TAG: "Stroke"

Bone marrow stem cells show promise in stroke treatment

UC Irvine analysis reveals that they trigger repair mechanisms, limit inflammation.

Steven Cramer, UC Irvine

Stem cells culled from bone marrow may prove beneficial in stroke recovery, scientists at UC Irvine’s Sue & Bill Gross Stem Cell Research Center have learned.

In an analysis of published research, neurologist Dr. Steven Cramer and biomedical engineer Weian Zhao identified 46 studies that examined the use of mesenchymal stromal cells – a type of multipotent adult stem cells mostly processed from bone marrow – in animal models of stroke. They found MSCs to be significantly better than control therapy in 44 of the studies.

Importantly, the effects of these cells on functional recovery were robust regardless of the dosage, the time the MSCs were administered relative to stroke onset or the method of administration. (The cells helped even if given a month after the event and whether introduced directly into the brain or injected via a blood vessel.)

“Stroke remains a major cause of disability, and we are encouraged that the preclinical evidence shows [MSCs’] efficacy with ischemic stroke,” said Cramer, a professor of neurology and leading stroke expert. “MSCs are of particular interest because they come from bone marrow, which is readily available, and are relatively easy to culture. In addition, they already have demonstrated value when used to treat other human diseases.”

He noted that MSCs do not differentiate into neural cells. Normally, they transform into a variety of cell types, such as bone, cartilage and fat cells. “But they do their magic as an inducible pharmacy on wheels and as good immune system modulators, not as cells that directly replace lost brain parts,” he said.

In an earlier report focused on MSC mechanisms of action, Cramer and Zhao reviewed the means by which MSCs promote brain repair after stroke. The cells are attracted to injury sites and, in response to signals released by these damaged areas, begin releasing a wide range of molecules. In this way, MSCs orchestrate numerous activities: blood vessel creation to enhance circulation, protection of cells starting to die, growth of brain cells, etc. At the same time, when MSCs are able to reach the bloodstream, they settle in parts of the body that control the immune system and foster an environment more conducive to brain repair.

“We conclude that MSCs have consistently improved multiple outcome measures, with very large effect sizes, in a high number of animal studies and, therefore, that these findings should be the foundation of further studies on the use of MSCs in the treatment of ischemic stroke in humans,” said Cramer, who is also clinical director of the Sue & Bill Gross Stem Cell Research Center.

The analysis appears in the April 8 issue of Neurology. Quynh Vu, Kate Xie and Mark Eckert of UC Irvine contributed to the project, which received support from UC Irvine’s Institute for Clinical & Translational Science through the National Center for Research Resources (grant 5M011 RR-00827-29) and the National Institutes of Health (grants K24HD074722 and R01 NS059909).

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Stroke study finding a ‘game-changer’

Quick magnesium treatment fails to improve stroke outcomes, but study has silver lining.

Jeffrey Saver, UCLA

In the first study of its kind, a consortium led by UCLA physicians found that giving stroke patients intravenous magnesium within an hour of the onset of symptoms does not improve stroke outcomes.

However, the 8-year trial did find that with the help of paramedics in the field, intravenous medications can frequently be administered to stroke victims within that so-called “golden hour,” during which they have the best chance to survive and avoid debilitating, long-term neurological damage.

The latter finding is a “game-changer,” said Dr. Jeffrey Saver, director of the UCLA Stroke Center and a professor of neurology at the David Geffen School of Medicine at UCLA. Saver served as co-principal investigator on the research, which was presented Feb. 13 at the American Stroke Association’s International Stroke Conference.

“Stroke is a true emergency condition. For every minute that goes by without restoration of blood flow, 2 million nerve cells are lost,” Saver said. “Since time lost is brain lost, we wanted to develop a method that let us get potentially brain-saving drugs to the patient in the earliest moments of onset of the stroke. If these patients don’t get protective drugs until two, three or four hours later, irreversible brain damage has already occurred.”

While the Phase 3 clinical trial found that magnesium does not improve stroke-related disability, the search is now on for new drugs and treatments that can be administered in the field to improve long-term outcomes. The infrastructure to treat patients quickly was created by this study is in place, and that is a major accomplishment, Saver said.

The trial, called Field Administration of Stroke Therapy–Magnesium, or FAST–MAG, involved collaboration among 315 ambulances, 40 emergency medical-service agencies, 60 receiving hospitals and 2,988 paramedics in Los Angeles and Orange counties. Conducted between 2005 and 2013, the study showed that 74 percent of the 1,700 study patients were treated in the first hour, with the magnesium administered within a median time of 45 minutes.

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New NIH network revolutionizes stroke clinical research

UCLA, UC San Diego, UCSF fight stroke as key centers for nationwide effort.

Brett Meyer, UC San Diego

Brett Meyer, UC San Diego

A network of 25 nationally recognized stroke centers has been created to rapidly address the three core features of stroke research and care: prevention, treatment and recovery. The regional coordinating centers (RCCs), working with nearby satellite facilities, will span the country and have teams of researchers representing every stroke-related medical specialty, with the primary goal of bringing new therapies and strategies to the stroke community more rapidly. The centers, which include UCLA, UC San Diego and UC San Francisco as grant recipients, were announced Dec. 12 by the National Institutes of Health.

“The new system is intended to streamline stroke research, by centralizing approval and review, lessening time and costs of clinical trials, and assembling a comprehensive data sharing system,” said Petra Kaufmann, M.D., associate director for clinical research at the National Institute of Neurological Disorders and Stroke (NINDS).

NINDS, which will fund and manage the NIH Stroke Trials Network, or NIH StrokeNet, has a strong history of successful stroke clinical trials over the past 40 years, leading to critical advances in treatment and prevention of the disease, including the first treatment for acute stroke in 1995, the rt-PA clot-buster.

UC San Diego Health System and its health partners were integral to the rt-PA approval and numerous other stroke developments such as using hypothermia for stroke, telemedicine for rt-PA decision-making, novel endovascular approaches for clot removal and new neuroprotective approaches. In 2012, UC San Diego Health System had one of the first five facilities in the country to be certified as a Comprehensive Stroke Center (CSC), the newest level of certification for advanced stroke care awarded by The Joint Commission.

The new StrokeNet program will enable novel and critical research to be performed at a more rapid and collaborative pace since it encourages other San Diego health care systems to collaborate as partners with UC San Diego Health System.

“NIH Stroke Net has enabled UC San Diego to partner with the ‘best of the best’ in our California clinical community to provide cutting-edge stroke clinical trial opportunities to as many community members as possible, irrespective of geographical location,” said Brett C. Meyer, M.D., vascular neurologist, co-director of the UCSD Stroke Center and medical director of UC San Diego Health System Enterprise Telemedicine.

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Rendered speechless

Aphasia/stroke victim, UC Irvine expert to launch lecture series.

AphasiaBefore it happened, Carl McIntyre was an actor – not exactly a Hollywood phenom but a successful actor nonetheless, with a couple of film roles and a steady stream of television, stage and commercial gigs to his credit. Communication was his commodity.

But on the evening of Sept. 15, 2005, while rocking his young son to sleep, McIntyre’s right arm and leg suddenly grew tingly and then went completely dead. A large blood clot had dislodged from his heart, traveled up to his brain and wedged itself inside a major artery, cutting off the blood supply and depriving most of his left cerebral hemisphere of oxygen.

Brain tissue starved of oxygen dies within minutes, and once dead, it doesn’t regenerate. This was a stroke, and it was massive.

McIntyre didn’t know it at the time, but the stroke had destroyed virtually all of his brain’s language control circuits. In his prime at age 44, with a wife and three small children, he acquired severe aphasia the loss of language ability due to brain injury.

Aphasia affects more Americans than spinal cord injury and cerebral palsy combined. It’s as prevalent as Parkinson’s disease or schizophrenia, yet relatively few people have heard of aphasia or realize its devastating impact.

The disorder is caused by brain lesions that interfere with the neurological process that translates thought into speech.

For the past 10 years, Gregory Hickok, professor of cognitive sciences at UC Irvine and director of the campus’s Center for Language Science, has been using fMRI to study the brain and the neural abnormalities that impair language ability in stroke victims.

He has received more than $6 million from the National Institutes of Health to fund his work, including a landmark aphasia study in which McIntyre is a participant.

Exhaustive therapy has helped McIntyre regain his faculty for speech, though he still has difficulty with sentences longer than a few words.

Hickok and McIntyre will kick off the School of Social Sciences’ 2013-14 Expert Speaker Series on Monday, Nov. 18, with a 6 p.m. program in Room 1517 of the Social & Behavioral Sciences Gateway building.

McIntyre will screen his award-winning short film “Aphasia,” a documentary about his experience. He and Hickok will then give a brief presentation and answer questions about aphasia research at UC Irvine. A reception will follow.

The event is sponsored by the Multisite Aphasia Research Consortium and the university’s Center for Language Science, Center for Hearing Research and School of Social Sciences.

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Microbleeds important to consider in brain-related treatments

Stroke prevention strategies should address both blood clotting, protection of vessels.

Mark Fisher, UC Irvine

Mark Fisher, UC Irvine

As growing numbers of America’s baby boomers reach retirement, neuroscientists are expanding their efforts to understand and treat one of the leading health issues affecting this population: age-related neurological deterioration, including stroke and dementia.

One factor coming under increased study is cerebral microbleeds, experienced by nearly 20 percent of people by age 60 and nearly 40 percent by age 80. Research into these small areas of brain bleeding, caused by a breakdown of miniscule blood vessels, is shedding light on how the condition may contribute to these neurological changes.

With microbleeds common in older individuals, physicians need to take it into consideration when treating other brain-related issues, said Dr. Mark Fisher, professor of neurology, anatomy & neurobiology, and pathology & laboratory medicine at UC Irvine. This is especially important with stroke prevention measures, which often involve medications that interfere with blood clotting and could exacerbate microbleeds. Stroke risk escalates with age, especially after 55, making stroke one of the leading causes of disability and death in the elderly.

In two current papers published online in Frontiers in Neurology and Stroke, Fisher writes about the brain’s intricate system to protect itself against hemorrhaging. This system seems to break down as we get older, resulting in microbleeds that develop spontaneously and become increasingly common with aging.

“The next step in stroke prevention will require that we address both blood clotting and protection of the blood vessels,” he said. “This seems to be the best way to reduce the risk of microbleeds when it’s necessary to limit blood clotting for stroke prevention.”

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UCLA, UC Irvine, USC get $2M to develop stroke center network

Center will marshal network of 49 acute stroke, rehabiliation medical centers in Southland.

Jeffrey Saver, UCLA

Jeffrey Saver, UCLA

Stroke is the second leading cause of death in Los Angeles County and the fourth in the U.S. In order to cut those numbers, it’s imperative that new treatments be developed and refined for stroke prevention, acute therapy and recovery after stroke.

Now, a three-way partnership between the UCLA Stroke Center at Ronald Reagan UCLA Medical Center, the USC Comprehensive Stroke and Cerebrovascular Center at Keck Medicine of USC, and UC Irvine has been awarded a $2 million grant from the National Institutes of Health to address these three stroke priorities.

Together, the three universities will form the Los Angeles–Southern California Regional Coordinating Center, which will marshal a network of 49 acute stroke and rehabilitation medical centers throughout Los Angeles and Orange counties. Combined, these centers will perform five to 10 stroke-related clinical trials that will examine ways to improve prevention and enhance therapies and recovery. Within this network, 12 working groups with expertise in specific neurovascular research will facilitate the implementation of these trials and serve as a resource to the Regional Coordinating Center’s leadership and the individual sites.

Ronald Reagan UCLA Medical Center and Keck Medicine of USC will jointly lead the center.

“This research network is built upon the robust foundation of two decades of cooperative clinical care and clinical trials in cerebrovascular disease in Southern California,” said Dr. Jeffrey Saver, director of the UCLA Stroke Center and a professor of neurology. “The close collaboration of all three academic medical centers in the region — UCLA, USC and UCI — represents a natural and important evolution of our extensive past collaborations.”

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Which hospitals provide the best stroke care?

Hospitals in GWTG-stroke program more likely to provide recommended treatment.

Gregg Fonarow, UCLA

Gregg Fonarow, UCLA

Timely stroke treatment is critical to ensuring good outcomes for patients. A new national study compared two programs designed to help hospitals adhere to nationally accepted standards and guideline recommendations for stroke treatment and found that hospitals participating in the Get With The Guidelines–Stroke program were more likely than Primary Stroke Center–certified hospitals to provide all the guideline-based measures of care for patients.

The study appears in the Oct. 14 issue of the Journal of the American Heart Association.

The American Heart Association/American Stroke Association’s Get With The Guidelines–Stroke (GWTG–Stroke) Performance Achievement Award (PAA) recognizes hospitals that meet specific criteria in following research-based guidelines for stroke care.

Primary Stroke Center (PSC) certification, given by the American Heart Association/American Stroke Association and the Joint Commission, the entity that accredits U.S. hospitals, provides a framework for consistent clinical processes and program structure to help hospitals meet established standards of care.

The study authors, led by UCLA’s Dr. Gregg Fonarow, compared quality stroke-care performance indicators for 400,707 acute ischemic patients at 1,356 hospitals between 2010 and 2012. These indicators included giving stroke patients the clot-busting drug tPA (tissue plasminogen activator) within three hours of stroke-symptom onset, blood thinners within 48 hours of admission, and prescriptions for high cholesterol and atrial fibrillation, if needed, at discharge.

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Clot-busting simulations test potential stroke treatment

Researchers investigating combination of microbubbles and ultrasound.

The array transducer in position above the calvaria (skull). Shown are the ends of the array elements above the computational model of the skull.

The array transducer in position above the calvaria (skull). Shown are the ends of the array elements above the computational model of the skull.

Researchers are using computer simulations to investigate how ultrasound and tiny bubbles injected into the bloodstream might break up blood clots, limiting the damage caused by a stroke in its first hours.

Strokes are the most common cause of long-term disability in the United States and the third most common cause of death. More than 795,000 Americans suffer a stroke every year, which happens when a clot blocks an artery or blood vessel and restricts blood flow to the brain. The longer the clot stays intact, the more brain tissue dies, the higher the chance of severe damage and the lower a victim’s chance of survival.

Now, researchers from UC Berkeley and UC San Diego suspect these clots could be broken up — without surgery or drugs — using a combination of microbubbles and high intensity focused ultrasound (HIFU). The team used supercomputers at the Department of Energy’s National Energy Research Scientific Computing Center (NERSC), a division of Lawrence Berkeley National Laboratory, to figure out how this might work. Their findings were published in Journal of the Acoustical Society of America.

“One day, HIFU could be a useful medical treatment for people who are stroke victims. But before this can happen, we need to establish some fundamental background work, which includes understanding how HIFU accelerates damage to a clot when bubbles are present,” says Andrew Szeri, professor of mechanical engineering at UC Berkeley and co-author of the paper.

According to Szeri, the team’s NERSC allocation was incredibly valuable because it allowed them to generate the preliminary data needed to write a research proposal for funding in a new area. “Without some kind of preliminary data, it’s a non-starter; there’s just no way for us to find funding,” Szeri adds.

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UC Irvine named Orange County’s 1st Comprehensive Stroke Center

National designation reflects highest stroke care available.

Vivek Jain, UC Irvine

Vivek Jain, UC Irvine

UC Irvine Medical Center has become the first hospital in Orange County to receive certification as a Comprehensive Stroke Center from The Joint Commission.

Reserved for those hospitals capable of receiving and treating the most complex stroke cases, the designation confirms that UC Irvine Health meets the highest level of stroke care certification for the treatment of patients suffering ischemic and hemorrhagic strokes, and transient ischemic attacks.

“This designation reflects our entire team’s commitment to every aspect of stroke care, from emergency treatment to rehabilitation,” said Dr. Vivek Jain, director of the UC Irvine Health Stroke & Cerebrovascular Center.

UC Irvine Health offers state-of-the-art diagnosis and treatment for stroke patients and others with diseases affecting the blood vessels that supply the brain. The UC Irvine Health team offers specialty care by stroke neurologists, neurosurgeons, neuro-interventionalists and radiologists who are specially trained to use catheters to remove stroke-causing clots. The team also includes nurses, pharmacists and therapists.

The Joint Commission now certifies two levels of stroke care: “primary” and “comprehensive.” The new “comprehensive” level of certification recognized the significant resources in infrastructure, staff and training that comprehensive stroke centers must have to provide state-of-the-art complex stroke care.

Comprehensive Stroke Center Certification was developed in collaboration with the American Heart Association/American Stroke Association and derived from the Brain Attack Coalition’s “Recommendations for Comprehensive Stroke Centers” (Stroke, 2005), and Metrics for Measuring Quality of Care in Comprehensive Stroke Centers” (Stroke, 2011), as well as on recommendations from a multidisciplinary advisory panel of experts in complex stroke care.

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Researchers to study epileptic seizure mechanisms to ID new therapy targets

$1.7M NIH grant to UC Riverside will support investigation of hyperexcitability in the brain.

The image shows reactive astrocytes in a mouse brain after seizures. Blood vessels are seen in yellow/green, astrocytes in red and cell nuclei in purple.

The image shows reactive astrocytes in a mouse brain after seizures. Blood vessels are seen in yellow/green, astrocytes in red and cell nuclei in purple.

Ten percent of Americans experience a seizure in their lifetime, with three million diagnosed with epilepsy, a chronic neurological disorder. Anticonvulsant medications can mitigate the hyperactivity of neurons that leads to seizures, but not without severe side effects, including cognitive impairment.

Now, researchers Todd Fiacco, Ph.D., and Devin Binder, M.D., Ph.D., at UC Riverside will spend the next five years studying the causes of neuronal hyperexcitability with the goal of developing more effective treatments for brain disorders like epilepsy.  The researchers will share a National Institutes of Health (NIH) grant totaling more than $1.7 million awarded to them as co-principal investigators of the project.

Besides improving our understanding of how brain cells communicate with each other, the research has the potential to lead to treatments for brain disorders and diseases such as epilepsy, stroke and Alzheimer’s disease.

“We’re very excited about the opportunity to work together on this project,” said Binder, a clinician and an associate professor of biomedical sciences in the School of Medicine. “We’ve collaborated over the past two years, generating a lot of supporting data for this research.”

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Simple two-drug combo proves effective in reducing risk of stroke

Clinical trial, designed in partnership with UCSF, could change standard of care in U.S.

Results of a phase three clinical trial showed that a simple drug regimen of two anti-clotting drugs – clopidogrel and aspirin – lowered the risk of stroke by almost one-third, compared to the standard therapy of aspirin alone, when given to patients who had minor or transient stroke symptoms to prevent subsequent attacks.

Described this week in the New England Journal of Medicine, the clinical trial was conducted at multiple sites in China and designed in partnership with a physician at UC San Francisco.

The trial involved 5,170 people who were hospitalized after suffering minor ischemic strokes or stroke-like events known as transient ischemic attacks, or TIAs, in which blood flow to the brain is briefly blocked. All patients were randomized into two groups and treated for three months with either aspirin alone or aspirin plus clopidogrel, which is marketed as Plavix. The three-month period following stroke is considered the most critical for medical intervention.

Overall, 8.2 percent of patients taking both drugs suffered subsequent strokes in the three months of follow-up compared to 11.7 percent of patients taking aspirin alone.

“The results were striking,” said S. Claiborne Johnston, M.D., Ph.D., a professor of neurology and associate vice chancellor of research at UCSF who was a senior author on the study.

The Chinese trial, called CHANCE (Clopidogrel in High-risk Patients with Acute Non-disabling Cerebrovascular Events), is nearly identical to a National Institutes of Health-sponsored trial that is already enrolling patients in the United States, including at UCSF, called POINT (Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke).

“If POINT confirms CHANCE, then we’re done – the two-drug combination becomes the standard of care,” said Johnston. “Anybody with a transient ischemic attack or minor stroke will get clopidogrel plus aspirin.”

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$11M grant aims to lower stroke risk among blacks, young adults

Grant to focus on reducing high blood pressure.

Kristen Bibbins-Domingo, UC San Francisco

A new $11 million grant to Kaiser Permanente Northern California and UC San Francisco will support a multifaceted research program aimed at lowering stroke risk among black populations and younger stroke victims by targeting high blood pressure, also known as hypertension.

“Hypertension is much more common in blacks than in whites and is less likely to be controlled. Despite dramatic improvements in blood pressure control among Kaiser Permanente members in Northern California over the past decade, there is currently a 5 percent disparity between our black and white members,” said Stephen Sidney, M.D., M.P.H., director of research clinics with the Kaiser Permanente Division of Research.

Sidney is director of the new Stroke Prevention / Intervention Research Program, awarded by the National Institute of Neurological Disorders and Stroke (NINDS), and principal investigator for Kaiser Permanente Northern California. “The goal of the first study in this research program is to decrease the disparity by 4 percent over one year,” Sidney said.

“Hypertension is on the rise in the United States, despite the fact that we know what causes it, and we know how to treat it,” said UCSF’s Kirsten Bibbins-Domingo, M.D., Ph.D., director of the UCSF Center for Vulnerable Populations at San Francisco General Hospital and Trauma Center. Bibbins-Domingo is principal investigator of the research program for UCSF and lead investigator for two of the program’s four main components.

In the United States, blacks are twice as likely as whites to experience a first stroke; blacks are also more likely to die as a result of a stroke.

Younger adults are also a major focus of the new grant. Recent studies suggest that strokes among younger adults are becoming more common, due to an increase in risk factors such as high blood pressure.

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