Host, heal thyself: Immune system self-organizes to minimize biological cost of pathogenic infections

Schematic of a statistical model of antigen recognition by the adaptive immune system. After infection, antigen a encounters immune receptor r at random with a rate λa(t). An encounter leads to a successful recognition with a probability fr,a that reflects the matching between a given antigen–receptor pair. 

15 may 2015—The adaptive immune system – a subsystem of the overall immune system – comprises specialized cells and processes that eliminate or prevent pathogen growth by using the experience of past infections to prepare its limited repertoire of specialized receptors to protect organisms from future threats. Recently, scientists at CNRS and Ecole Normale Superieure, Paris and the University of Pennsylvania developed a general theoretical framework from first principles that allowed them to predict the composition of receptor repertoires optimally adapted to minimize the biological cost of infections from a given pathogenic environment. Their theory predicts that the immune system will have more receptors for rare antigens; individuals exposed to the same infections will have largely different repertoires; and competitive antigen/receptor binding and selective amplification of stimulated receptors are key to creating optimal repertoires. Their findings explain how limited populations of immune receptors can self-organize to provide effective immunity against highly diverse pathogens, and moreover inform the design and interpretation of experiments surveying immune repertoires.

Researchers Thierry Mora and Aleksandra M. Walczak discussed the paper that they and their colleagues published in Proceedings of the National Academy of Sciences. "A great deal of very interesting theoretical work has been done on the problem of avoiding autoimmunity – that is, recognizing self-proteins – essentially viewing the immune system as a device for discrimination," Mora tells Medical Xpress. "We wanted to study the problem from a different perspective: As, in essence, introduced by Sir Frank Macfarlane Burnet's theory of clonal selection1, an adaptive immune system adapts to its pathogenic or antigenic environment. We wanted to see how far we could take the idea that the composition and diversity of the immune repertoire reflects that of the environment – in other words, the repertoire is an internal representation of its environment – aimed at minimizing the cost of infections to the tissues of the organism." In short, Mora says, this is one way to look at the complicated problem of the structure of immune repertoires.

This approach allowed the scientists to create a new framework that makes it unnecessary to explicitly model intracellular communication, cell differentiation, activation of cofactors, coordination of different cell types, the interaction with the innate immune system, and the full complexity of the recognition process. "Our goal was to make concrete predictions about adaptive immune repertoires that are general and not specific to one kind of cell type in specific conditions. While these features all play an important role in the functioning of real immune systems, we wanted to see what the essence was, what an optimal but simplified immune system would look like," Walczak points out. "We didn't want to concentrate on the fine details of repertoires, but rather took a step back and try to see what we could learn from global properties while still being realistic enough to make concrete statements about real immune systems – for example, the fact that two individuals in similar environments can have very different optimal immune repertoires." The scientists discovered that their assumption – that is, the system needs to minimize the cost of infection given a limited number of encounters – actually structures the repertoire.

At a high level, the scientists wanted their model to define an effective cost that could encompass and summarize all the aforementioned factors. They found that the surprisingly simple mathematical equation F_a(m) – a general cost function that measures the harm to an organism caused by non-recognition of a pathogen by the immune receptors associated with antigen a that have had m encounters with any pathogen. "Due to its phenomenological generality," Mora says, "there was no particular challenge in defining it – but we nonetheless considered several possible scenarios because there may be issues in deciding what its exact form and values should be." In short, F_a(m) describes how the harm effectively increases with the number of encounters.

"This is an approach that is common in physics, especially statistical physics," Walczak tells Medical Xpress, "where rather than describing the motion of all the particles that make up a gas, we write an effective equation of the state of the gas, or describe the change in the density distribution of the gas. In this study we do something similar: Since we know that there are many processes contributing to how harm increases with the number of infections, that it's impossible to describe them all, and that their detailed form does not really change the effect, we simply ask how we can describe their effect on the immune system. For example," she illustrates, "if the antigen population increases exponentially in real time – which seems like a sensible assumption seeing that non-inhibited pathogens will proliferate exponentially – and the harm to the organism increases with non-recognition also increases exponentially in real time. A simple calculation shows that this means F_a(m) will be linear in relation to the number of encounters."

At the same time, Walczak illustrates, it is easy to imagine that certain infections do not initially harm the organism, and/or that some do significant harm very quickly and then the harm saturates. In other words, one can imagine different costs – so because one can obtain the same effective cost from different molecular processes due to different instances of the infection, the researchers studied effective cost in different specific forms of this function.

"One of our predictions is that the optimal repertoires of two individuals sensing practically the same environment can be very different" Walczak continues. "The concrete position of the receptors in recognition space does not matter, as long as globally they tile antigenic space and provide good coverage. We showed that the immune system can find many optimal solutions to the same problem, so we should not be surprised if two individuals that live in the same conditions and are genetically close have very different repertoires." While these repertoires are optimal and thereby idealized, she notes, the scientists showed they are reached through traditional dynamics long considered when studying lymphocytes, or white blood cells in vertebrate immune systems.

"We also found that, in many situations, optimal repertoires cover the rare pathogens more thoroughly than we would have expected from just their frequency," Mora notes. "If a pathogen is, for example, 100 times more common than another, an adaptive immune system should probably not devote 100 times, but perhaps only 10 times, more resources."

The immune repertoire can self-organize to a state that minimizes cost and provides protection against infections via competitive evolution of receptor populations stimulated by antigens. 

The study's central finding is that limited populations of immune receptors can self-organize to provide effective immunity against highly diverse pathogens. "It's long been known that receptors and antigens are cross-reactive – that is, one receptor can recognize more than one pathogen and vice versa – which in principle allows the pathogenic space to be covered by a reasonably small number of receptors," Mora explains. "However, this does not have to be the case." Walczak notes that while the optimization problem they solve does not try to minimize the diversity of receptors, the optimal repertoires they found do have this limited diversity. "Cross-reactivity tells us that this is possible, but it being optimal surprised us."

The paper also reports that the fact that cross-reactivity (in which a receptor can bind to a variety of antigens) causes the optimal repertoire to fragment is related to the concept of limiting similarity due to competitive exclusion in ecological settings. "Cross reactivity eliminates the need for a unique receptor specific to each antigen – but only if the receptor can recognize the antigen," Walczak notes. "This means that different regions of the pathogen recognition space can have receptors and no receptors, respectively. In a way, it would be a waste to have receptors in places already covered by the cross-reactivity of other receptors." Their research demonstrates this by showing that tiling patterns emerge in the antigenic space as a result of repertoire dynamics in which receptors compete for antigens if one receptor "wins" another cannot be in the same place, a process similar to that found in ecology when species cannot live in the same niche. The organisms compete and one "wins," the other having to go elsewhere – a salient factor in speciation as the two groups evolutionarily diverge.

"Thanks to cross-reactivity," Mora adds, "it doesn't matter exactly where you put a receptor, as long as the entire antigenic space is covered – an observation related to stochastic hyperuniformity2,3 in disordered systems – that is, local randomness but global order."

The study's results follow from a tension between the statistics of pathogen detection, which favor a broader receptor distribution, and the effects of cross-reactivity, which tend to concentrate the optimal repertoire onto a few highly abundant clones. "There are two features that drive the form of the optimal repertoires," Mora explains. "On the one hand, it's important to protect yourself from the rare pathogens, not just the common ones - so you want to place receptors more or less evenly in recognition space. On the other hand, cross reactivity tells you that you do not have to put a receptor at every point of that space—you just have to space them out so there are no blind spots. It's these two properties that drive the form of the solution.

The paper also details the conceptual connection between the immune repertoire and ecological organization. "Since receptors divide and proliferate upon recognition of the antigens, the latter can be seen as resources on which the receptors thrive. Receptors recognizing the same antigens compete against each other – they belong to the same ecological niche, so to speak." Since each niche has limited capacity, only a few receptors may survive in each of them – a process known as competitive exclusion.

As described above, in order to achieve the tiling patterns of optimal repertoires receptors must compete for antigens. "One of the key results about optimal repertoires is that you want to protect yourself both from the rare antigens and the common ones – so resources must be distributed relatively evenly, depending on the details of how fast the cost grows with the number of unsuccessful encounters between receptors and antigen. Moreover, the system must keep the receptors that are good fits against common antigens from dominating. In terms of dynamics, this is achieved by a limited carrying capacity for each niche." Carrying capacity is the maximum population size of a given species that an environment's resources can sustain indefinitely without significantly depleting or degrading those resources.

Within this ecological context, the paper notes that living systems must often sense, internally represent, and respond to salient aspects of complex exogenous influences – and do so using limited resources, such as cell types or genes. For example, in the retina2 and the mammalian olfactory system3 the limited repertoire of resources constrains information processing, forcing these living systems to judicially parse resources in terms of priorities, costs and limitations in order to adapt to the environment. The scientists comment that they "have shown that these elements also shape the optimal form of the immune repertoire."

The scientists assumed that although the immune system cannot predict precisely which antigens it will encounter and when, it incorporates an estimate of the probabilities of their occurrences. "While the immune system cannot know with certainty when and what it will encounter, its goal is to protect us from the unknown," Walczak points out. "It's also very hard to characterize the set of pathogens because the space is just too big. However, if the set of potential threats was completely random from the point of view of the repertoire, the immune system would not be very efficient." In other words, the fact that the immune system is able to respond efficiently suggests that it has adapted to a specific environment, which in turn translates into it incorporating an estimate of the probabilities of the antigenic environment.

Moving forward, the scientists would like to measure recognition space by testing their predictions in high-throughput surveys of receptor and pathogen diversity. "In order to do this," Walczak comments, "we'd need to figure out how to map the sequence of receptors to recognition or affinity, or measure affinity in a high-throughput way." (Affinity measures the strength of interaction between an epitope – the part of an antigen recognized by the immune system – and an antibody's antigen binding site.)

The researchers expect that the new framework and their results will extend to other distributed protection systems where diverse threats are addressed by an array of specific responses. "Yes," Walczak agrees, "the framework is very general, which is why, as discussed, we see very similar properties in systems as diverse as ecology, neuroscience and the physics of disordered systems." In addition, the immune system of bacteria, or the Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) system could be studied within a similar framework to predict the relative abundance of CRISPR spacers and corresponding viruses in a coevolving population of bacteria and viruses. "There's a tradeoff between a large number of threats/impulses and limited resources/processing abilities – and the immune system wants to minimize the chances of missing a threat/signal – and in our paper, she says, we've formalized this idea and made concrete predictions."

In addition to the connections with ecology, neuroscience and the physics of disordered systems discussed above, the study's results also inform the design and interpretation of experiments surveying immune repertoires. "There's a lot of interest in how different individuals – that is, either humans or genetically identical mice – respond to the same antigenic environments, and how different their natural repertoires are," Walczak says. "Our results show that it should not be surprising that the responses can be different, because even if their repertoires were optimal, two individuals would have different repertoires."

"Our predictions are about similarity in an effective recognition space," Mora concludes. "Most large scale probing of immune repertoires is based on sequencing the receptors – so mapping recognition space to receptor sequences is an important challenge for future experiments."

More information: How a well-adapted immune system is organized, Proceedings of the National Academy of Sciences (2015) published online before print, DOI:10.1073/pnas.1421827112

Mediterranean diet plus olive oil or nuts associated with improved cognitive function

Credit: Wikipedia.

Supplementing the plant-based Mediterranean diet with antioxidant-rich extra virgin olive oil or mixed nuts was associated with improved cognitive function in a study of older adults in Spain but the authors warn more investigation is needed, according to an article published online by JAMA Internal Medicine.

14 may 2015--Emerging evidence suggests associations between dietary habits and cognitive performance. Oxidative stress (the body's inability to appropriately detoxify itself) has long been considered to play a major role in cognitive decline. Previous research suggests following a Mediterranean diet may relate to better cognitive function and a lower risk of dementia. However, the observational studies that have examined these associations have limitations, according to the study background.

Emilio Ros, M.D., Ph.D., of the Institut d'Investigacions Biomediques August Pi Sunyer, Hospital Clinic, Barcelona, and Ciber Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid, and coauthors compared a Mediterranean diet supplemented with olive oil or nuts with a low-fat control diet.

The randomized clinical trial included 447 cognitively healthy volunteers (223 were women; average age was nearly 67 years) who were at high cardiovascular risk and were enrolled in the Prevencion con Dieta Mediterranea nutrition intervention.

Of the participants, 155 individuals were assigned to supplement a Mediterranean diet with one liter of extra virgin olive oil per week; 147 were assigned to supplement a Mediterranean diet with 30 grams per day of a mix of walnuts, hazelnuts and almonds; and 145 individuals were assigned to follow a low-fat control diet.

The authors measured cognitive change over time with a battery of neuropsychological tests and they constructed three cognitive composites for memory, frontal (attention and executive function) and global cognition. After a median of four years of the intervention, follow-up tests were available on 334 participants.

At the end of the follow-up, there were 37 cases of mild cognitive impairment: 17 (13.4 percent) in the Mediterranean diet plus olive oil group; eight (7.1 percent) in the Mediterranean diet plus nuts group; and 12 (12.6 percent) in the low-fat control group. No dementia cases were documented in patients who completed study follow-up.

The study found that individuals assigned to the low-fat control diet had a significant decrease from baseline in all composites of cognitive function. Compared with the control group, the memory composite improved significantly in the Mediterranean diet plus nuts, while the frontal and global cognition composites improved in the Mediterranean diet plus olive oil group. The authors note the changes for the two Mediterranean diet arms in each composite were more like each other than when comparing the individual Mediterranean diet groups with the low-fat diet control group.

"Our results suggest that in an older population a Mediterranean diet supplemented with olive oil or nuts may counter-act age-related cognitive decline. The lack of effective treatments for cognitive decline and dementia points to the need of preventive strategies to delay the onset and/or minimize the effects of these devastating conditions. The present results with the Mediterranean diet are encouraging but further investigation is warranted," the study concludes.

More information: JAMA Intern Med. Published online May 11, 2015. DOI: 10.1001/jamainternmed.2015.1668

Provided by The JAMA Network Journals

Can diet and exercise prevent muscle loss in old age?

Scientists at the University of Southampton have shown that although some studies find diet can enhance the effects of exercise to prevent muscle loss in later life, current evidence about what works is inconsistent.

13 may 2015--Between the ages of 40 and 80, an estimated 30 to 50 per cent of muscle mass is lost, resulting in lower strength and less ability to carry out everyday tasks. This process - known as sarcopenia - is common and clearly linked to frailty and poorer health in older people. The associated health care costs are substantial.

Exercise training and diet supplementation have been shown to be effective in preventing sarcopenia in some studies, but little is known about the combined effects of training with supplements, particularly in older people.

In the study, published in Clinical Interventions in Aging, scientists from the Medical Research Council (MRC) Lifecourse Epidemiology Unit at the University of Southampton carried out a review of combined diet and exercise training trials in men and women aged over 65 years old. Almost 5,000 scientific articles were screened, with more than 100 reviewed in detail and 17 of these were included in the review. The review shows that findings differ across studies and suggests more research is needed.

Professor Sian Robinson, who led the review, says, "Poor diets and being physically inactive are common in older age. Understanding the benefits of maintaining sufficient levels of physical activity and diet quality to prevent sarcopenia is therefore a priority.

"Although some studies have found enhanced effects of exercise training when combined with diet supplementation, our review shows that current evidence is incomplete and inconsistent. Further research to determine the benefits of supplementation and exercise training for older people is therefore needed."

Professor Cyrus Cooper, Professor of Rheumatology and Director of the MRC Lifecourse Epidemiology Unit, adds: "This study is part of an important programme of research at the MRC Lifecourse Epidemiology Unit that aims to improve our understanding of the effects of environment and lifestyle on musculoskeletal health and the process of ageing."

Professor Avan Aihie Sayer, Professor of Geriatric Medicine at the MRC Lifecourse Epidemiology Unit who oversaw the work, comments: "Sarcopenia is now recognised as a major clinical problem for older people. Gaining insights into the effects of lifestyle on losses of muscle mass and strength will be essential for the development of future public health strategies to promote better health in later life."

The study Prevention and optimal management of sarcopenia: A review of combined exercise and nutrition interventions to improve muscle outcomes in older people was funded by the Medical Research Council.

More information: Prevention and optimal management of sarcopenia: A review of combined exercise and nutrition interventions to improve muscle outcomes in older people, Clinical Interventions in Aging, 2015.

Provided by University of Southampton

Vitamin D supplements might help some lose weight

Italian study suggests that daily pill may boost dieting efforts in those already low in the nutrient.

12 may 2015—For obese Americans who are low on vitamin D, taking a supplement of the nutrient might help them lose weight, a new study suggests.

According to an Italian team, led by Luisella Vigna of the University of Milan, prior research has shown that vitamin D deficiency is associated with a higher risk of obesity and obesity-related complications.

However, studies on the use of vitamin D supplements to curb obesity have so far been inconclusive, the team said.

The new study included 400 overweight and obese people with vitamin D deficiency who were put on a low-calorie diet and then divided into three groups. One group took no vitamin D supplements, while the two other groups took either 25,000 international units (IU) or 100,000 IU of vitamin D per month.

After six months, participants in both vitamin D supplementation groups had lost more weight and had greater reductions in their waistlines than those who hadn't taken the supplements, Vigna's team said.

The study was to be presented Thursday at the European Congress on Obesity. Experts note that studies presented at medical meetings are typically considered preliminary until published in a peer-reviewed journal.

"The present data indicate that in obese and overweight people with vitamin D deficiency, vitamin D supplementation aids weight loss and enhances the beneficial effects of a reduced-calorie diet," Vigna's team wrote. The researchers suggest that all overweight and obese people should have their vitamin D levels tested.

Previous studies have suggested that about 40 percent of North American adults are vitamin D-deficient, according to the study.

Two experts in the United States said the findings might have merit for some.

"This study is somewhat reminiscent of a few years back, when there was an explosion of research on the effect of calcium in aiding in weight loss [and weight loss maintenance]," said Dr. Christopher Ochner, an expert in nutrition, weight loss and obesity at The Mount Sinai Hospital in New York City. "However, it is very important to note that the effect of vitamin D appears limited to only those people who are vitamin D-deficient."

Getting the right amounts of vitamins and other nutrients is important, Ochner said. However, "this study does not suggest that everyone looking to lose weight should start taking large doses of vitamin D—or any other supplement," he stressed, adding that "most individuals are not vitamin D-deficient."

Toni Marinucci is a registered dietitian nutritionist at Staten Island University Hospital in New York City. She said vitamin D deficiency may undermine efforts to maintain a healthy weight.

The study suggests that "overweight and obese adults who are vitamin D-deficient can benefit by coupling their efforts on a reduced-calorie diet with consuming a vitamin D supplement," Marinucci said.

Vitamin D is nicknamed the "sunshine vitamin" because the body produces the nutrient when skin is exposed to sunlight. People can also get vitamin D through such foods as eggs, milk, yogurt, tuna, salmon, cereal and orange juice.

More information: More Information

The Harvard School of Public Health has more about vitamin D and health.

Perception of US care for the dying worsens

Surveys of loved ones who lost elderly relatives show that the perception of the quality of care for the dying in the United States has worsened over the last decade. For all the health care industry has done to try to make progress, huge gaps remain between how care is delivered and what patients and their loved ones want, reports a new study in the Journal of Palliative Medicine.

11 may 2015--"People are less satisfied with care at the close of life, and I think it's now urgent for us to start thinking about what interventions we can do to improve care at the end of life given that we are facing a Silver Tsunami," said Dr. Joan Teno, lead author of the study and professor of health services, policy and practice in the Brown University School of Public Health. The findings come less than a year after an Institute of Medicine report, co-authored by Teno, called for improvements inend-of-life care.

Teno and her co-authors compared data from two surveys—one conducted in 2000 and the National Health and Aging Trends Study done between 2011 and 2013—in which more than 1,200 people who had lost close loved ones in one of those periods rated aspects of the decedents' end-of-life care. In 2000, 56.7 percent of 622 respondents rated care as excellent, but a decade later only 47 percent of 586 people could say the same. Even after the researchers statistically controlled for various possible confounders, including age, race, ethnicity and even the nature of the decedents declining health, the latter sample was still 30 percent less likely to report that care was excellent.

The study concerned people 65 and older who resided in their community, rather than in nursing homes, at the time of death.

While the overall results suggest that care may not be improving for this population, other findings revealed more specific ways in which care either improved or fell short of patient and family desires. For example, a greater percentage of people (25.2 percent in 2011-13 vs. 15.5 percent in 2000) reported an unmet need for pain management, but health care providers improved in the frequency with which they discussed spiritual or religious concerns with patients and families.

Many quality indicators remained about the same, based on the survey respondents reports. Loved ones, for example, continued to report at about the same rates that decisions were made without enough of their input (13.8 percent in 2011-2013), or against the decedent's preferences (20.2 percent) when the patient was in intensive care in the last months of life.

The lack of improvement is disappointing, Teno said, because policymakers and health care providers have made many attempts over the last decade to improve end-of-life care.

Need for reform

The most important change has been a vast expansion in the availability of hospice and palliative care services. The new study, and some of Teno's prior work, suggests that while hospice improves care for the dying, it is frequently misapplied.

"It all relates to how we are using it," she said. "One of the concerns is that from a population perspective you may have more people receiving hospice but if they are not receiving enough of those services then it becomes really problematic."

Hospice did elevate the perception of end-of-life care in the new survey. Among a subset of people who lost loved ones between 2011 and 2013, 60.9 percent of those for whom hospice was involved rated care as excellent, compared to 46.7 percent for whom hospice was not involved.

But in the last decade, Teno's work has shown, more people have also been referred to hospice too late to do much good. People have also become more likely to end up in intensive care and to experience burdensome transitions between institutions in the last few days of life.

To a great extent, these trends are driven by how Medicare compensates health care providers. They are paid for performing procedures rather than for assessing the care preferences of patients and their families, wrote Teno and her colleagues in the journal. The private sector may lead the way to change, Teno noted, as providers respond to reforms that steer payments more toward quality and away from raw volume of services.

"Our findings support the 2014 IOM report that calls for improved advance care planning, a major restructuring of our health financing, increase in transparency, and more accountability of health care providers," the authors wrote.

Provided by Brown University

CDC: Mortality rate declining among aging boomers

10 may 2015—A new study finds mixed results for the health of America's aging "Baby Boom" generation, with nearly half of people ages 55 to 64 taking a prescription cardiovascular drug and about one in five dealing with diabetes. However, the report from the U.S. Centers for Disease Control and Prevention also finds that the overall mortality rate in this age group has gone down over the past decade.

The new data comes from an annual report from the CDC's National Center for Health Statistics, looking at 2014 statistics on the health of all Americans. This year, the CDC zeroed in on adults ages 55 to 64, who form the core of the "Boomer" generation. On average, people in this age range can expect to live anywhere from another 19 to 27 years. But they also face a growing risk of developing chronic health problems, the agency said.

Between 2009 and 2012, an estimated 19 percent of adults ages 55 to 64 had diabetes, 40 percent were obese, and 51 percent had hypertension—numbers the CDC said haven't changed from statistics taken a decade before. Due in large part to the prevalence of these chronic conditions, use of prescription drugs is high. In 2009 to 2012, approximately 45 percent of adults in this age group took a prescription cardiovascular drug, about 32 percent took a cholesterol-lowering drug, 16 percent used prescription drugs for gastric reflux, 15 percent used prescription analgesics, nearly 13 percent used some type of diabetes medication, and more than 14 percent took an antidepressant.

However, between 2003 and 2013, the overall mortality rate for Americans ages 55 to 64 fell, the CDC said. Cancer mortality rates are now higher than those for cardiovascular disease. Between 2002-2003 and 2012-2013, the rate of cigarette smoking among adults ages 55 to 64 fell from nearly 20 percent to just over 18 percent. However, high rates of smoking still afflict the poor, with rates three times higher among those living well below the poverty line compared to people from more affluent groups.

More information: More Information

Earlier distinction between Alzheimer's disease and frontotemporal dementia

In the white matter of the brain in particular, large differences can be measured between the brains of people with Alzheimer's disease and those with the behavioural variant frontotemporal dementia. Neuropsychologist Christiane Möller used advanced image analysis techniques on MRI brain scans from dementia patients in an early stage of the disease. She will defend her doctoral research on 1 May at the VU University Medical Centre. Her research was funded by the NWO's National Initiative Brain & Cognition.

09 may 2015--Alzheimer's disease and the behavioural variant of frontotemporal dementia (FTD) are the two most commonly occurring types of dementia at a young age. Medical specialists still find it difficult to make a distinction between the two types of disease at an early stage of the illness. Using existing imaging techniques the difference is often not visible to the naked eye on scans.

Möller used advanced analysis methods that can measure brain damage not yet visible to the human eye. "At a group level the diseases were found to exhibit large differences in the white matter of the brain in particular. In frontotemporal dementia there is a lot of damage to the white matter of the brain in the foremost parts of the brain, whereas in the brains of people with Alzheimer's disease no damage could be measured compared with FTD. A combination of different analysis methods made the distinction even clearer still."

The aim of the research was to detect changes in the brain as early as possible and to determine if there were differences in the brain between the two types of dementia. "For drug development in particular, a good diagnosis is a prerequisite", says Möller. The VU University Medical Center carried out the study together with Leiden University Medical Center and the Erasmus Medical Center in Rotterdam. This research falls under the programme 'Brain & Cognition: societal innovation' and is funded by the National Initiative Brain & Cognition, a unit of NWO.

In the Netherlands there are already about 250,000 people who suffer from dementia and it is expected that by 2040 this number will have increased to half a million people. Knowledge about the cause of dementia makes it possible to develop very specific therapies so that the disease can be cured.

Provided by Netherlands Organisation for Scientific Research (NWO)

FRAX fracture risk assessment tool output can now be modified by TBS

FRAX, launched by the WHO Collaborating Centre for Metabolic Bone Diseases in 2008, calculates 10-year probability of osteoporotic fracture based on scientifically validated clinical risk factors including bone mineral density (BMD) as an optional input. With calculator models for more than 50 countries, FRAX is considered the gold standard of fracture risk assessment and is endorsed by leading national osteoporosis management guidelines worldwide.

08 may 2015--A new feature of the online FRAX risk assessment tool was launched in April 2014. The output of FRAX can now be adjusted for Trabecular Bone Score (TBS). Calculated by TBS iNsight software which installs on existing DXA scanners, TBS is a simple method that estimates fracture risk based on a determination of bone texture (an index correlated to bone microarchitecture). The predictive ability of TBS is independent of FRAX clinical risk factors and femoral neck bone mineral density (BMD) values.

Similarly to the original FRAX model, the TBS-adjusted model of FRAX has been cross-validated in a population-based meta-analysis, based on data from more than 17 800 women and men, from 14 countries. Educational information and scientific publications about TBS are available at http://www.medimapsgroup.com/ .

By adding the patient's TBS value after the FRAX calculation, users will get a 10-year % of risk of hip fracture and major osteoporotic fracture adjusted for TBS.

Clinical advantages of using TBS-adjusted FRAX scores include:

• Increased accuracy of fracture prediction in the individual
• Reclassifies patients' risk for future fracture above or below an intervention threshold

Following the calculation of FRAX probabilities the TBS value can be manually input by clicking on the TBS button below the calculation results box. Entry of the TBS value, automatically calculated by TBS iNsight V.3.0 if installed on your densitometer, produces a 'FRAX Adjusted for TBS' score.

Dr. Eugene McCloskey, Professor in Adult Bone Disease and Honorary Consultant at the Metabolic Bone Centre, University of Sheffield UK, stated, "Several potential clinical consequences have been observed with the use of TBS-adjusted FRAX scores. There is a greater impact in the assessment of major osteoporotic fractures, particularly in the assessment of younger patients, which could impact on management decisions in those whose standard FRAX probabilities are around an intervention threshold."

He added, "By fine tuning the information provided by FRAX, TBS-adjusted FRAX gives clinicians more precise information that can aide them in making informed treatment decisions within the course of a clinical assessment."

Provided by International Osteoporosis Foundation

Search engine self-diagnosis and 'cyberchondria'

Dr Guido Zuccon researched the effectiveness of 'Dr Google.'

QUT research is aiming to improve search engines after finding online self-diagnosis of health conditions provides misleading results that can do more harm than good.

07 may 2015--Dr Guido Zuccon, from QUT's Information Systems School, found major search engines were providing irrelevant information that could lead to incorrect self-diagnosis, self-treatment and ultimately possible harm.

Dr Zuccon and colleagues from CSIRO in Brisbane and Vienna University of Technology, Austria, assessed the effectiveness of results from Google and Bing in response to medically-focused searches.

The rush to define ailments online is a significant chunk of internet searches, with Google reporting one in 20 of its 100 billion searches a month was for health-related information. Previous research found 35 per cent of US adults had gone online to self-diagnose a medical condition.

"People commonly turn to 'Dr Google' to self-diagnose illnesses or ailments," Dr Zuccon said.

"But our results revealed only about three of the first 10 results were highly useful for self-diagnosis and only half of the top 10 were somewhat relevant to the self-diagnosis of the medical condition."

The researchers showed participants medically-accurate images of common conditions like alopecia, jaundice and psoriasis and asked what the participant would search for in an attempt to diagnose it.

For jaundice, for example, queries including "yellow eyes", "eye illness", "white part of the eye turned green" were searched for.

"Because on average only three of the first 10 results were highly useful, people either keep searching or they get the wrong advice which can be potentially harmful for someone's health," Dr Zuccon said.

He warned it was also possible those seeking to self-diagnose online would experience "cyberchondria" - where subsequent searches could escalate concerns.

"If you don't get a clear diagnosis after one search you would likely be tempted to keep searching," Dr Zuccon said.

"So if you had searched for the symptoms of something like a bad head cold, you could end up thinking you had something far more serious, like an issue with the brain.

"This is partly down to searcher bias and partly down to the way the search engines work. For example, pages about brain cancer are more popular than pages about the flu so the user is driven to these results."

Dr Zuccon said search engines performed effectively if the name of the illness was already known.

"They are great for providing a wealth of information about illnesses and diseases, so if you search for something like jaundice you'll have a lot of useful results," he said.

"But our findings suggest it is not the best option for trying to find out what's wrong with you."

Dr Zuccon said further research was needed to identify how to improve search engines to provide searchers with the most effective results.

"We are currently developing methods for search engines to better promote the most useful pages," he said.

"For example, along with colleagues at the CSIRO, we have developed algorithms that return pages that consumers find easier to understand, while maintaining the relevancy and correctness of the medical information presented."

Provided by Queensland University of Technology

Accelerated brain aging in type 1 diabetes related to cognitive complications

Trevor Orchard. Credit: Tom Altany

The brains of people with type 1 diabetes show signs of accelerated aging that correlate with slower information processing, according to research led by the University of Pittsburgh Graduate School of Public Health.

06 may 2015--The findings indicate that clinicians should consider screening middle-aged patients with type 1 diabetes for cognitive difficulties. If progressive, these changes could influence their ability to manage their diabetes. The study, funded by the National Institutes of Health (NIH), is online and will be published in the May 19 issue of the journal Neurology.

"The severity of cognitive complications and cerebral small vessel disease—which can starve the brain of oxygen—is much more intense than we expected, but it can be measured in a clinical setting," said senior author Caterina Rosano, M.D., M.P.H., associate professor in Pitt Public Health's Department of Epidemiology. "Further study in younger patients is needed, but it stands to reason that early detection and intervention—such as controlling cardiometabolic factors and tighter glycemic control, which help prevent microvascular complications—also could reduce or delay these cognitive complications."

Type 1 diabetes usually is diagnosed in children and young adults and happens when the body does not produce insulin, a hormone that is needed to convert sugar into energy.

Dr. Rosano and her co-authors examined brain MRIs, cognitive assessments, physical exams and medical histories on 97 people with type 1 diabetes and 81 of their non-diabetic peers.

The people with type 1 diabetes were all participants in the Pittsburgh Epidemiology of Diabetes Complications Study, an ongoing investigation led by Pitt Public Health epidemiologist and study co-author Trevor Orchard, M.D., to document long-term complications of type 1 diabetes among patients diagnosed at Children's Hospital of Pittsburgh of UPMC between 1950 and 1980.

The MRIs showed that 33 percent of the people with type 1 diabetes had moderate to severe levels of white matter hyperintensities (markers of damage to the brain's white matter, present in normal aging and neurological disorders) compared with 7 percent of their non-diabetic counterparts.

On three cognitive tests that measure abilities such as information-processing speed, manual dexterity and verbal intelligence, the people with type 1 diabetes averaged lower scores than those without the condition.

Among only the participants with type 1 diabetes, those with greater volumes of white matter hyperintensities averaged lower cognitive scores than those with smaller volumes, though the difference was less pronounced.

The associations held even when the researchers adjusted for high blood pressure and glucose control, which are conditions that can worsen diabetes complications.

The study identified signs of nerve damage, such as numbness or tingling in extremities, as a risk factor for greater volumes of white matter hyperintensities.

"People with type 1 diabetes are living longer than ever before, and the incidence of type 1 diabetes is increasing annually," said lead author Karen A. Nunley, Ph.D., postdoctoral fellow in Pitt Public Health's neuroepidemiology program. "We must learn more about the impact of this disease as patients age. Long-term studies are needed to better detect potential issues and determine what interventions may reduce or prevent accelerated brain aging and cognitive decline."

Provided by University of Pittsburgh Schools of the Health Sciences

Dengue cases soar in Brazil, as death toll climbs

Cases of dengue have soared in Brazil where the disease has caused 229 fatalities this year, the Health Ministry said Monday, as authorities try to combat its spread using transgenic mosquitos.

05 may 2015--The health ministry said it had logged 745,900 cases nationwide in the first 15 weeks of the year—an annual increase of 234 percent.

That equates to 367.8 people infected per 100,000 residents, which falls into the category of an epidemic under parameters used by the World Health Organization.

The number of dengue deaths has climbed 44 percent from the same period last year, and most of the diagnosed cases have occurred in business hub Sao Paulo.

In all, Sao Paulo has seen 169 fatalities and 401,564 cases this year—a high since records began in 1990.

Cases of the mosquito-borne infectious tropical disease increased in the wake of a serious drought last year, the worst in living memory.

Severe water shortages led residents to store what they could in open receptacles, which facilitated the spread of dengue.

Last Thursday the city of Piracicaba, located 160 kilometers (100 miles) west of Sao Paulo, released its first batch of 100,000 transgenic male mosquitos in reaction to the growing crisis.

The genetically modified mosquitos pass on a modified gene during procreation that makes offspring incapable of reaching sexual maturity, causing the overall population to decline steadily.

Piracicaba authorities and British firm Oxitec last year opened a facility at Campinas, near Sao Paulo, able to produce 550,000 modified mosquitoes weekly.

Dengue symptoms include severe abdominal pain, persistent vomiting and circulatory system failure.

Vitamin D toxicity rare in people who take supplements, researchers report

Over the last decade, numerous studies have shown that many Americans have low vitamin D levels and as a result, vitamin D supplement use has climbed in recent years. Vitamin D has been shown to boost bone health and it may play a role in preventing diabetes, cancer, cardiovascular disease and other illnesses. In light of the increased use of vitamin D supplements, Mayo Clinic researchers set out to learn more about the health of those with high vitamin D levels. They found that toxic levels are actually rare.

04 may 2015--Their study appears in the May issue of Mayo Clinic Proceedings.

A vitamin D level greater than 50 nanograms per milliliter is considered high. Vitamin D levels are determined by a blood test called a serum 25-hydroxyvitamin D blood test. A normal level is 20-50 ng/mL, and deficiency is considered anything less than 20 ng/mL, according the Institute of Medicine (IOM).

The researchers analyzed data collected between 2002 and 2011 from patients in the Rochester Epidemiology Project, a National Institutes of Health-funded medical records pool that makes Olmsted County, Minn., the home of Mayo Clinic, one of the few places worldwide where scientists can study virtually an entire geographic population to identify health trends.

Of 20,308 measurements, 8 percent of the people who had their vitamin D measured had levels greater than 50 ng/mL, and less than 1 percent had levels over 100 ng/mL.

"We found that even in those with high levels of vitamin D over 50 ng/mL, there was not an increased risk of hypercalcemia, or elevated serum calcium, with increasing levels of vitamin D," says study co-author Thomas D. Thacher, M.D., a family medicine expert at Mayo Clinic.

Hypercalcemia, or high blood calcium, can occur when there are very high levels of vitamin D in the blood. Too much calcium in the blood can cause weakness, lead to kidney stones, and interfere with the heart and brain, and even be life threatening.

The Mayo researchers also found that women over age 65 were at the highest risk of having vitamin D levels above 50 ng/mL. The result was not surprising because that's a group that often takes vitamin D supplements, Dr. Thacher says.

Another notable outcome: The occurrence of high vitamin D levels over 50 ng/mL increased during the 10-year period of the study, from nine per 100,000 people at the start of the study up to 233 per 100,000 by the end.

"We were surprised by that degree of dramatic increase in vitamin D levels," Dr. Thacher says.

Only one case over the 10-year study period was identified as true acute vitamin D toxicity; the person's vitamin D level was 364 ng/mL. The individual had been taking 50,000 international units (IU) of vitamin D supplements every day for more than three months, as well as calcium supplements. The IOM-recommended upper limit of vitamin D supplementation for people with low or deficient levels is 4,000 IU a day.

It's important for doctors to ask their patients about the doses of vitamin D supplements that they are using, Dr. Thacher says, because even capsules containing as much as 50,000 IU of vitamin D are available without prescription. If taken on a daily basis, that amount could lead to toxicity.

Some natural sources of vitamin D include oily fish such as mackerel and salmon, fortified milk, and sunlight.

"Our bodies will naturally produce vitamin D when our skin is exposed to sunlight, however, we don't recommend excessive exposure to sun due to the risk of skin cancer," Dr. Thacher added.

In an accompanying editorial in Mayo Clinic Proceedings, Dr. Michael F. Hollick, Ph.D., M.D., describes vitamin D's dramatic medical history, the need for judicious dosing, but the importance of vitamin D supplementation in those with low or deficient levels.

"The evidence is clear that vitamin D toxicity is one of the rarest medical conditions and is typically due to intentional or inadvertent intake of extremely high doses," writes Hollick, a professor of medicine, physiology and biophysics at Boston University School of Medicine.

Provided by Mayo Clinic

Walking an extra two minutes each hour may offset hazards of sitting too long

Credit: Vera Kratochvil/public domain

A new study suggests that engaging in low intensity activities such as standing may not be enough to offset the health hazards of sitting for long periods of time. On the bright side, adding two minutes of walking each hour to your routine just might do the trick. These findings were published in the Clinical Journal of the American Society of Nephrology (CJASN).

03 may 2015--Numerous studies have shown that sitting for extended periods of time each day leads to increased risk for early death, as well as heart disease, diabetes and other health conditions. Considering that 80 percent of Americans fall short of completing the recommended amount of exercise, 2.5 hours of moderate activity each week, it seems unrealistic to expect that people will replace sitting with even more exercise.

With this in mind, scientists at the University of Utah School of Medicine investigated the health benefits of a more achievable goal, trading sitting for lighter activities for short periods of time. They used observational data from National Health and Nutrition Examination Survey (NHANES) to examine whether longer durations of low intensity activities (e.g. standing), and light intensity activities (e.g. casual walking, light gardening, cleaning) extends the life span of people who are sedentary for more than half of their waking hours.

They found that there is no benefit to decreasing sitting by two minutes each hour, and adding a corresponding two minutes more of low intensity activities. However, a "trade-off" of sitting for light intensity activities for two minutes each hour was associated with a 33 percent lower risk of dying.

"It was fascinating to see the results because the current national focus is on moderate or vigorous activity. To see that light activity had an association with lower mortality is intriguing," says lead author Srinivasan Beddhu, M.D., professor of medicine.

Beddhu explains that while it's obvious that it takes energy to exercise, strolling and other light activities use energy, too. Even short walks add up to a lot when repeated many times over the course of a week. Assuming 16 awake hours each day, two minutes of strolling each hour expends 400 kcal each week. That number approaches the 600 kcal it takes to accomplish the recommended weekly goal of moderate exercise. It is also substantially larger than the 50 kcal needed to complete low intensity activities for two minutes each awake hour over the course of one week.

"Based on these results we would recommend adding two minutes of walking each hour in combination with normal activities, which should include 2.5 hours of moderate exercise each week," says Beddhu. Moderate exercise strengthens the heart, muscles, and bones, and confers health benefits that low and light activities can't.

The study examined 3,243 NHANES participants who wore accelerometers that objectively measured the intensities of their activities. Participants were followed for three years after the data were collected; there were 137 deaths during this period.

"Exercise is great, but the reality is that the practical amount of vigorous exercise that can be achieved is limited. Our study suggests that even small changes can have a big impact," says senior author Tom Greene, Ph.D., director of the Study Design and Biostatistics Center at the Center for Clinical and Translational Science.

Beddhu adds that large, randomized, interventional trials will be needed to definitively answer whether exchanging sitting for light activities leads to better health.

More information: The study will appear as "Light-Intensity Physical Activities and Mortality in the United States General Population and CKD Subpopulation" in CJASN online on April 30, 2015

Provided by University of Utah Health Sciences

High-tech 'Smart Care' apartment aims to improve health care for seniors

UT Arlington Computer Science and Engineering Professors Manfred Huber and Gergely Zaruba test flooring with special sensors that will enable researchers to measure and evaluate changes in walking gaits and weight that might suggest illness or injury in residents. Credit: UT Arlington

University of Texas at Arlington nursing and engineering researchers will unveil a model "Smart Care" apartment next month that is infused with intelligent care technology designed to reduce risks encountered by older adults and those with disabilities who want to live independently in their own homes.

02 may 2015--The federal Health Resources and Services Administration provided more than $600,000 in funding for the five-year project, which has been a collaborative effort involving premier faculty from the UT Arlington College of Nursing and Health Innovation and the College of Engineering. U.S. Rep Joe Barton, R-Arlington, advocated for the funding and said he is eager to see how the project - described as the first of its kind in Texas - will improve lives.

A grand opening event is scheduled at the Smart Care apartment at 10 a.m. May 7, 2015, at the Lakewood Village Senior Living Community, 5100 Randol Mill Road?in Fort Worth.

"UT Arlington is at the forefront of life-changing and innovative research in the area of Health and the Human Condition," Barton said. "Ultimately, Smart Care will positively impact senior citizens, people with disabilities, and injured veterans. It will also save money for people across the Dallas-Fort Worth area and nationwide by reducing the number of repeated trips to hospitals for some residents."

Christian Care Senior Living Communities generously contributed use of a 900-square foot, two-bedroom apartment at its Lakewood Village Senior Living Community in Fort Worth for the project.

"The entire Smart Care concept attracted us from the beginning because it just truly aligned with our mission to compassionately care for adults well into their golden years," said Phil Elmore, president and chief executive officer of Christian Care Senior Living Communities. "This has been a wonderful symbiotic partnership and we are proud to be a part of the work that UT Arlington is doing to expand horizons for senior citizens and people with physical challenges."

Carolyn Cason, co-principal investigator and professor of nursing, created the concept for establishing a Smart Care center at UT Arlington and a Smart Care apartment. She said the growing senior population and increasing number of Americans living with disabilities urgently demand research such as this.

"The technologies developed in the context of Smart Care will enable a significant improvement in preventive in-home health care for the aging, improve the efficiency and cost effectiveness of care by health care professionals, and improve the ability to directly involve family and friends into the care process."

Among other technologies, the Smart Care apartment includes:

• Sensors underneath tiles on the floor that will allow researchers to measure and evaluate changes in walking gaits and weight that might suggest illness or injury;
• A special camera embedded in a bathroom mirror that will tell researchers about day-to-day heart rate, facial expression, and skin color. Changes in expression and skin color can reveal aspects of the overall health status as well as about oxygen content of the blood;
• Lift chair to help residents stand;
• Smart appliances such as an LG microwave, range and refrigerator;
• Connected exercise equipment, including a recumbent bike and interactive Kinect-based Tai Chi trainer;
• Other systems that will detect whether medication is being properly managed or if the resident is not sleeping well or staying in bed too long.

Kathryn Daniel, an associate professor and director of the Adult-Gerontology Primary Care Nurse Practitioner Program in the College of Nursing and Health Innovation, serves as program manager for Smart Care. During a tour of the apartment in early April, she provided a behind-the-scenes look at the technology and explained how it will benefit clinicians, patients, families, and facility administrators. Watch a short video here.

The congressionally earmarked funding that Barton championed was used to purchase the high-tech kitchen appliances, a special toilet, automated beds, living room furniture, and other equipment in use at the Smart Care apartment, as well as at the center located in the UT Arlington Engineering Research Building.

The lab serves as mission control where researchers can unobtrusively monitor patients, interpret behavioral information and other data, and evaluate remote capabilities, health technologies and other protocols.

"Ultimately, the goal is to have these technologies in homes so that people could have warning signs if something is changing; you could also detect if something has already happened and there is a need to call for help," said Manfred Huber, co-principal investigator and professor in the UT Arlington Department of Computer Science and Engineering. "Again, the hope is that people can stay home much longer than they can currently." Watch a short video here.

Provided by University of Texas at Arlington

Lifestyle advice for would-be centenarians

For the past 50 years, researchers at Sahlgrenska Academy have followed the health of 855 Gothenburg men born in 1913. Now that the study is being wrapped up, it turns out that ten of the subjects lived to 100 and conclusions can be drawn about the secrets of their longevity.

01 may 2015--Over the past half century, the University Gothenburg has hosted one of the world's first prospective studies of aging. The subjects are 855 Gothenburg men born in 1913.

The first surveys were conducted in 1963.Now that it has been determined that ten of the men lived to 100, the study is being wrapped up.

Promotes longevity

Various surveys at the age of 54, 60, 65, 75, 80 and 100 permitted the researchers to consider the factors that appear to promote longevity.

A total of 27% (232) of the original group lived to the age of 80 and 13% (111) to 90. All in all, 1.1% of the subjects made it to their 100th birthday.

According to the study, 42% of deaths after the age of 80 were due to cardiovascular disease, 20% to infectious diseases, 8% to stroke, 8% to cancer, 6% to pneumonia and 16% to other causes.

A total of 23% of the over-80 group were diagnosed with some type of dementia.

Unique design

"The unique design has enabled us to identify the factors that influence survival after the age of 50," says Lars Wilhelmsen, who has been involved in the study for the past 50 years. "Our recommendation for people who aspire to centernarianism is to refrain from smoking, maintain healthy cholesterol levels and confine themselves to four cups of coffee a day."

Correlation with the mother's age

It also helps if you paid a high rent for a flat or owing a house at age 50 (indicating good socio-econmic standard), enjoy robust working capacity at a bicycle test when you are 54 and have a mother who lived for a long time.

"Our findings that there is a correlation with maternal but not paternal longevity are fully consistent with a previous studies," Dr. Wilhelmsen says. "Given that the same associations have been demonstrated in Hawaii, the genetic factor appears to be a strong one." But still we found that this "genetic factor" was weaker than the other factors. So factors that can be influenced are important for a long life.

No smokers

Two of the 100-year-olds dropped out of the study due to dementia and one for personal reasons. Facts about the other seven:

• Two lived at home and five in assisted living facilities
• None of them smoked
• All of them exhibited good temporal and spatial cognition
• All of them wore hearing aids
• Most of them wore glasses, were able to read and watch TV
• All of them were slim and had good postures
• All of them used walkers

"Normally we conducted the surveys at hospitals, but we visited the seven centenarians at home," Dr. Wilhelmsen says. all of them were clinically healthy, satisfied with their circumstances and pleased to be living where they were."

More information: "Men born in 1913 followed to age 100 years." By Wilhelmsen L, Dellborg M, Welin L, Svärdsudd K. Published in Scandinavian Cardiovascular Journal. Link to abstract: www.ncbi.nlm.nih.gov/pubmed/25658252

Provided by University of Gothenburg