Gut Microbiota in Acute Ischemic Stroke: From Pathophysiology to Therapeutic Implications

I also conclude that this told us nothing that will help stroke survivors. 

Gut Microbiota in Acute Ischemic Stroke: From Pathophysiology to Therapeutic Implications

Denise Battaglini^1,2, Pedro Moreno Pimentel-Coelho³, Chiara Robba¹, Claudia C. dos Santos⁴, Fernanda Ferreira Cruz^5,6, Paolo Pelosi^1,2 and Patricia Rieken Macedo Rocco^5,6*

• ¹Anesthesia and Intensive Care, San Martino Policlinico Hospital, IRCCS for Oncology and Neuroscience, Genoa, Italy
• ²Department of Surgical Sciences and Integrated Diagnostics, University of Genoa, Genoa, Italy
• ³Laboratório de Neurobiologia Comparada e do Desenvolvimento, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
• ⁴Keenan and Li Ka Shing Knowledge Institute, University Health Toronto—St. Michael's Hospital, Toronto, ON, Canada
• ⁵Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
• ⁶Rio de Janeiro Network on Neuroinflammation, Carlos Chagas Filho Foundation for Supporting Research in the State of Rio de Janeiro (FAPERJ), Rio de Janeiro, Brazil

The microbiota–gut–brain axis is considered a central regulator of the immune system after acute ischemic stroke (AIS), with a potential role in determining outcome. Several pathways are involved in the evolution of gut microbiota dysbiosis after AIS. Brain–gut and gut–brain signaling pathways involve bidirectional communication between the hypothalamic–pituitary–adrenal axis, the autonomic nervous system, the enteric nervous system, and the immune cells of the gut. Alterations in gut microbiome can be a risk factor and may also lead to AIS. Both risk factors for AIS and gut-microbiome composition are influenced by similar factors, including diabetes, hypertension, hyperlipidemia, obesity, and vascular dysfunction. Furthermore, the systemic inflammatory response after AIS may yield liver, renal, respiratory, gastrointestinal, and cardiovascular impairment, including the multiple organ dysfunction syndrome. This review focus on biochemical, immunological, and neuroanatomical modulation of gut microbiota and its possible systemic harmful effects after AIS, as well as the role of ischemic stroke on microbiota composition. Finally, we highlight the role of gut microbiota as a potential novel therapeutic target in acute ischemic stroke.

Introduction

Acute ischemic stroke (AIS) is the second leading cause of death worldwide, accounting for up to 25% of global lifetime risk (1). Great effort has been invested into identifying risk factors, elucidating pathogenesis, and discovering implications for outcomes (2). Post-AIS infection has been identified as a key cause of death and prolonged hospitalization after stroke (3). Recent advances have demonstrated, for instance, that peripheral adaptive immunity is activated and recruited into the brain within the first few hours/days after AIS (4), and that its cells might regulate and be regulated by the gut microbiota (5). A microbiota is defined as an ecological unit composed of microorganisms within a specific (micro) environment, while the microbiome is the genetic material of these microorganisms (6). Dysbiosis is defined as a microbial imbalance in composition and function of the microbiota, occurring in several animal models of AIS which demonstrates that gut microbiota can regulate the neuroinflammatory response, influencing brain recovery (7). Several studies have focused on the relationship between the intestinal microbiome and AIS, confirming the existence of a bidirectional microbiota–gut–brain axis (8). In fact, alterations in gut microbiome can be a risk factor for AIS, and vice-versa; AIS may lead to changes in gut microbiome, impacting on peripheral organs and leading to severe liver, renal, respiratory, gastrointestinal and cardiovascular impairment, including the multiple organ dysfunction syndrome (MODS) (9). The aim of this review is to highlight the pathophysiology potentially involved in gut microbiota modulation after AIS, and its implication for therapy and outcome.

Lots in between:

Conclusions

Translational microbiome research against the enhanced systemic inflammatory immune and neuroendocrine responses and on the impact of modulation of the environment, diet, and drugs on the so-called halobiont in AIS patients are limited. Since only few of these studies have demonstrated that antibiotic treatment, probiotics, exercise, or environmental changes could be essential for microbiota and outcome modulation, microbiota dysregulation after AIS remains a challenging target for new therapies.

Impact of Rehabilitation on Outcomes in Patients With Ischemic Stroke

I would argue that your conclusion is wrong, these people just had better spontaneous recovery.  The people who can stand intensive early rehab were likely less disabled by the stroke to begin with. I don't see any objective diagnosis of stroke damage here so this research is not repeatable.
http://stroke.ahajournals.org/content/48/3/740?etoc=

A Nationwide Retrospective Cohort Study in Japan

Maiko Yagi, Hideo Yasunaga, Hiroki Matsui, Kojiro Morita, Kiyohide Fushimi, Masashi Fujimoto, Teruyuki Koyama, Junko Fujitani

https://doi.org/10.1161/STROKEAHA.116.015147

Stroke. 2017;48:740-746

Originally published January 20, 2017

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Abstract

Background and Purpose—We aimed to examine the concurrent effects of timing and intensity of rehabilitation on improving activities of daily living (ADL) among patients with ischemic stroke.

Methods—Using the Japanese Diagnosis Procedure Combination inpatient database, we retrospectively analyzed consecutive patients with ischemic stroke at admission who received rehabilitation (n=100 719) from April 2012 to March 2014. Early rehabilitation was defined as that starting within 3 days after admission. The average rehabilitation intensity per day was calculated as the total units of rehabilitation during hospitalization divided by the length of hospital stay. A multivariable logistic regression analysis with multiple imputation and an instrumental variable analysis were performed to examine the association of early and intensive rehabilitation with the proportion of improved ADL score.

Results—The proportion of improved ADL score was higher in the early and intensive rehabilitation group. The multivariable logistic regression analysis showed that significant improvements in ADL were observed for early rehabilitation (odds ratio: 1.08; 95% confidence interval: 1.04–1.13; P<0.01) and intensive rehabilitation of >5.0 U/d (odds ratio: 1.87; 95% confidence interval: 1.69–2.07; P<0.01). The instrumental variable analysis showed that an increased proportion of improved ADL was associated with early rehabilitation (risk difference: 2.8%; 95% confidence interval: 2.0–3.4%; P<0.001) and intensive rehabilitation (risk difference: 5.6%; 95% confidence interval: 4.6–6.6%; P<0.001).

Conclusions—The present results suggested that early and intensive rehabilitation improved ADL during hospitalization in patients with ischemic stroke.

Cheese consumption and risk of cardiovascular disease: a meta-analysis of prospective studies

No fucking clue what the conclusions and results mean. Insiders talking to insiders, stroke survivors be damned. So they should tell us if this new research invalidates or confirms this one:

Dairy products and the risk of stroke and coronary heart disease: the Rotterdam Study 

The latest here:

Cheese consumption and risk of cardiovascular disease: a meta-analysis of prospective studies

Authors

• Guo-Chong Chen, 

  Guo-Chong Chen

  • Department of Nutrition and Food Hygiene, School of Public HealthSoochow University
• Yan Wang, 

  Yan Wang

  • Yili Innovation CenterInner Mongolia Yili Industrial Group Co., Ltd.
• Xing Tong, 

  Xing Tong

  • Department of Nutrition and Food Hygiene, School of Public HealthSoochow University
• Ignatius M. Y. Szeto, 

  Ignatius M. Y. Szeto

  • Yili Innovation CenterInner Mongolia Yili Industrial Group Co., Ltd.
• Gerrit Smit, 

  Gerrit Smit

  • Yili R&D Center
• Zeng-Ning Li, 

  Zeng-Ning Li

  • Department of NutritionThe First Hospital of Hebei Medical University
• Li-Qiang Qin

  Li-Qiang Qin

  Email author

  • Department of Nutrition and Food Hygiene, School of Public HealthSoochow University

Original Contribution

First Online:

12 August 2016

Received:

10 March 2016

Accepted:

06 August 2016

DOI: 10.1007/s00394-016-1292-z

Cite this article as:

Chen, G., Wang, Y., Tong, X. et al. Eur J Nutr (2016). doi:10.1007/s00394-016-1292-z

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Abstract

Purpose

Cheese contains a high content of saturated fatty acids but also lists of potentially beneficial nutrients. How long-term cheese consumption affects the development of cardiovascular disease (CVD) is unclear. A meta-analysis of prospective observational studies was conducted to evaluate the risks of total CVD, coronary heart disease (CHD), and stroke associated with cheese consumption.

Methods

Potentially eligible studies were identified by searching PubMed and EMBASE databases and by carefully reviewing the bibliographies of retrieved publications and related reviews. The summary relative risks (RRs) with 95 % confidence intervals (CIs) were calculated using the random-effects model.

Results

The final analyses included 15 prospective studies. Most of the studies excluded prevalent CVD at baseline (14/15) and had a duration >10 years (13/15). The summary RR for high vs. low cheese consumption was 0.90 (95 % CI 0.82–0.99) for total CVD (7 studies, 8076 events), 0.86 (95 % CI 0.77–0.96) for CHD (8 studies, 7631 events), and 0.90 (95 % CI 0.84–0.97) for stroke (7 studies, 10,449 events), respectively. The restricted cubic model indicated evidence of nonlinear relationships between cheese consumption and risks of total CVD (P_nonlinearity < 0.001) and stroke (P_nonlinearity = 0.015), with the largest risk reductions observed at the consumption of approximately 40 g/d.

Conclusions

This meta-analysis of prospective studies suggests a nonlinear inverse association between cheese consumption and risk of CVD.

Moderate drinking has risks and benefits, heavy drinking heightens short- and long-term risk of heart attack, stroke

They seemed not to come up with the appropriate conclusion based upon the results. In order to lessen your chance of stroke or heart attack you should never have a period that is immediately after starting drinking. You need the protection after 24 hours constantly. So the obvious conclusion is to be drinking alcohol everyday. These people had to be stupid not to understand the obvious conclusion from this research.  But don't do this.
http://medicalxpress.com/news/2016-03-moderate-benefits-heavy-heightens-short-.html

Drinking alcohol is associated with an immediate higher risk of suffering a heart attack or stroke. The risk lessens and can become protective after 24 hours for moderate drinking but remains high for heavy drinking, according to research presented at the American Heart Association's Epidemiology and Prevention/Lifestyle 2016 Scientific Sessions.

The study, a systematic review and dose-response meta-analysis of previous research, will also be published simultaneously in the American Heart Association's journal Circulation.
"There appears to be a transiently higher risk of heart attack and strokes in the hours after drinking an alcoholic beverage but within a day after drinking, only heavy alcohol intake seems to pose a higher cardiovascular risk," said Elizabeth Mostofsky, Sc.D., study lead author, instructor at the Harvard T.H. Chan School of Public Health and post-doctoral fellow at Beth Israel Deaconess Medical Center in Boston, Massachusetts.
Previous research has described cardiovascular risks following moderate and heavy alcohol consumption, but the immediate risks have not been well documented.
"Ours is the first to synthesize all the available information to gain new knowledge on the acute risk of heart attacks and strokes in the hours after drinking and the risk in the following week for different amounts of alcohol consumed," Mostofsky said.
Researchers analyzed evidence on the risk of heart attacks and strokes in the hours and days after drinking alcohol from 23 studies that included nearly 30,000 participants.
Immediately following alcohol intake, there are both harmful and protective physical responses. Within one to three hours, a single dose of alcohol increases heart rate and disrupts the heart's normal pacing but by 24 hours, moderate alcohol intake improves blood flow, blood vessels' lining function and reduces clotting.
Moderate drinking - up to six drinks a week in this study - was associated with an immediately higher cardiovascular risk but within a day was considered protective and associated with a lower risk of a having heart attack or stroke from bleeds and within the week was associated with a lower risk of strokes from clots.
However, heavy alcohol use was associated with higher heart attack and stroke risks at all times studied: six to nine drinks in a day nearly doubled the risk and 19 to 30 drinks in a week elevated the risk by up to six times more.
Heavy drinking is typically described for men as consuming 15 or more drinks per week and more than 8 drinks per week for women. According to the 2015 Dietary Guidelines for Americans, moderate drinking is up to 1 drink per day for women and up to 2 drinks per day for men.
"Just after drinking, blood pressure rises and blood platelets become stickier, increasing the risk of heart attacks and strokes," Mostofsky said. "However, regularly drinking small amounts of alcohol in the long term appears to both increase levels of HDL cholesterol (high density lipoprotein cholesterol), the so-called good cholesterol, and reduce the tendency to form blood clots."
"If you drink alcohol, do so in moderation," she said.
Likewise, the American Heart Association recommends consuming alcohol in moderation if you already drink but cautions people to not start drinking and consult your doctor on your risks and benefits of consuming alcohol in moderation.

People With Brain Injuries Heal Faster If They Get Up And Get Moving

The conclusions from this could just as easily be explained by those people able to get moving earlier had less severe strokes.
http://www.npr.org/sections/health-shots/2015/07/06/419519145/people-with-brain-injuries-heal-faster-if-they-get-up-and-get-moving
When Kate Klein began working as a nurse in the Cleveland Clinic's Neurointensive Care Unit, one of the first things she noticed was that her patients spent a lot of time in bed. She knew patients with other injuries benefitted from getting up and moving early on, and she wondered why not patients with brain injuries.
"I asked myself that question. I asked my colleagues that question," Klein says. "Why aren't these patients getting out of bed? Is there something unique about patients with neurologic injury?"

Doctors have long encouraged their surgical patients to get out of bed as soon as it's safe to do so. Movement increases circulation, reduces swelling, inflammation and the risk of blood clots, and it speeds healing.
But that wasn't the thinking with brain injuries, explains Edward Manno, director of the Neurointensive Care Unit at the Cleveland Clinic and one of the neurologists who works with Klein. "The predominant thinking was that rest was better suited for the brain," Manno says.
Often the damaged brain is susceptible to lack of blood flow. Increased activity may make things worse if initiated too quickly, Manno says. "So many of us thought for quite some time that we needed to put the brain to rest after the initial insult of stroke or other neurologic injury."

i

Nancy Albert, Kate Klein and Nancy Kaser collaborated on a study of early mobility for patients with brain injuries.

Dustin Franz for NPR

But some doctors, including Manno, suspected patients with brain injuries could benefit from getting out of bed sooner. They just didn't have any proof.
Although plenty of research had been done on early mobilization of patients with other injuries, Klein discovered that no one had actually studied whether it was safe or beneficial for patients with brain injuries caused by seizures, stroke or head trauma to start rehabilitation right away. So she designed a study of her own.
Over the course of a year, Klein tracked more than 600 patients with brain injury, getting more than half of them up and out of bed as early as the first day they were admitted to the ICU. What she found was that getting up and moving had clear benefits. Patients who started their rehabilitation earlier spent less time in the ICU and less time in the hospital. "They have less pressure ulcers, less infections and spend less time on the ventilator if they need ventilator therapy," says Klein. And most say they feel a lot better.
One of the barriers to getting patients with brain injury up is how difficult it is. It took two nurses more than half an hour to get patient Patricia Weeden out of bed and into a chair to visit with her daughter. Weeden, 66, from Cleveland, has suffered severe seizures that damaged her brain. She's hooked to a ventilator, so she can't speak. And she's unable to sit, stand or walk on her own.
"It is difficult to get these patients up," explains Klein.
As a result of her study, the Cleveland Clinic has installed ceiling mounted lifts at each patient's bedside in the Neurointensive Care Unit. Nurses receive other equipment and training to make moving patients safer and easier.
And although it seems like a lot of effort for a few steps from bedside to chair, Klein says it represents huge progress for a patient like Weeden. The benefits may go beyond preventing bed sores or infections. Manno says it may also speed the recovery of the brain.
The brain rewires itself, explains Jeffrey Kleim, an associate professor of biomedical engineering at Arizona State University who studies what happens to the brain after injury.

"And it does this by forming new synapses, forming new connections," says Kleim. "The neural circuits begin to change and adapt, and that's how these new functions begin to emerge in the remaining brain areas."
That neuroplasticity has been shown to be heightened immediately after injury in studies with animals. If the same is true in humans, the sooner patients get up and engage their brains the better their chances of recovery.
Kleim says much of the animal research has been focused on finding ways to jumpstart the rewiring process with drugs or electrical stimulation. But in people, he says, there is a much simpler way to drive the recovery process.
By getting patients up and out of bed early, even taking them outside, Klein and Manno say they are attempting to provide the sort of familiar experiences that are already known to stimulate the brain's natural rewiring process. Those experiences can be powerful, explains Klein, recalling a patient who suddenly began to speak after being outside for the first time.
"She was listening to the traffic, feeling the wind on her face, and then her sons came and they said 'Hi Mom,' and she looked up and said, 'Well, how are you doing?' Those were her first words," Klein says.
But as dramatic as those moments are, Manno says they only illustrate how much we still don't know about the recovery of the brain. For example, it's still unclear if all kinds of brain injuries can or should be treated the same.
"We are just scratching the surface here," says Manno. "There's a tremendous amount of work to be done in this area."

Prehospital use of magnesium sulfate as neuroprotection in acute stroke

There is no way that they should be using Rankin scores as endpoint determination if this worked or not. There is nothing objective or discriminatory enough about the scores to give you any fucking idea if this worked at all. Except for score 6 - Dead.  They should be doing 3 dimensional MRIs and PET scans to objectively measure the dead and damaged areas.  A great stroke association would be contacting these researchers to make sure they actually know how to run research. With 1220 collaborators one would think that at least one person would know how to run research and draw conclusions. But NO. 

Prehospital use of magnesium sulfate as neuroprotection in acute stroke

Saver JL, Starkman S, Eckstein M, Stratton SJ, Pratt FD, Hamilton S, Conwit R, Liebeskind DS, Sung G, Kramer I, Moreau G, Goldweber R, Sanossian N; FAST-MAG Investigators and Coordinators.

Collaborators (1220)

Abstract

BACKGROUND:

Magnesium sulfate is neuroprotective in preclinical models of stroke and has shown signals of potential efficacy with an acceptable safety profile when delivered early after stroke onset in humans. Delayed initiation of neuroprotective agents has hindered earlier phase 3 trials of neuroprotective agents.

METHODS:

We randomly assigned patients with suspected stroke to receive either intravenous magnesium sulfate or placebo, beginning within 2 hours after symptom onset. A loading dose was initiated by paramedics before the patient arrived at the hospital, and a 24-hour maintenance infusion was started on the patient's arrival at the hospital. The primary outcome was the degree of disability at 90 days, as measured by scores on the modified Rankin scale (range, 0 to 6, with higher scores indicating greater disability).

RESULTS:

Among the 1700 enrolled patients (857 in the magnesium group and 843 in the placebo group), the mean (±SD) age was 69±13 years, 42.6% were women, and the mean pretreatment score on the Los Angeles Motor Scale of stroke severity (range, 0 to 10, with higher scores indicating greater motor deficits) was 3.7±1.3. The final diagnosis of the qualifying event was cerebral ischemia in 73.3% of patients, intracranial hemorrhage in 22.8%, and a stroke-mimicking condition in 3.9%. The median interval between the time the patient was last known to be free of stroke symptoms and the start of the study-drug infusion was 45 minutes (interquartile range, 35 to 62), and 74.3% of patients received the study-drug infusion within the first hour after symptom onset. There was no significant shift in the distribution of 90-day disability outcomes on the global modified Rankin scale between patients in the magnesium group and those in the placebo group (P=0.28 by the Cochran-Mantel-Haenszel test); mean scores at 90 days did not differ between the magnesium group and the placebo group (2.7 in each group, P=1.00). No significant between-group differences were noted with respect to mortality (15.4% in the magnesium group and 15.5% in the placebo group, P=0.95) or all serious adverse events.

CONCLUSIONS:

Prehospital initiation of magnesium sulfate therapy was safe and allowed the start of therapy within 2 hours after the onset of stroke symptoms, but it did not improve disability outcomes at 90 days. (Funded by the National Institute of Neurological Disorders and Stroke; FAST-MAG ClinicalTrials.gov number, NCT00059332.).

How Do Stroke Units Improve Patient Outcomes?

The answer is simple! CREATE EXACT 100% RECOVER PROTOCOLS! And you're too fucking dumb to see that!

This is 1997 data so you'll have to ask your doctor or stroke association for something more recent. But this just proves how long and badly stroke is run. There is nothing objective about any of the outcomes measured except for death. Nothing lists the 3d size and location of the dead area or penumbra. Without that, none of these research results are comparable. 

How Do Stroke Units Improve Patient Outcomes? 

1. Stroke Unit Trialists’ Collaboration

1. Correspondence to P. Langhorne, PhD, MRCP, Academic Section of Geriatric Medicine, 3rd Floor, Center Block, Royal Infirmary, Glasgow G4 0SF, Scotland. E-mail P.Langhorne@clinmed.gla.ac.uk

 

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Abstract

Background and Purpose 

We sought to clarify the way in which organized inpatient (stroke unit) care can produce reductions in case fatality and in the need for institutional care after stroke.

Methods 

We performed a secondary analysis of a collaborative systematic review of all randomized trials that compared organized inpatient (stroke unit) care with contemporary conventional care. Nineteen trials were included, of which 18 (3246 patients) could provide outcome data on death, place of residence, and final functional outcome. Data were less complete (but always available for at least 12 trials; 1611 patients) for subgroup analyses examining timing and cause of death and outcomes in patients with different levels of severity of initial stroke.

Results 

The reduction in case fatality of patients managed in a stroke unit setting developed between 1 and 4 weeks after the index stroke. The reduction in the odds of death was evident across all causes of death and most marked for those deaths considered to be secondary to immobility. However, data were insufficient to permit a firm conclusion. The relative increase in the number of patients discharged home from stroke units as opposed to conventional care was largely attributable to an increase in the number of patients returning home physically independent. Across the range of stroke severity, stroke unit care was associated with nonsignificant increases in the number of patients regaining independence.

Conclusions 

Within the limitations of the available data, we conclude that organized inpatient stroke unit care probably benefits a wide range of stroke patients in a variety of different ways, ie, reducing death from secondary complications of stroke and reducing the need for institutional care through a reduction in disability.(This conclusion is not supportable from the data given)