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Total ankle arthroplasty offers patients greater range of motion and less pain

Surgical reconstruction is a life changer for people with end-stage ankle arthritis, a painful condition that limits patients’ abilities to go up and down stairs, get out of a car and even walk. Now researchers from The Rothman Orthopedic Institute at Jefferson Health demonstrate that surgical reconstruction boosts patients’ range of motion by more than 60 percent and that translates to significantly less pain and better function completing everyday activities with improvement continuing for at least the first two years following surgery.

The findings will enable surgeons to not only best inform patients about what improvements to expect as they recover during the first two years after surgery and but also what the surgical repair can do for them — namely, provide a superior quality of life.

“They’re really dramatically better than they were before surgery on average,” said Steven Raikin, MD, Director of Foot and Ankle Service at the Rothman Orthopedic Institute at Jefferson Health and professor of Orthopedic Surgery at Jefferson Medical College, who published the work September 5th in the Journal of Bone and Joint Surgery.

Traumatic injury or repeated sprains wear down cartilage that usually cushions the ankle joint. Bone-on-bone grinding and arthritis can occur as the protective buffer erodes away. As a result, patients with ankle arthritis have limited range of motion in their ankle. Together with debilitating pain, the condition prevents patients from doing everyday activities as simple as getting up from a chair. When non-surgical options such as medications, steroid injections or bracing have failed, surgery becomes the only option.

Total ankle arthroplasty, or a complete surgical replacement of the ankle joint, has only become a viable choice in the last decade. With new methods and updated devices, results from total ankle arthroplasty appear effective, but patients wanted to know more about the recovery period.

“The whole idea was to try to create expectation parameters for patients getting ankle replacements at different time periods in the first two years following surgery,” he said.

Dr. Raikin and a team of surgeons and researchers from The Rothman Institute and Thomas Jefferson University Hospital assessed more than 100 patients’ range of motion, pain levels and function completing everyday activities before surgery and then again at three months, six months, one year and two years after total ankle arthroplasty surgery.

On average, surgery improved patients’ ankle range of motion in the sagittal plane by 66 percent, from a 20.7-degree angle before surgery to a peak of 34.3 degrees six months post-surgery. As patients’ range of motion improved, so did their quality of life.

“We are able to give a dramatic improvement in range of motion and pain with these ankle replacements,” said Dr. Raikin. Patients’ pain scores plummeted from 74 on a 100-point scale to 15 and their ability to complete everyday tasks shot up from 50 to 80 out of 100 over the two-year follow-up. What’s more these improvements correlated strongly with enhanced ankle flexibility.

When the team analyzed surgical outcomes, they found that the critical recovery window happened much earlier than they thought. The first six months post-surgery were crucial, according to their data.

“The vast majority of the improvement patients get, they actually get in the first six months,” said Dr. Raikin. “This is very important because we have to really motivate patients earlier on.”

Patients’ range of motion peaked at the 6-month mark with improvement slowing down from there for example. Pain and functionality followed the same trend. Dr. Raikin is now pushing his patients in their recovery earlier and quicker as a result of this study.

That said, patients do continue to improve both their range of motion and their pain and functionality until about 2 years. “So, if they’re not where we expect them to be, they can still catch up,” Dr. Raikin said.

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Brainwaves synchronize to the speed of talking, influencing the way we hear words

Have you ever found yourself finishing someone else’s sentences, even though you don’t really know them that well? Fortunately, the ability to predict what someone is going to say next isn’t the preserve of turtle doves or those in long-term relationships. Our brain processes all kinds of information to estimate what’s going to come next, and the speed at which the speaker is talking, or speech rate, plays an important role.

This study, published in the journal Current Biology, delved deeper to find out what happens on a neural level. “The findings show neural dynamics predict the timing of future speech items based on past speech rate, and this influences how ongoing words are heard,” says Anne Kösem of the MPI and the Lyon Neuroscience Research Center, and first author of the research paper.

Speech rhythms and perception

“We asked native Dutch participants to listen to Dutch sentences that suddenly changed in speech rates: the beginning of the sentence was either compressed or expanded in duration, leading to a fast or a slow speech rate, while the final three words were consistently presented at the original recorded speech rate.”

The final word of the sentence contained an ambiguous vowel, which could be interpreted, for example, as either a short “a” or a long “aa” vowel. Crucially, the speed of the beginning of the sentence could influence the way this ambiguous vowel is heard, leading to the perception of words with radically different meanings. For example, in Dutch, the ambiguous word is more likely to be perceived as a long “aa” word when someone was initially talking quickly (e.g. taak, word “task” in Dutch), and as a short “a” when someone was talking slowly (tak, “branch” in Dutch).

Participants reported how they perceived the last word of the sentence. The team recorded participants’ brain activity with magnetoencephalography (MEG) while they listened to the sentences, and investigated whether neural activity synchronised to the initial speech rate and whether that influenced how participants comprehended the last word.

Just like riding a bike

The study showed that our brain keeps following past speech rhythms after a change in speech rate. If it synchronizes to the preceding slow speech rate we are more likely to hear the last ambiguous word with a short vowel, and if it synchronises to the preceding fast speech rate we are more likely to hear a long vowel word. “Our findings suggest that the neural tracking of speech dynamics is a predictive mechanism, which directly influences perception,” adds Kösem.

“Imagine the brain acting like a bicycle wheel. The wheel turns at the speed imposed by pedalling, but it continues rolling for some time after pedalling has stopped because it is dependent on the past pedalling speed.” This sustained synchronisation between brainwaves and speech rate helps us predict the length of future syllables, ultimately causally influencing the way we process and hear words.

Fundamental research with future potential

The team believes that, in the future, these findings may help researchers improve speech perception in adverse listening conditions and for the hearing impaired. Kösem added: “One follow-up study currently being performed tests if word perception can be modulated by directly modifying brain oscillatory activity with transcranial alternating current stimulation.”

This study was a collaboration between scientists from the Max Planck Institute for Psycholinguistics (MPI), the Donders Institute for Brain, Cognition, and Behaviour in Nijmegen, the Lyon Neuroscience Research Center and the University of Birmingham.

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Visceral leishmaniasis on the rise in Brazil, study finds

The parasitic disease leishmaniasis is spread to humans through the bites of sandflies, and is endemic in a number of countries, including Brazil. Despite control efforts, the incidence of visceral leishmaniasis — the most severe form of the disease — rose in Brazil between 1990 and 2016, researchers have reported in PLOS Neglected Tropical Diseases.

Leishmaniasis can be classified into two clinical forms — visceral (VL) and tegumentary, which encompasses both cutaneous and mucocutaneous leishmaniasis (CML). The World Health Organization estimates that there are 400,000 new cases of VL and 1 million new cases of CML around the globe each year. In the Americas, 96% of cases occur in Brazil, where the fatality rate of VL is 7.4%.

In the new work, Juliana Bezerra, of the Universidade Federal de Minas Gerais, Brazil, and colleagues analyzed the burden of VL and CML using data from the Global Burden of Disease (GBD) study. Since 1990, GBD has quantified and compared the magnitude of health loss due to diseases around the world. The researchers relied on GBD data for Brazil and all of its 27 federated units.

Overall, the age-standardized rate of leishmaniasis in Brazil decreased 48.5% from 1990 to 2016, and the disability-adjusted life years — a measure of health loss — increased by 83.6%. However, that decrease was mostly due to a drop in the rate of CML; the incidence rate of VL increased by 52.9% during the same time period, and an even higher increase was seen in children under the age of 1. Additionally, different regions of Brazil saw different burdens of disease, with rates increasing the Northeast and Southeast but decreasing in the Northern states.

“Understanding the burden of these diseases and their regional differences is of great relevance for the establishment of adequate and region-specific surveillance and control measures,” the authors say. In addition, it can help in the rational use of available resources and in decision making aimed at reducing the transmission of the parasite and the burden of this disabling and potentially lethal disease.”

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Human gut study questions probiotic health benefits

Probiotics are found in everything from chocolate and pickles to hand lotion and baby formula, and millions of people buy probiotic supplements to boost digestive health. But new research suggests they might not be as effective as we think. Through a series of experiments looking inside the human gut, researchers show that many people’s digestive tracts prevent standard probiotics from successfully colonizing them. Furthermore, taking probiotics to counterbalance antibiotics could delay the return of normal gut bacteria and gut gene expression to their naïve state. The research publishes as two back-to-back papers on September 6 in the journal Cell.

“People have thrown a lot of support to probiotics, even though the literature underlying our understanding of them is very controversial; we wanted to determine whether probiotics such as the ones you buy in the supermarket do colonize the gastrointestinal tract like they’re supposed to, and then whether these probiotics are having any impact on the human host,” says senior author Eran Elinav, an immunologist at the Weizmann Institute of Science in Israel. “Surprisingly, we saw that many healthy volunteers were actually resistant in that the probiotics couldn’t colonize their GI tracts. This suggests that probiotics should not be universally given as a ‘one-size-fits-all’ supplement. Instead, they could be tailored to the needs of each individual.”

While past studies have investigated similar questions, they have all used patients’ excrement as a proxy for microbe activity in the GI tract. Instead, Elinav, his colleague Eran Segal, (a computational biologist at the Weizmann Institute), and their teams spearheaded by Niv Zmora, Jotham Suez, Gili Zilberman Schapira, and Uria Mor of the Elinav lab collaborated with Zamir Halpern, Chief of Gastroenterology at the Tel Aviv Medical Center to measure gut colonization directly.

In the first study, 25 human volunteers underwent upper endoscopies and colonoscopies to sample their baseline microbiome in regions of the gut. 15 of those volunteers were then divided into two groups. The first group consumed generic probiotic strains, while the second was administered a placebo. Both groups then underwent a second round of upper endoscopies and colonoscopies to assess their internal response before being followed for another 2 months.

The scientists discovered that the probiotics successfully colonized the GI tracts of some people, called the “persisters,” while the gut microbiomes of “resisters” expelled them. Moreover, the persister and resister patterns would determine whether probiotics, in a given person, would impact their indigenous microbiome and human gene expression. The researchers could predict whether a person would be a persister or resister just by examining their baseline microbiome and gut gene expression profile.

They also found that stool only partially correlates with the microbiome functioning inside the body, so relying on stool as was done in previous studies for many years could be misleading.

“Although all of our probiotic-consuming volunteers showed probiotics in their stool, only some of them showed them in their gut, which is where they need to be,” says Segal. “If some people resist and only some people permit them, the benefits of the standard probiotics we all take can’t be as universal as we once thought. These results highlight the role of the gut microbiome in driving very specific clinical differences between people.”

In the second study, the researchers questioned whether patients should be taking probiotics to counter the effects of antibiotics, as they are often told to do in order to repopulate the gut microbiota after it’s cleared by antibiotic treatment. To look at this, 21 volunteers were given a course of antibiotics and then randomly assigned to one of three groups. The first was a “watch-and-wait” group that let their microbiome recover on its own. The second group was administered the same generic probiotics used in the first study. The third group was treated with an autologous fecal microbiome transplant (aFMT) made up of their own bacteria that had been collected before giving them the antibiotic.

After the antibiotics had cleared the way, the standard probiotics could easily colonize the gut of everyone in the second group, but to the team’s surprise, this probiotic colonization prevented the host’s normal microbiome and gut gene expression profile from returning to their normal state for months afterward. In contrast, the aFMT resulted in the third group’s native gut microbiome and gene program returning to normal within days.

“Contrary to the current dogma that probiotics are harmless and benefit everyone, these results reveal a new potential adverse side effect of probiotic use with antibiotics that might even bring long-term consequences,” Elinav says. “In contrast, replenishing the gut with one’s own microbes is a personalized mother-nature-designed treatment that led to a full reversal of the antibiotics’ effects.”

Segal adds, “This opens the door to diagnostics that would take us from an empiric universal consumption of probiotics, which appears useless in many cases, to one that is tailored to the individual and can be prescribed to different individuals based on their baseline features.”

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Forecasting risk of deadly vascular condition from genome sequence

A new approach that distills deluges of genetic data and patient health records has identified a set of telltale patterns that can predict a person’s risk for a common, and often fatal, cardiovascular disease, according to a new study from the Stanford University School of Medicine.

Although the method, which uses a form of artificial intelligence called machine learning, has so far only been used to predict the likelihood of this particular condition — called abdominal aortic aneurysm, or AAA — it’s proof that such an approach could decipher the molecular nuances that put people at risk for just about any complex genetic disease.

“Right now, genome sequencing is starting to make its mark,” said Michael Snyder, PhD, professor and chair of genetics at Stanford. “It’s being used a lot in cancer, or to solve mystery diseases. But there’s still a big open question: How much can we use it for predicting disease risk?”

It turns out, quite a bit.

Typically, researchers and health care providers use genetic testing to look for DNA sequences that may correspond to an increased risk for a particular illness. Mutations in the BRCA1 and BRCA2 genes, for instance, may signal an increased risk of breast cancer. But the method that Snyder and his colleagues developed doesn’t work like that. It’s not looking for one standout gene or mutation; it’s looking for a slew of complex mutational patterns, and how those genetic errors play into a person’s health and risk for disease.

The method seeks to identify any likely disease-causing culprits in an “agnostic” manner, meaning that it combs through an onslaught of genetic information from patients with AAA, looking for commonalities. This, Snyder said, is the key to unraveling any number of genetic diseases. It’s not often the case that one, two or even a handful of genes take sole responsibility for a condition. Far more likely is that it’s a whole bunch of them. The idea is that it takes a village to cause a disease, and by using this new method, those villagers can be identified.

The study will be published Sept. 6 in Cell. Snyder and Philip Tsao, PhD, professor of medicine, share senior authorship. Instructor Jingjing Li, PhD; research manager Cuiping Pan, PhD; and postdoctoral scholar Sai Zhang, PhD, are the lead authors.

Often diagnosed at death

AAA afflicts upward of 3 million people every year and is the 10th-leading killer in the United States. Patients with AAA have an enlarged aorta, the main artery of the body, which slowly balloons over time until, in the worst of cases, it ruptures. To make matters worse, these types of aneurysms rarely show symptoms. So in many cases, the condition silently escalates, which is in part what makes it so dangerous.

Yet AAA is pretty amenable to behavioral change. Things like smoking and high blood pressure intensify the condition, while higher levels of HDL, or “good” cholesterol, help decrease the risk. So, if people know they are at risk early on, they can ideally adjust their lifestyle to avoid exacerbation or onset altogether.

“What’s important to note about AAA is that it’s irreversible, so once your aorta starts enlarging, it’s not like you can un-enlarge it. And typically, the disease is discovered when the aorta bursts, and by that time it’s 90 percent lethal,” said Snyder, the Stanford W. Ascherman, MD, FACS, Professor in Genetics. “So here’s this irreversible disease, no way to predict it. No one has ever set up a predictive test for it and, just from a genome sequence, we found that we could actually predict with about 70 percent accuracy who is at high risk for AAA.” When other details from electronic patient records were added, like whether a patient smoked and his or her cholesterol levels, accuracy increased to 80 percent, Snyder said.

The method Snyder and his team devised relies on an algorithm they call the Hierarchical Estimate From Agnostic Learning, or HEAL, which analyzed genomic data from 268 patients with AAA and scanned the mass of information for any genes that were found to be mutated across the population. The algorithm identified 60 genes that were hypermutated in the AAA patients. Some genes played roles in blood-vessel function and aneurysm development — a nod to HEAL’s accuracy — but others, more surprisingly, were associated with regulation of immune function, revealing that the mutational landscape of this disease is complex, involving niches of physiology that weren’t necessarily expected.

The team further confirmed their findings using HEAL in a control group, double-checking that the AAA-related mutational patterns were not seen among 133 healthy individuals. And indeed, there was no significant overlap.

“HEAL could, therefore, uncover new research directions and potential therapeutic targets for devastating diseases such as AAA” said Tsao, who is also the director of the Veterans Affairs Palo Alto Epidemiology Research and Information Center for Genomics.

Any disease with a genetic component

The key, Snyder said, is that the findings were entirely unbiased. The researchers didn’t say, “We think gene X, Y and Z might play a role in AAA.” They fed the genetic information into HEAL and asked if there were genes or sets of genes that were enriched for mutation. “We let machine learning figure it out, and that’s something that, to our knowledge, has never been done before,” Snyder said.

Even for diseases that have these big “red flag” genomic markers, HEAL could offer a leg up, Snyder said. “For example, in familiar cases like breast cancer, for which we know of specific ‘culprit’ genes, you have to remember that these genes — BRCA1, BRCA2 and a couple others — only explain about 30 percent of the genetics of the disease,” Snyder said. “That means 70 percent is still unexplained. There are probably multiple genes and mutations involved, and that’s where we think HEAL may kick in big time.”

In their next phase of work, Snyder and his group are looking into using HEAL to detect the elusive genetic underpinnings of preterm birth and autism.

“I see a future in which everyone will be born with their genome sequenced, or shortly thereafter,” Snyder said. “Both your single-gene and your complex disease risk will be used to predict your overall disease risk, and then you can take action based on that information.”

The work is an example of Stanford Medicine’s focus on precision health, the goal of which is to anticipate and prevent disease in the healthy and precisely diagnose and treat disease in the ill.

Other Stanford authors of the study are Joshua Spin, MD, PhD, clinical assistant professor of cardiovascular medicine; life science research assistant Alicia Deng; professor of medicine Lawrence Leung, MD; and Ronald Dalman, MD, professor of vascular surgery.

Snyder and Tsao are members of Stanford Bio-X and the Stanford Child Health Research Center. Snyder is also a member of the Stanford Cancer Institute and the Stanford Neurosciences Institute. Snyder and Tsao are members of the Stanford Cardiovascular Institute.

The research was funded by National Institutes of Health (grants CEGS 5P50HG00773504, 1P50HL083800, 1R01HL101388, 1R01HL122939 and S10OD020141), the University of California and the Veterans Affairs Office of Research and Development.

Stanford’s Department of Genetics also supported the work.

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Stray proteins cause genetic disorders

The seizures typically begin in the first months of life. It often takes years, however, before those suffering from the rare glucose transporter type 1 (Glut1) deficiency syndrome obtain a correct diagnosis. If the disorder goes untreated, affected children experience developmental delay and frequently have neurological problems. Various defects in one gene underlie the syndrome. They cause the Glut1 protein to lose its function in the cell membrane: the protein no longer transports glucose from the blood into the brain.

Miniscule changes in previously little-noticed flexible segments of the Glut1 protein could lead to severe cellular disturbances — other genetic disorders might be caused by the same mechanism. These are the findings of a study led by Professor Matthias Selbach of the Max Delbrück Center for Molecular Medicine (MDC) and published in the current issue of the journal Cell.

A fundamental problem

Selbach’s team wanted to answer a basic question: How do defective genes cause diseases? Within the Glut1 gene there are many places where a mutation can disrupt the Glut1 protein’s three-dimensional structure, leading to loss of function. Malformed and contorted, the protein can no longer carry out its task in the cellular machinery and thus triggers the syndrome. The same process is at work in most genetically determined disorders. “But the mechanism involved in genetically determined diseases — or, in other words, the cause at the molecular level — is often unclear,” says Katrina Meyer, a doctoral student in Selbach’s lab.

In one-fifth of all genetic diseases, according to the scientist, the protein structure doesn’t appear to be damaged at all. In such cases, she says, the mutation occurs in flexible loops in the proteins, which until recently were thought to have no function because they lack a defined structure. But appearances can be deceiving: “These so-called intrinsically disordered regions (IDRs) can snuggle up to other proteins as if they were soft pillows, thereby manipulate them.”

Many cellular processes are based on such interactions between proteins. The molecules interlock with each other like cogs, transfer energy, or move levers and conveyor belt systems. Even a single protein in the wrong place can have drastic consequences. Meyer therefore began by looking into which of the cell’s proteins come into contact with flexible mutated protein regions.

Subtle change with a big impact

The doctoral student did this by recreating 258 flexible protein regions in test tubes — both “healthy” variants as well as disease-related ones — and then adding human cell extracts. The next step involved using mass spectrometry to determine which proteins interact with the artificial proteins.

In Meyer’s experiment the mutated and “healthy” regions mostly docked onto the same binding partners. But some of the mutated proteins completely lost this ability or bound to other proteins and thus disrupted the operation of the cellular machinery. Some genetic changes even affect intracellular protein transport through this process. An example is a mutation in the gene for the Glut1 protein that causes two specific building blocks of protein, namely leucines, to lie next to one another, creating a so-called dileucine motif. “This pattern is known to attract proteins that aid the cell in transporting other proteins inside its interior,” says Meyer.

Right protein, wrong place

It was a special moment when Meyer made this discovery. Could it be that in people affected by this mutation the Glut1 protein is not defective but has instead ended up in the wrong place in the cell? “If the protein itself is not affected but only the transport function, there is a chance that the underlying cause can be treated — not just the symptom,” explains Meyer.

She searched databases and found a patient with Glut1 deficiency syndrome in whom the protein region contained a mutation creating the dileucine motif. The patient donated cells to her. In tests on cell cultures Meyer showed that the mutated Glut1 protein was no longer present on the cell surface, where it takes up glucose. The protein was instead in the cell’s interior as if it had gotten lost.

The cellular apparatus involved in pinching off vesicles from the cell membranes and transporting them into the cell’s interior via endocytosis is partially responsible for misrouting the Glut1 protein. Meyer was able to confirm her hypothesis: When she blocked this process, the Glut1 protein found its way back to the cell surface and resumed glucose uptake. “This could theoretically be blocked by medications,” says Meyer.

A new mechanism for numerous diseases

These medications don’t exist yet, says Matthias Selbach, head of the laboratory, but the discovery has implications beyond Glut1. By searching databases, the research team found the dileucine motif eleven times in the flexible regions of eight proteins, including in the protein that triggers the metabolic disorder cystic fibrosis.

“We have identified a promising target against a wide range of diseases,” says Selbach. “I see considerable potential here for developing new medications.” Future studies will need to determine whether these diseases can be systematically fought with endocytosis blockers.

Even though it often takes years for people affected by Glut1 deficiency syndrome to be correctly diagnosed, says Selbach, it is now relatively well treatable. Pasta, bread, and ice cream, however, are off limits to patients. They must follow a strict ketogenic diet, which involves avoiding foods that contain sugar and starch. Such a regimen usually causes the seizures to stop because the brain cells receive their energy from a different source. “But the disorder remains incurable,” says Selbach. “And patients must drastically restrict their diet.”

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How exercise generates new neurons, improves cognition in Alzheimer's mouse

A study by a Massachusetts General Hospital (MGH) research team finds that neurogenesis -inducing the production of new neurons — in the brain structure in which memories are encoded can improve cognitive function in a mouse model of Alzheimer’s disease. Their investigation shows that those beneficial effects on cognition can be blocked by the hostile inflammatory environment present in the brain of patients with Alzheimer’s disease and that physical exercise can “clean up” the environment, allowing new nerve cells to survive and thrive and improving cognition in the Alzheimer’s mice.

“In our study we showed that exercise is one of the best ways to turn on neurogenesis and then, by figuring out the molecular and genetic events involved, we determined how to mimic the beneficial effects of exercise through gene therapy and pharmacological agents,” says Rudolph Tanzi, PhD, director of the Genetics and Aging Research Unit, vice-chair of the Department of Neurology and co-director of the Henry and Alison McCance Center for Brain Health at MGH and senior author of the paper published in Science.

Lead author, Se Hoon Choi, Ph.D., of the Genetics and Aging Research Unit adds, “While we do not yet have the means for safely achieving the same effects in patients, we determined the precise protein and gene targets for developing ways to do so in the future.”

Adult neurogenesis — production of new neurons occurring after the embryonic and, in some animals, neonatal periods — takes place in the hippocampus and another brain structure called the striatum. While adult hippocampal neurogenesis is essential to learning and memory, how the process impacts neurodegenerative conditions like Alzheimer’s disease has not been well understood. The MGH team set out to investigate how impairment of adult hippocampal neurogenesis (AHN) contributed to Alzheimer’s disease pathology and cognitive function in a mouse model and whether increasing AHN could reduce symptoms.

Their experiments showed that AHN could be induced in the model either by exercise or by treatment with drugs and gene therapy that promoted the birth of neural progenitor cells. Behavioral testing of animals revealed limited cognitive benefits for animals in which neurogenesis had been induced pharmacologically and genetically. But animals in which AHN was induced by exercise showed improved cognitive performance and reduced levels of beta-amyloid.

“Although exercise-induced AHN improved cognition in Alzheimer’s mice by turning on neurogenesis, trying to achieve that result by using gene therapy and drugs did not help,” Tanzi explains. “That was because newly born neurons, induced by drugs and gene therapy, were not able to survive in brain regions already ravaged by Alzheimer’s pathology, particularly neuroinflammation. So we asked how neurogenesis induced by exercise differs.”

Choi says, “We found the key difference was that exercise also turned on the production of brain-derived neurotrophic factor or BDNF — known to be important for the growth and survival of neurons — which created a more hospitable brain environment for the new neurons to survive. By combining drugs and gene therapy that both induced neurogenesis and increased BDNF production, we were able to successfully mimic the effects of exercise on cognitive function” Choi is an assistant professor of Neurology at Harvard Medical School (HMS).

Tanzi adds,”The lesson learned was that it is not enough just to turn on the birth of new nerve cells, you must simultaneously ‘clean up’ the neighborhood in which they are being born to make sure the new cells survive and thrive. Exercise can achieve that, but we found ways of mimicking those beneficial cognitive effects by the application of drugs and gene therapy that simultaneously turn on neurogenesis and BDNF production.”

In another part of the study, the investigators found that blocking neurogenesis in young Alzheimer’s mice shortly after birth led to more pronounced cognitive deficits later in life. “We will next explore whether safely promoting neurogenesis in Alzheimer’s patients will help alleviate the symptoms of the disease and whether doing so in currently healthy individuals earlier in life can help prevent symptoms later on,” says Tanzi, the Joseph P. and Rose F. Kennedy Professor of Neurology at HMS. “We are very excited to now investigate ways of implementing our new findings to more effectively treat and prevent this terrible disease.”

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Facial plastic surgeons call for reduction of opioid prescriptions after rhinoplasty

A team of surgeons at Massachusetts Eye and Ear found that, of 173 patients undergoing rhinoplasty, a common procedure performed in the facial plastic and reconstructive surgery field, only two refilled their opioid prescriptions after the procedure — with some patients not filling their initial opioid prescription at all. Published online today in JAMA Facial Plastic Surgery, these results suggest that patients experienced less pain than expected, and that the optimal number of opioid tablets to manage postoperative rhinoplasty pain may be lower than expected.

“When we looked at the number of patients who needed refills, we found this near-negligible number,” said corresponding author David A. Shaye, MD, MPH, a facial plastic and reconstructive surgeon at Mass. Eye and Ear and an instructor in otolaryngology at Harvard Medical School. “This tells us that, as a field, we’re probably overprescribing in rhinoplasty.”

The team reviewed 173 rhinoplasty cases performed at Mass. Eye and Ear over a one-year period. Of the 173 patients, 168 were prescribed opioids in addition to acetaminophen, at an average of 28 pills per patient. Refills were found to be extremely rare, with only two patients refilling, and with some patients (11.3 percent) not filling their initial opioid prescription at all. The team confirmed the refill rate by querying the Massachusetts State Registry.

“After analyzing our data, we were pleasantly surprised by the lack of opioids patients actually required after rhinoplasty, which is especially significant given the current opioid epidemic, said co-author Linda N. Lee, MD, a facial plastic and reconstructive surgeon at Mass. Eye and Ear and an instructor in otolaryngology at Harvard Medical School. “Understanding this data, we as surgeons have a duty to responsibly prescribe opioids and limit the potential for abuse, particularly for cosmetic or elective surgeries.”

A reduction in narcotic prescriptions after rhinoplasty may limit the opportunity for opioid abuse — an epidemic in the United States, where less than five percent of the world’s population consumes two-thirds of the world’s opioid supply. Opioid-related deaths have increased by 200 percent since 2000. Studies show that nearly 60 percent of adults in the United States have leftover opioids in their homes.

As a result of their findings, the authors have reduced the number of opioid tablets they prescribe to patients by at least 50 percent.

In addition to Drs. Shaye and Lee, authors on the JAMA Facial Plastic Surgery letter include Rosh K. V. Sethi, MD, Olivia E. Quatela and Kayla G. Richburg, of Massachusetts Eye and Ear/Harvard Medical School.

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How our immune system detects broken DNA

Our immune system is working every day to protect us from bacteria, viruses, and parasites, but it can also detect when our own cells are damaged.

Research led by Lancaster University has now discovered how skin cells alert the immune system, when their DNA is damaged in the absence of infection. This DNA damage can come from a variety of sources, such as the sun’s UV rays, chemical agents like cigarette smoke, or from genotoxic drugs used in chemotherapy.

There have been few studies carried out on the immediate effects of DNA damage on the immune response, and fewer still on the role that skin cells could play in this response. Skin is our primary barrier against the outside world, and is constantly exposed to viruses and bacteria, but also to UV light and environmental toxins.

The study, published in Molecular Cell, found that DNA damage can lead to an immune response similar to that observed during viral infection.

The scientists damaged the DNA in skin cells using the chemotherapy drug Etoposide, and found that the damage was detected by some of the proteins in the cell that also recognise DNA from viruses. The damaged skin cells produced immune messenger molecules such as interferons and other cytokines that usually alert the body to infections. While this response required many components of our anti-viral defences, it activated them in a different way, making use of the proteins that are responsible for repairing our DNA after damage.

Using CRISPR-Cas9 gene editing technology, researchers were able to modify skin cells to delete certain immune genes and determine their role in this pathway. Specifically, they focused on components of the DNA sensing pathway that our cells deploy to detect viruses. Our cells use the protein cGAS to recognise virus DNA in the cytoplasm. cGAS then activates the immune adaptor STING (STimulator of INterferon Genes), which switches on an anti-viral immune response. The scientists found that STING could be activated in a different way after DNA damage, even when cGAS was absent. This involved a DNA binding protein in the nucleus, IFI16, which could activate STING with help from DNA repair factors.

Lead author Dr. Leonie Unterholzner from Lancaster University said: “We have discovered a new way in which our cells can switch on an immune response in the skin. It is possible that our immune cells use this alarm system to detect damaged skin cells, and prevents them from becoming cancerous. This is a very exciting first step, but much more work needs to be done to find out how this discovery may be used for medical applications, for instance in cancer immunotherapy.”

The research was led by Lancaster University with funding from the Medical Research Council and North West Cancer Research, and collaboration from the University of St. Andrews, Trinity College Dublin, and Aarhus University.

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Predict the onset and course of Huntington's disease

An MDC research team reports in the journal Molecular Cell that short protein fibers precede the formation of larger deposits that accumulate in the brains of those affected by the incurable Huntington’s disease, sometimes called Huntington’s chorea. These results could improve diagnosis and help in the search for new medications.

“What are the particles that are toxic to the brain?” This is an unanswered question that lies at the heart of many neurodegenerative diseases, explains Professor Erich Wanker. In Huntington’s disease, for example, protein clusters in the nerve cells of patients form deposits. But why these are harmful, what exactly triggers the disease and what the molecular trigger consists of remains basically unknown.

Together with his team, Prof. Wanker of the Max Delbrück Center for Molecular Medicine (MDC) in Berlin has identified very small precursors of these deposits: protein chains that clump together to form small fibers. Unlike the already known and relatively large protein deposits, these fibers are about ten thousandths of a millimeter long and consist of mutated huntingtin proteins that are attached to one another. Their properties allow to predict the onset and course of the disease. The results have been published in the scientific journal Molecular Cell.

Enables prediction months prior to disease onset

Anne Ast, a doctoral student in Erich Wanker’s team, found the minute huntingtin fibers in the brains of deceased patients, but also in fruit flies, worms, and mice whose cells produced the mutated protein. These fibers formed in mice before larger protein deposits formed and long before the onset of the disease, enabling the scientist to predict months in advance whether an animal would fall ill.

The researchers observed the formation of the fibers in a test tube experiment. They fused the mutated huntingtin protein with a fluorescent protein and introduced this artificially produced protein into extracted cerebral tissue. The fluorescent proteins attached themselves to the huntingtin protein chains in the brain extract, elongating the fibrous strand. They were easily detected through their fluorescence.

The research team used this method to determine how fast the harmful fibers would grow and how great their potential was to trigger the formation of new protein chains. After specifically triggering the formation of fibers in the cells, they were able to measure how quickly the fibers formed and thus predict the severity of Huntington’s disease in the genetically modified worms, flies, and mice: The stronger the activity of the particles, the stronger the animals were affected.

Best indication to date

“Our results are the best indication to date that seeding-competent huntingtin fibers are actually responsible for the disorder,” says Wanker. His team’s methods, he explains, have rendered something visible that could not be seen before. “We believe this is the best evidence so far that the misfolded protein also triggers Huntington’s,” Wanker continues, explaining that it makes the hypothesis that protein deposits are merely a waste product of the disease even less probable. “This is a huge step for the field.”

Improved research

One of the areas of application for these results would be diagnosis. Wanker explains how, currently, a gene analysis can confirm that a patient will definitely develop Huntington’s disease and die prematurely. However, he continues, being able to provide additional information as to whether the disease will emerge at the age of 40 or 60, or details as to how severe it will be, can help patients cope with the disease. “It would be amazing if we could one day determine the disease progression,” says Wanker. However, the test is still a very long way from having any clinical application.

At the moment, the new method has great potential for research and the search for new drugs. The mutated huntingtin proteins can be extracted from tissue in their earlier stage and tested with pharmaceutical substances to try and inhibit their harmful activity. Wanker hopes that this will lead to the discovery of new agents that could be used to combat the cause of Huntington’s disease.