Category: Stroke

— In the past few months, a slew of papers have indicated that the therapeutic potential of a promising type of stem cell, called induced pluripotent stem (iPS) cells, might be limited by reprogramming errors and genomic instability. iPS cells are engineered by reprogramming fully differentiated adult cells, often skin cells, back to a primitive, embryonic-like state. Given these problems, a team of researchers at Sanford-Burnham Medical Research Institute (Sanford-Burnham), Chung-Ang University in Korea, the University of British Columbia, Harvard Medical School and elsewhere wondered if there might be a better way to regenerate lost tissue to treat conditions like heart disease and stroke.

Writing March 4 in the Proceedings of the National Academy of Sciences, they outline a method to obtain a new kind of stem cell they call "induced conditional self-renewing progenitor (ICSP) cells."

With the addition of a single gene, the team instructed neural progenitor cells — a type of brain cell that can generate other types of brain cells — to self-renew in a laboratory dish. Once they had enough, the researchers moved the ICSP cells to a rodent stroke model, where the cells stopped proliferating, started differentiating and improved brain function.

"It's amazingly cool that we can dial adult cells all the way back to embryonic-like stem cells, but there are a lot of issues that still need to be addressed before iPS cells can be used to treat patients," said Evan Y. Snyder, M.D., Ph.D., director of Sanford-Burnham's Stem Cells and Regenerative Biology Program and corresponding author of the study. "So we wondered… if we just want to treat a brain disease, do we really have to start with a skin cell, which has nothing to do with the brain, and push it all the way back to the point that it has potential to become anything? In this study, we developed ICSP cells using a cell from the organ we're already interested in — the nervous system, in this case — and pushed it back just enough so it continued to divide, giving us a quantity that we were able to apply efficiently, safely and effectively to treat stroke injury in a rodent model."

Here's how ICSP cells work. Researchers use a viral vector to introduce a gene called v-Myc into neural progenitor cells. Myc, one of four standard genes already used to generate iPS cells, triggers self-renewal, guiding cells through the replication process. Scientists are sometimes cautious when it comes to adding genes like Myc — if cells keep dividing after transplantation in a patient, cancer could develop — but v-Myc is known to be safer than other flavors of Myc. What's more, the v-Myc used here is conditionally expressed. This means that ICSP cells can only produce v-Myc when the researchers add a compound called tetracycline to laboratory cultures. When tetracycline is removed, the cells cease dividing and start differentiating. Then, once transplanted into to an animal model, ICSP cells are no longer exposed to tetracycline and take their growth and differentiation cues from their new environment.

In this study, ICSP cells differentiated into active neurons and other brain cell types with therapeutic payoff for an adult rat model of intracerebral hemorrhagic stroke — the rodents show improved behavioral performance. Although the long-term genomic stability of ICSP cells remains to be seen, no adverse effects have arisen over five months of observation. The team envisions that this ICSP approach will also extend to progenitor cells obtained from other organs, such as heart, pancreas, or muscle, potentially accelerating the use of stem cell therapies for a broad range of diseases.

This study was funded by the Korean Ministry of Health and Welfare, the Canadian Myelin Research Initiative, Sanford Children's Health Research Center at Sanford-Burnham, the California Institute for Regenerative Medicine (CIRM), the A-T Children's Project and the Nancy Lurie Marks Family Foundation.

Original paper Kim KS, Lee HJ, Jeong HS, Li J, Teng YD, Sidman RL, Snyder EY, Kim SU. Self-renewal induced efficiently, safely, and effective therapeutically with one regulatable gene in a human somatic progenitor cell. Proceedings of the National Academy of Sciences. March 4, 2011

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Journal Reference:

1. K. S. Kim, H. J. Lee, H. S. Jeong, J. Li, Y. D. Teng, R. L. Sidman, E. Y. Snyder, S. U. Kim. Self-renewal induced efficiently, safely, and effective therapeutically with one regulatable gene in a human somatic progenitor cell. Proceedings of the National Academy of Sciences, 2011; DOI: 10.1073/pnas.1019743108

Faced with the risk of developing side effects, even ones as mild as fatigue, nausea and fuzzy thinking, many older patients are willing to forego medications that provide only average benefit in preventing heart attack, according to a report by Yale School of Medicine researchers.

"These patients are willing to take medications for cardiovascular disease prevention, but only if they are not linked to what are generally considered to be acceptable side effects," said first author Terri R. Fried, M.D., professor of internal medicine/geriatrics at Yale School of Medicine, and the VA Connecticut Healthcare System.

The report by Fried and co-authors is available online in the Archives of Internal Medicine, and will be published in the June 27 print issue of the journal.

Clinical practice guidelines recommend medications for primary prevention based on the patient's risk for developing an illness and the likelihood that the medication will reduce this risk. But Fried and her team suspected that this might not be consistent with how older persons think about the benefit and harms of medications.

To find out, the team evaluated older persons' willingness to take a medication for primary prevention of cardiovascular disease based on its benefits and harms. They conducted in-person interviews with 356 people living in the community who were age 65 years or older.

The participants were asked about their willingness to take medication for primary prevention of heart attack (myocardial infarction).

Most participants (88 percent) said they would take the medication if it had no adverse effects and offered about the average risk reduction of currently available medications. In contrast, large proportions (48 to 69 percent) were unwilling or uncertain about taking such medication if it caused mild fatigue, nausea, or fuzzy thinking, and only 3 percent would take medication with adverse effects severe enough to affect daily functioning.

"Our results show that these 'side effects,' more aptly considered as adverse events, are as important to older persons as the medication's benefits, and need to be considered important outcomes in their own right," said Fried.

The study was supported by a grant from the Robert Wood Johnson Foundation and by the Claude D. Pepper Older Americans Independence Center at Yale School of Medicine. Fried is supported by a grant from the National Institutes of Health/National Institute on Aging.

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Journal Reference:

1. Terri R. Fried, Mary E. Tinetti, Virginia Towle, John R. O’Leary, Lynne Iannone. Effects of Benefits and Harms on Older Persons' Willingness to Take Medication for Primary Cardiovascular Prevention. Arch Intern Med., February 28, 2011 DOI: 10.1001/archinternmed.2011.32

A new study shows that African Americans have a better survival rate compared to whites after being hospitalized for a stroke. This conclusion contradicts prevailing wisdom and is one piece in a growing body of evidence that points to the important role that patients — and the decision they and their families make in terms of treatment — may play on mortality rates.

The study found that — after adjusting data for variables such as age, socioeconomic status, and risk factors — that African Americans who were hospitalized for acute ischemic stroke had a significantly lower mortality rate than whites. The survival advantage was most pronounced early after the stroke but persisted for up to one year. The study also found that African Americans were also more likely during their hospitalization to have received more aggressive treatment measures, such as kidney dialysis, a tracheostomy, or cardiopulmonary resuscitation. They were also less likely to use hospice care. These results were recently published in the Annals of Internal Medicine.

"These results fly in the face of conventional wisdom that says that black patients with strokes have worse outcomes," said University of Rochester Medical Center (URMC) neurologist Robert Holloway, M.D., M.P.H. a co-author of the study. "Even though we do not know the exact reasons for these differences, these data highlight the potential importance of treatment intensity, and the expression of patient preference for different treatments on survival and mortality. This is not such a far-fetched idea for physicians who take care of a lot of stroke patients."

"We know that African Americans have a higher prevalence of stroke and higher risk factors for stroke," said Ying Xian, M.D., Ph.D., a former graduate student in Health Services Research and Policy with URMC Department of Community and Preventive Medicine and now a fellow with the Duke Clinical Research Institute and co-author of the study. "But this data shows that African Americans have lower mortality rates than whites. It also shows that African Americans are more likely to be treated aggressively and we suspect that this may have an impact on their mortality outcomes."

The study used data from the New York State Statewide Planning and Research Cooperative System, a reporting system that collects detailed information on every hospital and emergency department admission in the state. They compiled information for all non-Hispanic blacks and non-Hispanic whites age 18 and older who were admitted to a hospital with a diagnosis of acute ischemic stroke in 2005 and 2006.

The researchers used a novel statistical approach to minimize the difference between two pools of black and white patients in terms of demographic profiles, co-morbidities, and the type of hospital where they received their care. They then looked at mortality rates for several incremental periods beginning at 7 days and up to a year after the stroke and what life-sustaining interventions the patients received during their hospitalization. The authors found that over the course of the year African American patients had a statistically lower rate of mortality and at the same time were more likely to receive aggressive life-sustaining treatments.

While the data used for the study does not illustrate the role of patient preference — either expressed intent or in the form of do not resuscitate orders, health care proxies, or living wills — or the decisions made by family member on their behalf, the authors believe the evidence indicates that there might be a link between the treatment decisions made by patients and their families when seriously ill with stroke and survival rates.

"Although we don't show any causal relationship, the association of lower risk of death and increased use of life-sustaining interventions is actually very consistent with the idea that preference sensitive end-of-life care may have an important impact on short-term mortality," said Holloway. "We were unable to measure health or quality of life in those patients who survived, which is a critically important question. We also need much more research on ways to measure the quality of the decision process itself to make sure that the treatments patients receive are consistent with their underlying values and preferences."

"Even though people who receive aggressive life-sustaining care have lower mortality it does not mean they have better quality of care or quality of life," said Xian. "Mortality is important measure but not only measure."

Other authors of the study include Katia Noyes, Ph.D., M.P.H.; Manish N. Shah, M.D., M.P.H.; and Bruce Friedman, Ph.D., M.P.H. with URMC. The study was supported by funding from the American Heart 

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Journal Reference:

1. Ying Xian et al. Racial Differences in Mortality Among Patients With Acute Ischemic Stroke An Observational Study. Annals of Internal Medicine, February 1, 2011 vol. 154 no. 3 152-159 

Widespread screening or routine ultrasound for blocked neck arteries to determine stroke risk isn't necessary, according to new guidelines from the American Heart Association/American Stroke Association, American College of Cardiology and other groups.

Carotid endarterectomy and carotid stenting are reasonable and effective ways to treat blocked neck arteries, though some patients may be a better candidate for one procedure over the other, the guidelines also state.

When the carotid arteries on the side of the neck or vertebral arteries alongside the spinal column become clogged, less blood gets to the brain and the risk of stroke increases.

The guidelines writing committee, which included a wide range of specialists on stroke prevention, agreed there isn't sufficient evidence of benefit for widespread screening. "However, if your doctor hears abnormal blood flow when listening to your neck arteries, or if you have two or more risk factors for stroke (such as high cholesterol or a family history), then it is a reasonable approach," said Jonathan L. Halperin, M.D., co-chair of the writing committee and Professor of Medicine at the Mount Sinai School of Medicine in New York.

"The guidelines will provide new information and evidence to help clinicians select treatment approaches with their patients," said Thomas G. Brott, M.D., committee co-chair, Professor of Neurology and director of research at the Mayo Clinic campus in Jacksonville, Fla.

Stroke risk factors include age, family history of stroke, high blood pressure, high blood cholesterol, diabetes, obesity, atrial fibrillation, physical inactivity, sickle cell disease and other heart or blood vessel diseases.

Among dozens of recommendations, the writing group also noted that two often competing procedures are used to restore adequate blood flow to the brain past severely narrowed arteries. In carotid endarterectomy, used for half a century, plaque buildup is surgically removed. In stenting, which has been available for about 15 years, a balloon catheter is inserted to open the vessel and a metal mesh tube (stent) is left in place to keep the blood vessel open.

After reviewing the evidence, including two recent head-to-head comparisons, the writing committee concluded that both approaches are reasonable and safe when arteries are more than 50 percent blocked.

"The guidelines support carotid surgery as a tried-and-true treatment for most patients," Brott said. "However, for patients who have a strong preference for less invasive treatments, carotid stenting offers a safe alternative. Because of the anatomy of their arteries or other individual considerations, some patients may be more appropriate for surgery and others for stenting."

Furthermore, medications offer a better alternative than either surgery or stenting for many patients, according to the guidelines. In the latest clinical trials comparing the procedures, all patients received optimal medical treatment and there were no medication-only groups.

"The risks of these procedures have fallen considerably, but you need to make sure you have very experienced practitioners performing the latest techniques," Halperin said.

The full text of the guidelines will be published in Circulation: Journal of the American Heart Association; Stroke: Journal of the American Heart Association, and Journal of the American College of Cardiology. The guideline executive summary will be in Catheterization and Cardiovascular Interventions, Journal of Cardiovascular Computed Tomography, Journal of NeuroInterventional Surgery, Journal of Vascular Surgery, and Vascular Medicine.

The guidelines were developed with the American Association of Neuroscience Nurses; American Association of Neurological Surgeons; American Society of Neuroradiology; American College of Radiology; Congress of Neurological Surgeons; Society for Atherosclerosis Imaging and Prevention; Society for Cardiovascular Angiography and Interventions; Society of Interventional Radiology; Society for NeuroInterventional Surgery; Society for Vascular Medicine; and Society for Vascular Surgery.

The American Academy of Neurology and the Society of Cardiovascular Computed Tomography collaborated in the process.

Co-authors on the writing committee are: Suhny Abbara, M.D.; J. Michael Bacharach, M.D.; John D. Barr, M.D.; Ruth L. Bush, M.D., M.P.H.; Christopher U. Cates, M.D.; Mark A. Creager, M.D.; Susan B. Fowler, Ph.D.; Gary Friday, M.D.; Vicki S. Hertzberg, Ph.D.; E. Bruce McIff, M.D.; Wesley S. Moore, M.D.; Peter D. Panagos, M.D.; Thomas S. Riles, M.D.; Robert H. Rosenwasser, M.D.; and Allen J. Taylor, M.D.

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Journal Reference:

1. Thomas G. Brott, Jonathan L. Halperin, Suhny Abbara, J. Michael Bacharach, John D. Barr, Ruth L. Bush, Christopher U. Cates, Mark A. Creager, Susan B. Fowler, Gary Friday, Vicki S. Hertzberg, E. Bruce McIff, Wesley S. Moore, Peter D. Panagos, Thomas S. Riles, Robert H. Rosenwasser, and Allen J. Taylor. 2011 ASA/ACCF/AHA/AANN/AANS/ACR/ASNR/CNS/SAIP/SCAI/SIR/SNIS/SVM/SVS Guideline on the Management of Patients With Extracranial Carotid and Vertebral Artery Disease: Executive Summary: A Report of the American College of Cardiology Foundation/American Heart. Circulation, January 31, 2011 DOI: 10.1161/CIR.0b013e31820d8d78

 Exposure to noise from road traffic can increase the risk of stroke, particularly in those aged 65 years and over, according to a study published online on January 26 in the European Heart Journal.

The study, which is among the first to investigate the links between road traffic noise and the risk of stroke, found that for every 10 decibels more noise the risk of having a stroke increased by 14% among the 51,485 study participants. When the Danish researchers looked at the data more closely, they found that for people aged less than 65 years there was no statistically significant increased risk of stroke; however, the risk increased by 27% for every 10dB of higher road traffic noise in those aged 65 years and over. Furthermore, in the older people they found indications of a threshold limit at approximately 60 dB, above which the risk for stroke seemed to increase even more.

Dr Mette Sørensen, senior researcher at the Institute of Cancer Epidemiology, Danish Cancer Society in Copenhagen, Denmark, who led the research, said: "Our study shows that exposure to road traffic noise seems to increase the risk of stroke. Previous studies have linked traffic noise with raised blood pressure and heart attacks, and our study adds to the accumulating evidence that traffic noise may cause a range of cardiovascular diseases. These studies highlight the need for action to reduce people's exposure to noise.

"This is the first study ever to investigate the association between exposure to road traffic noise and risk of stroke, and, therefore, more research is needed before any firm conclusions can be made."

The study was based on the Danish "Diet, Cancer, and Health" cohort study, which recruited a total of 57,053 people aged between 50 and 64, in the Copenhagen and Aarhus areas between 1993 and 1997. Medical and residential histories were available for 51,485 of the participants and their average follow-up time was ten years. A total of 1,881 suffered a stroke in this time.

Dr Sørensen and her colleagues made allowances in their calculations for the effect of air pollution, exposure to railway and aircraft noise, as well as a range of other confounding life-style factors such as smoking, diet, alcohol and caffeine consumption. Data on the study participants and where they lived were linked to a noise calculation program that has been used to map noise levels in a variety of locations in Scandinavia for several years. The program takes account of traffic composition and speed, road type (motorways, rural highways etc) and surfaces, building polygons and the position and heights of people's homes above the roads.

At the time of joining the cohort 35% of people were exposed to noise levels greater than 60dB, and 72% lived at the same address throughout the period of the study. The researchers' lowest estimate for noise exposure was 40dB and the highest was 82dB.

Dr Sørensen said: "If we assume that our findings represent the true risk, and the association between traffic noise and stroke is causal, then an estimated eight percent of all stroke cases, and 19% of cases in those aged over 65, could be attributed to road traffic noise. The population in this study, however, lived mainly in urban areas and is, therefore, not representative of the whole population in terms of exposure to road traffic noise. However, if we take the exposure distribution of all dwellings in Denmark into account, we find that about 600 new cases of stroke could be attributed to road traffic noise in Denmark each year. There are 5.5 million inhabitants in Denmark and a total of 12,400 new cases of stroke each year."

As the study is epidemiological it cannot show that road traffic noise is the cause of the increased risk of stroke, only that there is an association. The mechanism by which noise could increase the risk of a range of cardiovascular problems is still unclear.

"The mechanisms involved are probably the same mechanisms believed to be involved in noise-induced hypertension and heart attacks, namely that noise acts as a stressor and disturbs sleep, which results in increased blood pressure and heart rate, as well as increased level of stress hormones. Taken together, all of these could increase the risk for cardiovascular diseases," she said.

"In addition, older people tend to have more fragmented sleep patterns and are more susceptible to sleep disturbances. This could explain why the association between road traffic noise and risk of stroke was seen mainly in the oldest participants."

Dr Sørensen plans to carry out further research into the effects of noise on a range of cardiovascular diseases and raised blood pressure.

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Journal Reference:

1. M. Sorensen, M. Hvidberg, Z. J. Andersen, R. B. Nordsborg, K. G. Lillelund, J. Jakobsen, A. Tjonneland, K. Overvad, O. Raaschou-Nielsen. Road traffic noise and stroke: a prospective cohort study. European Heart Journal, 2011; DOI: 10.1093/eurheartj/ehq466

An analysis of data on more than 45,000 patients who underwent coronary artery bypass graft (CABG) surgery at an academic medical center over the past 30 years finds that the occurrence of stroke after CABG has declined, despite an increase in risk profiles of patients, according to a study in the January 26 issue of JAMA.

Stroke is a devastating and potentially preventable complication of CABG surgery. Because it increasingly is being reserved for elderly patients with extensive coronary disease and co-existing conditions, prevalence of stroke after CABG is likely to remain substantial. Many studies have identified patient factors associated with post-CABG stroke; however, information about timing of perioperative (around the time of surgery) stroke and the influence of different surgical techniques remains limited, according to background information in the article.

Khaldoun G. Tarakji, M.D., M.P.H., of the Cleveland Clinic, and colleagues examined the prevalence and timing of perioperative stroke, along with associated patient and surgical factors. The study included data from 45,432 patients (average age, 63 years) who underwent primary or reoperative CABG surgery from 1982 through 2009 at a U.S. academic medical center. Strokes occurring following CABG were recorded prospectively and classified as having occurred intraoperative or postoperatively. Data also included information on 4 different CABG operative strategies: off-pump (not on heart-lung machine), on-pump with beating heart, on-pump with arrested heart, on-pump with hypothermic circulatory arrest (in which a heart-lung machine is used to cool the body during surgery, which lowers blood pressure and slows circulation to near standstill).

Among the patients in the study, 705 (1.6 percent) experienced a stroke. Occurrence of stroke peaked in 1988 at 2.6 percent, then slowly declined by 4.69 percent per year, despite increasing patient risk profile, such as higher prevalence of preoperative stroke, hypertension, and diabetes. Of the 705 patients experiencing stroke, intraoperative stroke occurred in 40 percent (n = 279) and postoperative stroke in 58 percent (n = 409), with timing undetermined in 17 patients.

Risk factors common to both intraoperative and postoperative stroke included older age, previous stroke, preoperative atrial fibrillation, and on-pump CABG with hypothermic circulatory arrest. As number of arteriosclerotic (hardening and thickening of the walls of the arteries) co-existing conditions increased, stroke risk increased.

Different surgical techniques were associated with different risks of intraoperative stroke. Unadjusted rates of stroke were highest among patients who had on-pump CABG with hypothermic circulatory arrest (5.3 percent) and lowest among those who had off-pump CABG (0.14 percent) and on-pump beating-heart CABG (0 percent). Risk of intraoperative stroke was intermediate for those undergoing on-pump arrested-heart CABG (0.50 percent)

Patients who experienced a stroke had substantially worse hospital outcomes, even after adjustment for preoperative factors: 19 percent mortality vs. 3.7 percent; 44 percent prolonged ventilation vs. 15 percent; and 13 percent renal failure vs. 4.3 percent. They also experienced substantially longer intensive care unit and postoperative lengths of stay.

The authors speculate that the reason the occurrence of stroke among patients undergoing CABG has decreased over the last 3 decades despite an increasing patient risk profile may be the result of improving preoperative assessment, intraoperative anesthetic and surgical techniques, and postoperative care.

"Further studies are needed to develop better strategies to minimize the occurrence of stroke among patients undergoing CABG," the researchers conclude.

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Journal Reference:

1. K. G. Tarakji, J. F. Sabik, S. K. Bhudia, L. H. Batizy, E. H. Blackstone. Temporal Onset, Risk Factors, and Outcomes Associated With Stroke After Coronary Artery Bypass Grafting. JAMA: The Journal of the American Medical Association, 2011; 305 (4): 381 DOI: 10.1001/jama.2011.37

Patients who had an ischemic stroke and were admitted to hospitals designated as primary stroke centers had a modestly lower risk of death at 30 days, compared to patients who were admitted to non-designated hospitals, according to a study in the January 26 issue of JAMA.

Stroke is the leading cause of serious long-term disability and the third leading cause of death in the United States. Responding to the need for improvements in acute stroke care, the Brain Attack Coalition (BAC) published recommendations for the establishment of primary stroke centers in 2000, and in 2003 the Joint Commission began certifying stroke centers based on these recommendations, according to background information in the article. Now, nearly 700 of the 5,000 acute care hospitals in the United States are Joint Commission-certified stroke centers, with some states establishing their own designation programs using the BAC core criteria. "Despite widespread support for the stroke center concept, there is limited empirical evidence demonstrating that admission to a stroke center is associated with lower mortality," the authors write.

Ying Xian, M.D., Ph.D., of the Duke Clinical Research Institute, Durham, N.C., and colleagues conducted a study to evaluate the association between admission to stroke centers for acute ischemic stroke and the rate of death. Using data from the New York Statewide Planning and Research Cooperative System, the researchers compared mortality for patients admitted with acute ischemic stroke (n = 30,947) between 2005 and 2006 at designated stroke centers and nondesignated hospitals. Patients were followed up for mortality for 1 year after hospitalization through 2007. To assess whether the findings were specific to stroke, the researchers also compared mortality for patients admitted with gastrointestinal hemorrhage (n = 39,409) or heart attack (n = 40,024) at designated stroke centers and nondesignated hospitals.

Among the patients with acute ischemic stroke, 49.4 percent (n = 15,297) were admitted to designated stroke centers (n=104) and 50.6 percent to non-designated hospitals. The overall 30-day all-cause mortality rate was 10.1 percent for patients admitted to designated stroke centers and 12.5 percent for patients admitted to nondesignated hospitals, with analysis indicating that admission to a designated stroke center hospital was associated with a 2.5 percent absolute reduction in 30-day all-cause mortality. Use of thrombolytic therapy (dissolving blood clots) was 4.8 percent for patients admitted at designated stroke centers and 1.7 percent for patients admitted at nondesignated hospitals (adjusted difference in use, 2.2 percent). Among patients surviving to hospital discharge, there was no difference in rates of 30-day all-cause readmission and discharge to a skilled nursing facility.

"Differences in mortality also were observed at 1-day, 7-day, and 1-year follow-up. The outcome differences were specific for stroke, as stroke centers and nondesignated hospitals had similar 30-day all-cause mortality rates among those with gastrointestinal hemorrhage or acute myocardial infarction," the authors write.

"Even though the differences in outcomes between stroke centers and nondesignated hospitals were modest, our study suggests that the implementation and establishment of a BAC-recommended stroke system of care was associated with improvement in some outcomes for patients with acute ischemic stroke."

Editorial: Preventing Death One Stroke at a Time

In an accompanying editorial, Mark J. Alberts, M.D., of the Stroke Program, Northwestern University School of Medicine, Chicago, comments on the future of acute stroke care.

"A multitiered system of stroke care is developing, with the comprehensive stroke center (CSC) at the top of the pyramid, the primary stroke center (PSC) in the middle, and the acute stroke ready hospital (ASRH) at the base. Within a geographical region, a small number of CSCs would provide care for patients with the most complicated stroke cases; a larger number of PSCs would provide care for the patients with typical, uncomplicated cases; and the ASRH would provide initial screening and triage and begin acute care for patients in a rural, small urban, or suburban setting. Emergency medical services personnel would perform initial screening and triage and would transport patients with a clearly defined stroke to the closest stroke center facility. Using telemedicine technologies, hospital personnel could communicate and transfer patients to the facility with the most appropriate level of care. Many states and guidelines now support and even mandate the diversion of patients suspected of having a stroke to the nearest stroke center facility."

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Journal References:

1. M. J. Alberts. Preventing Death One Stroke at a Time. JAMA: The Journal of the American Medical Association, 2011; 305 (4): 408 DOI: 10.1001/jama.2011.29
2. Y. Xian, R. G. Holloway, P. S. Chan, K. Noyes, M. N. Shah, H. H. Ting, A. R. Chappel, E. D. Peterson, B. Friedman. Association Between Stroke Center Hospitalization for Acute Ischemic Stroke and Mortality. JAMA: The Journal of the American Medical Association, 2011; 305 (4): 373 DOI: 10.1001/jama.2011.22

New research led by UC Davis scientists provides insight into why some body organs are more susceptible to cell death than others and could eventually lead to advances in treating or preventing heart attack or stroke.

In a paper published Jan. 21 in the journal Molecular Cell, the UC Davis team and their collaborators at the National Institutes of Health and Johns Hopkins University report that Bax, a factor known to promote cell death, is also involved in regulating the behavior of mitochondria, the structures that provide energy inside living cells.

Mitochondria constantly split and fuse. The proteins that control the splitting of mitochondria also promote a process called apoptosis, or programmed cell death. In contrast, the proteins that control mitochondrial fusion help protect against cell death. Cell death can happen when cells are starved of oxygen, for example during a heart attack or stroke.

Yeast have a single protein that controls outer membrane fusion, but both human and mouse cells have two proteins, called MFN1 and MFN2, which control outer membrane fusion. Using mitochondria from cells derived from genetically modified "knockout" mice, Suzanne Hoppins, a postdoctoral researcher at UC Davis, and Jodi Nunnari, a professor of molecular cell biology, studied how these two proteins work together and the role specific genes play in that process.

The research team discovered that these proteins combine with themselves or each other to form a tether between two mitochondria, leading to fusion. All three combinations — MFN1/MFN1, MFN1/MFN2 and MFN2/MFN2 — can promote membrane fusion, but the combination of MFN1/MFN2 is by far the most efficient, Hoppins said.

Hoppins also found that a soluble form of Bax, a protein that triggers apoptosis, can also stimulate mitochondria to fuse. It acts only through the MFN2/MFN2 combination, she found.

The form of Bax that promotes mitochondrial fusion is different from the type that leads to cell death, Nunnari said. Bax leads to cell death when it inserts itself in the mitochondrial membrane. In its soluble, free-floating form, it causes mitochondria to fuse instead.

MFN1 and MFN2 are found in different amounts in different body organs. MFN2 is more abundant in the brain and heart — tissues where cell death can have disastrous consequences.

The paper shows how MFN2 could act to protect the brain or heart from cell death, by using Bax in a different form, Nunnari said.

"This shows that the fusion machine is both positively and negatively regulated in cells and opens doors to finding the regulatory mechanisms and discovering ways to increase or decrease the sensitivity of cells to apoptosis," Hoppins said. That could lead to new drugs that save cells, for heart disease and stroke, or that kill cells, for cancer.

Co-authors of the study are UC Davis graduate student Megan Cleland; UC Davis postdoctoral researchers Frank Edlich and Soojay Banerjee; and Richard Youle, a senior investigator at the National Institute for Neurological Disorders and Stroke; and J. Michael McCaffery, a professor at Johns Hopkins University.

The research was supported by grants from the National Institutes of Health. Hoppins recently received a K99 "Young Investigator" award from the NIH.

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Journal Reference:

1. Suzanne Hoppins, Frank Edlich, Megan M. Cleland, Soojay Banerjee, J. Michael McCaffery, Richard J. Youle, Jodi Nunnari. The Soluble Form of Bax Regulates Mitochondrial Fusion via MFN2 Homotypic Complexes. Molecular Cell, 2011; 41 (2): 150 DOI: 10.1016/j.molcel.2010.11.030

Researchers were surprised to discover what may be a potential new treatment for difficult-to-control high blood pressure, according to a case report published in the January 25, 2011, print issue of Neurology®, the medical journal of the American Academy of Neurology.

The report involved one man who received a deep brain stimulator to treat his pain from central pain syndrome that developed after a stroke. Deep brain stimulation uses a surgical implant similar to a cardiac pacemaker to send electrical pulses to the brain.

The 55-year-old man was diagnosed with high blood pressure at the time of the stroke, and his blood pressure remained high even though he was taking four drugs to control it.

While the electrical stimulation did not permanently alleviate his pain, researchers were surprised to see that stimulation decreased his blood pressure enough that he could stop taking all of the blood pressure drugs.

"This is an exciting finding as high blood pressure affects millions of people and can lead to heart attack and stroke, but for about one in 10 people, high blood pressure can't be controlled with medication or they cannot tolerate the medication," said Nikunj K. Patel, BSc MBBS, MD, FRCS, of Frenchay Hospital in Bristol, UK, who wrote the case study.

Patel noted that the decrease in blood pressure was a response to the deep brain stimulation, and not a result of changes to his other conditions.

The man's blood pressure gradually decreased after the deep brain stimulator was implanted in the periaqueductal-periventricular grey region of the brain, which is involved in regulating pain. His blood pressure was controlled for the nearly three years of follow-up; at one point he went back on an anti-hypertension drug for a slight increase in blood pressure, but that drug was withdrawn when the blood pressure went down again.

At one point researchers tested turning off the stimulator. This led to an increase of an average of 18/5 mmHg in blood pressure. When the stimulator was turned back on, blood pressure dropped by an average of 32/12 mmHg. Repeating the tests produced the same results.

"More research is needed to confirm these results in larger numbers of people, but this suggests that stimulation can produce a large, sustained lowering of blood pressure," Patel said. "With so many people not responding to blood pressure medications, we are in need of alternative strategies such as this one."

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Journal Reference:

1. N.K. Patel, S. Javed, S. Khan, M. Papouchado, A.L. Malizia, A.E. Pickering, J.F.R. Paton. Deep brain stimulation relieves refractory hypertension. Neurology, 2011; 76: 405-407 DOI: 10.1212/WNL.0b013e3182088108

 The cost to treat heart disease in the United States will triple by 2030, according to a policy statement published in Circulation: Journal of the American Heart Association.

"Despite the successes in reducing and treating heart disease over the last half century, even if we just maintain our current rates, we will have an enormous financial burden on top of the disease itself," said Paul Heidenreich, M.D., chair of the American Heart Association expert panel issuing the statement.

The panel estimated future medical costs based on the current rates of disease and used Census data to adjust for anticipated population shifts in age and race. The rigorous methods they devised didn't double count costs for patients with multiple heart conditions.

"These estimates don't assume that we will continue to make new discoveries to reduce heart disease," Heidenreich said. "If our ability to prevent and treat heart disease stays where we are right now, costs will triple in 20 years just through demographic changes in the population."

The panel said effective prevention strategies are needed to limit the growing burden of cardiovascular disease — the leading cause of death in the United States that accounts for 17 percent of overall national health expenditures.

"Unhealthy behaviors and unhealthy environments have contributed to a tidal wave of risk factors among many Americans," said Nancy Brown, American Heart Association CEO. "Early intervention and evidence-based public policies are absolute musts to significantly reduce alarming rates of obesity, hypertension, tobacco use and cholesterol levels."

Currently, 1 in 3 Americans (36.9 percent) have some form of heart disease, including high blood pressure, coronary heart disease, heart failure, stroke and other conditions. By 2030, approximately 116 million people in the United States (40.5 percent) will have some form of cardiovascular disease, the panel said. The largest increases are anticipated in stroke (up 24.9 percent) and heart failure (up 25 percent).

Between 2010-30, the cost of medical care for heart disease (in 2008 dollar values) will rise from $273 billion to $818 billion, the authors predicted. "We were all surprised at the remarkable increase in costs that are expected in the next two decades," Heidenreich said. "We need to continue to invest resources in the prevention of disease, the treatment of risk factors and early treatment of existing disease to reduce that burden."

Heart disease will also cost the nation billions more in lost productivity, increasing from an estimated $172 billion in 2010 to $276 billion in 2030. Productivity losses include days missed from home or work tasks because of illness and potential lost earnings due to premature death.

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Journal Reference:

1. Paul A. Heidenreich, Justin G. Trogdon, Olga A. Khavjou, Javed Butler, Kathleen Dracup, Michael D. Ezekowitz, Eric Andrew Finkelstein, Yuling Hong, S. Claiborne Johnston, Amit Khera, Donald M. Lloyd-Jones, Sue A. Nelson, Graham Nichol, Diane Orenstein, Peter W.F. Wilson, Y. Joseph Woo, and on behalf of the American Heart Association Advocacy Coordinating Committee, Stroke Council, Council on Cardiovascular Radiology and Intervention, Council on Clinical Cardiology, Council on Epidemiology and Prevention, Council on Arteriosclerosis, Thrombo. Forecasting the Future of Cardiovascular Disease in the United States: A Policy Statement From the American Heart Association. Circulation, January 24, 2011 DOI: 10.1161/CIR.0b013e31820a55f5