GSK3 as a Sensor Determining Cell Fate in the Brain

More stuff to research on hyperacute therapies.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3275790/
Glycogen synthase kinase 3 (GSK3) is an unusual serine/threonine kinase that controls many neuronal functions, including neurite outgrowth, synapse formation, neurotransmission, and neurogenesis. It mediates these functions by phosphorylating a wide range of substrates involved in gene transcription, metabolism, apoptosis, cytoskeletal dynamics, signal transduction, lipid membrane dynamics, and trafficking, amongst others. This complicated list of diverse substrates generally follow a more simple pattern: substrates negatively regulated by GSK3-mediated phosphorylation favor a proliferative/survival state, while substrates positively regulated by GSK3 favor a more differentiated/functional state. Accordingly, GSK3 activity is higher in differentiated cells than undifferentiated cells and physiological (Wnt, growth factors) and pharmacological inhibitors of GSK3 promote the proliferative capacity of embryonic stem cells. In the brain, the level of GSK3 activity influences neural progenitor cell proliferation/differentiation in neuroplasticity and repair, as well as efficient neurotransmission in differentiated adult neurons. While defects in GSK3 activity are unlikely to be the primary cause of neurodegenerative diseases, therapeutic regulation of its activity to promote a proliferative/survival versus differentiated/mature functional environment in the brain could be a powerful strategy for treatment of neurodegenerative and other mental disorders.

Genetic Manipulation of Cell Death and Neuroplasticity Pathways in Traumatic Brain Injury

Something similar needs to be done for stroke.

http://scholar.google.com/scholar_url?hl=en&q=http://www.springerlink.com/index/NJUL186353100QW8.pdf&sa=X&scisig=AAGBfm34RZH6OQdFVEVqZN_qGKq9eVXxvQ&oi=scholaralrt

Abstract

Traumatic brain injury (TBI) initiates a complex cascade of secondary neurodegenerative mechanisms contributing to cell dysfunction and necrotic and apoptotic cell death. The injured brain responds by activating endogenous reparative processes to counter the neurodegeneration or remodel the brain to enhance functional recovery. A vast array of genetically altered mice provide a unique opportunity to target single genes or proteins to better understand their role in cell death and endogenous repair after TBI. Among the earliest targets for transgenic and knockout studies in TBI have been programmed cell death mediators, such as the Bcl-2 family of proteins, caspases, and caspase-independent pathways. In addition, the role of cell cycle regulatory elements in the posttraumatic cell death pathway has been explored in mouse models. As interest grows in neuroplasticity in TBI, the use of transgenic and knockout mice in studies focused on gliogenesis, neurogenesis, and the balance of growth-promoting and growth-inhibiting molecules has increased in recent years. With proper consideration of potential effects of constitutive gene alteration, traditional transgenic and knockout models can provide valuable insights into TBI pathobiology. Through increasing sophistication of conditional and cell-type specific genetic manipulations, TBI studies in genetically altered mice will be increasingly useful for identification and validation of novel therapeutic targets.

Mending the brain with a mechanical glove

Just think, students came up with this. 

Mending the brain with a mechanical glove

Northeastern University student-researchers have created a post-stroke rehabilitation glove designed to increase hand strength through finger extension and improve cognitive ability to complete everyday tasks such as picking up a glass, turning a doorknob or unscrewing a soda bottle.

The innovative device, dubbed “Excelsior,” was designed for a senior capstone project under the direction of Constantinos Mavroidis, Distinguished Professor of Engineering, and Richard Ranky, a mechanical engineering doctoral candidate. The undergraduate team members included Aaron Bickel, Abhishek Singhal, Craig Pacella and Nisha Parekh, whose work was supported by a three-year, $270,000 grant from the National Science Foundation.

According to the Centers for Disease Control and Prevention, some 800,000 stroke cases occur in the United States each year. Ranky said survivors require physical therapy and ongoing exercise to regain mobility and dexterity. As he put it, “A major goal for patients post-stroke is regaining their fine motor control.”

Excelsior – which was developed using 3-D additive manufacturing with embedded sensors and can be customized to fit a patient’s hand – was designed with that goal in mind.

To improve cognitive function, users match colored LEDs (light-emitting diodes) on the device’s fingertips with those on external objects fashioned into household shapes, such as cups or doorknobs.

In preparation for designing the prototype, students interviewed physical therapists at Spaulding Rehabilitation Hospital in Boston who shed light on patient needs.

Pacella, a senior mechanical engineering major, praised his group’s final design. “No other device assists with opening the hand and has cognitive exercises like this,” he said. “Most commercial hand motion rehab devices don’t use sensors to measure range of motion and control of the fingers.”

Mavroidis, who has filed a provisional patent on the glove, plans to license and commercialize the rehab device, which would cost patients approximately $200. But there’s work to be done. “It still needs to become more user-friendly, stronger and thinner,” Mavroidis explained.

Pacella said programming and developing circuit boards for the prototype forced him outside of his comfort zone, which, he said, would serve him well in his first professional job.

“There’s no such thing as a job in only mechanical engineering,” Pacella said. “In the real world, you need to understand other disciplines, which you can only learn through experience.”

Ranky agreed, highlighting the value of experiential learning. “Working on a capstone project is different from solving a problem in class where there is only one solution,” he said. “Capstone is as close as you can get to the real world.”

Technology To Prevent Stroke Demonstrated In JoVE

Practically anything would be better than rat poison. 

Technology To Prevent Stroke Demonstrated In JoVE

In the United States alone, approximately 6 million people suffer from an irregular heartbeat called atrial fibrillation (AF), and since the incidence increases with age, it is predicted that 15.9 million Americans will be affected by 2050. The most devastating side effect of AF is stroke, but a new device from Boston Scientific may prevent them from occurring.

Researchers from Atritech, now part of Boston Scientific, developed the WATCHMAN device, a small mesh umbrella that can be inserted into part of the heart cavity to prevent the formation of blood clots that cause strokes.

Currently, the anti-coagulant drug warfarin is used to prevent strokes, but the drug comes with other risks.

"Warfarin has a lot of side-effects. One major side-effect is the bleeding risk," said paper author Dr. Sven Mobius-Winkler. "Therefore, only 50 percent of the patients who should take Warfarin actually take it."

The WATCHMAN device gives patients another option. It has already been approved for use in the European Union and Australia, and secured investigational approval from the FDA in 2009.

To help train doctors how to use the device, doctors from the University of Leipzig Heart Center in Germany are publishing the full WATCHMAN placement procedure in the Journal of Visualized Experiments (JoVE), the world's first and only peer-reviewed, PubMed indexed, science and medicine video journal.

"Intervention and closure of the left atrial appendage is a complex procedure," said Dr. Mobius- Winkler. "For inexperienced physicians, it is hard to learn this procedure and therefore the video can help by doing step-by-step the implantation."

"The WATCHMAN device will give patients with atrial fibrillation another option rather than anti-coagulant drugs," said JoVE Editor Dr. Robert Dolan. "This article demonstrates the implantation of the device and will help clinicians gain expertise with the procedure, helping many of the patients who are unable or unwilling to take warfarin."

Study: Old flu drug speeds brain injury recovery

Lets start studying this for stroke.
http://www.lasvegassun.com/news/2012/feb/29/us-med-brain-injury-drug/

Researchers are reporting the first treatment to speed recovery from severe brain injuries caused by falls and car crashes: a cheap flu medicine whose side benefits were discovered by accident decades ago.

Severely injured patients who were given amantadine got better faster than those who received a dummy medicine. After four weeks, more people in the flu drug group could give reliable yes-and-no answers, follow commands or use a spoon or hairbrush _ things that few of them could do at the start. Far fewer patients who got amantadine remained in a vegetative state, 17 percent versus 32 percent.

"This drug moved the needle in terms of speeding patient recovery, and that's not been shown before," said neuropsychologist Joseph Giacino of Boston's Spaulding Rehabilitation Hospital, co-leader of the study. He added: "It really does provide hope for a population that is viewed in many places as hopeless."

Many doctors began using amantadine for brain injuries years ago, but until now there's never been a big study to show that it works. The results of the federally funded study appear in Thursday's New England Journal of Medicine.

A neurologist who wasn't involved in the research called it an important step. But many questions remain, including whether people less severely injured would benefit, and whether amantadine actually improves patients' long-term outcome or just speeds up their recovery.

Each year, an estimated 1.7 million Americans suffer a traumatic brain injury. Falls, car crashes, colliding with or getting hit by an object, and assaults are the leading causes. About three-quarters are concussions or other mild forms that heal over time. But about 52,000 people with brain injuries die each year and 275,000 are hospitalized, many with persistent, debilitating injuries, according to government figures.

With no proven remedies to rely on, doctors have used a variety of medicines approved for other ailments in the hopes that they would help brain injury patients. Those decisions are based on "hunches and logic rather than data," said Dr. John Whyte, of the Moss Rehabilitation Research Institute in suburban Philadelphia. He led the study along with Giacino.

Amantadine (uh-MAN'-tah-deen), an inexpensive generic, was approved for the flu in the mid-1960s. The first inkling that it might have other uses came a few years later when it appeared to improve Parkinson's symptoms in nursing home patients who got it. It was found to have an effect on the brain's dopamine system, whose many functions include movement and alertness, and it was later approved for Parkinson's.

It's now commonly used for brain injuries, and the researchers felt it was important to find out "whether we're treating patients with a useful drug, a harmful drug or a useless drug," Whyte said.

The study was done in the U.S., Denmark and Germany and involved 184 severely disabled patients, about 36 years old on average. About a third were in a vegetative state, meaning unconscious but with periods of wakefulness. The rest were minimally conscious, showing some signs of awareness. They were treated one to four months after getting injured, a period when a lot of patients get better on their own, Giacino noted.

They were randomly assigned to receive amantadine or a dummy drug daily for four weeks. Both groups made small but significant improvement, but the rate of recovery was faster in the group getting amantadine. When treatment stopped, recovery in the drug group slowed. Two weeks later, the level of recovery in the two groups was about the same.

There was no group difference in side effects, which included seizure, insomnia and rigid muscles.

The study was short, and the effect on long-term outcome is unknown. But Giacino said the drug still has value even if it only hastens recovery.

"What condition would we not jump for joy if we could have it over with faster?" he said.

The study didn't include those with penetrating head injuries, like the gunshot wound former Rep. Gabrielle Giffords suffered, but Giacino said the drug should have similar effects in those patients. Whether it would work in patients with brain injuries not caused by trauma, such as a stroke, isn't known.

Whyte said the researchers want to test the drug for longer periods.

Dr. Ramon Diaz-Arrastia said the results were welcome news in a field that has seen many failed efforts. He is director of clinical research at the government's Center for Neuroscience and Regenerative Medicine, which works with the military and government scientists on brain injury research.

"It's an important step toward developing better therapies," he said.

Since amantadine is so commonly used, he said U.S. troops with severe brain injuries in Iraq or Afghanistan probably get it, or should get it now. Since 2000, some 233,000 troops have suffered traumatic brain injuries, including about 6,100 serious cases, many of them from bomb blasts or shrapnel.

Laura Bacon said amantadine seems to be helping her brother recover from a car accident in Vermont last October. Nicholas Gnazzo, 47, of Rochester, N.H., was in a coma for weeks before he was taken for rehabilitation to Spaulding, where doctors put him on amantadine in January.

Since then he has been more alert, able to communicate with nods or gestures _ like pointing to his eyes when he wants his glasses, his sister said. Giacino agreed her brother has gotten better, but whether it is because of the drug can't be determined. Gnazzo wasn't part of the study.

"It's been four months now, and we know we still have a long way to go," Bacon said. "Anything that could be faster _ or feel faster to us _ is a positive."

Antibodies in Spinal Fluid Post-Stroke Puzzling

I think these researchers are looking at this wrong, they are assuming that these antibodies are the cause of the stroke rather than a result.
http://www.medpagetoday.com/Cardiology/Strokes/31410?utm_source=cardiodaily&utm_medium=email&utm_content=aha&utm_campaign=02-29-12&eun=gd3r&userid=424561&email=oc1dean@yahoo.com&mu_id=

Patients with acute stroke were more likely than those with other conditions to have antibodies in their cerebrospinal fluid, researchers found.

Of patients who received a lumbar puncture, nearly a quarter (24.8%) of those with acute stroke had intrathecal antibodies, compared with just 2.5% of patients with other conditions (P<0.001), according to Harald Prüss, MD, of the Charité University of Medicine Berlin, and colleagues.

"The strong association between cerebrospinal fluid-specific immunoglobulin synthesis and stroke suggests a role in the development of cerebral ischemia and might constitute an immunologically defined stroke subgroup," the researchers wrote online in Archives of Neurology.

The finding "demands a systematic prospective analysis of cerebrospinal fluid and serum samples to determine the time kinetics and pathogenicity of antibodies," they wrote.

Immune mechanisms have been considered to explain some ischemic strokes, but the role of intrathecal antibodies remains unclear because diagnostic tests are not routinely performed on cerebrospinal fluid in patients after cerebral ischemia.

In the current study, Prüss and colleagues examined data from 3,050 consecutive patients with ischemic stroke who were hospitalized at their center from 2005 to 2009.

Only 318 (10.4%) underwent a lumbar puncture within 96 hours after symptom onset. Indications included seizures, suspected central nervous system infection or vasculitis, pronounced agitation or disorientation, suspected leptomeningeal carcinomatosis, mitochondriopathy, vasculopathy, or diagnostic uncertainty.

The researchers matched those 318 patients with 79 control patients who did not have a stroke but received a lumbar puncture during a diagnostic workup for headache, diabetic oculomotor or abducens nerve palsy, idiopathic facial nerve palsy, or dizziness.

The patients with stroke were more likely to have cerebrospinal fluid-specific immunoglobulin synthesis than the controls, as measured by the presence of oligoclonal immunoglobulin bands.

The high, nearly 25% prevalence of antibodies in the cerebrospinal fluid of patients with stroke "may point to a direct association between cerebrospinal fluid-specific immunoglobulin synthesis and focal cerebral ischemia," the authors wrote.

Among the patients with stroke, one-third had blood-brain barrier dysfunction and 18.1% had pleocytosis, with no differences in the rates based on the presence or absence of the antibodies.

There were also no differences in the frequency of oligoclonal bands, pleocytosis, increased protein in the fluid, age, and sex based on whether the patients had had a prior stroke.

Of the patients with stroke who did not have intrathecal antibodies after the first lumbar puncture, 12 underwent a second puncture. Half had antibodies after the second puncture, which suggests that "the percentage of patients with oligoclonal band-positive stroke might increase further with longer follow-up," according to Prüss and colleagues.

They noted that stroke-associated intrathecal immunoglobulin synthesis could result from one of three options:

• Unidentified inflammatory disease
• Undetected previous ischemic degeneration of neuronal tissue with repeated presentation of central nervous system antigen to the immune system
• Polyclonal nonspecific B-cell activation secondary to brain damage

"The second explanation might be relevant to the high proportion of patients with oligoclonal bands already present at the time of their first clinically detected stroke," the authors wrote. "The finding of oligoclonal bands in patients with transient ischemic attacks supports this notion and implies relevance for predisease stages."

A Novel Mechanism For Protecting The Adult Brain In Times Of Oxygen Deprivation Inspired By Naked Mole-Rats

Another option for stopping the cascade of neuronal death. Who is going to push researchers to find out more and create a therapeutic approach to this?
http://www.medicalnewstoday.com/releases/242172.php
Could blind, buck-toothed, finger-sized naked mole-rats harbor in their brain cells a survival secret that might lead to better heart attack or stroke treatments?

University of Illinois at Chicago biologist Thomas Park and colleagues at UIC and the University of Texas Heath Science Center at San Antonio think the subterranean lifestyle of the pasty-looking rodents may indeed hold clues to keeping brain cells alive and functioning when oxygen is scarce. The key may lie in how brain cells regulate their intake of calcium.

"Normally, calcium in brain cells does wonderful things, including forming memories," says Park, who is professor of biological sciences at UIC. "But too much calcium makes things go haywire."

Brain cells starved of oxygen can't regulate calcium entry, and too much calcium in the cell is lethal. When a heart attack or stroke prevents oxygenated blood from reaching the brain, brain damage or death results.

Naked mole-rats, however, are very tolerant to oxygen deprivation, or hypoxia -- as are human newborns, whose brain cells have calcium channels that close during oxygen deprivation, protecting the cells from calcium overdose. With age, these calcium channels no longer close, which normally isn't a problem -- except during a heart attack.

Naked mole-rats retain a tolerance for oxygen deprivation into adulthood. Park and his colleagues measured calcium entry in brain tissue that had been kept under oxygen-poor conditions, reporting their findings online Feb. 21 in PLoS One.

"We knew the adults of this unusual mammal had brains that, like infant humans, were very tolerant to oxygen deprivation," he said. "We wanted to know if the adult naked mole-rats used the same strategy as babies to prevent calcium entry. This is exactly what we found."

Park thinks this strategy is an evolutionary adaptation by mole-rats, which live in the hundreds underground in tight, oxygen-deprived conditions.

"Imagine 200 mice living in a shoe box buried four feet under the ground -- things are going to get bad fast," he said.

The researchers think they have identified a novel mechanism for protecting the adult brain in times of oxygen deprivation.

"Developing this target into a clinical application is our next goal," he said. "We need to find a way to rapidly up-regulate the infant-type of calcium channels. Adult humans actually have some of these channels already, but far fewer than infants."

Park, who for years has studied naked mole-rats and their unusual adaptations, thinks the latest findings "are just the tip of the iceberg" of what we can learn from the rodents. Their homes are not only oxygen-poor, but rich in carbon dioxide and ammonia -- conditions that would make most animals ill. Yet mole-rats have evolved to suppress pain and even cancer.

"The more we study these creatures," said Park, "the more we learn."

Ephrin-A1-Mediated Dopaminergic Neurogenesis and Angiogenesis in a Rat Model of Parkinson's Disease

I know this is for Parkinsons but it does have some interesting possibilities in migration and signalling.
http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0032019

Abstract Top

Cells of the neural stem cell lineage in the adult subventricular zone (SVZ) respond to brain insult by increasing their numbers and migrating through the rostral migratory stream. However, in most areas of the brain other than the SVZ and the subgranular zone of the dentate gyrus, such a regenerative response is extremely weak. Even these two neurogenic regions do not show extensive regenerative responses to repair tissue damage, suggesting the presence of an intrinsic inhibitory microenvironment (niche) for stem cells. In the present study, we assessed the effects of injection of clustered ephrin-A1-Fc into the lateral ventricle of rats with unilateral nigrostriatal dopamine depletion. Ephrin-A1-Fc clustered by anti-IgG(Fc) antibody was injected stereotaxically into the ipsilateral lateral ventricle of rats with unilateral nigrostriatal lesions induced by 6-hydroxydopamine, and histologic analysis and behavioral tests were performed. Clustered ephrin-A1-Fc transformed the subventricular niche, increasing bromodeoxyuridine-positive cells in the subventricular area, and the cells then migrated to the striatum and differentiated to dopaminergic neurons and astrocytes. In addition, clustered ephrin-A1-Fc enhanced angiogenesis in the striatum on the injected side. Along with histologic improvements, behavioral derangement improved dramatically. These findings indicate that the subventricular niche possesses a mechanism for regulating both stem cell and angiogenic responses via an EphA–mediated signal. We conclude that activation of EphA receptor–mediated signaling by clustered ephrin-A1-Fc from within the lateral ventricle could potentially be utilized in the treatment of neurodegenerative diseases such as Parkinson's disease.

Roles of 5HT1A receptor in CNS neurogenesis and ADAM21 in spinal cord injury

Even if this is for spinal cord injury we need the knowledge gained by this.
http://gradworks.umi.com/34/89/3489325.html
Abstract:
These studies set out to identify strategies to rescue and repair the adult nervous system. First, we investigated the role of ciliary neurotrophic factor (CNTF) in 5HT1A receptor-induced neurogenesis in the rodent brain. Systemic treatment with an agonist, 8-OH-DPAT, increased neurogenesis only in rats and not mice, and only in one of the two neurogenic regions. This increase was not mediated by CNTF. These data suggest that translation of 5HT1A-based studies to human cell replacement therapies should be reconsidered. Secondly, the role of the plasticity-associated metalloprotease ADAM21 after spinal cord injury was investigated by comparing ADAM21-deficient mice to their wildtype littermates. No differences in behavioral or histology were found. However, a comprehensive metalloproteinase gene array revealed that ADAM21 regulates a cluster of inflammatory genes following injury. This leaves a potential for discovery of specific pharmaceutical ADAM21 inhibitors to reduce detrimental inflammatory processes following spinal cord injury.
full dissertation here:

Billiards stroke rehab

I was in northern Minnesota this weekend visiting a friend who owns a bowling alley. My bowling was not good the balls that fit my fingers were 14-16 lbs and at that weight I can't really control the swing very well, my regular bowling is with a 10 lb. ball. But the really fun part was playing bottle billiards. The official rules are listed here. Our rules are slightly different, you can't start scoring until you Carom the cue ball off both object balls, either object ball sank in a pocket is 1 point, a carom during a game is 2 points. We use an empty plastic soda bottle. This requires you to really stretch your arm out straight, loosen your fingers or thumb to guide the cue stick. My modification is to place the cue in crook of my wrist or sometimes underneath my wrist. I tried once to put the cue between my fingers but that only resulted in not being able to move the cue at all due to finger spasticity. We played 4 games and a lot of fun was had by all, especially the last game where my team won 31-0. The bars up there had dart games also so that would probably be another therapeutic possibility. So join your friends at the bars and play pool or darts with them. Ordering a diet Coke is acceptable.

Stroke Rehabilitation with PEMF Therapy

I'm really skeptical on this one, they talk about regular therapy at the same time so it is impossible to determine which one actually works.
http://www.drpawluk.com/stroke-rehabilitation-with-pemf-therapy/

In a just published study (Kakuda), high-intensity, low-frequency pulsed electromagnetic fields were used in patients’ stroke rehabilitation. The patients had their strokes within one year to nine a half years before treatment with the PEMFs. During a 15 day elective hospitalization set up specifically for this program, each patient received 22 treatment sessions of 20-min low-frequency PEMF and 120-min intensive OT daily. The PEMF of 1 Hz was applied to the side of the head opposite the area of the stroke, i.e. on the same side as the paralysis. The intensive OT, consisting of 60-min one-to-one training and 60-min self-exercise, was provided after the application of low-frequency PEMF, using standardized protocols and objective measures for the impact of treatment. Improvements were persistently seen up to 4 weeks after discharge in 79 of the 204 studied patients. Longer-term assessments were not conducted. Statistical analysis found no significant relationship between baseline parameters and indexes of improvement in motor function. The authors concluded that the 15-day inpatient PEMF treatment plus OT protocol is a safe, feasible, and clinically useful neurorehabilitative intervention for post-stroke patients with upper limb paralysis. The response to the treatment was not influenced by age or time after stroke onset. The major drawback of this study was that there was no comparison group using sham PEMF treatment.

PEMFs are expected to influence nerve cell firing/function of selected brain areas. It appears to be that low-frequency ≤ 1 Hz suppresses while high-frequency ≥ 5 Hz activates local neural activities. There was the question of which side of the brain to stimulate, the side with the lesion or the opposite side. Several randomized controlled trials have confirmed that low-frequency PEMF applied to the brain hemisphere opposite to the side of damage (non-lesional) can significantly improve motor function of the affected upper limb in post-stroke patients. It is speculated that exposure to the non-lesional hemisphere reduces possibly protective nerve function inhibition by the non-lesional hemisphere towards the lesional hemisphere, leading to facilitation of beneficial functional reorganization in the lesional hemisphere. Intensive occupational therapy (OT), especially using constraint-induced movement therapy (CIMT) for upper limb hemiparesis also appears to activate areas around the stroke lesion in chronic stroke patients. In chronic stroke, CIMT is currently considered to be most useful. In another study using high-frequency PEMF with CIMT over the lesional hemisphere daily for two weeks, compared to patients treated with CIMT only, improvement of motor function was not significantly different.

To be in the study the patients had to meet the following criteria: 1) ability, at least subjectively, to flex all the fingers of the affected upper limb in full range of motion. 2) Age between 18-90 years. 3) Time after the stroke more than 12 months. 4) Only a single-sided stroke. 5) No cognitive impairment with a pretreatment Mini Mental State Examination score of more than 26. 6) Being in a plateau state for at least 3 months. 7) No history of seizure within preceding year. 9) No documented epileptic discharge on pretreatment electroencephalogram. 10) No current use of antiepileptic medications for the prevention of seizure. 11) No pathological conditions known to be contraindications for PEMF.

In the current study, follow-up evaluation after discharge showed persistent improvement of motor function of the affected upper limb up to four weeks after treatment ended. The duration of improvement of motor function of the affected upper limb appears to be relatively short after a single session of low-frequency PEMF. A different study reported that the improvement induced by application of low-frequency PEMF to the non-lesional hemisphere daily for five consecutive days was maintained for two weeks after intervention. In yet another study, the improvement of motor function of the affected upper limb in patients who received CIMT was also maintained up to several months after the intervention. Whether there are longer-term effects using each of the two interventions remains unknown for now. What is also not known is whether continued use of PEMFs in the home setting long-term may continue to show improvements. This may be expected to be true given that the brain tends to repair very slowly, even given appropriate stimuli.

This study also showed no significant relationship between any of the six tested baseline parameters and the response to the intervention. The intervention can produce beneficial functional reorganization even in elderly patients and in those whose strokes were years earlier. Since this study did not include acute/subacute stroke patients within one year after onset, it remains unknown if earlier application of the protocol during the acute/subacute phase of stroke can produce more functional improvement than those seen in our patients. It has been reported that beneficial functional reorganization is higher in acute/subacute phase than in later phases of stroke.

While more research clearly needs to be done, this study is encouraging in showing that the combination of higher intensity PEMF and occupational therapy improves function, even in patients who had their strokes over a year earlier, and in some cases up to nine years earlier. Additionally, this study was performed in a hospital setting for a limited period of time using very expensive rTMS PEMF, with limited availability equipment. While not proven, it may not be unreasonable to expect that a home-based, high intensity PEMF system may produce similar results. A combination of low and high frequencies may be even better, some reducing nerve cell firing, as would be desirable with spasticity, and others increasing nerve cell firing, where there is a reduction in neuron function. It is generally axiomatic in medicine that little gain in function is likely to happen in these patients after the first 3 to 6 months following a stroke, with conventional PT/OT alone. So any therapeutic approach that is not likely be toxic or invasive, such as higher intensity PEMF , has a good chance of being able to provide benefit, and may well be worth considering.

Another just recently published study (Avenanti) of higher intensity, low frequency PEMF for stroke, investigated the long-term behavioral and neurophysiologic effects of combined higher intensity PEMF and physical therapy (PT) in chronic stroke patients with mild motor disabilities more than 6 months poststroke. In this study, thirty patients were enrolled in a double-blind, randomized, single-center clinical trial. They each received 10 daily sessions of 1 Hz higher intensity PEMF over the intact, that is nonaffected, motor cortex, with either real (R) or sham (S) approaches, administered either immedi­ately before or after PT. Outcome measures included dexterity, force, interhemispheric inhibition, and corticospinal excitability and they were assessed for 3 months after the end of treatment. The researchers found that treatment induced progressive rebalancing of excitability in the 2 brain hemispheres and a reduc­tion of inter-hemispheric inhibition in the R groups. PT produced improvements in all groups. The aspects of functions that were trained showed only small and transitory improvements in the S patients. The R group had greater behavioral and neurophysiologic improvements especially in the group re­ceiving R treatment before PT (R-PT), with robust and stable improvements. The post PT-R group showed a slight decline in their improvement over time. They concluded that priming PT with inhibitory higher intensity PEMF before the PT (in the hemisphere opposite to the stroke lesion) is optimal to boost brain plasticity related to the functions trained with PT and rebalance motor excitability and suggests that higher intensity PEMF is a valid and promising approach for chronic stroke patients with mild motor impairment.

These patients were enrolled as outpatients in a Neurorehabilitation clinic. They were included if they had a unilateral stroke, greater than six months after the first ever stroke, and had mild upper limb motor deficit. Anyone with a seizure disorder was excluded. The higher intensity PEMF was applied immediately before or after PT. There were eight patients in each experimental group with a total of 14 patients in the sham treatment arm. Treatment lasted for 10 days with two PEMF sessions per day, of 25 min. each, and 45 min. of standard task oriented upper limb exercises. The PEMF was applied to the motor cortex. The sham was the same activated coil applied perpendicularly to the scalp so that no current was induced in the brain. To check stability, two pretreatment evaluations were performed two weeks and one day before starting treatment. Post treatment evaluations were performed at 1, 7, 14, 30, and 90 days post treatment. Neural excitability of both hemispheres was assessed at baseline, pretreatment, day six [pre treatment] and at each of the post treatment follow-ups.

The exciting aspect of this study was that they actually checked for cortical excitability. Chronic stroke patients typically show less excitability on the affected side of the brain compared to the opposite side of the brain. In a normal non-stroke brain there is a cross communication between the sides of the brain where each side balances the other with inhibition and stimulation. Because of the damage to the side affected by the stroke the opposite side becomes uninhibited and can irritate the affected side, creating spasticity in the affected extremity. Before the study, the researchers believed that doing higher intensity PEMF before PT could potentially prime functional neural networks for the PT intervention to work better, leading to superior outcomes. This study provided evidence that higher intensity PEMF stimulation induces reduction of interhemispheric inhibition from the intact side of the brain to the affected side, long-term potentiation of excitability of the affected side leading to improved and obvious functional improvements, in particular when PT is preceded by the higher intensity PEMF. One to three months after treatment the group receiving PT first started to show a decline in performance and excitability of the affected side. In the group receiving higher intensity PEMF first, the outcomes remained stable over time by boosting brain plasticity caused by use of the brain and the affected extremity, mainly by stabilizing the physical learning processes of the brain. They found evidence of a daily, cumulative lowering of excitability in the intact hemisphere. This was paralleled by a strong cumulative increase in the excitability of the affected hemisphere. This study provides direct neurophysiologic evidence that 10 days is more effective than five days of higher intensity PEMF treatment. The sham PEMF stimulation group showed only a modest improvement lasting only a few weeks with no significant changes in excitability. This is not surprising since the PT was relatively short, patients were all chronic poststroke, and all had already received cycles of rehabilitation before. Even though it is known that PT this late after stroke is less effective, this study indicates that brain stimulation may overcome this limitation.

The practical importance of this randomized controlled trial, is that, even post stroke, at least up to six months afterward the stroke, the use of higher intensity PEMFs and PT may produce significant improvements in function, that was thought to be lost permanently. The questions that ultimately remain is whether similar benefits can be seen more than six months after the stroke and whether various higher intensity PEMF systems may produce similar results. Given the lack of toxicity for PEMF therapies, below the level of inducing seizures or contractions, post stroke patients may find significant benefit from these therapies.

Higher intensity PEMF therapy systems that could be considered for stroke management, in the light of the studies above, would include the PEMF 100, Curatron XP/PC, Sota and Almag. The PEMF 100 and Curatron would be expected to provide the better results, because of their frequencies and intensities.

The mystery of the missing brain cells

Does neurogenesis exist in humans? Register at the site to read it all.
http://www.newscientist.com/article/mg21328521.600-the-mystery-of-the-missing-brain-cells.html

The idea that we can grow new neurons has brought tantalising hope of repairing the brain after injury and disease. But could it be based on wishful thinking?

I AM sitting at a lab bench peering down the microscope at the brain of a chicken embryo. Dense networks of delicate young nerve fibres surround patches of newborn cells with their DNA stained dark brown.

I am witnessing the end products of neurogenesis, the birth of new brain cells. It is one of the hottest topics in neuroscience, and the idea that we can boost the growth of new brain cells with various kinds of physical or mental exercise seems to have equally taken hold of the public imagination. On top of this is the exciting prospect that we could one day use new neurons to repair the brain after injury or disease.

But does it really happen? While there is good evidence that adult neurogenesis takes place in animals, there is reason to believe that does not necessarily apply to our own species. "Everyone wants to believe that functional neurogenesis happens in adult humans, everyone wants to believe that we can repair damaged brains," says Andrew Lumsden, head of the MRC Centre for Developmental Neurobiology at King's College London, where I saw the chicken brain. "But there's precious little evidence for it."

The current faith in our brains' regenerative abilities is in fact something of a reversal. For most of the last century, it was thought that neurogenesis was restricted to our time in the womb. "Once development was ended the founts of growth dried up irrevocably," wrote Santiago Ramón y Cajal, the 19th-century Spanish anatomist seen as the founder of modern neuroscience. "In the adult, the nerve paths are immutable."

One basis of this belief was our limited capacity to recover after a stroke or a blow to the head. Such injuries can have long-lasting effects on abilities like speech and movement. Plus the brain is so much more complex than organs with proven regenerative powers, such as the skin and liver. "How would new neurons usefully integrate into complex neural networks after the connectional plan of the brain is complete?" asks Lumsden. "One side effect of having a large and complex brain is that you wouldn't want naive newcomers barging in."

What Makes Good Cholesterol Go Bad?

And maybe they will eventually find out why cholesterol turns into plaque.
http://www.everydayhealth.com/high-cholesterol/0223/what-makes-good-cholesterol-go-bad.aspx

Researchers have discovered how specific proteins in the blood transform HDL cholesterol (the good kind) into LDL Cholesterol (the bad kind). Here's how it works, plus ways to amp up your good cholesterol levels through diet and exercise.

Blame it on a tiny, banana-shaped protein molecule called CETP, which stands for cholesteryl ester transfer protein.

Research from the U.S. Department of Energy (DOE)’s Lawrence Berkeley National Laboratory (Berkeley Lab) has revealed how CETP turns good cholesterol (high density lipoproteins, or HDL) into bad cholesterol (low density lipoproteins, LDL).

Lipoproteins are substances that carry cholesterol throughout the body. LDLs do so in a way that can clog arteries — blocking blood flow, and potentially causing heart disease or stroke. Hence the “bad” label. HDLs, on the other hand, carry cholesterol out of the bloodstream and into the liver, where it’s excreted. That way, it doesn’t build up in the arteries.

It turns out that CETP molecules transfer cholesterol from those good HDLs to bad LDLs via a tunnel that runs through its center.

The findings, published in the journal Nature Chemical Biology, could lead to more efficient ways of preventing the development of heart disease. “Our model identifies new interfaces of CETP that interact with HDL and LDL and delineates the mechanism by which the transfer of cholesterol takes place,” says Gang Ren, PhD, of Berkeley Lab’s Molecular Foundry, who led the study. “This is an important step toward the rational design of next generation CETP inhibitors for treating cardiovascular disease.”

Athersys, University Hospitals partner for clinical trials of MultiStem for stroke

Earlier I posted about using this for TBI. I can't tell if this is for chronic or acute. I do wonder how they plan to get thru the blood-brain barrier. Everyone should clamor to get involved.
http://www.medcitynews.com/2011/09/athersys-reveals-plans-for-phase-2-stroke-clinical-trial/
Stem cell developer Athersys (NASDAQ:ATHX) has taken the next of many steps toward commercializing its MultiStem therapy for stroke, the most promising application for the therapy.

The Cleveland-based company detailed its plans for a phase 2 ischemic stroke clinical trial that’s estimated to involve about 140 patients, according to ClinicalTrials.gov, a website maintained by the National Institutes of Health.

The double-blind, randomized, placebo-controlled study is designed to evaluate the safety and effectiveness of treating stroke patients with MultiStem, an off-the-shelf stem cell treatment derived from the bone marrow of adults or other nonembryonic sources.

The trial is scheduled to start enrollment this month, with October 2013 estimated as the time frame for final data collection. The trial is expected to be completed by November 2014.

A company official declined comment.

The company believes MultiStem could represent a significant advancement in treating ischemic stroke patients. The technology has shown promise in reducing inflammation, protecting damaged tissue and forming new blood vessels.

Ischemic stroke is caused by a blood clot in the brain and accounts for 87 percent of all stroke cases.

As for the reason that stroke is the most promising application of MultiStem — which is also being investigated for the treatment of heart attack, inflammatory bowel disease, orthopedics and blood diseases — it’s simple: stroke represents the largest market.

CEO Gil Van Bokkelen has pegged the potential stroke market at $15 billion.

Still, the company faces a long, bumpy road to commercialization, with any application of MultiStem unlikely to hit the market for at least four or five years.

Chantix Shows Promise for Ataxia

And since stroke can cause ataxia research is needed to see if it would help stroke survivors.
http://www.dddmag.com/news-Chantix-Shows-Promise-for-Ataxia-22312.aspx

A nicotinic drug approved for smoking cessation significantly improved the walking ability of patients suffering from an inherited form of ataxia, reports a new clinical study led by University of South Florida researchers.

The randomized controlled clinical trial investigated the effectiveness of varenicline (Chantix) in treating spinocerebellar ataxia type 3, or SCA3. The findings were published online earlier this month in Neurology, the journal of the American Academy of Neuroscience.

Lead author Dr. Theresa Zesiewicz and colleagues at the USF Ataxia Research Center collaborated with researchers from Beth Israel Deaconess Medical Center in Boston, MA, and from the David Geffen School of Medicine at UCLA in Los Angeles, CA.

Spinocerebellar ataxia impairs the brain and spinal cord causing progressive difficulty with coordination of movements, including walking. The uncoordinated movements, or ataxia, is a neurological symptom with no treatment or cure and can lead to serious fall-related injuries.

"This is the first clinical trial in patients with ataxia showing that nicotinic acetycholine agonists improve symptoms associated with the ability to stand straight and walk," said Dr. Zesiewicz, professor of neurology and director of the USF Ataxia Research Center. "Patients receiving varenicline could walk with more ease, with less help and faster than those in the placebo group."

The double-blind multicenter study evaluated 20 adult patients with genetically confirmed SCA3. Half the patients received 1 mg. of varenicline twice a day, and the other half received placebo. At the end of the eight-week study, patients taking varenecline performed significantly better on measures of gait, stance, rapid alternating movements and a timed 25-foot walk than those who did not. The drug was fairly well tolerated, with mild nausea being the most common side effect.

The study authors suggest that varenicline's ability to improve ataxia may be associated with the drug's ability to act at several different sites in the brain affected by nicotine.

Study co-author Lynn Wecker, PhD, a distinguished research professor at USF Health, is investigating the cellular and molecular mechanisms mediating the effects of varenicline and other nicotinic agonists. Dr. Wecker and colleagues, supported by a five-year grant funded by the National Institute of Neurological Disorders and Stroke, have shown that several drugs affecting neuronal nicotinic receptors improve gait and balance in an animal model of SCA3.

Further preclinical research is needed to understand how nicotinic acetylcholine agonists improve ataxia, and larger clinical studies with more patients are needed to identify other neurodegenerative diseases that may benefit from nicotinic medications, the authors conclude.

Invade and conquer: Nicotine's role in promoting heart and blood vessel disease

The bad side of nicotine, you'll have to consult your doctor for the benefits during rehabilitation.
http://www.eurekalert.org/pub_releases/2012-02/aiop-iac022312.php
Cigarette smoke has long been considered the main risk factor for heart disease. But new research from Brown University in Providence, R.I., shows that nicotine itself, a component of cigarette smoke, can contribute to the disease process by changing cell structure in a way that promotes migration and invasion of the smooth muscle cells that line blood vessels. In particular, invading cells can remodel structures called podosomes, and this leads to further degradation of vessel integrity.
Ultimately, this cellular migration and invasion process gives rise to the formation of vessel-clogging fatty deposits known as plaque – the hallmark of heart and blood vessel disease. The results on the nicotine-podosome link will be presented at the 56th Annual Meeting of the Biophysical Society (BPS), held Feb. 25-29 in San Diego, Calif.
If confirmed in further studies, the finding that nicotine itself promotes vessel damage by changing podosomes appears to question the health benefits of helping people quit smoking through smokeless nicotine delivery agents such as gum or patches.
"The finding that nicotine is as effective as cigarette smoke in enhancing cellular structural changes, and breakdown of scaffold proteins by vascular smooth muscle cells, suggests that replacing cigarette smoking by nicotine treatment may have limited beneficial effects on atherosclerosis," notes lead researcher Chi-Ming Hai, professor of medical science in the department of molecular pharmacology, physiology, and biotechnology at Brown University.
Hai's research illuminates the multistep process of plaque formation, and suggests that a new powerful player, nicotine, may be involved. The plaque formation process begins as a response to cellular injury, and progresses to destructive and chronic inflammation of the vessel walls that attracts mobs of white blood cells, further inflaming the vessels. This damage-causing inflammation can be triggered by chemical insults from high blood sugar, modified low-density lipoproteins (LDL, the "bad cholesterol"), physical stress from high blood pressure, or chemical insult from tobacco smoke. Now nicotine itself appears to remodel key structures in a way that primes and enhances the invasion of smooth muscle lining the vessel wall.
Identifying a possible nicotine-posodome link in the invasion step of plaque formation process suggests a new means of intervening in the process: targeting the cell structures that are changed by nicotine and that promote invasion of the smooth muscle lining the vessel wall. If a therapy could prevent, slow, or reverse that step, it would likely interrupt the plaque-production cycle.
Fatty deposits accumulate in blood vessels beginning as young as age 10 and progress over a person's lifetime. Heart disease results if the deposits continue to build and harden into vessel-clogging plaque. When plaque ruptures, it can block blood flow, starving the heart or brain of oxygen and leading to a heart attack or stroke.
The presentation, "Cigarette smoke and nicotine-induced remodeling of actin cytoskeleton and extracellular matrix by vascular smooth muscle cells," is at 1:45 p.m. on Sunday, Feb. 26, 2012, in the San Diego Convention Center, Hall FGH. ABSTRACT: http://tinyurl.com/73e836j

Lab Studies Raise Flags About New Alzheimer's Drugs

I know this is specifically about Alzheimers but the article talks about axonal development and targeting which I think are extremely important in neuroplasticity and neurogenesis.
http://www.medpagetoday.com/Neurology/AlzheimersDisease/31255?utm_content=&utm_medium=email&utm_campaign=DailyHeadlines&utm_source=WC&eun=g424561d0r&userid=424561&email=oc1dean@yahoo.com&mu_id=
An enzyme that drives plaque formation in Alzheimer's disease also has a key role in normal axonal development and targeting, which might be disrupted by a new class of drugs that inhibit the enzyme, studies in mice suggested.
Animals with a genetically engineered deficiency in the enzyme BACE1 produced offspring with mistargeted olfactory sensory neuron axons, indicating defective axon guidance.
As compared with wild-type mice, the enzyme-deficient offspring had smaller olfactory bulbs that often had malformed glomeruli with randomly oriented, poorly bundled olfactory sensory neuron axons, according to a report published online in Molecular Neurodegeneration.
The findings suggest that newly developed BACE1 inhibitors might disrupt neuronal function and possibly worsen the memory impairment the drugs were designed to treat.
"Let's proceed with caution," Robert Vassar, PhD, of Northwestern University in Chicago, said in a statement. "We have to keep our eyes open for potential side effects of these drugs."
Vassar headed a team of researchers that discovered BACE1 and uncovered its role in amyloid plaque formation, a hallmark finding in the brains of Alzheimer's patients. The observations helped fuel ongoing research and development of BACE1 inhibitors for treatment of Alzheimer's disease.
Aside from the link to amyloid plaque, little was known about BACE1 function. BACE1-deficient mice exhibit hippocampus-based memory deficits, have abnormal EEG findings, and are prone to seizures, Vassar and co-authors wrote. Hypomyelination is another characteristic of mice with genetically engineered enzyme deficiency.
The finding that BACE1 co-localizes with presynaptic neuronal markers has indicated that the enzyme has a role in the development and function of axons or terminals. Studies have also indicated that axon guidance molecules might be targets of BACE1, suggesting a possible role for the enzyme in axon guidance.
To learn more about BACE1 function, investigators studied mice that are homozygous for BASE1 deficiency. Specifically, they examined the role of BACE1 in axon guidance of olfactory sensory neurons, a well-established model of axon targeting.
The highest levels of BACE1 in the olfactory bulb are found in the olfactory sensory neuron axon terminals in glomeruli, suggesting a role for the enzyme.
Subsequent studies revealed several key findings, which were reported simultaneously at the American Association for the Advancement of Science meeting in Vancouver. As compared with wild-type animals, BACE1-deficient mice had:

• Smaller olfactory bulbs that weighed significantly less than those of wild-type animals (P=0.00856), suggesting perturbed olfactory sensory neuron axon guidance.
• Diminished visual clarity of olfactory sensory neuron axon bundles and glomeruli under magnification, suggesting abnormal organization or structure of axons.
• Axon guidance defects in olfactory sensory neurons that expressed specific odorant receptors.

Taken together, the results strongly implied that BACE1-deficient mice had olfactory systems that were "poorly wired."
"It's like a badly wired house," said Vassar. "If the electrician doesn't get the wiring pattern correct, our lights won't turn on and the outlets won't work."
The observed defects in the olfactory system of the enzyme-deficient mice probably originates in the brain, quite possibly the hippocampus, Vassar continued. If true, the hippocampus would be particularly vulnerable to BACE1 inhibition, which might induce and perpetuate disruption of axon guidance.
"It's not all bad news," Vassar said. "These BACE1 blockers might be useful at a specific dose that will reduce the amyloid plaques but not high enough to interfere with the wiring. Understanding the normal function of BACE1 may help us avoid potential drug side effects."

Motor area of brain involved in learning as well as acting

Research from 2001 saying they followed 162 individual neurons as a monkey learned new tasks. Which should have immediately opened up a new line of research asking, How does the neighboring neuron know it needs to come to assist. Nowadays they could use nanowires to listen in.
http://web.mit.edu/press/2001/movement-0718.html

MIT researchers have found that a subpopulation of brain cells in the part of the cortex that controls movements acquires novel firing patterns while an animal learns a new set of voluntary movements.

The results were published in the May issue of the journal Neuron by Emilio Bizzi, the E. McDermott Professor of Brain and Cognitive Sciences; MIT graduate student Camillo Padoa-Schioppa; and Chiang-Shan Ray Li of Chang Gung University in Taiwan.

The data indicate that the nervous system constantly reorganizes itself to deal with new motor acts needed in a new environment. Any time the nervous system encounters a new environment, a subpopulation of neurons change to accommodate the new conditions. This "suggests that neural plasticity is the rule rather than the exception," the authors wrote.

MONKEY SEE, MONKEY DO

The researchers concentrated on an area of the brain called "the primary motor cortex" responsible for voluntary movements. Motor commands issued elsewhere in the brain seem to be funneled through M1 before they are executed.

While other studies have shown that repeated finger movements by musicians, for instance, rapidly alter the area of M1 dedicated to that particular movement, the researchers say that no other studies have explored changes in neuronal activity during learning that involved a change in movement dynamics.

In this study, monkeys had to learn to move a joystick a new way to overcome a slight force when using a previously learned movement. This changes the dynamic of the movement, although the movement itself (the kinematics) looks identical once it is learned.

CHANGING THE BRAIN

Because learning new skills causes physical changes in the brain, the researchers' goal was to get a sense of what happens in the area of the brain devoted to movement before, during and after adaptation to a new movement dynamic.

Monkeys were taught to move a joystick that controlled a small square cursor at the center of a computer screen. They were supposed to move the cursor to targets that appeared sequentially at eight different locations around the screen.

Once they learned to do this quickly and accurately, they had to perform the same movements while an orthogonal force was being exerted on the joystick. At first, the monkeys' movements were shaky, but eventually they got just as good at reaching the targets with the force in effect (a process called adaptation).

The researchers tracked how these movements affected 162 individual neurons within the monkeys' brains. "We found that two different classes of memory cells coexist and balance each other after exposure to the force field," Padoa-Schioppa said.

The changes in memory cells suggested that the monkeys created an internal model for how to move the joystick to reach the target. This involves motor learning, not just motor performance.

These results may help explain the brain's ability to learn new things while not losing prior knowledge. "The network picks up new information and still acts properly when the information is not needed," Padoa-Schioppa said. "You want to learn something new without forgetting something old."

While it is known that the brain modifies itself to learn new things, this two-tiered cell function may be the mechanism that allows the network to simultaneously deal with old and new situations.

This work is supported by the National Institutes of Health.

Familiar Stroke Tool Predicts Early Death Risk

I wasn't told what mine was but taking it now and assuming how I did I scored 10 - moderate. After a researcher looked at my scans he was amazed I could walk and talk.

I would think that looking at MRI scans on a daily basis would provide a much more scientific basis for any predictions on recovery or death.
http://www.medpagetoday.com/Cardiology/Strokes/31308?utm_source=cardiodaily&utm_medium=email&utm_content=aha&utm_campaign=02-22-12&eun=gd3r&userid=424561&email=oc1dean@yahoo.com&mu_id=

The NIH stroke scale (NIHSS) score is a strong predictor of 30-day mortality among Medicare beneficiaries with acute ischemic stroke, even without other clinical information, researchers found.

In a model that included NIHSS score alone, there was "excellent" discrimination of mortality risk, especially when the score was used as a continuous variable (c-statistic 0.82), according to Gregg Fonarow, MD, of the University of California Los Angeles, and colleagues.

The score also yielded high discrimination when divided into four categories ranging from mild to extremely severe stroke (c-statistic 0.80), the researchers reported in the online Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease.

Adding demographic and clinical variables to the model only slightly increased the performance of the model (c-statistic 0.84).

"These findings suggest that it may be critical to collect and include stroke severity for optimal risk stratification and risk adjustment of 30-day mortality for Medicare beneficiaries with acute ischemic stroke," the authors wrote.

The NIHSS is well validated for assessing initial stroke severity, and the scores have been associated with mortality risk in acute ischemic stroke, although those studies have been subject to various limitations, including small sample sizes and single-center settings.

To overcome some of those weaknesses, Fonarow and colleagues examined data from 33,102 fee-for-service Medicare beneficiaries. They were treated for acute ischemic stroke at 404 hospitals participating in the Get With the Guidelines-Stroke (GWTG-Stroke) program from April 2003 through December 2006. The mean age of the patients was 79.

Patient data were linked with enrollment files and inpatient claims from the Centers for Medicare & Medicaid Services (CMS).

The median NIHSS score (5) fell in the mild stroke range. It was significantly higher in the 13.6% of patients who died at 30 days (17 versus 4, P<0.0001).

NIHSS score was related to 30-day mortality in a near-linear fashion, with death rates ranging from 2.3% for a score of zero to greater than 75% for a score of 40 or higher.

The 30-day mortality rates for patients based on NIHSS scores were:

• Mild stroke (0 to 7): 4.2%
• Moderate stroke (8 to 13): 13.9%
• Severe stroke (14 to 21): 31.6%
• Extremely severe stroke (22 to 42): 53.5%

Without contribution for any other factors, the NIHSS scores provided high discrimination of mortality risk as a continuous variable (c-statistic 0.82), when broken into four categories (c-statistic 0.80), and when broken into three categories (c-statistic 0.79).

The findings were similar regardless of age, sex, or prior history of stroke or transient ischemic attack.

The discrimination achieved with the NIHSS scores alone outperformed a model that included demographic and clinical variables without NIHSS (c-statistic 0.71).

According to Edward Jauch, MD, of the Medical University of South Carolina in Charleston, the "results reinforce the importance of using the NIHSS as a risk modifier in prognostic models used for stroke center certification, public reporting, and perhaps for pay-for-performance reimbursement in the future."

Current models used by CMS do not include the initial NIHSS score, which "may lead to unintentional financial disincentives in stroke centers which care for a disproportionate share of the most severe stroke patients," he wrote in an accompanying editorial. "Given the current modest payment rates for stroke, this may lead to the unintended consequence of decreasing access to stroke expertise in stroke systems of care."

Fonarow and colleagues pointed out some limitations of the study, including the applicability only to patients 65 and older in fee-for-service Medicare; the inclusion of hospitals participating in the GWTG-Stroke program only; the dependence on medical records for data; and the lack of information on the timing of NIHSS assessment, other metrics of stroke severity, and other clinical outcomes.

You can take the test scale here:
http://www.ninds.nih.gov/doctors/NIH_Stroke_Scale.pdf

Oranges, grapefruits lower women's stroke risk

Correlation or cause? Ask your doctor. 

Oranges, grapefruits lower women's stroke risk

A diet rich in citrus fruits, such as oranges and grapefruits, may reduce women's risk of stroke, a new study says.

In the study, women who ate the most citrus fruit had a 19 percent lower risk of having an ischemic stroke than women who ate the least. In an ischemic stroke, blood flow to the brain is blocked, sometimes by clogged arteries.

While other studies have looked at the benefits of eating fruit in general, in the new study, the researchers looked at different types of fruit. Prior research has shown that compounds called flavonoids found in fruit — and also in vegetables, dark chocolate and red wine — may benefit health, but not all flavonoids appear to have the same effect on stroke.

In the new study, there was no link between overall flavonoids consumption and stroke risk, the researchers said.

But citrus fruit contains a subgroup of flavaonoids, called flavanones, and it's these compounds that the new study linked with lower stroke risk.

While flavanones can be found in citrus juices, the researchers recommended eating more citrus fruit, rather than drinking more juice, because commercial fruit juices tend to contain a lot of sugar.

The study will be published in April issue of the Stroke: Journal of the American Heart Association.

The study followed 69,622 women for 14 years, with participants reporting their food intake (including details on fruit and vegetable consumption) every four years. The researchers examined analyzed the women's diets, looking for the six main subclasses of flavonoids — flavanones, anthocyanins, flavan-3-ols, flavonoid polymers, flavonols and flavones.

Flavanones may reduce risk of stroke through several mechanisms, including improving blood vessel health and countering inflammation, said study researcher Aedín Cassidy, a professor of nutrition at the University of East Anglia in the United Kingdom.

Previous studies on fruit consumption and stroke risk have had mixed results. For instance, one study found a link between increased consumption of white fruits like apples and pears and lower stroke risk, but found no link for yellow and orange fruits.

More studies are needed to confirm the association between flavanone consumption and stroke risk, and to gain a better understanding of the link, the researchers said.

Health and Human Resources releases National Alzheimer's Plan draft

Just think if we had forward looking stroke associations that would promote something similar. Only 33 pages and the hard work is already done, all you have to do is ask the Alzheimers Association if you can reuse it.
http://www.alz.org/documents_custom/National_Plan_to_Address_Alzheimers.pdf?WT.mc_id=enews2012_02_22
Their goals;
1. Prevent and Effectively Treat Alzheimer’s Disease by 2025
Strategy 1.A: Identify research priorities and milestones
Action 1.A.1: Convene an Alzheimer’s disease research summit with national and international scientists to identify priorities, milestones, and a timeline
Action 1.A.2: Solicit public and private input on Alzheimer’s disease research priorities.
Action 1.A.3: Regularly update the National Plan and refine Goal 1 strategies and action items based on feedback and input.
Action 1.A.5: Update research priorities and milestones
Strategy 1.B: Expand research aimed at preventing and treating
Alzheimer’s disease.
Action 1.B.1: Expand research to identify the molecular and cellular mechanisms underlying Alzheimer’s disease, and translate this information into potential targets for intervention.
Action 1.B.2 Expand genetic epidemiologic research to identify risk and protective factors for Alzheimer’s disease.
Action 1.B.3: Increase enrollment in clinical trials and other clinical research through community, national, and international outreach.
Action 1.B.5: Conduct clinical trials on the most promising pharmacologic interventions.
Strategy 1.D: Coordinate research with international public and private entities
Strategy 1.E: Facilitate translation of findings into medical practice and public health programs.
Action 1.E.1: Identify ways to compress the time between target identification and release of pharmacological treatments.
Action 1.E.2: Leverage public and private collaborations to facilitate dissemination, translation, and implementation of research findings.
Action 1.E.3: Educate the public about the latest research findings.
Action 1.D.1: Inventory Alzheimer’s disease research investments.
Action 1.D.2: Expand international outreach to enhance collaboration.
2. Optimize Care Quality and Efficiency
3. Expand Supports for People with Alzheimer’s Disease and Their Families
4. Enhance Public Awareness and Engagement
5. Track Progress and Drive Improvemen

Modulating the motor system by action observation: Implications for stroke rehabilitation

A good dissertation and they even tested this on chronic patients, so as a result therapy departments need to get videos of all kinds of movements for patients to study. This will lead to my looking for hand videos.
Video here: Finger Independence Exercise
and here:Finger Extension
And here:Advanced Finger Fitness Guide DVD Dance
And Here:Greg Irwin-Finger BalletDon't listen to me(I know nuthin) this needs to come from your therapists.

http://gradworks.umi.com/34/87/3487903.html
Abstract:
The first study used functional magnetic resonance imaging (fMRI) to measure activity in motor-related brain regions during action observation. 12 participants with chronic middle cerebral artery stroke and moderate to severe dominant right hand paresis, and 12 matched right-handed non-disabled participants observed precision reach to grasp actions (e.g. lift pencil ) made using the left and right hand. Observed actions were difficult or impossible for participants with stroke to perform using the paretic right hand, but easy to perform using the non-paretic left hand. All participants performed the actions using each hand to the best of their ability after the MRI. We find that non-disabled participants show bilateral, symmetric activation of cortical motor regions during left or right hand action observation. After stroke, a similar bilateral, symmetric activation of cortical motor regions is found during left hand action observation; yet during right (paretic) hand action observation, cortical motor activity is lateralized toward the left lesioned hemisphere. Overall, for non-disabled participants, left hand more than right hand action observation engaged cortical motor regions and more so in the right hemisphere; whereas for participants with stroke, right (paretic) hand more than left hand action observation engaged cortical motor regions, and more so in the left lesioned hemisphere. In addition, we find that activity in the motor system during action observation is related to motor capability to perform the observed actions, such that longer movement times using the paretic right hand, indicating great impairment, are associated with greater activity during right hand action observation in the inferior frontal gyrus of the left lesioned hemisphere. Results suggest that despite chronic non-use, cortical representations of the paretic limb in the damaged motor cortex are preserved and may be accessed by action observation in stroke rehabilitation.
The second fMRI study assessed how activity in the putative mirror neuron system and other cortical motor regions during action observation differs between participants with stroke and different lesion locations. 6 participants with stroke involving the internal capsule, and 6 participants with stroke broadly involving the cortex and internal capsule, observed reach to grasp actions made using the left and right hand. All patients had chronic middle cerebral artery stroke of the dominant left hemisphere and moderate to severe right hand paresis. Results indicate a consistent finding related to stroke that is independent of lesion information in this study: participants with stroke show strong cortical motor activity in the left lesioned hemisphere during right (paretic) hand action observation. Yet within the overall stroke group pattern, we find differences between lesion groups, indicating a specific effect of lesion on MNS activity after stroke, including: (1) stroke involving the cortex and internal capsule is associated with more widespread, bilateral activity than stroke limited to the internal capsule; (2) stroke involving the left ventral inferior frontal gyrus (IFG) is associated with greater activity in the left pars triangularis of the IFG; and (3) for stroke involving the internal capsule, less motor capability to perform the observed actions is related to greater activity in the left IFG; whereas for stroke involving the cortex and internal capsule, this relation is found in the premotor cortex. Findings from this study suggest plasticity in the putative mirror neuron system to support action observation and imitation after stroke.
The third study uses fMRI to evaluate whether action observation and execution share a common neural substrate after stroke affecting the motor system. 4 participants with chronic dominant left hemisphere stroke and moderate right hand paresis and 4 matched right-handed non-disabled participants took part in the study. During fMRI participants observed and performed a reach to grasp action (grasp tennis ball ) using their left hand and right hand to the best of their ability. For each single subject we assessed activity during action observation, execution, and overlap between conditions. We find that single subject MNS maps are variable in the healthy brain and after stroke. We discuss contributions to variability related to age and stroke. We attempt to interpret single subject MNS maps related to stroke and related to the potential for a given individual with stroke to benefit from rehabilitative methods that engage the MNS. We find that MNS maps provide information that may be relevant to clinical applications, or may be used to evaluate cortical motor activity before and after an intervention that engages the MNS and related to functional gains. (Abstract shortened by UMI.)
full dissertation here:
http://gradworks.umi.com/cgi-bin/redirect?url=http://gateway.proquest.com/openurl%3furl_ver=Z39.88-2004%26res_dat=xri:pqdiss%26rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation%26rft_dat=xri:pqdiss:3487903

Burke Medical Research Institute Scientists Awarded Research Grant from Dana Foundation for Stroke Research

While this is good they are looking at this wrong because they are looking for those patients that will respond well to traditional therapies That is a mistake because traditional therapies will not be enough for the coming 'tsunami' of stroke patients. We have to actually prevent survivors from needing those traditional therapies. Stop the dying neurons in the cascade of death.
http://www.mdnews.com/news/2012_02/burke-medical-research-institute-scientists
The Dana Foundation is a private philanthropic organization that supports brain research through grants, publications and educational programs. This particular grant, called the Clinical Neuroscience Research Grant, will fund the study of ischemic stroke patients to help identify epigenetic markers that play a role in stroke recovery.

The team of investigators includes: Rajiv R. Ratan, M.D., Ph.D., executive director of the Burke Medical Research Institute and professor of neurology and neuroscience at Weill Cornell Medical College; Jessica F. Elder, Ph.D., instructor of biostatistics and epidemiology at The Burke Medical Research Institute and Weill Cornell Medical College; as well as Giovanni Coppola, M.D., director of the Semel Center for Informatics and Personalized Genomics at UCLA.

“In order to help patients reach their maximum recovery potential, we must first identify the (many) factors that influence recovery,” Elder said. “Only then can we modify behaviors or biological mechanisms to improve patient outcomes."

The study could have significant impact because the researchers will be looking to identify epigenetic markers that could help determine how well a patient may do in post stroke rehabilitation. Traditional indicators of how well a patient may do in post stroke rehabilitation have been limited to individual factors such as initial impairment or disability and the type, size and location of stroke a patient suffers.

It is the hope that someday a simple blood test can serve as an indicator of how well a patient will respond to traditional rehabilitation methods. “This new research can open the door for tremendous breakthroughs in stroke research and rehabilitation. The benefits could be far reaching as it can help physicians counsel patients about what comes after a debilitating brain injury and also provide information to scientists that may be key to future rehabilitation programs,” Ratan stated. “This type of grant is significant because it extends much of the work being done in the Institute to the patient bedside. Specifically, the grant will focus on epigenetic biomarkers that can help determine how a patient will do in post stroke rehabilitation.

“Understanding more about why some patients recover from stroke and other brain injuries can lead to changes in how we approach rehabilitation and ultimately help patients,” he added.

Funded by grants and private donations, Burke’s Medical Research Institute is involved in cutting-edge basic, translational and clinical research, providing new knowledge that can become the basis for future rehabilitation therapies in the areas of stroke, traumatic brain injury and spinal cord injury. The Institute has recently added new research laboratories in the areas of pain, vision restoration and motor recovery. The institute strives to assist patients to recover more fully, not just decrease disability which has been the focus of mainstream rehabilitation research historically.

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About Burke Rehabilitation Hospital
Burke Rehabilitation Hospital is a private, not-for-profit, acute rehabilitation hospital. Founded in 1915, it is the only hospital in Westchester County dedicated solely to rehabilitation medicine. Burke offers both inpatient and outpatient programs for those who have experienced a disabling illness, traumatic injury or joint replacement surgery. Burke is both an acute rehabilitation hospital and medical research center. Burke’s world renowned doctors and therapists provide state-of-the-art treatment, while its research scientists at the Burke Medical Research Institute explore the frontiers of neurological and rehabilitation medicine. All share the Burke mission to ensure that every patient makes the fullest possible recovery from illness or injury regardless of their ability to pay.

Promising New Compound For Treating Stroke

These researchers are after my heart following some of my ideas. Taking bets on how long before this gets approved in the US, I'll say 20 years.

http://www.medicalnewstoday.com/releases/241951.php
Researchers at the University of Copenhagen have designed, produced and patented a new chemical compound for the possible treatment of brain damage caused by stroke. The compound binds 1,000 times more effectively to the target protein in the brain than the potential drug currently being tested on stroke victims. The results of biological tests have just been published in the renowned journal PNAS - Proceedings of the National Academy of Sciences of the United States of America..

More than 140,000 people die each year from stroke in the United States. Stroke causes the brain to release large amounts of glutamate, an activating signal compound, all at once. This overactivates the receptors in the surrounding healthy tissue, causing the level of calcium in the cells to rise dramatically. This then kick-starts a toxic chain reaction causing cell death. Scientists believe that this process is the cause of the brain damage that occurs in the wake of a stroke. Therefore they are looking for compounds that can limit cell death:

"Research on animal models shows that the new compound we have designed and produced reduces the dead area in the brain after a stroke by 40 per cent. In addition, we can show that our compound is far more biologically effective than the potential drug currently being tested in clinical trials," explains Anders Bach, medicinal chemist and postdoc at the Faculty of Health and Medical Sciences.

Improving motor function in animals

A research project based at the Faculty of Health and Medical Sciences is the catalyst for the development of drugs to treat brain damage resulting from stroke. A new chemical compound has shown to be extremely potent, binding 1,000 times better than the potential drug currently under clinical development. Biological tests also indicate that the new compound shows high biological activity in animal models and is able to pass through the nearly impermeable blood-brain barrier, which is otherwise a fundamental challenge in clinical drug development.

"Our compound is able to pass through the blood-brain barrier, but also interesting is that it improves motor function in the animals that have been subject to stroke, for example, seen as increased grip strength in the paws of the mice," relates Anders Bach.

Alternative angle to drug development

Previously the development of drugs to combat brain damage resulting from stroke focused on blocking the receptors for signal compounds in the brain, such as glutamate. While this protected the receptor against the danger of overactivation, it unfortunately also influenced the normal vital functions of the receptor, causing unacceptable side effects.

Therefore in recent years there has been increased interest in an alternative strategy where the drug does not influence the receptor directly, but instead acts on the interactions between the receptor and the proteins in the cell. This is an important area of focus for the Chemical Biology research team at the University of Copenhagen:

"Our research is concentrated on disrupting the interaction between the so-called NMDA receptor and the intracellular protein PSD-95. Other scientists have shown interest in the same area - one group has developed a particularly interesting compound that is currently undergoing clinical development. However, we have reconsidered the design of the compounds in this area and come up with a new one that is more effective," states Anders Bach.

Detailed understanding of the molecular mechanism

In order to find compounds that can detach the PSD-95 protein from the NMDA receptor, one must have a method for measuring the extent to which the compounds bind to PSD-95.

"We have established a method - fluorescence polarisation - that has been very successful in helping us develop a number of potent compounds over a long period of time," recounts Anders Bach. He adds that scientists have committed many resources to finding out exactly how the compounds bind to PSD-95 - using for example sophisticated biophysical methods. This has resulted in detailed understanding of the molecular mechanisms that cause the high level of activity.

Anders Bach hopes that the new compound can form the basis for a new drug on the global market, but he emphasises that such a process is long and complicated:

"Although we are very satisfied with the new results in terms of the possible treatment of brain damage due to stroke, many things can go wrong in the long drug development process. So even though the compound binds effectively in laboratory studies and shows promising biological activity in animal models, we will still have many challenges to overcome," concludes Anders Bach.

The PSD-95 protein is also involved in chronic pain as well as Alzheimer 's disease - so the new compound may also prove interesting to examine in connection with other conditions.

Antidepressant-like effects of Ginsenoside Rg1 produced by activation of BDNF signaling pathway and neurogenesis in the hippocampus

It wasn't clear to me exactly what they are trying to say, if only I had access to complete articles.
http://onlinelibrary.wiley.com/doi/10.1111/j.1476-5381.2012.01902.x/full

Summary

Background and purpose. Background and purpose: Ginsenoside Rg1 (Rg1) is one of the major bioactive ingredients of Panax Ginseng with little toxicity and has been shown to have neuroprotective effects. In this study, we investigated the antidepressant-like effect of Rg1 in models of depression in mice.

Experimental approach. Experimental approach: The effects of Rg1 were assessed in the forced swim test (FST) and tail suspension test (TST) in mice. Rg1 was also investigated in the chronic mild stress (CMS) mouse model of depression with imipramine being a positive control. Changes in hippocampal neurogenesis and spine density, the brain derived neurotrophic factor (BDNF) signaling pathway, and serum corticosterone level after chronic stress and Rg1 treatment were then investigated. The tryptophan hydroxylase inhibitor and the tyrosine kinase B (TrkB) inhibitor were also used in determining the antidepressive mechanism of Rg1.

Key Results. Key results: Ginsenoside Rg1 exhibited antidepressant-like activity in the FST and TST in mice without affecting locomotor activity. It was also effective in the CMS mice model of depression. Furthermore, Rg1 up-regulated the BDNF signaling pathway in the hippocampus and down-regulated serum corticosterone level during CMS procedure. In addition, Rg1 was able to reverse the decrease in dendritic spine density and hippocampal neurogenesis caused by CMS. However, Rg1 has no discernable effect on the monoaminergic system.

Conclusions and Implications. Conclusions and Implications: In conclusion, our results provide the first evidence that Rg1 has antidepressant activity via activation of BDNF signaling pathway and up-regulation of hippocampal neurogenesis.

Folic acid enhances Notch signaling, hippocampal neurogenesis, and cognitive function in a rat model of cerebral ischemia

Not sure how useful this is since the rats were pre-treated with folic acid prior to their induced stroke.
http://www.ingentaconnect.com/content/maney/nns/pre-prints/1476830511Y.0000000025

Abstract:

Increasing neurogenesis may restore cognitive functions that are impaired in ischemia stroke. Folic acid has been reported to play an important role in neuronal development and reduce the risk of ischemic stroke in primary prevention. Folic acid supplementation stimulates Notch signaling and cell proliferation in neural progenitor cells cultured from neonatal brain. The present study determined whether folic acid supplementation stimulates Notch signaling and neurogenesis and improves cognitive function after ischemic stroke in adult brain. Rats were randomly assigned to four groups: sham operation plus vehicle (Sham), middle cerebral artery occlusion plus vehicle (MCAO), MCAO plus low-dose folic acid (4 mg/(kg day)), and MCAO plus high folic acid (12 mg/(kg day)). The vehicle and folic acid were administered by oral gavage for 28 days prior to sham or MCAO operation and up to 14 days after surgery. Newborn hippocampal neurons were detected at 3, 7, and 14 days post-MCAO. Cognitive function (learning and memory in Y-maze tests) and the protein expression levels of components of the Notch signaling system (Notch1, Hes1, and Hes5) were measured at 7 days post-MCAO. The results showed that MCAO impaired Y-maze performance and stimulated Notch signaling and hippocampal neurogenesis in brain. Folic acid prevented the impairment of Y-maze performance. The nutrient also increased further the expression of Notch1, Hes1, and Hes5 and the number of the newborn hippocampal neurons. Folic acid enhances the stimulation by ischemia of Notch signaling and hippocampal neurogenesis in adult brain and lessens the impairment of cognitive function that occurs after experimental stroke.

Melatonin ameliorates neural function by promoting endogenous neurogenesis through MT2 melatonin receptor in ischemic stroke mice.

Another hyperacute possibility, but it doesn't say how it was administered.
http://www.ncbi.nlm.nih.gov/pubmed/22330064

Abstract

Melatonin has many protective effects against ischemic stroke, but the underlying neuroprotective mechanisms are not fully understood. Our aim was to explore the relationship between melatonin's neuroprotective effects and activation of the MT2 melatonin receptor in a murine ischemic stroke model. Male ICR mice were subjected to a transient middle cerebral ischemic/reperfusional injury and melatonin (5 and 10mg/kg, i.p.) was administrated once daily starting 2h after ischemia. More than 80% of the mice died within 5days after stroke without treatment. Melatonin treatment significantly improved the survival rates and neural functioning with modestly prolonged lifespan of the stroke mice by preserving blood-brain barrier (BBB) integrity via a reduction in the enormous amount of stroke-induced free radical production and significant gp91(phox) cell infiltration. These protective effects of melatonin were reversed by pretreatment with MT2 melatonin receptor antagonists (4-phenyl-2-propionamidotetralin (4P-PDOT) and luzindole). Moreover, treatment with melatonin after stroke dramatically enhanced endogenous neurogenesis (doublecortin-positive) and cell proliferation (ki67-positive) in the peri-infarct regions. Most ki67-positive cells were nestin-positive and NG2-positive neural stem/progenitor cells that co-expressed two neurodevelopmental proteins (adam11 and adamts20) and MT2 melatonin receptor. RT-PCR revealed that the gene expression level of doublecortin, ki67, adamts20 and adam11 are markedly reduced by stroke, but are restored by melatonin treatment; furthermore, pretreatment with 4P-PDOT and luzindole antagonized melatonin's restorative effect. Our results support the hypothesis that melatonin is able to protect mice against stroke by activating MT2 melatonin receptors, which reduces oxidative/inflammatory stress. This results in the preservation of BBB integrity and enhances endogenous neurogenesis by up-regulating neurodevelopmental gene/protein expression.