Charlie Norwood of Georgia, from Idiopathic Pulmonary Fibrosis earlier this year, Congressman Brian Baird (WA-03) joined Congressman Nathan Deal (R-GA) in introducing a resolution to bring much needed attention to this devastating disease. The resolution passed the U.S. House of Representatives today with overwhelming support.

“Pulmonary fibrosis is an often overlooked degenerative and debilitating disease,” said Congressman Baird. “My own father died of this disease, and my good friend and colleague Charlie Norwood died just a few months ago. We must aggressively pursue and support research opportunities into the causes of the disease, a treatment, and eventual cure. It is my hope that with passage of this resolution we can increase awareness about this devastating disease.”

Idiopathic pulmonary fibrosis is a serious lung disorder causing progressive, incurable lung scarring and an irreversible loss of the lung tissue’s ability to transport oxygen. There is no known cause for this disease which affects approximately 128,000 Americans, with 48,000 new cases diagnosed each year, representing a 158 percent rise in mortality since 2001. Approximately 40,000 patients die each year, or one person every 13 minutes.

The resolution calls for the designation of a “National Idiopathic Pulmonary Fibrosis” week; supports the work of advocates and organizations in educating and supporting those who suffer from pulmonary fibrosis and their families; and urges research into the causes, a treatment and eventual cure.

Office of Congressman Brian Baird
Washington, DC
house/baird

New Guidelines Help Clinicians Assess Risk Of Post-surgical Pulmonary Complications

Pulmonary complications, including pneumonia and respiratory failure, are a common – and dangerous – problem for patients following major surgery. To address this issue, a comprehensive systematic review and meta-analysis in the April 2006 issue of The Annals of Internal Medicine provides clinicians with new guidelines to use prior to surgery in assessing a patient’s risk of developing pulmonary problems postoperatively.

“Independent of surgical complications, such as infections and bleeding, there are three major types of medical risks that accompany major surgery,” explains the study’s lead author Gerald W. Smetana, MD, an internist in the division of general medicine and primary care at Beth Israel Deaconess Medical Center (BIDMC) and Associate Professor of Medicine at Harvard Medical School. “These include cardiac risks such as a heart attack, the risk of blood clot formation, and pulmonary risks.”

Nearly 30 years ago risk indices and guidelines were developed to assess post-surgical cardiac risks, he adds, but until now, the issue of pulmonary risk factors had not been formally addressed.

“Many physicians will be surprised to learn that we found pulmonary complications to be as prevalent as cardiac complications,” says Smetana. The reason, he says, is that patients’ lung volumes are lower following both surgery and the administration of general anesthesia. As a result, small areas of lung become vulnerable to collapse, thereby increasing patients’ chances of developing pneumonia, suffering respiratory failure or experiencing a worsening of existing lung disease, such as emphysema.

Smetana, together with coauthors Valerie Lawrence, MD, and John Cornell, PhD, of the South Texas Veterans Health Care System, performed a systematic review of nearly 1,000 medical studies published between 1980 and 2005 in order to develop the guidelines for the American College of Physicians. After calculating summary estimates of risk, the authors divided their findings into patient-related risk factors and surgery-related risk factors, according to Smetana.

“Among the patient-related risk factors we made several clear observations,” he adds. “Most notably, even among otherwise healthy patients, advanced age [over 70] increased a person’s risk of developing pulmonary complications four-fold to six-fold. Given that age is not a risk factor for post-surgical cardiac complications, we were quite surprised by this finding.” Other patient-related factors that increased the risk of complications included preexisting emphysema, functional dependence (patients’ inability to care for themselves), congestive heart failure and smoking cigarettes.

Among pulmonary risk factors related to the surgical procedure, he adds, location of the surgical site was of greatest impact.

“The closer the surgery was to the diaphragm – any thoracic, upper abdominal, gallbladder or aortic surgery for example – the greater the risk of complications,” notes Smetana. In addition, emergency surgery or surgery lasting more than three hours also increased the likelihood that patients would develop postoperative pulmonary problems.

In an accompanying paper, the authors also evaluated the value of various interventions to reduce the risk of pulmonary complications, and found that two simple treatments that increase lung volume, deep breathing exercises and incentive spirometry, proved to be the most effective strategies.

“We hope that our findings will help doctors provide their patients with a good estimate of pulmonary risk prior to surgery,” says Smetana. “In fact, this review points out the importance of the doctor-patient relationship. Medical consultations are extremely important for patients as they prepare for surgery and this provides both doctors and patients with another tool to use in their decision-making processes.”

This study was funded, in part, by grants from the Veterans Evidence-based Research, Dissemination, and Implementation Center (VERDICT).

Beth Israel Deaconess Medical Center is a patient care, research and teaching institution of Harvard Medical School and ranks fourth in National Institutes of Health funding among independent hospitals nationwide. BIDMC is clinically affiliated with the Joslin Diabetes Center and is a research partner of the Dana-Farber/Harvard Cancer Center. BIDMC is the official hospital of the Boston Red Sox. For more information, visit bidmc.harvard/.

Contact: Bonnie Prescott
bprescotbidmc.harvard
Beth Israel Deaconess Medical Center

Clues To New Genes Behind Rheumatoid Arthritis Revealed By University Of Manchester Researchers

Researchers at the University of Manchester have identified evidence of several new genes behind the chronic inflammatory disease rheumatoid arthritis (RA), which affects 387,000 people in the UK.

Professor Jane Worthington and her team at the University’s arthritis research campaign (arc) Epidemiology Unit made their findings as part of the largest ever study of the genetics behind common diseases.

The ??9M Wellcome Trust Case Control Consortium (WTCCC), which today publishes its results in the journals Nature and Nature Genetics, has given a major boost to the understanding of genetics of seven common diseases, including RA. As well as providing insights into what leads some people to develop the diseases and offering new avenues for treatments, the success of the approach heralds exciting advances in the study of the genetics of disease. It has identified a wealth of genes implicated in coronary heart disease, type 1 and type 2 diabetes, Crohn’s disease, bipolar disorder and hypertension, as well as RA. Some of these genes are novel whilst others were known about and have been confirmed by the current study.

Professor Worthington and her team have implicated several genes in the development of RA for the first time. Previously two genes were known to explain 50% of genetically determined susceptibility. Now the team have replicated their results for one of the new genes and are working to validate others.

RA is a chronic inflammatory disease that can affect nearly all joints in the body, particularly the hands and feet. Complications such as lung disease can occur. In addition, patients with RA are more likely to die from cardiovascular disease and some cancers. Some people respond well to treatment, but most suffer a lifetime of disability.

The team will now carry out further work to validate the findings and understand how the variation within key genes influences the development of RA, the course of the disease and the response to treatment.

Dr Anne Barton, a clinician on the team, said: “These are exciting results as RA is a complex, heterogeneous disease with some people suffering inflammation of the hands and feet which comes and goes whilst others develop a progressive form which can quite rapidly result in marked disability. We believe the genes we have found may determine who develops RA or how the severe the disease becomes.

“We also hope that this study may help us to discover why 40-50% of people do not respond to therapy. This therapy is expensive – ??8,000 per patient per year for the newest biologic agents that block the inflammatory mediator TNF – and this work could show whether someone would respond well or not in advance, rather than by costly trial and error.”

Professor Worthington said: “The WTCCC has been a fantastic example of collaborative effort in the UK. It has taken us to the place we are now, more rapidly and efficiently than if we had tried to undertake this study on our own.

“We had 2,000 DNA samples from patients with RA. By contacting other RA clinicians and researchers in the UK, we now have a further 5,000 samples to take this work forward.

“We are also indebted to the arthritis research campaign (arc), which provided the funding to collect the samples used. This was a huge investment, collecting samples from RA patients over two decades, but it was the sample collection which made it a high quality study.”

Professor Peter Donnelly, Chair of the WTCCC, based at the University of Oxford, said: “Many of the most common diseases are very complex, involving both ‘nature’ and ‘nurture’, genes interacting with our environment and lifestyles. By identifying the genes underlying these conditions, our study should enable scientists to understand better how disease occurs, which people are most at risk and, in time, to produce more effective, more personalised treatments.”

The ??9 million WTCCC has been one of the UK’s largest and most successful academic collaborations to date, involving 50 leading research groups and over 200 scientists in the field of human genetics from dozens of institutions. For these papers, part of a number of studies due to be published over the next year, the researchers analysed 17,000 DNA samples taken from people in the UK – two thousand patients for each disease and three thousand control samples – to identify common genetic variations for seven major diseases.

Although the human genome is made up of more than three billion sub-units of DNA, called nucleotides (or bases), most of these show little in the way of differences between individuals. The International HapMap Consortium and related efforts demonstrated that a substantial part of the variation in DNA sequence between individuals is due to single-nucleotide polymorphisms (differences), also known as SNPs. There are approximately 8 million common SNPs in European populations. Fortunately, because SNPs that lie close together on chromosomes often tell quite similar stories, researchers in the WTCCC were able to explore this variation through analysing a subset of these SNPs (in fact approximately 500,000).

“Human genetics has a chequered history of irreproducible results, but this landmark collaboration of scientists in Britain has shown conclusively that the new approach of analysing a large subset of genetic variants in large samples of patients and healthy individuals works,” says Professor Donnelly. “We are now able to effectively scan most of the common variation in the human genome to look for variants associated with diseases. This approach will undoubtedly herald major advances in how we understand and tackle disease in the future.”

The findings have been welcomed by Dr Mark Walport, Director of the Wellcome Trust, the UK’s largest medical research charity. The Wellcome Trust not only funded the WTCCC, but also co-funded the Human Genome Project and HapMap.

“Just a few years ago it would have been thought wildly optimistic that it would be possible in the near future to study a thousand genetic variants in each of a thousand people,” says Dr Mark Walport, Director of the Wellcome Trust, the UK’s largest medical research charity, which funded the study. “What has been achieved in this research is the analysis of half a million genetic variants in each of seventeen thousand individuals, with the discovery of more than ten genes that predispose to common diseases.

“This research shows that it is possible to analyse human variation in health and disease on an enormous scale. It shows the importance of studies such as the UK Biobank, which is seeking half a million volunteers aged between 40 and 69, with the aim of understanding the links between health, the environment and genetic variation. New preventive strategies and new treatments depend on a detailed understanding of the genetic, behavioural and environmental factors that conspire to cause disease.”

1. The Wellcome Trust is the largest charity in the UK. It funds innovative biomedical research, in the UK and internationally, spending around ??500 million each year to support the brightest scientists with the best ideas. The Wellcome Trust supports public debate about biomedical research and its impact on health and wellbeing. wellcome.ac/

The Wellcome Trust Case Control Consortium was supported by: the Medical Research Council, British Heart Foundation, Juvenile Diabetes Research Foundation, Diabetes UK, the Arthritis Research Campaign, the National Association for Colitis & Crohn’s Disease and MDF The Bipolar Organisation

2. The University of Manchester Arthritis Research Campaign (arc) Epidemiology Unit aims to advance understanding of the major rheumatic and musculoskeletal disorders. The unit celebrated its 50th anniversary in 2004, and is one of the world-leading research groups in this field. Around 100 individuals work on a wide variety of different programmes and projects, and the size and strength of the unit permits it to undertake the very large scale, long-term prospective studies which are necessary to truly identify the cause of disease. Recent advances in genetics, molecular biology, biostatistics and computing have had major implications for the types of questions that can be answered using epidemiological methods.

Contact: Mikaela Sitford

University of Manchester

Dementia Risk Is Higher In People With Both Stroke And Irregular Heartbeat

Stroke patients who also suffer from an irregular heartbeat are at double the risk of developing dementia, according to a new study by the University of East Anglia (UEA).

Published tomorrow in the journal Neurology, the findings show that stroke survivors with an irregular heartbeat – or atrial fibrillation – are 2.4 times more likely to develop dementia than stroke survivors without the heart condition.

The researchers analysed 15 studies with more than 45,000 participants and an average age of 72. They compared patients with and without atrial fibrillation, and followed up to determine which developed dementia over time. Around a quarter of patients with both stroke and atrial fibrillation were subsequently found to have developed dementia.

“These results offer convincing evidence of a link between irregular heartbeat and dementia in patients with stroke and could help us identify treatments that delay or even prevent the onset of dementia,” said lead author Dr Phyo Myint of Norwich Medical School at UEA.

“Options include more rigorous management of cardiovascular risk factors or of atrial fibrillation, particularly in stroke patients.”

The study is the first high-quality meta-analysis of the potential role of atrial fibrillation in the development of dementia. Though the results show a clear association in stroke patients, Dr Myint warned that signs of a link in the general population – as suggested by some earlier studies – were inconclusive.

“There remains considerable uncertainty about any link in the broader population,” he said.

Atrial fibrillation is more common as people age. It affects around one in 20 people over 65 in the UK and more than two million in the US. The heart’s two upper chambers do not beat effectively in the condition, resulting in an irregular heart rhythm. This can lead to blood pooling and clotting which significantly increases the risk of stroke. Around 15 per cent of strokes occur in people with atrial fibrillation. Other risk factors for stroke include smoking, high blood pressure and a sedentary lifestyle.

There are around 750,00O people with dementia in the UK and 60,000 deaths are attributed to the disease every year. The number of dementia cases is expected to rise by around 150 per cent over the next 40 years. The disease is little understood but the risk of developing dementia is thought to be multifactorial. Risk factors include older age, high blood pressure, diabetes and smoking.

Dr Myint said further high quality research was now needed to establish whether the link between atrial fibrillation and dementia in stroke patients was causal.

Dr Susanne Sorensen, head of research at the Alzheimer’s Society, said: “This important research suggests that those with atrial fibrillation who have previously had a stroke need to be identified and monitored more closely. We now need more research involving stroke survivors with this type of cardiovascular disease to determine whether controlling atrial fibrillation with medication could reduce the risk of getting dementia later in life.

“Cardiovascular disease and stroke are well known risk factors for dementia. The best way to reduce risk of dementia is to take regular exercise, maintain a healthy weight, eating a healthy diet rich in fruit and vegetables and ensuring that your blood pressure and cholesterol are checked regularly.”

Citation

“Atrial fibrillation and incidence of dementia: a systematic review and meta-analysis”
S Kwok (UEA), Y K Loke (UEA), R Hale (UEA), J F Potter (UEA) and P K Myint (UEA)
Neurology (American Academy of Neurology), March 8 2011

Snail Toxin May Spur New Meds For Alzheimer’s, Parkinson’s, Depression

University of Utah researchers isolated an unusual nerve toxin in an ocean-dwelling snail, and say its ability to glom onto the brain’s nicotine receptors may be useful for designing new drugs to treat a variety of psychiatric and brain diseases.

“We discovered a new toxin from a venomous cone snail that may enable scientists to more effectively develop medications for a wide range of nervous system disorders including Parkinson’s disease, Alzheimer’s disease, depression, nicotine addiction and perhaps even schizophrenia,” says J. Michael McIntosh.

Discovery of the new cone snail toxin will be published Friday, Aug. 25 in The Journal of Biological Chemistry by a team led by McIntosh, a University of Utah research professor of biology, professor and research director of psychiatry, member of the Center for Peptide Neuropharmacology and member of The Brain Institute.

McIntosh is the same University of Utah researcher who – as an incoming freshman student in 1979 – discovered another “conotoxin” that was developed into Prialt, a drug injected into fluid surrounding the spinal cord to treat severe pain due to cancer, AIDS, injury, failed back surgery and certain nervous system disorders. Prialt was approved in late 2004 in the United States and was introduced in Europe last month.

Prialt, sold by Ireland’s Elan Pharmaceuticals, took roughly 25 years to reach market after its discovery in venom from the fish-eating cone snail Conus magus or magician’s cone. McIntosh says he expects it will take 10 to 20 years to develop new medications based on what is learned from the new toxin – named alpha conotoxin OmIA (oh-em-one-ay) – isolated from a cone snail species named Conus omaria, which lives in the Pacific and Indian oceans and eats other snails. It ranges from 1? to 3? inches long.

McIntosh discovered and analyzed the new toxin with help from University of Utah cone snail research pioneer Baldomero “Toto” Olivera, who is a distinguished professor of biology, and lab technicians Sean B. Christensen and Cheryl Dowell.

Other coauthors of the study are Palmer Taylor, professor and dean of pharmacology at the University of California, San Diego, and his associates – Todd Talley, Igor Tsigelny and Kwok-Yiu Ho – as well as Kyou-Hoon Han at the Korea Research Institute of Bioscience and Biotechnology.

Diseases that Might Benefit from the New Snail Toxin

McIntosh says the OmIA toxin will be useful in designing new medicines because it fits like a key into certain lock-like “nicotinic acetylcholine receptors” found on nerve cells in the brain and the rest of the nervous system.

“Those are the same types of receptors you activate if you smoke a cigarette,” he says, explaining that nicotine in cigarette smoke “binds” to the receptor to trigger the release of a neurotransmitter, which is a chemical that carries a nerve impulse from one nerve cell to another, allowing nerve cells to communicate.

“Nicotine acts on those receptors in our brain, but they are in our brain for better reasons than to enjoy a cigarette,” McIntosh says. Different forms or subtypes of nicotinic receptors control the release of different neurotransmitters. “That’s important because if you had compounds to facilitate the release of one neurotransmitter and not another neurotransmitter, that opens up medicinal potential,” he says.

“For instance, one receptor modifies the release of dopamine. There are inadequate amounts of dopamine in Parkinson’s disease,” so a medicine designed to fit into a certain subtype of nicotinic receptor would produce more dopamine and thus protect against the development of tremors and other Parkinson’s symptoms. Indeed, other studies have found that smoking seems to forestall Parkinson’s disease.

A medicine that could block certain nicotinic receptors could be used to help people stop smoking cigarettes, and the same method might work for alcoholism because nicotinic receptors may be involved in alcohol addiction, McIntosh says.

Other nicotinic receptors trigger the release of neurotransmitters involved in memory, so activating the right receptors might lessen Alzheimer’s memory loss.

“One reason people smoke is they feel their thinking may be a little better, with increased attention and focus,” McIntosh says, noting that pharmaceutical companies “would like to mimic that positive benefit without all the downsides of cigarette smoke.”

Other nicotinic receptors influence “the release of serotonin and norepinephrine, two neurotransmitters strongly implicated in mood disorders” such as depression, so a drug to activate those receptors might treat depression, he adds.

Schizophrenics tend to smoke heavily because something in cigarette smoke “seems to help them filter out irrelevant stimuli. They can focus better,” McIntosh says. So a drug aimed at certain nicotinic receptors might treat schizophrenia.

New Neurotoxin is a Key for Designing New Medicines

McIntosh says the new toxin itself is unlikely to become a drug because it blocks rather than stimulates nicotinic receptors. But because it can act on some types of nicotinic receptors and not others – like a key that opens some locks but not others – it has great potential as a tool for precisely identifying the shape and structure of the receptor “locks,” thus making it easier to design new medicines or “keys” to fit those receptors and trigger them to release desired neurotransmitters.

In the new study, about 70 compounds from numerous cone snail species were screened in collaboration with Taylor’s lab at the University of California, San Diego.

Taylor uses “acetylcholine binding protein” as a model for nicotinic receptors. In other words, cone snail toxin “keys” that fit into nicotinic receptor “locks” also fit into highly similar “locks” made of this binding protein. So the binding protein was used as a way to find toxins that also would fit into nicotinic receptors. The new OmIA toxin was most interesting because it tightly fits some nicotinic receptors but not others. A drug that tightly fits desired receptors but not others is less likely to have undesirable side effects.

Unlike nicotinic receptors, the binding protein can be grown in crystal form, allowing Taylor’s team to use X-ray crystallography to make detailed microscopic pictures of how the toxin fit into the binding protein. Meanwhile, Han in South Korea used nuclear magnetic resonance to make pictures showing the structure of the new toxin.

Together, the images provide a highly detailed picture of how the cone snail toxin fits into the binding protein, and thus how it also would fit into a nicotinic receptor.

“By putting the two together, you can get a high-resolution picture of the binding site,” says McIntosh. “That allows for rational drug development. It allows you to design compounds that will bind to the same [nicotinic receptor] site, and it allows you to begin to understand how to bind to one receptor subtype and not another” to trigger the release of whatever neurotransmitter is needed to treat or prevent a particular disease.

“It is the picture of the binding site and the ability to distinguish one type of nicotinic receptor from another that makes the toxin so valuable,” he adds.

How the Study was Performed

The snails from which the new toxin was obtained were collected by divers in Olivera’s native Philippines. Venomous snails use a dart-like tooth to zap fish, snails and other prey, injecting them with an immobilizing toxin. Venom from the collected snails was extracted at a lab in the Philippines, and then sent to Utah.

Once the screening process identified OmIA as promising, McIntosh and colleagues purified the toxin – one of perhaps 200 components in Conus omaria venom. They determined its chemical structure and then synthesized more of the toxin, since they had only a small amount of the natural version.

Next, the synthetic toxin was tested to see how well it acted as a “key” to fit into the “locks” represented both by binding proteins (from freshwater snails and a sea slug) and by actual nicotinic receptors, which came from rat cells but were grown in frog eggs. That allowed the researcher to grow various subtypes of the nicotinic receptors and see how well the toxin fit them.

Taylor and Han provided pictures of the physical structures of the binding protein “locks” and toxin “key,” and then “used computer simulation to dock the two structures together,” says McIntosh. “That generates a picture of the binding site – the points of contact between the toxin and the binding protein.”

The site is the place a new drug would be designed to fit.

“The whole idea is to make the model of the nicotinic receptor so predictive that you can then really speed up the development of drugs,” McIntosh says. “If you have an accurate model of the receptor, you can plug in a model of your drugs and do a lot of ‘virtual screening.’ Rather than synthesizing a million compounds and having all but one be duds, you can synthesize a few thousand compounds based on the model and come up with a better drug with less time and resources.”

The Center for Peptide Neuropharmacology studies neurotransmitters and receptors that enable rapid information transfer in the brain. The Brain Institute includes more than 100 University of Utah scientists unlocking mysteries of the human brain via interdisciplinary collaboration. The institute supports scientists in turning research advances into technologies and treatments for brain disorders.

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