Toxin from tobacco smoke could increase pain in spinal cord injury

A neurotoxin called acrolein found in tobacco smoke that is thought to increase pain in people with spinal cord injury has now been shown to accumulate in mice exposed to the equivalent of 12 cigarettes daily over a short time period.

One implication is that if acrolein is exacerbating pain its concentration in the body could be reduced using the drug hydralazine, which has been approved by the U.S. Food and Drug Administration for hypertension, said Riyi Shi (pronounced Ree Shee), a professor in Purdue University's Department of Basic Medical Sciences, College of Veterinary Medicine, and Weldon School of Biomedical Engineering.

The drug has been shown to be effective in reducing acrolein levels in research animals, and Shi is working to develop a low-dose version for that purpose in humans.

Mice were exposed to a level of acrolein equivalent to 12 cigarettes per day over three weeks. Previous research has focused on acrolein accumulation in the respiratory system but not in the bloodstream and spinal cord. It is known that acrolein is accumulated in urine in human smokers after years of smoking.

"This is the first animal study demonstrating that an acute short term of weeks of smoking could also cause acrolein to accumulate in urine and more importantly in spinal cord tissue, a part of central nervous system known to be vulnerable to acrolein, he said.

The researchers documented the concentration of biochemical markers for acrolein in the urine and spinal cord. Findings, appearing this week in the journal Neuroscience Bulletin, indicate the accumulation of the toxin was about 50 percent higher than normal, a level known to have pathological implications.

"The data indicated that acrolein is absorbed into the circulatory system and some enters the nervous system," Shi said. "It is expected that these findings may facilitate further studies to probe the pathological role of acrolein in the nervous system resulting from smoke and other external sources through long and short term, both active and passive exposure."

The research paper was authored by Melissa Tully, a graduate student at Purdue and the Indiana University School of Medicine; Purdue graduate students Lingxing Zheng, Glen Acosta, and Ran Tian; and Shi.

Acrolein is produced within the body after nerve cells are damaged. In spinal cord injury and in multiple sclerosis, the myelin insulation surrounding nerve cells is destroyed and the nerve fibers themselves are damaged by acrolein. The toxin acrolein also is found in air pollutants including tobacco smoke and auto exhaust.

"It is already known that smoking can increase pain for people with spinal cord injury and worsen the condition of multiple sclerosis, but we don't know exactly why," Shi said. "I am saying that acrolein might be the key culprit here and that inhaled acrolein could intensify multiple sclerosis and increase pain sensation."

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Brain representations of social thoughts accurately predict autism diagnosis

Carnegie Mellon University researchers have created brain-reading techniques to use neural representations of social thoughts to predict autism diagnoses with 97 percent accuracy. This establishes the first biologically based diagnostic tool that measures a person's thoughts to detect the disorder that affects many children and adults worldwide.

Psychiatric disorders -- including autism -- are characterized and diagnosed based on a clinical assessment of verbal and physical behavior. However, brain imaging and cognitive neuroscience are poised to provide a powerful advanced new tool.

Carnegie Mellon University researchers have created brain-reading techniques to use neural representations of social thoughts to predict autism diagnoses with 97 percent accuracy. This establishes the first biologically based diagnostic tool that measures a person's thoughts to detect the disorder that affects many children and adults worldwide.

Published in PLoS One, the study combined functional magnetic resonance imaging (fMRI) and machine-learning techniques first developed at Carnegie Mellon that use brain activation patterns to scan and decode the contents of a person's thoughts of objects or emotions. The previous work also demonstrated that specific thoughts and emotions have a very similar neural signature across normal individuals, suggesting that brain disorders may display detectable alterations in thought activation patterns.

Now, the research team led by CMU's Marcel Just has successfully used this approach to identify autism by detecting changes in the way certain concepts are represented in the brains of autistic individuals. They call these alterations "thought-markers" because they indicate abnormalities in the brain representations of certain thoughts that are diagnostic of the disorder.

"We found that we could tell whether a person has autism or not by the their brain activation patterns when they think about social concepts. This gives us a whole new perspective to understanding psychiatric illnesses and disorders," said Just, the D. O. Hebb University Professor of Psychology in the Dietrich College of Humanities and Social Sciences and a leading researcher into the neural basis of autism. "We've shown not just that the brains of people with autism may be different, or that their activation is different, but that the way social thoughts are formed is different. We have discovered a biological thought-marker for autism."

For the study, Just and his colleagues scanned the brains of 17 adults with high-functioning autism and 17 neurotypical control participants. The participants were asked to think about 16 different social interactions, such as "persuade," "adore" and "hug."

The resulting brain images showed that the control participants' thoughts of social interaction clearly included activation indicating a representation of the "self," manifested in the brain's posterior midline regions. However, the self-related activation was near absent in the autism group. Machine-learning algorithms classified individuals as autistic or non-autistic with 97 percent accuracy based on the fMRI thought-markers.

"When asked to think about persuading, hugging or adoring, the neurotypical participants put themselves into the thoughts; they were part of the interaction. For those with autism, the thought was more like considering a dictionary definition or watching a play -- without self-involvement," Just said.

Implications of this research could extend to other psychiatric disorders, such as being suicidal or having obsessive-compulsive disorder, in which certain types of thoughts are altered. By providing a brain-based measure of the altered thoughts to use in conjunction with clinical assessments, this new research could enable clinicians to make quicker and more certain diagnoses and more quickly implement targeted therapies that focus on the alteration.

"This is a potentially extremely valuable method that could not only complement current psychiatric assessment. It could identify psychiatric disorders not just by their symptoms but by the brain systems that are not functioning properly. It may eventually be possible to screen for psychiatric disorders using quantitative biological measures of thought that would test for a range of illnesses or disorders," Just said.

This neuroscience research is on the vanguard of two fronts: it advances the scientific mission of classifying and diagnosing mental disorders based on behavioral and neurobiological measures (rather than conventional symptoms), and it integrates the conception of brain and mind by assessing thoughts in terms of brain function.

For more information about how brain representations of social thoughts accurately predict autism diagnosis, watch Just discuss the research at Youtube.com.

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People putting their lives at risk by dismissing cancer symptoms

People could be putting their lives at risk by dismissing potential warning signs of cancer as less serious symptoms, according to a Cancer Research UK-funded study* published in PLOS ONE today (Tuesday).

More than half (53 per cent) of 1,700 people who completed a health questionnaire said they had experienced at least one red-flag cancer 'alarm' symptom during the previous three months. But only two per cent of them thought that cancer was a possible cause.

Researchers sent the questionnaire listing 17 symptoms -- including 10 widely-publicised potential cancer warning signs, such as an unexplained cough, bleeding, and a persistent change in bowel or bladder habits -- to people, aged 50 and over, registered with three London general practices.

Cancer was not mentioned, but they were asked which of the symptoms they had experienced, what they thought caused them, if they were concerned that symptoms were serious and whether they had consulted their GP.

The results showed that people rarely attributed potential signs of cancer to the disease, putting them down to other reasons instead, such as age, infection, arthritis, piles and cysts.

Dr Katriina Whitaker, senior research fellow at University College London and lead study author, said: "Most people with potential warning symptoms don't have cancer, but some will and others may have other diseases that would benefit from early attention. That's why it's important that these symptoms are checked out, especially if they don't go away. But people could delay seeing a doctor if they don't acknowledge cancer as a possible cause.

"It's worrying that even the more obvious warning symptoms, such as unexplained lumps or changes to the appearance of a mole, were rarely attributed to cancer, although they are often well recognised in surveys that assess the public's knowledge of the disease. Even when people thought warning symptoms might be serious, cancer didn't tend to spring to mind. This might be because people were frightened and reluctant to mention cancer, thought cancer wouldn't happen to them, or believed other causes were more likely."

Overall, people taking part in the study appraised the cancer warning 'alarm' symptoms as more serious than 'non alarm' symptoms, such as sore throat and feeling tired, on the questionnaire list. Over half (59 per cent) of them contacted a doctor about their 'alarm' symptoms.

Sara Hiom, director of early diagnosis at Cancer Research UK, said: "Making that doctor's appointment is important. It's not a waste of time for the GP or the patient -- it really could save your life. Diagnosing cancer early saves lives because it gives patients a better chance that treatments will be successful.

"Most cancers are picked up through people going to their GP about symptoms, and this study indicates that opportunities for early diagnosis are being missed. Its results could help us find new ways of encouraging people with worrying symptoms to consider cancer as a possible cause and to get them checked out straightaway with a GP."

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Stressed-out cancers may provide drug target

Research at the University of Adelaide has discovered cancer cells may be particularly susceptible to metabolic stress -- opening the way for new targeted therapy that won't harm normal cells.

The researchers showed that chromosomal instability -- which is a hallmark of rapidly dividing cancer cells -- makes them stressed and vulnerable to mild metabolic disruption. Metabolism is the normal process by which the body turns food into energy.

"A common problem in treating cancers is that they don't respond to chemotherapy, or they respond for a while, but then come back," says lead author Dr Stephen Gregory, Senior Postdoctoral Fellow with the University's School of Molecular and Biomedical Sciences.

"One reason this happens is because a tumour is usually not made up of identical cells but rather a diverse population of cells that changes all the time, losing and gaining chromosomes as they divide -- so-called chromosomal instability. Sooner or later they change enough to be able to resist chemotherapy drugs.

"Our research has shown that chromosomal instability has some consequences for cells -- they get stressed, and it only takes a small metabolic push to kill them."

Current chemotherapy is also very toxic to all dividing cells, particularly affecting cells in hair follicles, the gut lining and blood, often causing hair loss, pain and making patients unwell.

"We need to find ways to target cancer cells without affecting other normal dividing cells," says Dr Gregory.

The researchers induced chromosomal instability in small experimental flies, Drosophila, and found that the unstable cells were "on the edge" of how much stress they could tolerate.

"This is significant because a change in metabolism is something people cope with very well normally," says Dr Gregory. "That means that we hope to be able to develop treatments that have no side effects on patients, but are able to kill off the unstable tumour cells that cause relapses."

Dr Gregory says this may give some validity to theories of alternative treatments such as going on a radical diet.

"People who have advanced cancer which isn't responding to chemotherapy often try a range of different treatments such as a radical diet in the hope it may help," he says. "In some situations, it may in fact work; but we hope to be able to point the way to a more targeted approach -- finding the most appropriate steps for intervention in the metabolic process that will give the best results."

The research has been published in the journal Oncogene. It is funded by the National Health and Medical Research Council and continues with a recent NHMRC project grant of $593,000.

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Vitamin D reduces lung disease flare-ups by over 40 percent

Vitamin D supplements can reduce COPD lung disease flare-ups by over 40% in patients with a vitamin D deficiency -- according to new research from Queen Mary University of London. COPD (chronic obstructive pulmonary disease) includes conditions such as chronic bronchitis and emphysema, and is thought to affect more than 3 million people in the UK.

The NIHR-funded randomised trial, published in the journal Lancet Respiratory Medicine, included 240 patients with COPD in and around London. Half of the patients (122) received vitamin D supplements (6 x 2-monthly oral doses of 3mg) and the other half (118) received an equivalent placebo. The risk, severity and duration of flare-ups was then compared between the two groups.

Flare-ups (also referred to as 'exacerbations') are when a COPD patient's usual symptoms (coughing, excess mucus, shortness of breath, tightness in chest) get worse and stay worse, sometimes resulting in hospitalisation.

Patients with a vitamin D deficiency benefited dramatically from taking the supplements but the striking reduction in flare-ups was not seen among patients who had a higher vitamin D status at the start of the trial. However, researchers did find vitamin D supplementation modestly reduced the severity and duration of flare-up symptoms in all patients in the vitamin D group, regardless of their baseline vitamin D levels, compared to the placebo group.

This is the first clinical trial to investigate the impact of vitamin D supplementation on severity and duration of COPD symptoms. One previous trial has linked vitamin D to a reduction in COPD disease flare ups but this was limited to patients with very severe conditions. This trial is larger and studied patients with a much broader spectrum of diseases, ranging from mild to severe.

Professor Adrian Martineau, Lead Author, Queen Mary University of London, comments: "Flare-ups of chronic bronchitis and emphysema (COPD) can be debilitating for patients, sometimes leading to hospitalisation and even death. Our research has shown how an inexpensive vitamin supplement can significantly reduce the risk of flare-ups for patients who are vitamin D deficient, which could have a major public health benefit. Our findings suggest that patients with COPD should have their vitamin D status tested and should begin taking supplements if their levels are found to be low."

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Risk-based screening misses breast cancers in women in their forties

A study of breast cancers detected with screening mammography found that strong family history and dense breast tissue were commonly absent in women between the ages of 40 and 49 diagnosed with breast cancer. Results of the study were presented today at the annual meeting of the Radiological Society of North America (RSNA).

"Screening recommendations for this age group continue to be debated," said Bonnie N. Joe, M.D., Ph.D., associate professor in residence and chief of women's imaging at University of California, San Francisco (UCSF). "Recent publications have suggested risk-based screening based on family history and breast density. However, our study shows that this approach would miss a significant percentage of invasive cancers and could potentially be dangerous."

The retrospective study, conducted at UCSF, included 136 women between the ages of 40 and 49 with breast cancer identified by screening mammography between 1997 and 2012. Symptomatic patients undergoing diagnostic mammography and those with a personal history of breast cancer were excluded from the study. Patient family history, breast density, type of malignancy, lymph node status, and tumor receptor status were recorded.

"Notably, we found that almost 90 percent of the invasive cancers we would have missed using risk-based triage had positive receptor status, meaning they were very treatable and worth finding early," Dr. Joe said.

Of the 136 breast cancer cases identified, 50 percent were diagnosed as invasive, and 50 percent were diagnosed as ductal carcinoma in situ (DCIS), an early noninvasive form of breast cancer, although 88 percent of DCIS cases were intermediate or high grade.

A very strong family history was absent in 90 percent of patients, and extremely dense breast tissue was absent in 86 percent. Seventy-eight percent of patients had neither strong family history nor extremely dense breasts, including 79 percent of the cases of invasive disease.

"Our results show that by exclusively using a risk-based approach to screening mammography, we could potentially miss more than 75 percent of breast cancers in women in their 40s, thereby eliminating most of the survival benefit from screening mammography that has been previously shown in randomized controlled trials," Dr. Joe said.

Dr. Joe urges proponents of risk-based screening to continue research to find more effective means of risk-based triage.

"Neither family history nor breast density in combination or alone are sufficient risk factors to safely triage patients in risk-based screening," she explained.

Routine annual screening mammography has traditionally been recommended by organizations such as the American Cancer Society (ACS) and the American Medical Association (AMA) for all women beginning at age 40. In 2009, the United States Preventive Services Task Force (USPSTF) issued controversial new guidelines recommending screening with mammography every two years beginning at age 50.

"Based on our current knowledge and evidence shown in previous trials, it is still safest to get annual mammograms starting at age 40 in order to maximize the survival benefit of screening mammography," Dr. Joe said.

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3-D mammography improves cancer detection in dense breasts

A malignancy easily missed on 2-D mammography was clearly seen on 3-D mammography.

A major new study being presented at the annual meeting of the Radiological Society of North America (RSNA) has found that digital breast tomosynthesis, also known as 3-D mammography, has the potential to significantly increase the cancer detection rate in mammography screening of women with dense breasts.

Breasts are considered dense if they have a lot of fibrous or glandular tissue but not much fatty tissue. Research has shown that dense breasts are more likely to develop cancer, a problem compounded by the fact that cancer in dense breasts can be difficult to detect on mammograms.

Other imaging modalities like ultrasound and MRI are often used to help find cancers that can't be seen on mammograms, but both modalities have higher rates of false-positive findings, which are suspicious findings that turn out not to be cancer. This higher false-positive rate often results in more tests and unnecessary biopsies, making MRI and ultrasound expensive to implement in high-volume screening programs, according to study lead author Per Skaane, M.D., Ph.D., from the Department of Radiology at Oslo University Hospital in Oslo, Norway.

Dr. Skaane and colleagues have been studying tomosynthesis as a promising breast cancer screening option that addresses some of the limitations of mammography by providing 3-D views of the breast.

"Tomosynthesis could be regarded as an improvement of mammography and would be much easier than MRI or ultrasound to implement in organized screening programs," Dr. Skaane said. "So the intention of our study was to see if tomosynthesis really would significantly increase the cancer detection rate in a population-based mammography screening program."

The researchers compared cancer detection using full-field digital mammography (FFDM) versus FFDM plus digital breast tomosynthesis in 25,547 women between the ages of 50 and 69. Breast density was classified based on the American College of Radiology's Breast Imaging-Reporting and Data System (BI-RADS). The BI-RADS breast density scale runs from 1 to 4, with 1 being the least dense and 4 being the most dense.

There were 257 malignancies detected on FFDM and a combination of FFDM and tomosynthesis in the study group, including 105 in the density 2 group and 110 in density 3. Of the 257 cancers, 211, or 82 percent were detected with FFDM plus tomosynthesis, a significant improvement over the 163, or 63 percent, detected with FFDM alone.

FFDM plus tomosynthesis pinpointed 80 percent of the 132 cancer cases in women with dense breasts, compared to only 59 percent for FFDM alone.

"Our findings are extremely promising, showing an overall relative increase in the cancer detection rate of about 30 percent," Dr. Skaane said. "Stratifying the results on invasive cancers only, the relative increase in cancer detection was about 40 percent."

Tomosynthesis not only improved the cancer detection rate in women with dense breasts, it also helped increase detection for women in the "fatty breast" BI-RADS categories. The addition of tomosynthesis to FFDM improved the cancer detection rate from 68 percent to 84 percent in women with BI-RADS density 1 or 2 breasts.

"Our results show that implementation of tomosynthesis might indicate a new era in breast cancer screening," Dr. Skaane said.

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Antacids linked to better survival in head and neck cancer

Patients with head and neck cancer who used antacid medicines to control acid reflux had better overall survival, according to a new study from the University of Michigan Comprehensive Cancer Center.

Reflux can be a common side effect of chemotherapy or radiation treatment for head and neck cancer. Doctors at the University of Michigan frequently prescribe two types of antacids – proton pump inhibitors or histamine 2 blockers – to help treat this side effect.

The researchers looked at 596 patients who were treated for head and neck cancer. More than two-thirds of the patients took one or both types of antacid medication after their diagnosis.

Patients who were taking antacids had significantly better overall survival than those who did not take them. Proton pump inhibitors, which include drugs such as Prilosec, Nexium and Prevacid, had the biggest effect: a 45 percent decreased risk of death, compared to patients who did not take antacids. Patients taking histamine 2 blockers, such as Tagamet, Zantac or Pepcid, saw a 33 percent decreased risk of death.

“We had suspicions that these medications somehow had a favorable impact on patient outcomes. This led us to review our large cohort of patients and screen them for common medications, focusing on antacids. In fact, our study did show that people taking antacids are doing better,” says lead study author Silvana Papagerakis, M.D., Ph.D., research assistant professor of otolaryngology—head and neck surgery at the University of Michigan Medical School and an adjunct clinical assistant professor at the U-M School of Dentistry.

Results of the study are published in the December issue of Cancer Prevention Research.

The researchers are not clear why these medications affect the cancer, although they have begun additional work to understand the mechanisms involved.

“Currently, patients might be on and off of this medication according to their symptoms of acid reflux. We believe this medication can also be beneficial at stopping cancer progression. Perhaps longer duration of treatments may have significant effect in terms of outcome survival,” Papagerakis says.

In addition, the researchers would like to understand if using antacids in people with reflux disease or people with precancerous lesions might reduce their risk of developing head and neck cancer.

Antacids are seen as relatively safe and typically have little or no adverse side effects. More importantly, Papagerakis notes, head and neck cancer patients are already taking these medications.

“What this study makes clear is these medications may be more beneficial to the patients than just controlling side effects,” she says.

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Triple-negative breast cancer patients should undergo genetic screening

Most patients with triple-negative breast cancer should undergo genetic testing for mutations in known breast cancer predisposition genes, including BRCA1 and BRCA2, a Mayo Clinic-led study has found. The findings come from the largest analysis to date of genetic mutations in this aggressive form of breast cancer. The results of the research appear in the Journal of Clinical Oncology.

"Clinicians need to think hard about screening all their triple-negative patients for mutations because there is a lot of value in learning that information, both in terms of the risk of recurrence to the individual and the risk to family members. In addition, there may be very specific therapeutic benefits of knowing if you have a mutation in a particular gene," says Fergus Couch, Ph.D., professor of laboratory medicine and pathology at Mayo Clinic and lead author of the study.

The study found that almost 15 percent of triple-negative breast cancer patients had deleterious (harmful) mutations in predisposition genes. The vast majority of these mutations appeared in genes involved in the repair of DNA damage, suggesting that the origins of triple-negative breast cancer may be different from other forms of the disease. The study also provides evidence in support of the National Comprehensive Cancer Network (NCCN) guidelines for genetic testing of triple-negative breast cancer patients.

Triple-negative breast cancer is a specific subset of breast cancer that makes up about 12 to 15 percent of all cases. The disease is difficult to treat because the tumors are missing the estrogen, progesterone and HER-2 receptors that are the target of the most common and most effective forms of therapy. However, recent studies have suggested that triple-negative breast cancer patients might harbor genetic mutations that make them more likely to respond to alternative treatments like cisplatin, a chemotherapy agent, or PARP inhibitors, anti-cancer agents that inhibit the poly (ADP-ribose) polymerase (PARP) family of enzymes.

Dr. Couch and his colleagues decided to assess the frequency of mutations in predisposition genes in patients with triple-negative breast cancer to further delineate the role of genetic screening for individuals with the disease. The researchers sequenced DNA from 1,824 triple-negative breast cancer cases seen at 12 oncology clinics in the U.S. and Europe, as part of the Triple-Negative Breast Cancer Consortium.

They found deleterious mutations in almost 15 percent of triple-negative breast cancer patients. Of these, 11 percent had mutations in the BRCA1 and BRCA2 genes and the rest had mutations in 15 other predisposition genes, including the DNA repair genes PALB2, BARD1, and RAD51C. No mutations were found in predisposition genes involved in other processes like the cell cycle.

"Triple-negative breast cancers are different from all the other breast cancers," says Dr. Couch. "Other studies have suggested that this form of the disease might be associated with some defect in DNA repair, and our study verifies that. Our findings generate a whole new set of hypotheses about how triple-negative breast cancer might be arising, which could give us better ideas for prevention or new therapies for this disease."

The study also found that individuals with mutations in predisposition genes were diagnosed at an earlier age and had higher-grade tumors than those without mutations. The researchers used their dataset to assess whether the current screening guidelines would identify all the triple-negative individuals with mutations in the two most common predisposition genes, BRCA1 and BRCA2.

They found that the NCCN guidelines, which recommend screening when there is a family history of cancer or a diagnosis under age 60, missed only 1 percent of patients carrying mutations. In contrast, the UK's National Institute for Clinical Excellence (NICE) guidelines, which use the probability of actually finding a mutation to determine who should be tested, missed 24 percent of mutation carriers.

"Our results confirm that the NCCN guidelines are good, and provide evidence to support what they have recommended," says Dr. Couch. "But we think the NICE guidelines could be expanded to include more of the triple-negative breast cancer patients with mutations."

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Diabetes in midlife linked to significant cognitive decline 20 years later

People diagnosed with diabetes in midlife are more likely to experience significant memory and cognitive problems during the next 20 years than those with healthy blood sugar levels, new Johns Hopkins Bloomberg School of Public Health research suggests.

The researchers found that diabetes appears to age the mind roughly five years faster beyond the normal effects of aging. For example, on average, a 60-year-old with diabetes experiences cognitive decline on par with a healthy 65-year-old aging normally. Decline in memory, word recall and executive function is strongly associated with progression to dementia, a loss of mental capacity severe enough to interfere with a person's daily functioning.

A report on the research is published in the Dec. 2 issue of the journal Annals of Internal Medicine. The study is believed to be the longest of its kind following a cross-section of adults as they age.

"The lesson is that to have a healthy brain when you're 70, you need to eat right and exercise when you're 50," says study leader Elizabeth Selvin, PhD, MPH, an associate professor of epidemiology at the Johns Hopkins Bloomberg School of Public Health. "There is a substantial cognitive decline associated with diabetes, pre-diabetes and poor glucose control in people with diabetes. And we know how to prevent or delay the diabetes associated with this decline."

For the study, Selvin and the team used data from the Atherosclerosis Risk in Communities Study (ARIC), which in 1987 began following a group of 15,792 middle-aged adults in communities in Maryland, North Carolina, Minnesota and Mississippi. Participants were seen at four visits approximately three years apart beginning between 1987 and 1989, and were seen a fifth time between 2011 and 2013. Cognitive function was evaluated at visits two (1990-1992), four (1996-1998) and at visit five.

The researchers compared the amount of cognitive decline associated with aging with the amount of decline found in the ARIC participants. They determined that there was 19 percent more decline than expected in those participants with poorly controlled diabetes, as well as smaller declines for those with controlled diabetes and pre-diabetes. The outcomes were the same whether the participants were white or black.

Selvin says the results underscore the importance of using a combination of weight control, exercise and a healthy diet to prevent diabetes. Even losing just five to 10 percent of body weight, she says, can keep someone from developing diabetes. Diabetes is a function of elevated sugar (glucose) levels in the blood. This excess glucose can damage tissues and the vascular system throughout the body and diabetes is associated with blindness, nerve damage in the extremities and kidney disease. While diabetes can often be controlled through medication, exercise and changes to diet, disease prevention is the preferred goal.

"If we can do a better job at preventing diabetes and controlling diabetes, we can prevent the progression to dementia for many people," Selvin says. "Even delaying dementia by a few years could have a huge impact on the population, from quality of life to health care costs."

Nationwide, dementia costs in 2010 were estimated to be upwards of $159 billion a year and, with the aging of the population, are expected to increase by nearly 80 percent by 2040.

Researchers are increasingly aware of the importance of many other causes of dementia besides Alzheimer's disease, particularly cognitive impairment linked to abnormalities in blood vessels in the brain.

"There are many ways we can reduce the impact of cerebral blood vessel disease -- by prevention or control of diabetes and hypertension, reduction in smoking, increase in exercise and improvements in diet," says co-author A. Richey Sharrett, MD, DrPH, an adjunct professor at the Johns Hopkins Bloomberg School of Public Health. "Knowing that the risk for cognitive impairments begins with diabetes and other risk factors in mid-life can be a strong motivator for patients and their doctors to adopt and maintain long-term healthy practices."

Research has shown that the single best predictor of type 2 diabetes is being obese or overweight and, in the United States alone, more than one-third of adults (more than 72 million people) are obese, defined as having a Body Mass Index of 30 or more about 30 pounds overweight. Meanwhile, the diabetes epidemic has grown rapidly over the past several decades, affecting approximately 10 percent of American adults (21 million people).

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Anticholesterol rosuvastatin not associated with reduced risk for fractures

Treatment with the anticholesterol medicine rosuvastatin calcium did not reduce the risk of fracture among men and women who had elevated levels of an inflammatory biomarker, according to a report published online by JAMA Internal Medicine.

Fractures resulting from the bone-weakening disease osteoporosis are a burden facing an aging population. Cardiovascular disease (CVD) and osteoporosis may share common biological pathways with inflammation key to the development of atherosclerosis (hardening of the arteries) and possibly the development of osteoporosis. Several studies suggest statin users may have a reduced risk of fractures, while other studies find no association, according to the study background.

Jessica M. Pena, M.D., M.P.H., of Montefiore Medical Center and Albert Einstein College of Medicine, New York, and co-authors examined whether statin therapy reduced the risk of fracture in the JUPITER (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin) trial that enrolled 17,802 men (older than 50 years) and women (older than 60 years). Participants had inflammatory biomarker high-sensitivity C-reactive protein (hs-CRP) levels of at least 2 mg/L. Participants were divided equally in two groups: one group received 20 mg daily of rosuvastatin while the other received placebo.

There were 431 fractures reported during the study with 221 fractures among participants who took rosuvastatin compared with 210 fractures among individuals who received placebo, according to the study results. The incidence of fracture in the rosuvastatin group was 1.20 per 100 person-years and in the placebo group 1.14 per 100 person-years. Overall, higher baseline hs-CRP level was not associated with an increased risk of fracture.

"Our study does not support the use of statins in doses used for cardiovascular disease prevention to reduce the risk of fracture," the study concludes.

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Cheaper private health care prices mean more Medicare spending

When private prices for health care services decrease, Medicare spending increases, according to a new study. The finding raises the possibility that physicians and hospitals may be shifting some services to Medicare when they stand to make more money by doing so -- though further research will be needed to clearly identify the cause, according to the study's authors.

The study, conducted by the Leonard D. Schaeffer Center for Health Policy and Economics, is the first in a series of attempts to mine reams of health care spending data gathered by the Institute of Medicine in 2013.

"It turns out that what happens in private health care may not stay in private health care," said John Romley, research assistant professor at the USC Price School of Public Policy and lead researcher on the study. "If a private health plan manages to negotiate lower prices with health care providers, they may make up the difference by providing additional health care to Medicare beneficiaries."

Romley collaborated with Sarah Axeen, Darius Lakdawalla and Dana Goldman of the USC Schaeffer Center as well as Michael Chernew of Harvard University and Jay Bhattacharya of Stanford University. The findings were published online by Health Services Research on Nov. 27.

The team examined data from more than 300 geographic regions covering the United States, exploring Medicare spending on inpatient and outpatient care and prescription drugs for fee-for-service beneficiaries.

The researchers found that a 10 percent lower private price for health care is associated with a 3 percent increase in Medicare spending per member per year, and 4.3 percent more specialist visits.

Next, Romley plans to explore how mergers among insurers affect private health care prices, and ultimately Medicare utilization and spending.

"We've known for a long time that some parts of the U.S. have much higher Medicare spending than others, but not necessarily a higher quality of care. But Medicare is only 20 percent of U.S. health care spending, and we're only now beginning to understand how private health care differs throughout the U.S.," Romley said.

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Prompt, appropriate medical care for dislocated shoulder injuries

Prompt and appropriate treatment of a dislocated shoulder -- when the head of the upper arm bone (humerus) is completely knocked out of the shoulder socket (glenoid) -- can minimize risk for future dislocations as well as the effects of related bone, muscle and nerve injuries, according to a literature review appearing in the December issue of the Journal of the American Academy of Orthopaedic Surgeons (JAAOS).

The shoulder has the greatest range of motion of any joint in the human body and is the most common site for a full or partial dislocation. Shoulder dislocations are classified as "traumatic" or "atraumatic." Up to 96 percent of dislocations are traumatic, occurring most often during contact sports or when someone falls onto an outstretched hand. Atraumatic dislocations -- when the shoulder starts to slip part way out without trauma -- can cause limited shoulder movement in multiple directions.

In 2011, shoulder dislocations accounted for 175,641 emergency department visits in the U.S., although some patients choose to reset the joint without any medical assistance.

"We do not recommend self-setting of shoulder dislocations," says Richelle Takemoto, MD, an orthopaedic surgeon with Kauai Medical Clinic/Wilcox Memorial Hospital. Dr. Takemoto and her co-authors recommend immediate medical attention for a dislocated shoulder that includes radiographic images before and after reduction (resetting of the shoulder) to check for related fractures and other musculoskeletal injuries.

The cause of injury, the presence of an associated fracture and/or nerve injury, and the difficulty in resetting the shoulder all contribute to a patient's outcome.

"Acute shoulder dislocations can be effectively managed by closed reduction maneuvers," says lead study author Thomas Youm, MD, clinical assistant professor, New York University Hospital for Joint Diseases. "There are a plethora of closed reduction techniques available for relocation of a dislocated shoulder. A thorough understanding of these reduction techniques as well as immobilization strategy and rehabilitation regimens can successfully treat dislocations of the shoulder and hopefully prevent the need for surgery."

If you have dislocated your shoulder

• Promptly seek orthopaedic care -- at latest, within one week from injury -- to ensure the best diagnosis and treatment.
• Monitor for possible nerve damage pre- and post-reduction surgery.
• Once the ligaments have healed, appropriate counseling is needed to rehabilitate the injury and to prevent frozen shoulder. Among seniors, persistent weakness in the shoulder should be checked for a possible rotator cuff tear(s).

By the numbers

• Forty percent of shoulder dislocation patients have an associated structural (ligament or muscle) injury.
• One of three shoulder dislocation patients also has a rotator cuff tear.
• Males ages 10 to 20 have the highest rate of shoulder dislocation.
• Recurrent dislocations are most likely to occur within two years after an initial dislocation, most often in patients younger than 20.
• Six of 10 younger patients developed instability over two years and seven of 10 over five years following a dislocated shoulder.
• Men are more likely to have recurrent instability following a shoulder dislocation than women.

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Test for horse meat developed

For a test to be useful as a screening tool it needs to be quick and cheap. With this goal in mind, the team discovered that a couple of minutes shaking about a gram of meat in a solvent followed by a few minutes of data acquisition on Pulsar was enough to tell horse meat from beef. Software to carry out mathematical analysis of the spectral data has also been developed at IFR.

Scientists at the Institute of Food Research on the Norwich Research Park have teamed up with Oxford Instruments to develop a fast, cheap alternative to DNA testing as a means of distinguishing horse meat from beef. Because horses and cattle have different digestive systems, the fat components of the two meats have different fatty acid compositions, as the team report in the journal 'Food Chemistry'. The new method looks at differences in the chemical composition of the fat in the meats, using similar technology to a hospital MRI scanner.

In just ten minutes, a technician can determine whether a piece of raw meat is horse or beef. The method, developed with funding from Innovate UK and the Biotechnology and Biological Sciences Research Council (BBSRC) has recently been trialled in an industrial setting by a leading meat processor. It is currently being extended by the team of scientists to test for other meat species, including pork and lamb.

The horse meat scandal of 2013 was sparked by the discovery of horse meat in a number of beef burgers. Soon, horse meat was detected in other meat products, leading to millions of pounds worth of food being taken off supermarket shelves. The crisis exposed the potential vulnerability of the meat supply chain to fraud and even to threats to public health, and highlighted gaps in testing. The currently favoured method of meat species testing relies on DNA, which can tell one meat from another based on the genetic makeup of the source animals, but is relatively slow and expensive and prone to contamination if not used carefully.

In response to this, a new method using a totally different approach was developed by Oxford Instruments and IFR. The key technology is the 'Pulsar', a high resolution bench-top NMR spectrometer developed by Oxford Instruments. NMR spectroscopy is a well-respected analytical technique used in chemistry labs worldwide. However, conventional instruments are large and expensive, and rely on super-cooled magnets and highly trained personnel to run them. Pulsar in contrast is based on permanent magnets and ease of operation.

For a test to be useful as a screening tool it needs to be quick and cheap. With this goal in mind, the team discovered that a couple of minutes shaking about a gram of meat in a solvent followed by a few minutes of data acquisition on Pulsar was enough to tell horse meat from beef. Software to carry out mathematical analysis of the spectral data has also been developed at IFR.

"It's a stroke of luck really that some of the most important meats turn out to have fat signatures that we can tell apart so easily with this method," says Dr Kate Kemsley. "It's been very satisfying to see results from a real industrial setting sit right on top of those we generated in our two labs. We think this testing method should work well at key points in the supply chain, say at meat wholesalers and processors."

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Gene associated with an aggressive breast cancer uncovered

Scientists at A*STAR's Genome Institute of Singapore (GIS), in collaboration with local clinicians and colleagues in the USA, have identified a biomarker which is strongly associated with triple negative breast cancer (TNBC) , a highly aggressive carcinoma that often has early relapse and metastasis following chemotherapy. The newly identified biomarker, a gene called RASAL2, provides a target for developing new therapeutics designed to treat this often deadly disease.

TNBC is deadly because, unlike other types of breast cancers such as estrogen receptor (ER) positive or HER2 amplified breast tumours which have effective targeted therapy, TNBC tumours do not respond to targeted therapy.

Breast cancer has many subtypes, each with its own genetic makeup. As such, different subtypes behave differently in invasion and metastasis. Using breast cancer cell lines and genomic data from patient samples, molecular biologist Min Feng and her colleagues at the GIS adopted an integrated approach to search for genes whose deregulation may help explain the high metastatic potential of TNBC cells.

Dr Feng found that a small RNA, often called microRNA, is lost in highly metastatic TNBC cells but not in luminal breast cancer. As a result, RASAL2, which is negatively regulated by this microRNA, is up-regulated in a set of TNBC tumours. The study showed that TNBC patients whose tumours have high expression of RASAL2 tend to have a lower survival rate as compared to patients whose tumours have low levels of this gene. Additionally, the study showed that genetic knockdown of RASAL2 gene can lead to reduced metastasis in breast cancer mouse model.

The findings were published recently in the Journal of Clinical Investigation (JCI).

Intriguingly, previous research found that RASAL2 was lost in some of the luminal type of breast tumours, where it acts as a tumour suppressor.

Project leader of the study, Prof Qiang Yu, Senior Group Leader of Cancer Therapeutics and Stratified Oncology Programme at the GIS, said, "Cancer is an extremely heterogeneous disease, where many molecular processes have gone wrong in their own ways. Rather than a tumour suppressor, we show here that RASAL2 actually acts as a cancer promoting molecule in TNBC. This reminds us that the same molecule can function very differently in different subtypes of cancers, a phenomenon which has often been seen before."

The study is the result of intensive collaboration with both local and international colleagues, including Dr Ern Yu Tan at Tan Tock Seng Hospital, Singapore, and Dr Dave Hoon at the John Wayne Cancer Institute in Santa Monica, California.

Dr Tan, a breast cancer doctor, said, "Therapeutic options remain limited and women with TNBC have a higher risk of disease relapse, with prognosis being generally poor after a relapse. With this finding, RASAL2 could be a new potential biomarker that is associated with the high risk of TNBC, rather than all types of breast tumours. This illustrates an important aspect of breast cancer biology. With a better understanding of the genetic makeup of tumours, it is now recognized that breast cancer comprises a diverse mix of tumours. This explains why not everyone with tumours of the same disease stage responds the same way to similar treatment."

GIS Executive Director Prof Huck Hui Ng, said, "The study is a reflection of an adaptation of our efforts towards translational research. We are working hard to build up an ecosystem to allow close collaborations between researchers and clinicians. Because the laboratory findings do not always replicate the 'real world' of human tumours, validation with samples derived from actual human tumours remains the 'final proof' of whether novel laboratory findings can be applied to clinical practice."

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Breast cancer vaccine shows promise in small clinical trial

A breast cancer vaccine developed at Washington University School of Medicine in St. Louis is safe in patients with metastatic breast cancer, results of an early clinical trial indicate. Preliminary evidence also suggests that the vaccine primed the patients' immune systems to attack tumor cells and helped slow the cancer's progression.

The study appears Dec. 1 in Clinical Cancer Research.

The new vaccine causes the body's immune system to home in on a protein called mammaglobin-A, found almost exclusively in breast tissue. The protein's role in healthy tissue is unclear, but breast tumors express it at abnormally high levels, past research has shown.

"Being able to target mammaglobin is exciting because it is expressed broadly in up to 80 percent of breast cancers, but not at meaningful levels in other tissues," said breast cancer surgeon and senior author William E. Gillanders, MD, professor of surgery. "In theory, this means we could treat a large number of breast cancer patients with potentially fewer side effects.

"It's also exciting to see this work progress from identifying the importance of mammaglobin-A, to designing a therapeutic agent, manufacturing it and giving it to patients, all by investigators at Washington University," he added.

The vaccine primes a type of white blood cell, part of the body's adaptive immune system, to seek out and destroy cells with the mammaglobin-A protein. In the smaller proportion of breast cancer patients whose tumors do not produce mammaglobin-A, this vaccine would not be effective.

In the new study, 14 patients with metastatic breast cancer that expressed mammaglobin-A were vaccinated. The Phase 1 trial was designed mainly to assess the vaccine's safety. According to the authors, patients experienced few side effects, reporting eight events classified as mild or moderate, including rash, tenderness at the vaccination site and mild flu-like symptoms. No severe or life-threatening side effects occurred.

Although the trial was designed to test vaccine safety, preliminary evidence indicated the vaccine slowed the cancer's progression, even in patients who tend to have less potent immune systems because of their advanced disease and exposure to chemotherapy.

"Despite the weakened immune systems in these patients, we did observe a biologic response to the vaccine while analyzing immune cells in their blood samples," said Gillanders, who treats patients at Siteman Cancer Center at Barnes-Jewish Hospital and Washington University. "That's very encouraging. We also saw preliminary evidence of improved outcome, with modestly longer progression-free survival."

Of the 14 patients who received the vaccine, about half showed no progression of their cancer one year after receiving the vaccine. In a similar control group of 12 patients who were not vaccinated, about one-fifth showed no cancer progression at the one-year follow-up. Despite the small sample size, this difference is statistically significant.

Based on results of this study, Gillanders and his colleagues are planning a larger clinical trial to test the vaccine in newly diagnosed breast cancer patients, who, in theory, should have more robust immune systems than patients who already have undergone extensive cancer therapy.

"If we give the vaccine to patients at the beginning of treatment, the immune systems should not be compromised like in patients with metastatic disease," Gillanders said. "We also will be able to do more informative immune monitoring than we did in this preliminary trial. Now that we have good evidence that the vaccine is safe, we think testing it in newly diagnosed patients will give us a better idea of the effectiveness of the therapy."

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Is Schizophrenia a 'Real' Illness?

 The report comes at a pertinent time for mental health research; last year the same organisation questioned the value of psychiatric diagnosis altogether. This new document seems to cast doubt on many received wisdoms about schizophrenia, even questioning whether it is an illness. So what is happening here?

Radical shifts

Schizophrenia has been a controversial and shifting diagnosis since the word was coined by Eugen Bleuler in 1911. Its name has undergone quite radical changes in meaning, moving from being seen as a progressive brain disease, to being thought of as a series of “reactions” in the first DSM (the American manual of mental disorders) to increasingly being defined since the 1980s as a neuro-developmental disorder in psychiatric research.

In 1979, the trenchant critic of psychiatry Thomas Szasz called it “psychiatry’s sacred symbol” and wondered at length how psychiatry was able to get away with the perpetration of a crucial and profession-sustaining “myth”.

Some of the iconoclasm faded, but in recent years a new group of sceptics (referred to as “schizophrenia’s scientific critics” by the philosopher Jeffrey Poland) have challenged the diagnosis of schizophrenia with renewed rigour.

In 1991 the academic clinical psychologist Mary Boyle published a book with a strikingly bold thesis. Writing under the provocative title Schizophrenia: A Scientific Delusion? she proceeded to outline how putative psychological illness was far less coherent than it has long been taken to be. Consequently, she has argued, it should be dispensed with as soon as possible, as it only serves to perpetuate a confused view of mental health problems. A similar view recently found its way into a heated discussion on the comments section of an article on The Conversation.

Meanwhile, many academics continue to embrace schizophrenia more readily (though still not without caution). In his book-length introduction to the topic psychologist Michael Green says that the particular set of behaviours and experiences which currently attracts a DSM diagnosis of schizophrenia is unlikely to be underpinned by a single genetic profile. Future research should “let go” of schizophrenia as currently conceived and focus on different ways of classifying the problems we associate with that label. Thomas Insel, director of America’s National Institute for Mental Health, agrees with this view.

However, Green’s book still treats the diagnosis as a meaningful category with a real need for psychiatric intervention, and neither he nor Insel are social constructionists about schizophrenia. How can we square this with the way they also apparently encourage us to relinquish the idea, much as one gives up a bad habit?

Revolutionaries and reformists

We can think about the different views on schizophrenia as “revolutionary” and “reformist”. Reformers like Green recognise that the concept is unwieldy and insufficiently precise. They are not holding their breath for discovery of a single gene or simple biomarker for schizophrenia, and they may balk at the idea that it is a “progressive, degenerative brain disease”, but they have no problem with continuing to talk about schizophrenia the “disorder”, “illness” or “syndrome”.

Perhaps what puts most water between these two groups is the degree of urgency they respectively feel about getting rid of the label “schizophrenia”. For “revolutionaries”, schizophrenia is more of a barrier than an effective tool for clinical communication, useless at best and a form of denigration at worst.

“Schizophrenia” is used to justify coercive treatments, it exacerbates mental health stigma, and it has even evolved to become a moderately racist label. Suggestive research on the phenomenon of “stereotype threat” points to the possibility that being known to have the diagnosis may even, under certain conditions, have an exacerbating effect on the psychological and social difficulties of people who meet the criteria. “Get rid of the idea altogether!” say revolutionaries.

But one difficulty with such a move is in knowing what its implications should be for our understanding of the problems that merit a diagnosis. Some critics dispute the idea that these individuals are “ill”, though this doesn’t fit with everyone’s first-hand experience. Furthermore, in the absence of a widely agreed upon definition of “mentally ill” it’s hard to see how the question could be resolved one way or another. As psychologist Richard Bentall has said recently: “The problem has become not whether to replace schizophrenia, but what to replace it with”. There are many ideas, but we still lack consensus.

To ask whether schizophrenia “really exists” is somewhat beside the point. Revolutionaries can, with good reason, say “no”; Schizophrenia is a metaphor, and an often misleading, overly reified one at that. However, reformists can justly point out that while DSM schizophrenia is a historically contingent construction, there is nonetheless an important, often debilitating, set of experiences in its vicinity which we cannot wish away. Arguments over terminology aside, it is the nature of these experiences which holds the most interest to researchers and clinicians, and we still know far too little.

The BPS report should serve as a reminder to think wisely about the term “schizophrenia”. Without underplaying the seriousness of the problems it connotes, we should remain wary of it. We also urgently need to prevent its use from needlessly limiting the opportunities people have for living the life they want.

However the report is not without problems; arguably it focuses too much attention on hallucinations and delusions at the expense of “negative” or disorganised symptoms. Equally, it questionably concludes that CBT for psychosis can be effective, despite doubts from the very researchers that it cites. There is much to agree with in “Understanding Psychosis”, but many of the debates touched on here are far from settled.

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Many People with Dementia May Go Unscreened, Untreated

The majority of people with dementia in the United States may have never seen a doctor about their memory and thinking problems, according to a new study of older adults.

The researchers found that 55 percent of patients screened for dementia as part of the University of Michigan Health and Retirement Study had never been evaluated prior to participating in this study, despite showing a clear cognitive decline.

Although the study was small — it included 845 people — the results imply that upwards of 1.8 million Americans ages 70 and older with dementia also have either never been screened, or are not receiving treatment. 

This is a lost opportunity because intervention could substantially improve some people's quality of life, the researchers wrote in their study, published today (Nov. 26) in the journal Neurology. [10 Ways to Keep Your Mind Sharp]

"Early evaluation and identification of people with dementia may help them receive care earlier" and help reduce societal costs, said Dr. Vikas Kotagal, lead author on the paper and assistant professor of neurology at the University of Michigan Health System in Ann Arbor.

People with dementia may have any of a host of brain conditions that cause long-term difficulties in thinking and reasoning that are severe enough to affect daily life. The most common form is Alzheimer's disease.

Most forms of dementia have no cure, and treatment is limited. Nevertheless, screening for dementia at its earliest stages might help doctors slow the progression or better equip family members and the patient to deal with the disease, Kotagal said.

Some forms of dementia stem from poor nutrition and can be reversed. One common, reversible cause of dementia is vitamin B12 deficiency.

"There are [several] factors that commonly contribute to overall cognitive disability in patients with dementia that can get better with medical management, namely depression and sleep disorders," Kotagal told LiveScience. "Many dementias are caused by cardiovascular risk factors. Identifying these risk factors and modifying them in at-risk individuals can lead to a change in the natural [progression] of these conditions."

For non-reversible forms of dementia, some studies have shown that exercise, social interactions, and engaging the mind in puzzles and games may help slow the progression, although to a very limited degree. Medications, too, such as cholinesterase inhibitors, may have a small but positive effect in helping patients maintaining longer bouts of clear thinking.

The new study also found that people who were married were more than twice as likely to have had dementia screening as people who were not married.

"It's possible that spouses feel more comfortable than children [do] raising concerns," about dementia, Kotagal said. Another possibility could be that unmarried elderly people may be more reluctant to share their concerns with their doctor if they are worried about the impact it could have on their independence, he added.

Deciding when to see a doctor can be tricky, the researchers wrote, given that tests are not standardized and most seniors experience at least some cognitive decline that's not dementia.

The U.S. Preventive Services Task Force, a non-governmental panel of health experts, does not recommend universal screening for dementia because the benefits of pharmacological treatment might not outweigh the risks.

"Performing this testing in clinically symptomatic older individuals, however, is a different story," Kotagal added. For people with symptoms, a screening may be a great help.

People with a family member who needs more help with tasks that they have always been able to handle — specifically because of thinking and memory problems — should consider scheduling a visit to discuss this with the person's doctor, he said.

The symptoms of dementia usually first appear after age 60, and the risk increases with age. By age 85, between 25 and 50 percent of people exhibit signs of Alzheimer’s disease, according to the Centers for Disease Control and Prevention.

Under the Affordable Care Act, Medicare now reimburses people for Annual Wellness Visits that can include an assessment of cognitive function.

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System reveals how our brains, bodies change as we fall asleep

Sleep study participants are asked to squeeze a small ball with their hand in time with their breathing, and the force and timing of their motions are measured by the glove and by electrodes on a forearm muscle. By combining EEG brainwave data with information from the way squeezes decrease in frequency and strength as a participant falls asleep, investigators can now track the dynamic changes in brain and body during the sleep onset process.

Massachusetts General Hospital (MGH) investigators have developed a system to accurately track the dynamic process of falling asleep, something has not been possible with existing techniques. In their report in the October issue of the open-access journal PLOS Computational Biology, the research team describes how combining key physiologic measurements with a behavioral task that does not interfere with sleep onset gives a better picture of the gradual process of falling asleep. In addition to being a powerful tool for future research, the system could provide valuable insight into diagnosing and understanding sleep disorders.

"While our personal experience tells us that falling asleep is a gradual process, current clinical methods only define a single point in time at which one has fallen asleep," says Michael Prerau, PhD, of the MGH Department of Anesthesia, Critical Care and Pain Management, lead author of the report. "Our new research shows that it's not simply when you fall asleep that's important, it's how you fall asleep that really matters. We now have the power to chart the entire trajectory of your neurological, physiological and behavioral activity as you transition from wake to asleep, rather than simply reporting the time it takes."

In their report, the investigators describe developing a method that continuously estimates the degree to which an individual is awake at each point during the sleep onset process. "This is a real paradigm shift in the way we study sleep onset," says Patrick Purdon, PhD, MGH Department of Anesthesia, Critical Care and Pain Management and senior author of the study. "By quantifying the dynamic changes in brain activity and behavior during the transition from wakefulness to sleep, we now have a rigorous framework with which to study disorders of sleep onset, such as insomnia or narcolepsy."

To link changes in brain activity to loss of consciousness during sleep onset, the investigators developed a new, minimally disruptive means of tracking behavior as someone falls asleep. Earlier methods either used tasks in which a participant was asked to respond to auditory cues, something that could disrupt falling asleep, or actigraphy -- the method of measuring movement used in most clinical sleep devices and consumer wearables, which cannot distinguish between sleep and motionless wakefulness. To get around these problems the investigators developed an ingenious new behavioral task that is accurate without disturbing sleep.

Instead of responding to a sound, a participant holds a small rubber "stress ball" in one hand and is asked to squeeze the ball with every intake of breath and release it when exhaling. A special glove on that hand and electrodes on the forearm measure both the timing and the force of each squeeze. In this way, the participant's own breathing acts as the stimulus, and the squeezes act as the behavioral response. Tracking how well ball squeezes are aligned with an individual's breathing reflects a gradual process during which more and more squeezes are mistimed or totally absent. Measuring the force exerted by the forearm muscle also reflects how the strength of the squeezing motion drops with sleep onset.

At the same time as the ball-squeeze measurements are taken, EEG readings track three brain wave patterns previously associated with falling asleep, decreasing power in the alpha frequency range and increasing power in delta and theta frequencies. The combination of all of these measures -- the timing and strength of ball squeezes and the change in brain wave levels -- is used to calculate what the investigators call the wake probability, an estimate of the degree to which a participant is awake during the process of sleep onset.

Testing their model in healthy volunteers over several nights not only provided more accurate results than did traditional methods of sleep determination, it also revealed differences in the way sleep onset occurs in different individuals. Current clinical criteria define sleep as beginning when the power of an individual's alpha-range brainwaves disappears. While seven of the nine study participants followed this pattern, two participants continued to correctly time their ball squeezes for several minutes after alpha levels had dropped. Only when the power in their brainwaves at the theta and delta frequencies had risen did both the behavioral and physiological measures indicate that they were asleep.

"These participants continued to respond to the task, even though current clinical measures would say they were still asleep, which was clearly not the case," says Prerau. "These results suggest that it is the presence of delta and theta power, rather than the lack of alpha power, that is necessary for the cessation of behavior. We may need to carefully re-examine the way sleep onset is defined, since behavior is an essential component of the story that is not measured clinically."

By characterizing the trajectory of the sleep onset process in healthy individuals, Prerau and Purdon believe this study will ultimately shed light on what happens in patients who have trouble falling asleep, leading to an improved ability to understand and diagnose sleep disorders as well as to more precisely measure the effect of sleep medications. This method could also be used to track drowsiness in situations in which alertness is vital.

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'Off switch' for pain discovered: Activating the adenosine A3 receptor subtype is key to powerful pain relief

In research published in the medical journal Brain, Saint Louis University researcher Daniela Salvemini, Ph.D. and colleagues within SLU, the National Institutes of Health (NIH) and other academic institutions have discovered a way to block a pain pathway in animal models of chronic neuropathic pain including pain caused by chemotherapeutic agents and bone cancer pain suggesting a promising new approach to pain relief.

The scientific efforts led by Salvemini, who is professor of pharmacological and physiological sciences at SLU, demonstrated that turning on a receptor in the brain and spinal cord counteracts chronic nerve pain in male and female rodents. Activating the A3 receptor -- either by its native chemical stimulator, the small molecule adenosine, or by powerful synthetic small molecule drugs invented at the NIH -- prevents or reverses pain that develops slowly from nerve damage without causing analgesic tolerance or intrinsic reward (unlike opioids).

An Unmet Medical Need 

Pain is an enormous problem. As an unmet medical need, pain causes suffering and comes with a multi-billion dollar societal cost. Current treatments are problematic because they cause intolerable side effects, diminish quality of life and do not sufficiently quell pain.

The most successful pharmacological approaches for the treatment of chronic pain rely on certain "pathways": circuits involving opioid, adrenergic, and calcium channels.

For the past decade, scientists have tried to take advantage of these known pathways -- the series of interactions between molecular-level components that lead to pain. While adenosine had shown potential for pain-killing in humans, researchers had not yet successfully leveraged this particular pain pathway because the targeted receptors engaged many side effects.

A Key to Pain Relief 

In this research, Salvemini and colleagues have demonstrated that activation of the A3 adenosine receptor subtype is key in mediating the pain relieving effects of adenosine.

"It has long been appreciated that harnessing the potent pain-killing effects of adenosine could provide a breakthrough step towards an effective treatment for chronic pain," Salvemini said. "Our findings suggest that this goal may be achieved by focusing future work on the A3AR pathway, in particular, as its activation provides robust pain reduction across several types of pain."

Researchers are excited to note that A3AR agonists are already in advanced clinical trials as anti-inflammatory and anticancer agents and show good safety profiles. "These studies suggest that A3AR activation by highly selective small molecular weight A3AR agonists such as MRS5698 activates a pain-reducing pathway supporting the idea that we could develop A3AR agonists as possible new therapeutics to treat chronic pain," Salvemini said.

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