Posted on Leave a comment

Deaths of despair: The opioid epidemic is just part of the problem

Opioid-related deaths contributed to more than 60,000 U.S. lives lost in 2016 but absolute declines in life expectancy relative to other countries and in various measures of psychosocial well-being have been observed starting as early as 1980. Increases in despair over time have had a broad effect among all groups and regions of the country in the United States, not just less-educated Whites, who have been identified as the primary victims. Researchers at Columbia University Mailman School of Public Health provide an overview of trends toward both increasing despair and declining health observed among many groups of people in the United States. The paper is published in the American Journal of Public Health.

“The opioid epidemic is sitting on top of a much longer, and more poorly understood, decline in the health and well-being in the United States,” said Peter Muennig, MD, professor of Health Policy and Management at Columbia School of Public Health. “Virtually any social trend that might correlate over time with changes in health curves is a candidate.”

There are several plausible contributors to the term coined as “true deaths of despair” — defined broadly as a decline in measures of psychosocial well-being over time. “If there is anything to which one can point that makes the U.S. an outlier in global rankings of health measures it is rising medical costs which may be compromising Americans ability to satisfy basic needs,” noted Muennig. “These costs are eating into middle-class American’s disposable income.”

Muennig and colleagues describe some of the other more popular and plausible explanations.

  • Failure of democratic institutions and regulations. The United States is falling behind other nations with respect to educational performance, income equality, environmental protection, transportation, waste management, the rule of law, and private gun ownership regulations.
  • Economic stagnation since the 1980s for moderate income households of all races and ethnicities.
  • A slowdown in immigration. Immigrants are much healthier than native born people on average.
  • Earlier smoking among White women could be producing lagged mortality effects that are surfacing in middle and older ages.

“The answer rests in a combination of factors,” noted Muennig. “But the attention that has been given to Whites as the primary victims of declining health is distracting researchers and policymakers from much more serious, longer-term structural problems that affect all Americans.”

Story Source:

Materials provided by Columbia University’s Mailman School of Public Health. Note: Content may be edited for style and length.

Posted on Leave a comment

When neglected children become adolescents

Many migrant children separated from their parents at the U.S. border, some of them very young, have landed in shelters where they often experience stress, neglect and minimal social and cognitive stimulation. The latest findings of the long-running Bucharest Early Intervention Project (BEIP), involving children in Romanian orphanages, tells a cautionary tale about the psychiatric and social risks of long-term deprivation and separation from parents.

BEIP has shown that children reared in very stark institutional settings, with severe social deprivation and neglect, are at risk for cognitive problems, depression, anxiety, disruptive behavior and attention-deficit hyperactivity disorder. But BEIP has also shown that placing children with quality foster families can mitigate some of these effects, if it’s done early.

The latest BEIP study, published this week by JAMA Psychiatry, asked what happens to the mental health of institutionalized children as they transition to adolescence. Outcomes at ages 8, 12 and 16 suggest diverging trajectories between children who remained in institutions versus those randomly chosen for placement with carefully vetted foster families.

Researchers led by Mark Wade, PhD, and Charles Nelson, PhD, of the Division of Developmental Medicine at Boston Children’s Hospital, studied 220 children of whom 119 had spent at least some time in institutions. Of the 119, half had been placed in foster care.

Over the years, teachers and caregivers completed the MacArthur Health and Behavior Questionnaire, which includes subscales on depression, overanxious, social anxiety/withdrawal, oppositional defiant behavior, conduct problems, overt aggression, relational aggression and ADHD. The surveys revealed that children who were placed early in quality foster care, compared with those who remained in institutions, had less psychopathology, and in particular fewer externalizing behaviors such as rule-breaking, excessive arguing with authority figures, stealing or assaulting peers. Differences began to emerge at 12 years and became significant at 16 years.

While conditions at Romanian orphanages aren’t the same as those in U.S. immigration detention systems, the researchers think the findings underscore the importance of keeping families together.

“Our results add to a growing literature on what might happen to a child’s long-term psychological development when they experience separation from a primary caregiver early in development,” says Wade. “Although this picture is very complex, we now know that many children who experience early neglect are at risk for an array of mental health problems later on. The good news is that if they are placed in high-quality homes with good caregiving, this risk is reduced. Yet they still tend to have more difficulties than their peers who never experienced this form of deprivation. So what we really need is policies and social programs prevent separation from primary caregivers in the first place.”

Story Source:

Materials provided by Boston Children’s Hospital. Note: Content may be edited for style and length.

Posted on Leave a comment

New bird flu viruses in ducks after vaccines largely prevented H7N9 in chickens

In response to bird flu pandemics starting in 2013, officials in China introduced a new vaccine for chickens in September 2017. Recent findings suggest that the vaccine largely worked but detected two new genetic variations of the H7N9 and H7N2 subtypes in unvaccinated ducks. These findings will be published in the journal Cell Host & Microbe on September 27.

“It surprised me that the novel, highly pathogenic subtypes had been generated in and adapted so well to ducks, because the original highly pathogenic form of H7N9 has very limited capacity to replicate in ducks,” says Hualan Chen, a senior author on the paper and an animal virologist at the Harbin Veterinary Research Institute.

Chen’s team collected over 37,928 chickens and 15,956 duck genetic samples 8 months before and 5 months after the vaccine’s introduction. They isolated 304 H7N9 viruses before the vaccine’s release, and only 17 H7N9 viruses and one H7N2 virus after.

“Our data show that vaccination of chickens successfully prevented the spread of the H7N9 virus in China,” says Chen. “The fact that human infection has not been detected since February 2018 indicates that consumers of poultry have also been well-protected from H7N9 infection.”

The bird flu virus replicates in host cells and often mutates and reassorts over time. When Chen’s team looked closely at the genetic types of the disease-causing strains in ducks, they found that an H7N2 and an H7N9 virus had picked up certain gene segments from other duck influenza viruses, improving their ability to infect ducks.

“Influenza viruses mutate as long as they replicate, but it’s very difficult to predict when the H7N9 virus will obtain a particular harmful mutation,” says Chen. “It is possible that the virus may adapt in other species in the future if it cannot be eliminated soon.”

China produces roughly three billion ducks per year, which is not to the scale of chicken production. To prevent further human infection, Chen and her team believe that the virus should be eliminated in ducks as soon as possible.

“Fortunately, our study indicates that the current vaccine will work well in ducks, so we do not need to develop a new one,” says Chen. “We suggest applying the H7 vaccine in ducks immediately.”

Story Source:

Materials provided by Cell Press. Note: Content may be edited for style and length.

Posted on Leave a comment

How Natural Killer cells regulate protective HIV antibodies

In the quest to develop a vaccine that triggers the immune system to prevent HIV infection, researchers have focused on identifying and eliciting a particular type of antibody that is capable of neutralizing the virus.

These broadly neutralizing antibodies, or bnAbs, eventually arise naturally in about half of HIV-infected people, but they develop too late to be effective, long after the virus has repeatedly mutated and inserted itself into the genome of host cells.

Searching for a way to elicit bnAbs before HIV infection so they can block the virus if they encounter it, a research team led by the Duke Human Vaccine Institute identified an important protein that is highly active in people who develop bnAbs compared to those who don’t.

The protein, called RAB11FIP5, appears to be involved in changing the distribution and function of natural-killer cells, which are among the immune system’s early responders during a viral infection. Natural killer cells also play a role in autoimmune diseases, when the body’s immune system turns on itself.

“This type of immune cell wasn’t previously known to regulate bnAbs,” said Barton Haynes, M.D., director of the Duke Human Vaccine Institute and senior author of a study published online Sept. 27 in the journal Cell. “We found a new natural killer cell cargo-carrying pathway that appears to be important in regulating the bnAb production.”

Haynes and colleagues, including lead author Todd Bradley, Ph.D., designed the study to analyze the molecular differences between HIV-infected people who make bnAbs, and those who don’t. They identified 239 infected people, and screened them to find approximately 50 on each extreme — those with the highest numbers of bnAbs, and those with the lowest.

The researchers used RNA sequencing analyses to determine the molecular differences that distinguished between those who produce bnAbs and those who do not, finding a marked discrepancy in the RAB11FIP5 gene expression.

“These data suggest that natural killer cell dysfunction permits bnAb development, implicating Rab11 as a modulator of the HIV antibody response,” Bradley said. “This is a new pathway that we hope to modulate during vaccination to generate a better HIV antibody response.”

Story Source:

Materials provided by Duke University Medical Center. Note: Content may be edited for style and length.

Posted on Leave a comment

Skin is a battlefield for mutations

Normal skin contains a patchwork of mutated cells, yet very few go on to eventually form cancer and scientists have now uncovered the reason why. Researchers at the Wellcome Sanger Institute and MRC Cancer Unit, University of Cambridge genetically engineered mice to show that mutant cells in skin tissue compete with each other, with only the fittest surviving.

The results, published today (27 September) in Cell Stem Cell suggest that normal skin in humans is more resilient to cancer than previously thought and can still function while a battle between mutated cells takes place in the tissue.

Non-melanoma skin cancer in humans includes two main types: basal cell skin cancer and squamous cell skin cancer, both of which develop in areas of the skin that have been exposed to the sun. Basal cell skin cancer is the most common type of skin cancer, whereas squamous cell skin cancer is generally faster growing. There are over 140,000 new cases of non-melanoma skin cancer each year in the UK*.

However, every person who has been exposed to sunlight carries many mutated cells in their skin, and only very few of these may develop into tumours. The reasons for this are not well understood.

For the first time, researchers have shown that mutated cells in the skin grow to form clones that compete against each other. Many mutant clones are lost from the tissue in this competition, which resembles the selection of species that occurs in evolution. Meanwhile, the skin tissue is resilient and functions normally while being taken over by competing mutant cells.

Professor Phil Jones, lead author from the Wellcome Sanger Institute and MRC Cancer Unit, University of Cambridge, said: “In humans, we see a patchwork of mutated skin cells that can expand enormously to cover several millimetres of tissue. But why doesn’t this always form cancer? Our bodies are the scene of an evolutionary battlefield. Competing mutants continually fight for space in our skin, where only the fittest survive.”

In the study, scientists used mice to model the mutated cells seen in human skin. Researchers focussed on the p53 gene, a key driver in non-melanoma skin cancers.

The team created a genetic ‘switch’, which when turned on, replaced p53 with the identical gene including the equivalent of a single letter base change (like a typo in a word). This changed the p53 protein and gave mutant cells an advantage over their neighbours. The mutated cells grew rapidly, spread and took over the skin tissue, which became thicker in appearance. However, after six months the skin returned to normal and there was no visual difference between normal skin and mutant skin.

The team then investigated the role of sun exposure on skin cell mutations. Researchers shone very low doses of ultraviolet light (below sunburn level) onto mice with mutated p53. The mutated cells grew much faster, reaching the level of growth seen at six months in non-UV radiated clones in only a few weeks. However, despite the faster growth, cancer did still not form after nine months of exposure.

Dr Kasumi Murai, joint first author from the Wellcome Sanger Institute, said: “We did not observe a single mutant colony of skin cells take over enough to cause cancer, even after exposure to ultraviolet light. Exposure to sunlight continually created new mutations that outcompeted the p53 mutations. We found the skin looked completely normal after we shone UV light on the mice, indicating that tissues are incredibly well-designed to tolerate these mutations and still function.”

Dr Ben Hall, senior author from the MRC Cancer Unit, University of Cambridge said: “The reason that people get non-melanoma skin cancer is because so much of their skin has been colonised by competing mutant cells over time. This study shows that the more we are exposed to sunlight, the more it drives new mutations and competition in our skin. Eventually the surviving mutation may evolve into a cancer.”

Posted on Leave a comment

Women much less likely to ask questions in academic seminars than men

The bias, identified in a paper published today in PLOS ONE, is thought to be particularly significant because departmental seminars are so frequent and because junior academics are more likely to experience them before other kinds of scholarly events. They also feature at an early stage in the career pipeline when people are making major decisions about their futures.

“Our finding that women ask disproportionately fewer questions than men means that junior scholars are encountering fewer visible female role models in their field,” warns lead author, Alecia Carter.

Survey data

In addition to observational data, Carter and her co-authors drew on survey responses from over 600 academics ranging from postgraduates to faculty members (303 female and 206 male) from 28 different fields of study in 20 countries.

These individuals reported their attendance and question-asking activity in seminars, their perceptions of others’ question-asking behaviour, and their beliefs about why they and others do and do not ask questions.

The survey revealed a general awareness, especially among women, that men ask more questions than women. A high proportion of both male and female respondents reported sometimes not asking a question when they had one. But men and women differed in their ratings of the importance of different reasons for this.

Crucially, women rated ‘internal’ factors such as ‘not feeling clever enough’, ‘couldn’t work up the nerve’, ‘worried that I had misunderstood the content’ and ‘the speaker was too eminent/intimidating’, as being more important than men did.

“But our seminar observation data show that women are not inherently less likely to ask questions when the conditions are favourable,” says Dieter Lukas, who was a postdoctoral researcher at Cambridge during the data collection.

Question-asking behaviour

The researchers found that women were more likely to speak up, for instance, when more questions were asked. When 15 questions were asked in total, as opposed to the median of 6, there was a 7.6% increase in the proportion of questions asked by women.

But when the first question in a seminar was asked by a man, the proportion of subsequent questions asked by women fell 6%, compared to when the first question was asked by a woman. The researchers suggest that this may be an example of ‘gender stereotype activation’, in which a male-first question sets the tone for the rest of the session, which then dissuades women from participating.

“While calling on people in the order that they raise their hands may seem fair, it may inadvertently result in fewer women asking questions because they might need more time to formulate questions and work up the nerve,” said co-author Alyssa Croft, a psychologist at the University of Arizona.

The researchers were initially surprised to discover that women ask proportionally more questions of male speakers and that men ask proportionally more of female speakers.

“This may be because men are less intimidated by female speakers than women are. It could also be the case that women avoid challenging a female speaker, but may be less concerned for a male speaker,” said co-author Gillian Sandstrom, a psychologist at the University of Essex.

Linked to this, the study’s survey data revealed that twice as many men (33%) as women (16%) reported being motivated to ask a question because they felt that they had spotted a mistake.

Women were also more likely to ask questions when the speaker was from their own department, suggesting that familiarity with the speaker may make asking a question less intimidating. The study interprets this as a demonstration of the lower confidence reported by female audience members.

Welcoming the research, Professor Dame Athene Donald, Professor of Experimental Physics at the University of Cambridge and Master of Churchill College, Cambridge, said:

“asking questions at the end of talks is one of the activities that (still) makes me most nervous … Whatever anyone may think when they meet me about how assertive my behaviour is, it would seem that I too have internalised this gender stereotype’.

Recommendations

“This problem can only be addressed by lasting changes in the academic culture which break gender stereotypes and provide an inclusive environment,” Alecia Carter says.

The researchers accept that this will take time but make four key recommendations to improve the situation in departmental seminars:

  • Where possible, seminar organisers should avoid placing limits on the time available for questions. Alternatively, moderators should endeavour to keep each question and answer short to allow more questions to be asked.
  • Moderators should prioritise a female-first question, be trained to ‘see the whole room’ and maintain as much balance as possible with respect to gender and seniority of question-askers.
  • Seminar organisers are encouraged not to neglect inviting internal speakers.
  • Organisers should consider providing a small break between the talk and the question period to give attendees more time to formulate a question and try it out on a colleague.

“Although we developed these recommendations with the aim of increasing women’s visibility, they are likely to benefit everyone, including other underrepresented groups in academia,” said Carter.

“This is about removing the barriers that restrain anyone from speaking up and being visible.”

Posted on Leave a comment

Sugar-powered sensor developed to detect, prevent disease

Researchers at Washington State University have developed an implantable, biofuel-powered sensor that runs on sugar and can monitor a body’s biological signals to detect, prevent and diagnose diseases.

A cross-disciplinary research team led by Subhanshu Gupta, assistant professor in WSU’s School of Electrical Engineering and Computer Science, developed the unique sensor, which, enabled by the biofuel cell, harvests glucose from body fluids to run.

The research team has demonstrated a unique integration of the biofuel cell with electronics to process physiological and biochemical signals with high sensitivity.

Their work recently was published in the IEEE Transactions of Circuits and Systems journal.

Professors Su Ha and Alla Kostyukova from the Gene and Linda School of Chemical Engineering and Bioengineering, led design of the biofuel cell.

Many popular sensors for disease detection are either watches, which need to be recharged, or patches that are worn on the skin, which are superficial and can’t be embedded. The sensor developed by the WSU team could also remove the need to prick a finger for testing of certain diseases, such as diabetes.

“The human body carries a lot of fuel in its bodily fluids through blood glucose or lactate around the skin and mouth,” said Gupta. “Using a biofuel cell opens the door to using the body as potential fuel.”

The electronics in the sensor use state-of-the-art design and fabrication to consume only a few microwatts of power while being highly sensitive. Coupling these electronics with the biofuel cell makes it more efficient than traditional battery-powered devices, said Gupta. Since it relies on body glucose, the sensor’s electronics can be powered indefinitely. So, for instance, the sensor could run on sugar produced just under the skin.

Unlike commonly used lithium-ion batteries, the biofuel cell is also completely non-toxic, making it more promising as an implant for people, he said. It is also more stable and sensitive than conventional biofuel cells.

The researchers say their sensor could be manufactured cheaply through mass production, by leveraging economies of scale.

While the sensors have been tested in the lab, the researchers are hoping to test and demonstrate them in blood capillaries, which will require regulatory approval. The researchers are also working on further improving and increasing the power output of their biofuel cell.

“This brings together the technology for making a biofuel cell with our sophisticated electronics,” said Gupta. “It’s a very good marriage that could work for many future applications.”

Story Source:

Materials provided by Washington State University. Note: Content may be edited for style and length.

Posted on Leave a comment

'Cellular memory' of DNA damage in oocyte quality control

Females are born with a finite number of eggs that are steadily depleted throughout their lifetime. This reserve of eggs is selected from a much larger pool of millions of precursor cells, or oocytes, that form during fetal life. So there is a substantial amount of quality control during the process of forming an egg cell, or ovum, that weeds out all but the highest quality cells. New research from Neil Hunter’s laboratory at UC Davis reveals the surprising way that this critical oocyte quality control process works.

Previous research in the Hunter lab showed that a gene called Rnf212 is required for chromosomes to undergo crossing over during the early stages of oocyte development. The researchers were surprised to find a new, late function for Rnf212 in the oocyte selection process. The results are published Sept. 27 in the journal Molecular Cell.

During oocyte quality control, a decision is made whether each oocyte should continue and join the reserve of eggs, or undergo apoptosis — cellular death.

“We almost stumbled upon this role in oocyte quality control when Joe (Huanyu Qiao, joint first author) first noticed that the Rnf212 mutants had more oocytes in their ovaries,” said Hunter, professor of Microbiology and Molecular Genetics and an Investigator of the Howard Hughes Medical Institute. Hunter is senior author on the paper.

In mice, as in humans, developing females initially form very large number of oocytes. Around six million oocytes enter meiosis in humans, but a stunning 5 million are culled by birth. By puberty, the ovaries contain only around 250,000 oocytes, which are steadily depleted until menopause.

This drastic reduction reflects selection for only the highest quality oocytes. Oocytes that experienced defects in meiosis, including damage to their DNA, are culled. Only those that pass through quality control checkpoints can continue and become established in the ovarian reserve.

In mice that lacked Rnf212, more oocytes were able to pass through quality control checkpoints, increasing the overall size of the ovarian reserve.

A “cellular memory” of DNA damage

During the formation of gametes (sperm and eggs), portions of the parental chromosomes are swapped through the formation and repair of DNA breaks, a process called crossover. If the crossover process is defective, the repair of some DNA breaks is delayed. RNF212 helps tag these lingering breaks so that defective oocytes are sensitive to apoptosis.

The researchers found that RNF212 prevents the repair of lingering breaks to create a “cellular memory” of defects that occured in earlier stages of development. This allows the cell to assess how bad the defects were. If the number of unrepaired breaks passes a critical threshold of around ten, the cell is deemed to be of poor quality and undergoes apoptosis. If there are only a few lingering breaks, repair is reactivated and the oocyte is allowed to progress and become part of the ovarian reserve.

“It seems counterintuitive that a cell would actively impede DNA repair, but this is how oocytes gauge the success of earlier events. High levels of lingering breaks means there was a problem and the oocyte is likely to form a low quality egg,” Hunter said.

Bigger isn’t always better

Female fecundity depends primarily on two factors: the size of her ovarian reserve and the quality of eggs in it. Thus, the reproductive system must balance quality and quantity of oocytes for optimal fertility.

In mice without RNF212, lingering breaks are quickly repaired allowing significantly defective oocytes to sneak through quality control. Thus the overall size of the ovarian reserve is increased at the expense of oocyte quality. Many such oocytes would likely terminate early in a spontaneous miscarriage, causing fertility issues. Fetuses that develop further would have a higher risk of severe developmental defects.

“Basically, anything that goes wrong in the germline is a risk for congenital disease,” said Hunter.

Previous research has shown that variants of the Rnf212 gene affect the rate of chromosome crossovers. This new work suggests that Rnf212variants might also affect the size and quality of ovarian reserves.

Posted on Leave a comment

New gene variants associated with chronic back pain

Chronic back pain is the number one cause of years lived with disability worldwide. In a new study, Pradeep Suri of the Department of Veterans Affairs in Seattle, Washington, and colleagues in the United States and Europe, in association with Dr. Frances Williams from King’s College London’s Department of Twin Research and Genetic Epidemiology, identified three novel genetic variants associated with chronic back pain. The study, which was published in the open-access journal PLOS Genetics, links the risk for back pain with variants in genes controlling skeletal development, among other pathways. These findings may help to elucidate the basic biology underlying this common symptom, and point toward avenues for the eventual development of new therapies.

The researchers conducted a genome-wide association study in 158,000 adults of European ancestry, including over 29,000 individuals with chronic back pain, looking for gene variants that were associated with the presence of back pain. The strongest association was with a variant in the SOX5 gene, which is a transcription factor involved in virtually all phases of embryonic development. Inactivation of SOX5 has previously been linked to defects in cartilage and skeleton formation in mice, supporting the hypothesis that the variant discovered in this study may contribute to chronic back pain through its influence on some aspect of skeletal development. The association of the SOX5 variant with chronic back pain was replicated in another group of over 280,000 individuals, including over 50,000 individuals with chronic back pain. A second gene, previously associated with intervertebral disc herniation, was also linked to back pain, as was a third gene that plays a role in spinal cord development, possibly implicating pain sensation or mood in the risk for back pain.

“The results of our genome-wide association study point to multiple pathways that may influence risk for chronic back pain,” said Suri. “Chronic back pain is linked to changes in mood, and the role of the central nervous system in the transition from acute to chronic back pain is well-recognized. However, the top two genetic variants we identified suggest causes implicating the peripheral structures, such as the spine. We expect that further large-scale genetic studies will reveal the importance of both peripheral and central contributors to the complex experience of chronic back pain.”

Story Source:

Materials provided by PLOS. Note: Content may be edited for style and length.


Journal Reference:

  1. Pradeep Suri, Melody R. Palmer, Yakov A. Tsepilov, Maxim B. Freidin, Cindy G. Boer, Michelle S. Yau, Daniel S. Evans, Andrea Gelemanovic, Traci M. Bartz, Maria Nethander, Liubov Arbeeva, Lennart Karssen, Tuhina Neogi, Archie Campbell, Dan Mellstrom, Claes Ohlsson, Lynn M. Marshall, Eric Orwoll, Andre Uitterlinden, Jerome I. Rotter, Gordan Lauc, Bruce M. Psaty, Magnus K. Karlsson, Nancy E. Lane, Gail P. Jarvik, Ozren Polasek, Marc Hochberg, Joanne M. Jordan, Joyce B. J. Van Meurs, Rebecca Jackson, Carrie M. Nielson, Braxton D. Mitchell, Blair H. Smith, Caroline Hayward, Nicholas L. Smith, Yurii S. Aulchenko, Frances M. K. Williams. Genome-wide meta-analysis of 158,000 individuals of European ancestry identifies three loci associated with chronic back pain. PLOS Genetics, 2018; 14 (9): e1007601 DOI: 10.1371/journal.pgen.1007601

Cite This Page:

PLOS. “New gene variants associated with chronic back pain: Developmental genes may provide clues for understanding the occurrence of this common symptom.” ScienceDaily. ScienceDaily, 27 September 2018. <www.sciencedaily.com/releases/2018/09/180927145324.htm>.

PLOS. (2018, September 27). New gene variants associated with chronic back pain: Developmental genes may provide clues for understanding the occurrence of this common symptom. ScienceDaily. Retrieved September 27, 2018 from www.sciencedaily.com/releases/2018/09/180927145324.htm

PLOS. “New gene variants associated with chronic back pain: Developmental genes may provide clues for understanding the occurrence of this common symptom.” ScienceDaily. www.sciencedaily.com/releases/2018/09/180927145324.htm (accessed September 27, 2018).

Posted on Leave a comment

The hormone FGF23 is linked to structural deficits in the brain

Scientists at the Medical University of South Carolina (MUSC) have uncovered mechanisms by which high levels of a hormone called FGF23 can reduce brain health.

In results published in the journal PLoS ONE on September 7th, 2018, high levels of fibroblast growth factor 23 (FGF23) were associated with structural changes in the brain’s frontal lobes. High FGF23 levels are thought to lead to the vascular calcification seen in patients with chronic kidney disease. The study showed that such a process may also affect the brain in patients without chronic kidney disease but with elevated cardiovascular risk factors, according to Leonardo Bonilha, M.D., Ph.D., associate professor of neurology in the MUSC Department of Medicine and director of the study.

“We found that there is a relationship between high levels of FGF23 and a form of structural compromise in the brain,” said Bonilha.

FGF23 is produced in the bone. Normally, FGF23 works in the kidneys and the gut to regulate levels of calcium and phosphate in the body. It is thought to be increased in people who eat a diet high in phosphates, which are often found in foods with preservatives. In people with chronic kidney disease or in those who consume a diet high in phosphates, can be a calcification of their arteries, which can cause heart attack or stroke. FGF23 may be the reason.

Bonilha and graduate student Barbara Marebwa were interested in knowing if FGF23 could cause brain problems in people who had elevated cardiovascular risk factors, such as high blood pressure, diabetes, or high cholesterol. The idea was to determine if a high FGF23 level, present in people who did not have chronic kidney disease, was an indicator of problems in the brain.

Bonilha and Marebwa tested the idea that FGF23 and cardiovascular risk factors put together were an indicator of problems with communication in different parts of the brain. They recruited 50 patients for the study, about half of whom had elevated cardiovascular risk factors and about half of whom did not. All of the patients had normal kidney function. The researchers used magnetic resonance imaging to examine the connectomes in patients’ brains, which was a way to see how different regions of their brains were connected. The method allows researchers to examine the white matter of the brain, which is more vulnerable to the type of stress that can occur when vessels become calcified. The frontal lobes, which control learning and complex cognitive functions, have a particularly high density of white matter, and thus may be most vulnerable to this type of stress.

The team looked at a feature of the connectome called modularity, which can reveal how well different parts of the brain are organized. People with abnormally high modularity have higher levels of disconnection in the brain, which may indicate problems with brain health in those areas. The researchers found that, in patients with high levels of FGF23 and cardiovascular risk factors, modularity was also high. In patients without cardiovascular risk factors, FGF23 levels were not associated with increased modularity. These results mean that FGF23 is associated with problems with brain health in people who already have high blood pressure, diabetes, or high cholesterol. As a result, elevated FGF23 levels may lead to structural damage in parts of the brain that may put people at a higher risk of stroke or problems with stroke recovery.

“It is important to understand the factors that relate to brain health, because brain health is associated with aging and resilience to injury. For example, if you get a stroke and you already have compromised brain health, the stroke may be more severe and you may not recover as well,” explained Bonilha.

The work was part of a strategically focused research network (SFRN) grant funded by the American Heart Association to MUSC to examine disparities in stroke recovery. Myles Wolf, holder of an SFRN grant in cardiac and kidney research at Duke, contributed to the work. Together, the research team may have found a potential disparity in stroke recovery by highlighting vulnerability in the brains of patients with high FGF23 levels. For example, people without access to fresh foods may have high levels of FGF23 and thus an increased risk of stroke.

The next step, according to Bonilha, is to determine if lowering FGF23 levels in patients with cardiovascular risk factors can lead to better brain health or even to better outcomes following stroke. Previous work in other laboratories has revealed that FGF23 levels are elevated in people with cardiovascular risk factors and who consume a diet high in phosphates. The new results build on this finding and highlight the importance of a healthy diet in protecting the brain.

“This study is an important first step to lead to strategies to improve dietary habits and improve brain health,” said Bonilha.