Posts tagged neurology
Articles and news from the latest research reports.
Study debunks controversial MS theory
There is no evidence that impaired blood flow or blockage in the veins of the neck or head is involved in multiple sclerosis, says a McMaster University study.
The research, published online by PLOS ONE Wednesday, found no evidence of abnormalities in the internal jugular or vertebral veins or in the deep cerebral veins of any of 100 patients with multiple sclerosis (MS) compared with 100 people who had no history of any neurological condition.
The study contradicts a controversial theory that says that MS, a chronic, neurodegenerative and inflammatory disease of the central nervous system, is associated with abnormalities in the drainage of venous blood from the brain. In 2008 Italian researcher Paolo Zamboni said that angioplasty, a blockage clearing procedure, would help MS patients with a condition he called chronic cerebrospinal venous insufficiency (CCSVI). This caused a flood of public response in Canada and elsewhere, with many concerned individuals lobbying for support of the ‘Liberation Treatment’ to clear the veins, as advocated by Zamboni.
“This is the first Canadian study to provide compelling evidence against the involvement of CCSVI in MS,” said principal investigator Ian Rodger, a professor emeritus of medicine in the Michael G. DeGroote School of Medicine. “Our findings bring a much needed perspective to the debate surrounding venous angioplasty for MS patients”.
In the study all participants received an ultrasound of deep cerebral veins and neck veins as well as a magnetic resonance imaging (MRI) of the neck veins and brain. Each participant had both examinations performed on the same day. The McMaster research team included a radiologist and two ultrasound technicians who had trained in the Zamboni technique at the Department of Vascular Surgery of the University of Ferrara.
(Source: dailynews.mcmaster.ca)
There’s Life After Radiation for Brain Cells
Johns Hopkins researchers suggest neural stem cells may regenerate after anti-cancer treatment
Scientists have long believed that healthy brain cells, once damaged by radiation designed to kill brain tumors, cannot regenerate. But new Johns Hopkins research in mice suggests that neural stem cells, the body’s source of new brain cells, are resistant to radiation, and can be roused from a hibernation-like state to reproduce and generate new cells able to migrate, replace injured cells and potentially restore lost function.
“Despite being hit hard by radiation, it turns out that neural stem cells are like the special forces, on standby waiting to be activated,” says Alfredo Quiñones-Hinojosa, M.D., a professor of neurosurgery at the Johns Hopkins University School of Medicine and leader of a study described online today in the journal Stem Cells. “Now we might figure out how to unleash the potential of these stem cells to repair human brain damage.”
The findings, Quiñones-Hinojosa adds, may have implications not only for brain cancer patients, but also for people with progressive neurological diseases such as multiple sclerosis (MS) and Parkinson’s disease (PD), in which cognitive functions worsen as the brain suffers permanent damage over time.
In Quiñones-Hinojosa’s laboratory, the researchers examined the impact of radiation on mouse neural stem cells by testing the rodents’ responses to a subsequent brain injury. To do the experiment, the researchers used a device invented and used only at Johns Hopkins that accurately simulates localized radiation used in human cancer therapy. Other techniques, the researchers say, use too much radiation to precisely mimic the clinical experience of brain cancer patients.
In the weeks after radiation, the researchers injected the mice with lysolecithin, a substance that caused brain damage by inducing a demyelinating brain lesion, much like that present in MS. They found that neural stem cells within the irradiated subventricular zone of the brain generated new cells, which rushed to the damaged site to rescue newly injured cells. A month later, the new cells had incorporated into the demyelinated area where new myelin, the protein insulation that protects nerves, was being produced.
“These mice have brain damage, but that doesn’t mean it’s irreparable,” Quiñones-Hinojosa says. “This research is like detective work. We’re putting a lot of different clues together. This is another tiny piece of the puzzle. The brain has some innate capabilities to regenerate and we hope there is a way to take advantage of them. If we can let loose this potential in humans, we may be able to help them recover from radiation therapy, strokes, brain trauma, you name it.”
His findings may not be all good news, however. Neural stem cells have been linked to brain tumor development, Quiñones-Hinojosa cautions. The radiation resistance his experiments uncovered, he says, could explain why glioblastoma, the deadliest and most aggressive form of brain cancer, is so hard to treat with radiation.
(Source: hopkinsmedicine.org)
Robot uses steerable needles to treat brain clots
Surgery to relieve the damaging pressure caused by hemorrhaging in the brain is a perfect job for a robot.
That is the basic premise of a new image-guided surgical system under development at Vanderbilt University. It employs steerable needles about the size of those used for biopsies to penetrate the brain with minimal damage and suction away the blood clot that has formed.
The system is described in an article accepted for publication in the journal IEEE Transactions on Biomedical Engineering. It is the product of an ongoing collaboration between a team of engineers and physicians headed by Assistant Professor Robert J. Webster III and Assistant Professor of Neurological Surgery Kyle Weaver.
Brain clots are leading cause of death, disability
The odds of a person getting an intracerebral hemorrhage are one in 50 over his or her lifetime. When it does occur, 40 percent of the individuals die within a month. Many of the survivors have serious brain damage.
“When I was in college, my dad had a brain hemorrhage,” said Webster. “Fortunately, he was one of the lucky few who survived and recovered fully. I’m glad I didn’t know how high his odds of death or severe brain damage were at the time, or else I would have been even more scared than I already was.”
Steerable needle could prevent “collateral damage” during surgery
Operations to “debulk” intracerebral hemorrhages are not popular among neurosurgeons: They know their efforts are not likely to make a difference, except when the clots are small and lie on the brain’s surface where they are easy to reach. Surgeons generally agree that there is a clinical benefit from removing 25-50 percent of a clot but that benefit can be offset by the damage that is done to the surrounding tissue when the clot is removed. Therefore, when a serious clot is detected in the brain, doctors take a “watchful waiting” approach – administering drugs that decrease the swelling around the clot in hopes that this will be enough to make the patient improve without surgery.
For the last four years, Webster’s team has been developing a steerable needle system for “transnasal” surgery: operations to remove tumors in the pituitary gland and at the skull base that traditionally involve cutting large openings in a patient’s skull and/or face. Studies have shown that using an endoscope to go through the nasal cavity is less traumatic, but the procedure is so difficult that only a handful of surgeons have mastered it.
Last summer, Webster attended a conference in Italy where one of the speakers, Marc Simard, a neurosurgeon at the University of Maryland School of Medicine, ran through his wish list of useful imaginary neurosurgical devices, hoping that some engineer in the audience might one day be able to build one of them. When he described his wish to have a needle-sized robot arm to reach deep into the brain to remove clots, Webster couldn’t help smiling because the steerable needle system he had been developing was perfect for the job.
Webster’s design, which he calls an active cannula, consists of a series of thin, nested tubes. Each tube has a different intrinsic curvature. By precisely rotating, extending and retracting these tubes, an operator can steer the tip in different directions, allowing it to follow a curving path through the body. The single needle system required for removing brain clots was actually much simpler than the multi-needle transnasal system.
When Webster returned, he told Weaver about the potential new application. The neurosurgeon was quite supportive: “I think this can save a lot of lives. There are a tremendous number of intracerebral hemorrhages and the number is certain to increase as the population ages.”
Graduate student Philip Swaney, who is working on the system, likes the fact it is closest to commercialization of all the projects in Webster’s Medical and Electromechanical Design Laboratory. “I like the idea of working on something that will begin saving lives in the very near future,” he said.
Active cannula removed 92 percent of clots in simulations
The brain-clot system only needs two tubes: a straight outer tube and a curved inner tube. Both are less than one twentieth of an inch in diameter. When a CT scan has determined the location of the blood clot, the surgeon determines the best point on the skull and the proper insertion angle for the probe. The angle is dialed into a fixture, called a trajectory stem, which is attached to the skull immediately above a small hole that has been drilled to enable the needle to pass into the patient’s brain.
The surgeon positions the robot so it can insert the straight outer tube through the trajectory stem and into the brain. He also selects the small inner tube with the curvature that best matches the size and shape of the clot, attaches a suction pump to its external end and places it in the outer tube.
Guided by the CT scan, the robot inserts the outer tube into the brain until it reaches the outer surface of the clot. Then it extends the curved, inner tube into the clot’s interior. The pump is turned on and the tube begins acting like a tiny vacuum cleaner, sucking out the material. The robot moves the tip around the interior of the clot, controlling its motion by rotating, extending and retracting the tubes. According to the feasibility studies the researchers have performed, the robot can remove up to 92 percent of simulated blood clots.
“The trickiest part of the operation comes after you have removed a substantial amount of the clot. External pressure can cause the edges of the clot to partially collapse making it difficult to keep track of the clot’s boundaries,” said Webster.
The goal of a future project is to add ultrasound imaging combined with a computer model of how brain tissue deforms to ensure that all of the desired clot material can be removed safely and effectively.
Anemia Linked to Increased Risk of Dementia
Anemia, or low levels of red blood cells, may increase the risk of dementia, according to a study published in the July 31, 2013, online issue of Neurology®, the medical journal of the American Academy of Neurology.
“Anemia is common in the elderly and occurs in up to 23 percent of adults ages 65 and older,” said study author Kristine Yaffe, MD, with the University of California – San Francisco and a member of the American Academy of Neurology. “The condition has also been linked in studies to an increased risk of early death.”
For the study, 2,552 older adults between the ages of 70-79 were tested for anemia and also underwent memory and thinking tests over 11 years. Of those, 393 had anemia at the start of the study. At the end of the study, 445, or about 18 percent of participants, developed dementia.
The research found that people who had anemia at the start of the study had a nearly 41 percent higher risk of developing dementia than those who were not anemic. The link remained after considering other factors, such as age, race, sex and education. Of the 393 people with anemia, 89 people, or 23 percent, developed dementia, compared to 366 of the 2,159 people who did not have anemia, or 17 percent.
“There are several explanations for why anemia may be linked to dementia. For example, anemia may be a marker for poor health in general, or low oxygen levels resulting from anemia may play a role in the connection. Reductions in oxygen to the brain have been shown to reduce memory and thinking abilities and may contribute to damage to neurons,” said Yaffe.
NIH launches neurological drug development projects
New projects will target Fragile X syndrome, nicotine addiction, and age-related macular degeneration
The National Institutes of Health has launched three innovative projects that will focus on development of therapeutics for Fragile X syndrome, nicotine addiction, and age-related macular degeneration (AMD). These projects are funded through the NIH Blueprint Neurotherapeutics Network which provides access to a variety of drug development resources.
“We are excited about the opportunity to apply cutting-edge science to the pursuit of novel treatments for these debilitating disorders” said Rebecca Farkas, Ph.D., program director at NIH’s National Institute of Neurological Disorders and Stroke (NINDS), Office of Translational Research.
The purpose of the NIH Blueprint is to provide in-depth research capabilities to increase the success rate of innovative drug discovery efforts. The program uses a virtual pharma model to provide researchers with access to support and resources that have been traditionally available to large pharmaceutical companies.
Partnerships between NIH program staff and awarded research teams are designed to bridge the funding gap between ground-breaking laboratory research and industry adoption. NIH staff helps investigators work with veteran industry drug development consultants and contract research organization capabilities from the discovery stage through preliminary clinical trials. In addition, each investigator maintains sole ownership of intellectual property associated with his or her project
NIH launched the Blueprint Neurotherapeutics Network in 2011. Including these three awards, 14 drug discovery programs have been funded as part of the program and 10 are currently active (see: http://neuroscienceblueprint.nih.gov/bpdrugs/bpn.htm).
The newly-funded investigators and their organizations are:
- Sage Therapeutics, Cambridge, Mass.
Principal Investigator: Al Robichaud, Ph.D.
Disorder: Fragile X syndrome
Project Summary: Fragile X syndrome is a genetic disorder linked to a range of neurodevelopmental disorders including learning disabilities and cognitive impairment. Many patients experience general and social anxiety yet benzodiazepines, which are drugs typically used to treat anxiety disorders, provide little relief. Their anxiety has been linked to reduced activity in the brain by a protein called, the GABA A receptor. Sage Therapeutics is developing positive allosteric modulators, designed to enhance the receptor’s activity and possibly relieve the anxiety.
- The Scripps Research Institute, Jupiter, Fla.
Principal Investigator: Paul J. Kenny, Ph.D.
Disorder: nicotine addiction
Project Summary: Nicotine addiction has been attributed to the stimulatory effects of nicotine binding to brain proteins called orexin 1 receptors. Dr. Kenny and colleagues will develop selective receptor antagonists as potential smoking cessation aids to treat people who have attempted to quit smoking but faced high relapse rates and significant side effects.
- University of Utah, Salt Lake City
Principal Investigator: Dean Yaw Li, Ph.D.
Disorder: age-related macular degeneration
Project Summary: Age-related macular degeneration is a leading cause of blindness in the United States. One form, called wet AMD, is associated with inflammation and blood vessel leakage in the retina, the eye’s light-sensitive tissue. Dean Li and his colleagues are developing small molecules that inhibit the activity of Arf6, a molecule known to help control inflammation and blood vessel leakage. This novel approach may lead to effective therapies for treating patients who do not respond to current wet AMD therapies.
(Source: nih.gov)
Study finds evidence of nerve damage in around half of fibromyalgia patients
Small study could lead to identification of treatable diseases for some with chronic pain syndrome
About half of a small group of patients with fibromyalgia – a common syndrome that causes chronic pain and other symptoms – was found to have damage to nerve fibers in their skin and other evidence of a disease called small-fiber polyneuropathy (SFPN). Unlike fibromyalgia, which has had no known causes and few effective treatments, SFPN has a clear pathology and is known to be caused by specific medical conditions, some of which can be treated and sometimes cured. The study from Massachusetts General Hospital (MGH) researchers will appear in the journal PAIN and has been released online.
"This provides some of the first objective evidence of a mechanism behind some cases of fibromyalgia, and identifying an underlying cause is the first step towards finding better treatments," says Anne Louise Oaklander, MD, PhD, director of the Nerve Injury Unit in the MGH Department of Neurology and corresponding author of the Pain paper.
The term fibromyalgia describes a set of symptoms – including chronic widespread pain, increased sensitivity to pressure, and fatigue – that is believed to affect 1 to 5 percent of individuals in Western countries, more frequently women. While a diagnosis of fibromyalgia has been recognized by the National Institutes of Health and the American College of Rheumatology, its biologic basis has remained unknown. Fibromyalgia shares many symptoms with SFPN, a recognized cause of chronic widespread pain for which there are accepted, objective tests.
Designed to investigate possible connections between the two conditions, the current study enrolled 27 adult patients with fibromyalgia diagnoses and 30 healthy volunteers. Participants went through a battery of tests used to diagnose SFPN, including assessments of neuropathy based on a physical examination and responses to a questionnaire, skin biopsies to evaluate the number of nerve fibers in their lower legs, and tests of autonomic functions such as heart rate, blood pressure and sweating.
The questionnaires, exam assessments, and skin biopsies all found significant levels of neuropathy in the fibromyalgia patients but not in the control group. Of the 27 fibromyalgia patients, 13 had a marked reduction in nerve fiber density, abnormal autonomic function tests or both, indicating the presence of SFPN. Participants who met criteria for SFPN also underwent blood tests for known causes of the disorder, and while none of them had results suggestive of diabetes, a common cause of SFPN, two were found to have hepatitis C virus infection, which can be successfully treated, and more than half had evidence of some type of immune system dysfunction.
"Until now, there has been no good idea about what causes fibromyalgia, but now we have evidence for some but not all patients. Fibromyalgia is too complex for a ‘one size fits all’ explanation," says Oaklander, an associate professor of Neurology at Harvard Medical School. "The next step of independent confirmation of our findings from other laboratories is already happening, and we also need to follow those patients who didn’t meet SFPN criteria to see if we can find other causes. Helping any of these people receive definitive diagnoses and better treatment would be a great accomplishment."
(Source: massgeneral.org)
Statins Suppress Rett Syndrome Symptoms in Mice
Statins, a class of cholesterol-lowering drugs found in millions of medicine cabinets, may help treat Rett Syndrome, according to a study published today in Nature Genetics. The Rett Syndrome Research Trust (RSRT) funded this work with generous support from the Rett Syndrome Research Trust UK and Rett Syndrome Research & Treatment Foundation.
Rett Syndrome is a neurological disorder that affects girls. A seemingly typical toddler begins to miss developmental milestones. A regression follows as young girls lose speech, mobility, and hand use. Many girls have seizures, orthopedic and severe digestive problems, as well as breathing and other autonomic impairments. Most live into adulthood and require total, round-the-clock care. Rett Syndrome affects about 1 in 10,000 girls born in the U.S. each year.
The new study screened for randomly induced mutations in genes that modify the effect of the Rett gene, MECP2 (methyl-CpG-binding protein 2), in a mouse model. MECP2 turns other genes on or off by disrupting chromatin, the DNA-protein mix that makes up chromosomes.
The challenge of treating Rett Syndrome is what drove senior author Monica Justice, Ph.D., Professor in the Departments of Molecular and Human Genetics and Molecular Physiology and Biophysics at the Baylor College of Medicine, to look beyond MECP2, hoping to find new drug targets that might improve symptoms or even reverse the course of the disease. In 2007, Adrian Bird, Ph.D., Buchanan Professor of Genetics at the Wellcome Trust Centre for Cell Biology at the University of Edinburgh, showed that symptoms in mice are reversible regardless of the age of the animal.
Exploring cholesterol metabolism in neurological diseases is an emerging area, with statin drugs being tested in fragile X syndrome, neurofibromatosis, amyotrophic lateral sclerosis, and other conditions. But it hadn’t been on the radar for Rett Syndrome. “Our screen was to see if we could suppress the symptoms to reveal alternative pathways to treatment. The cholesterol hit was a big one,” Dr. Justice said. The screen was unbiased – the researchers were looking for any gene that would interact with MECP2 in a useful way, rather than employing a candidate gene approach based on hypotheses.
Dr. Justice and her team injected healthy male mice with a chemical called ENU (a form of nitrosourea) that mutates sperm stem cells randomly, then mated the males to Rett females. The researchers then looked for offspring that should have developed the syndrome (according to their genes), but didn’t (according to their good health).
Key to the investigation was being able to tell sick mice from healthy ones. Fortunately this turned out to be easy. The rescued mice didn’t develop the characteristic tremor, trouble breathing, poor limb-clasping, and general scruffiness of their affected cage-mates. They moved around more, performed better on mobility tests and lived longer.
Once the rescued mice had been identified the random gene mutations from the 24,000 genes that make up the mouse genome had to be pinpointed. “With next generation DNA sequencing, we are finding mutations so easily and quickly. It’s amazing,” said Dr. Justice, compared to the old days of setting up many more generations of crosses to narrow down a part of the genome harboring a gene of interest.
“We are only15% of the way through the screen, and so far we have identified 5 modifiers. The most drug-targetable is a gene called squalene epoxidase (Sqle), which encodes a rate-limiting enzyme in the cholesterol biosynthetic pathway. Frankly, this discovery was a surprise,” Dr. Justice said. It’s important to note that this enzyme is different from the rate-limiting enzyme (HMG CoA reductase) influenced by statin drugs.
Cholesterol is of course best known for its negative effects on the cardiovascular system, but the lipid has multiple roles in the brain: it helps to form the myelin insulation on neurons and takes part in membrane trafficking, dendrite remodeling, synapse formation, signal transduction, and neuropeptide synthesis.
The next step was to test several statins (fluvastatin and lovastatin) on Rett mice. Like the Sqle mutation, the drugs improved symptoms. Treated mice performed well on mobility and gross motor tests, had better overall health scores and lived longer. The drugs didn’t, however, improve breathing.
“When we saw the mutation in a cholesterol pathway enzyme, we immediately thought of statin drugs. Now that our eyes have opened to what is going on, we have a multitude of drugs that modulate lipid metabolism that we can try in addition to statins,” said first author Christie Buchovecky, graduate student in the Justice lab.
With additional RSRT funding, pediatric neurologist and Director of the Tri-State Rett Syndrome Center in the Bronx Dr. Sasha Djukic undertook a detailed review of lipid data in girls with Rett Syndrome. She found that a subset have elevated cholesterol levels which normalize as they age. These data are not included in the Nature Genetics publication but will be part of a subsequent paper. Dr. Djukic is now planning a clinical trial.
Drs. Justice and Djukic caution that carefully designed and rigorously executed clinical trials are essential to test whether what works in mice will also work in girls with Rett Syndrome. Clinical trials should also determine the most effective timeframe for treatment, ways to identify which girls are most likely to respond, (for example, will statins help girls with Rett who do not have elevated cholesterol?), which drugs to trial and what dosages are effective but not toxic.
“Although statins are blockbuster drugs taken by a large percentage of the population they are not without risks and side-effects, and data on statins in the general pediatric population are quite limited. One of the key objectives of the clinical trial will be to determine correct dosages for Rett symptoms. It’s important to note that the mice in Dr. Justice’s study received very low doses of statins. I urge parents to resist any temptation to medicate their children with off-label statins,” cautions Dr Djukic. “The only way to know if this class of drugs will be efficacious in Rett is through controlled trials. Working with Dr. Justice and RSRT we will be bringing families additional information as soon as possible.”
“The biggest finding is the discovery that this pathway is so important to the pathology of the disorder; it suggests new directions for trying to learn more about Rett Syndrome,” Dr. Justice explains. “Emerging evidence from both mice and humans suggest that Rett Syndrome may have a component of disease that is metabolic. Certainly, this study will further clarify our data, and may suggest avenues for treatment that were previously unexplored.”
(Source: rsrt.org)
Scientists Develop New Way to Measure Cumulative Effect of Head Hits in Football
Scientists at Wake Forest Baptist Medical Center have developed a new way to measure the cumulative effect of impacts to the head incurred by football players.
The metric, called Risk Weighted Cumulative Exposure (RWE), can capture players’ exposure to the risk of concussion over the course of a football season by measuring the frequency and magnitude of all impacts, said senior author of the study Joel Stitzel, Ph.D., chair of biomedical engineering at Wake Forest Baptist and associate head of the Virginia Tech - Wake Forest University School of Biomedical Engineering and Sciences.
The study is published in the current online edition of the Annals of Biomedical Engineering.
Based on data gathered throughout a season of high school football games and practices, the researchers used RWE to measure the cumulative risk of injury due to linear and rotational acceleration separately, as well as the combined probability of injury associated with both.
“This metric gives us a way to look at a large number of players and the hits they’ve incurred while playing football,” Stitzel said. “We know that young players are constantly experiencing low-level hits that don’t cause visible injury, but there hasn’t been a good way to measure the associated risk of concussion.”
Concussion is the most common sports-related head injury, with football players having the highest rate among high school athletes, according to the study. It is estimated that nearly 1.1 million students play high school football in the United States. However, research on the biomechanics of football-related head impacts traditionally has concentrated on the collegiate level rather than on the high school level.
With such a large number of players in the sport, it is critical to understand the risk associated with different levels of impact and accurately estimate cumulative concussion risk over the course of a practice, game, season or lifetime, Stitzel said.
In the Wake Forest Baptist study, the researchers measured the head impact exposure in 40 high school football players by using sensors placed in their helmets to record linear and rotational acceleration. A total of 16,502 impacts were collected over the course of one football season and the data were analyzed as a group and as individual players.
Impacts were weighted according to the associated risk from linear acceleration and rotational acceleration alone, as well as to the combined probability of injury associated with both. This is an improved method of capturing the cumulative effects from each impact because it accounts for nonlinear relationships between impact magnitude and the associated risk of injury, Stitzel said.
“All hits involve both linear and rotational acceleration, but rotation coveys the idea that your head is pivoting about the neck whereas linear acceleration is experienced from a direct blow in more of a straight line through the center of mass of the head,” Stitzel said.
The median impact for each player ranged from 15.2 to 27.0 g, with an average value of 21.7 g, which shows the wide variability in the force of impacts.
The study found that impact frequency was greater during games (15.5) than during practices (9.4). However, overall exposure over the course of the season was greater during practices.
This information may help teams reduce exposure to head impacts during practices by teaching proper tackling techniques that could reduce exposure to impacts that may result in a higher concussion rate, the researchers reported.
Additionally, the study found a wide variation in player exposure within the team, with a 22-fold variation in the exposure per impact for practices and a 47-fold variation in the exposure for impact for games.
Studies like this are vital to understanding the biomechanical basis of head injuries related to football, Stitzel said. The metric fully captures a player’s exposure over the course of the season and will be used in conjunction with other pre- and post-season evaluations, including MRI and neurological tests conducted as part of this study.
The research team hopes that this work may ultimately improve helmet safety and design to make football a safer sport.
(Image: Getty Images)
It’s About Time: Disrupted Internal Clocks Play Role in Disease
Study uncovers circadian disruption as risk factor in alcoholic liver disease
Thirty percent of severe alcoholics develop liver disease, but scientists have not been able to explain why only a subset is at risk. A research team from Northwestern University and Rush University Medical Center now has a possible explanation: disrupted sleep and circadian rhythms can push those vulnerable over the edge to disease.
The team studied mice that essentially were experiencing what shift workers or people with jet lag suffer: their internal clocks were out of sync with the natural light-dark cycle. Another group of mice had circadian disruption due to a faulty gene. Both groups were fed a diet without alcohol and next with alcohol, and the team then examined the physiological effects.
The researchers found the combination of circadian rhythm disruption and alcohol is a destructive double hit that can lead to alcoholic liver disease.
The study was published last month by the journal PLOS ONE.
“Circadian disruption appears to be a previously unrecognized risk factor underlying the susceptibility to or development of alcoholic liver disease,” said Fred W. Turek, the Charles E. and Emma H. Morrison Professor of Biology at Northwestern’s Weinberg College of Arts and Sciences and one of the senior authors of the paper.
“What we and many other investigators are doing is bringing time to medicine for the diagnosis and treatment of disease,” Turek said. “We call it circadian medicine, and it will be transformative. Medicine will change a great deal, similar to the way physics changed when Einstein brought time to physics.”
A number of years ago, Ali Keshavarzian, M.D., a gastroenterologist at Rush University Medical Center who has worked with and studied patients with gastrointestinal and liver diseases, had a hunch disrupted circadian rhythms could be a contributing factor to the disease.
Keshavarzian had noticed that some patients with inflammatory bowel disease (inflammation in the intestine and/or colon) had flare-ups of symptoms when working nights, but they could control the disease when working the day shift. He sought out Turek, director of Northwestern’s Center for Sleep and Circadian Biology, to help investigate the relationship between circadian rhythms and the disease.
The two investigators and their groups first studied the effect of circadian rhythm disruption in an animal model of colitis and noted that disruption of sleep and circadian rhythms (caused by modeling shift work and chronic jet lag in the animals) caused more severe colitis in mice.
Keshavarzian has been studying the effect of “gut leakiness” (the intestinal lining becomes weak and causes dangerous endotoxins to get into the blood stream) to bacterial products in gastrointestinal diseases for two decades. Because the mouse model of colitis is associated with leaky gut, he proposed that disruption of circadian rhythms from shift work could make the intestine more susceptible to leakiness. He wanted to test its effect in an animal model of alcoholic liver disease — where a subset of alcoholics develop gut leakiness and liver disease — in order to find out whether shift work is the susceptibility factor that promotes liver injury.
“Non-pathogen-mediated chronic inflammation is a major cause of many chronic diseases common in Western societies and developing countries that have adopted a Western lifestyle,” said Keshavarzian, one of the senior authors of the paper. He is director of the Division of Digestive Diseases and the Josephine M. Dyrenforth Chair of Gastroenterology.
Crohn’s and ulcerative colitis, Parkinson’s disease, diabetes, multiple sclerosis, autoimmune disease and cardiovascular disease are examples of these diseases, to name just a few.
“Recent studies have shown that intestinal bacteria are the primary trigger for this inflammation, and gut leakiness is one of the major causes,” Keshavarzian said. “The factor leading to gut leakiness is not known, however. Our study suggests that disruption of circadian rhythms and sleep, which is part of life in industrial societies, can promote it and explain the susceptibility.”
In the study, the Northwestern and Rush researchers used two independent approaches, studying both genetic and environmental animal models. The circadian rhythms of one group of mice were disrupted genetically: Each animal had a mutant CLOCK gene, which regulates circadian rhythms. The second group’s circadian rhythms were disrupted environmentally: The animals’ light-dark cycle was changed periodically, leading to a state similar to chronic jet lag.
Mice in both groups, prior to ingesting alcohol, showed an increase in gut leakiness.
Next, both groups of mice were fed alcohol. After only one week, animals in both groups showed a significant additional increase in gut leakiness, compared to control mice on an alcohol-free diet. At the end of the three-month study, mice in both groups were in the early stages of alcoholic liver disease.
“We have clearly shown that circadian rhythm disruption can trigger gut leakiness, which drives the more severe pathology in the liver,” said Keith Summa, a co-first author of the study and an M.D./Ph.D. candidate working in Turek’s lab.
“For humans, circadian rhythm disruption typically is environmental, not genetic, so individuals have some control over the behaviors that cause trouble, be it a poor sleep schedule, shift work or exposure to light at night,” he said.
Sleep and circadian rhythms are an integral part of biology and should be part of the discussion between medical doctors and their patients, the researchers believe.
“We want to personalize medicine from a time perspective,” Turek said. “Our bodies are organized temporally on a 24-hour basis, and this needs to be brought into the equation for understanding health and disease.”
Metabolic Molecule Drives Growth Of Aggressive Brain Cancer
- Genomic research has shown that glioblastoma, the most dangerous type of brain cancer, has four subtypes.
- This study examines two of the subtypes and identifies an abnormal metabolic pathway that drives the aggressive growth of one of them.
- The findings could lead to targeted therapies for treating an aggressive form of glioblastoma.
A study led by researchers at The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James) has identified an abnormal metabolic pathway that drives cancer-cell growth in a particular glioblastoma subtype. The finding might lead to new therapies for a subset of patients with glioblastoma, the most common and lethal form of brain cancer.
The physician scientists sought to identify glioblastoma subtype-specific cancer stem cells. Genetic analyses have shown that high-grade gliomas can be divided into four subtypes: proneural, neural, classic and mesenchymal.
This study shows that the mesenchymal subtype is the most aggressive subtype, that it has the poorest prognosis among affected patients, and that cancer stem cells isolated from the mesenchymal subtype have significantly higher levels of the enzyme ALDH1A3 compared with the proneural subtype.
The findings, published recently in the Proceedings of the National Academy of Sciences, show that high levels of the enzyme drive tumor growth.
“Our study suggests that ALDH1A3 is a potentially functional biomarker for mesenchymal glioma stem cells, and that inhibiting that enzyme might offer a promising therapeutic approach for high-grade gliomas that have a mesenchymal signature,” says principal investigator Ichiro Nakano, MD, PhD, associate professor of neurosurgery at the OSUCCC – James. “This indicates that therapies for high-grade gliomas should be personalized, that is, based on the tumor subtype instead of applying one treatment to all patients,” he says.
The National Cancer Institute estimates that 23,130 Americans will be diagnosed with brain and other nervous system tumors in 2013, and that 14,000 people will die of these malignancies. Glioblastoma accounts for about 15 percent of all brain tumors, is resistant to current therapies and has a survival as short as 15 months after diagnosis.
Little is known, however, about the metabolic pathways that drive the growth of individual glioblastoma subtypes – knowledge that is crucial for developing novel and effective targeted therapies that might improve treatment for these lethal tumors.
For this study, Nakano and his collaborators used cancer cells from 40 patients with high-grade gliomas, focusing on tumor cells with a stem-cell signature. The researchers then used microarray analysis and pre-clinical animal assays to identify two predominant glioblastoma subtypes, proneural and mesenchymal.
Key technical findings include:
- Genes involved in glycolysis and gluconeogenesis, particularly ALDH1A3, were significantly up-regulated in mesenchymal glioma stem cells compared to proneural stem cells;
- Mesenchymal glioma stem cells show significantly higher radiation resistance and high expression of DNA-repair genes;
- Radiation induces transformation of proneural glioma stem cells into mesenchymal-like glioma stem cells that are highly resistant to radiation treatment; inhibiting the ALDH1 pathway reverses this resistance.
- Inhibiting ALDH1A3-mediated pathways slows the growth of mesenchymal glioma stem cells and might provide a promising therapeutic approach for glioblastomas with a mesenchymal signature.
“Overall, our data suggest that a novel signaling mechanism underlies the transformation of proneural glioma stem cells to mesenchymal-like cells and their maintenance as stem-like cells,” Nakano says. Currently, their discoveries are in provision patent application, led by the Technology Licensing Office at University of Pittsburgh.
(Source: cancer.osu.edu)