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    Cannabis oil for epilepsy

    Epilepsy drugs don’t work well, or at all, for 1/3 of people with the condition. Unfortunately, these hard-to-treat epilepsies are associated with an increased risk of premature death.

    Anecdotal evidence suggests that cannabis oil may help some of these people control their seizures and potentially save their lives. A small number of studies have shown that adding cannabis oil to existing medication may be effective in devastating, hard-to-treat epilepsy in children and adolescents.

    One of those people is 12-year-old Billy Caldwell. Billy was in the news recently after the cannabis oil prescribed for him was confiscated at Heathrow airport by the authorities. Billy’s mother, Charlotte, was attempting to bring the cannabis oil into the UK from Canada, where cannabis oil is legal.

    Billy was seizure-free for more than 250 days when taking the oil, but seizures started again when his cannabis oil was withdrawn. The home secretary, Sajid Javid, was persuaded to intervene and one of the seven bottles of cannabis oil was returned, with a 20-day licence to administer the medicine.

    In a similar case, six-year-old Alfie Dingle, who suffers from severe epilepsy, had been successful treated with cannabis oil in the Netherlands. Alfie’s mother, Hannah Deacon, has been campaigning to allow her son to be provided with cannabis oil in the UK.

    The government has now also relented in Alfie’s case following the concerns raised around the confiscation and return of Billy Caldwell’s medicine.

    What the evidence shows

    So what do we know about cannabis oil and its effects on epileptic seizures?

    The two main constituents of cannabis oil are THC (tetrahydrocannabinol) and CBD. Oil containing CBD alone can be legally bought in the UK without a prescription because it contains only very low quantities of THC. But cannabis oil that contains THC at higher levels than is illegal. THC is a schedule 1 drug, that is to say, it is deemed to have no medicinal value.

    The reason that Billy’s cannabis oil was seized at Heathrow airport was that it didn’t just contain CBD, it also contained THC at higher levels than legally permitted.

    There is evidence that CBD is of benefit for specific epilepsies, such as Dravet syndrome and Lennox Gastaut syndrome. An advantage for the pharmaceutical industry is that these rare diseases with no cure can be fast-tracked for drug development. On this basis, the US Food and Drug Administration is widely expected to grant a licence for CBD (under the tradename Epidiolex) to treat these epilepsies. If so, Epidiolex is likely to be available in US by late 2018. European approval is likely to follow.

    It should be noted that Epidiolex is designed as standardised oral solution of pure plant-derived CBD. It is not the same as the non-standardised, viscous CBD oils that contain varying amounts of CBD and can be purchased in health food shops. There is currently no evidence that formulations of CBD oil (or indeed cannabis oil) are as effective on epilepsy seizures. Equally, there is no robust evidence – just anecdotal reports – that THC helps reduce epilepsy seizures human.

    In animal studies, THC has weak overall effects in reducing seizures and has also been shown to be a less effective anticonvulsant than CBD. THC, being a psychoactive substance, also has a number of side effects, including the well-known euphoric “high” associated with recreational use – which is a significant disincentive for the pharmaceutical industry to develop a medicine containing this compound.

    We now need to decide if we should expand human trials with better defined THC-containing cannabis oil, or if we should focus on CBD. The fact that Epidiolex has progressed towards approval in the US may encourage the latter course. CBD lacks psychoactive effects associated with THC and, in general, is regarded as a safe compound.

    If Epidiolex is granted regulatory approval, it will also need to be monitored in a larger number of patients – what’s known as “phase 4 post-marketing surveillance” – to ensure that it is safe and effective in a broader population. For any cannabis-based product, only large-scale clinical trials can provide definitive answers about effectiveness and safety.
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    Alexander Shulgin

    Vicious circle leads to loss of brain cells in old age: THC may help reverse the process

    The so-called CB1 receptor is responsible for the intoxicating effect of cannabis. However, it appears to act also as a kind of “sensor” with which neurons measure and control the activity of certain immune cells in the brain. A recent study by the University of Bonn at least points in this direction. If the sensor fails, chronic inflammation may result – probably the beginning of a dangerous vicious circle. The publication appears in the journal Frontiers in Molecular Neuroscience.

    The activity of the so-called microglial cells plays an important role in brain aging. These cells are part of the brain’s immune defense: For example, they detect and digest bacteria, but also eliminate diseased or defective nerve cells. They also use messenger substances to alert other defense cells and thus initiate a concerted campaign to protect the brain: an inflammation.

    This protective mechanism has undesirable side effects; it can also cause damage to healthy brain tissue. Inflammations are therefore usually strictly controlled. “We know that so-called endocannabinoids play an important role in this”, explains Dr. Andras Bilkei-Gorzo from the Institute of Molecular Psychiatry at the University of Bonn. “These are messenger substances produced by the body that act as a kind of brake signal: They prevent the inflammatory activity of the glial cells.”

    Endocannabinoids develop their effect by binding to special receptors. There are two different types, called CB1 and CB2. “However, microglial cells have virtually no CB1 and very low level of CB2 receptors,” emphasizes Bilkei-Gorzo. “They are therefore deaf on the CB1 ear. And yet they react to the corresponding brake signals – why this is the case, has been puzzling so far.”

    Neurons as “middlemen”

    The scientists at the University of Bonn have now been able to shed light on this puzzle. Their findings indicate that the brake signals do not communicate directly with the glial cells, but via middlemen – a certain group of neurons, because this group has a large number of CB1 receptors. “We have studied laboratory mice in which the receptor in these neurons was switched off,” explains Bilkei-Gorzo. “The inflammatory activity of the microglial cells was permanently increased in these animals.”

    In contrast, in control mice with functional CB1 receptors, the brain’s own defense forces were normally inactive. This only changed in the present of inflammatory stimulus. “Based on our results, we assume that CB1 receptors on neurons control the activity of microglial cells,” said Bilkei-Gorzo. “However, we cannot yet say whether this is also the case in humans.”

    This is how it might work in mice: As soon as microglial cells detect a bacterial attack or neuronal damage, they switch to inflammation mode. They produce endocannabinoids, which activate the CB1 receptor of the neurons in their vicinity. This way, they inform the nerve cells about their presence and activity. The neurons may then be able to limit the immune response. The scientists were able to show that neurons are similarly regulatory for the other major glial cell type, the astroglial cells.

    During ageing the production of cannabinoids declines reaching a low level in old individuals. This could lead to a kind of vicious circle, Bilkei-Gorzo suspects: “Since the neuronal CB1 receptors are no longer sufficiently activated, the glial cells are almost constantly in inflammatory mode. More regulatory neurons die as a result, so the immune response is less regulated and may become free-running.”

    It may be possible to break this vicious circle with drugs in the future. It is for instance hoped that cannabis will help slow the progression of dementia. Its ingredient, tetrahydrocannabinol (THC), is a powerful CB1 receptor activator – even in low doses free from intoxicating effect. Last year, the researchers from Bonn and colleagues from Israel were able to demonstrate that cannabis can reverse the aging processes in the brains of mice. This result now suggest that an anti-inflammatory effect of THC may play a role in its positive effect on the ageing brain.
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    CBD oil may prolong life for those suffering with ALS

    Based on some exciting new anecdotal evidence, the use of cannabis oil to treat ALS may actually prolong life in addition to relieving many of the diseases devastating day-to-day symptoms.

    ALS or Lou Gehrig's disease, named after the baseball legend, is a debilitating disorder that affects an estimated 30,000 people in the United States at any given time. You might remember ALS from that craze last summer when everyone decided to dump ice on their heads to raise awareness for the disease and to raise money for ALS research. Even Leafly hopped on the bandwagon for a good cause, and overall, the ALS Foundation received over $100 million in donations by the time the summer of the Ice Bucket Challenge was over.

    ALS is a degenerative neurological disorder that causes muscle weakness, wasting, and paralysis of the limbs, as well as those that control vital functions such as speech, swallowing, and breathing. It is often the deterioration of these crucial muscles that leads to respiratory failure; even with breathing aids or a tracheotomy, the risk of respiratory failure persists.

    Being diagnosed with ALS is devastating, and for many it can feel like a death sentence. The average life expectancy of a person with ALS is two to five years. However, more than half of all people with ALS live more than three years from diagnosis and there are definitely outliers, such as Stephen Hawking, one of the most iconic figures with ALS. Hawking was diagnosed in 1963, and now, more than 30 years later, he is among only 5% of those diagnosed with ALS who live more than 20 years after diagnosis.

    Cannabis has long been known as a viable treatment option to relieve symptoms of ALS, which was outlined in this handy chart created by the American Journal of Hospice and Palliative Medicine, but the most astonishing results have come from several ALS sufferers who have managed to slow the progression of the disease through regular, controlled doses of cannabis oil.

    Bob Strider began experiencing the symptoms of ALS in 1998, specifically the loss of function in his right arm and problems swallowing. An avid cannabis enthusiast, he had used cannabis heavily for decades, which he believes has kept the progression of his disease slow but steady. In 2012, Strider began manufacturing his own cannabis oils, dosing himself with approximately a gram a day for 60 days. Within 10 days of his regimen, he regained control of his right arm and was able to stop using opiates to manage his pain.

    Another remarkable case comes from Cathy Jordan, who was diagnosed with ALS in 1986 and given less than five years to live. In the winter of 1989, Jordan spent the holiday in Florida, preparing for the end of her life, when she made a crucial discovery. While walking on the beach one night, she smoked a joint of Myakka Gold and felt her symptoms cease, essentially experiencing the neuroprotective effects of cannabis before they'd been proven.

    Jordan never set out to be a cannabis activist, preferring instead to quietly continue treating her disease. She tried to tell her neurologist in 1989 that cannabis had helped her, and he tried to convince her husband to have her committed to a mental facility. In 1994, Jordan met a new doctor who was astonished by her progress. When he asked what shed been doing to stay alive, she informed him, and he advised her, Smoke all the cannabis you can and never tell a soul, because they will never believe you.

    Unfortunately, Donnie Clark, the grower of Myakka Gold, was arrested and sent to prison for 12 years until his sentence was commuted by former President Clinton. The strain itself, which Jordan credits with stopping the progression of her ALS, has since been eradicated by the DEA.

    Cathy Jordan, however, ended up becoming the inspiration for Amendment 2, the medical marijuana initiative in Florida that was edged out last November. Ironically, on February 25, 2013, the same day that the Cathy Jordan Medical Cannabis Amendment was announced, Jordan's home was raided and 23 plants were seized by local authorities, although charges were dropped when it became evident that she was using cannabis for medicinal purposes.

    Now, finally, years later, there has been more and more conclusive research indicating that these patients self-medicating regimen was beneficial, after all. Pre-clinical data shows that cannabis has powerful anti-oxidative, anti-inflammatory, and neuroprotective effects, and with regular applications, it may actually slow the progress of the disease and prolong the lives of the individuals affected by ALS.

    Amyotrophic Lateral Sclerosis is a qualifying condition for medical marijuana programs in Delaware, Washington, D.C., Georgia, Illinois, Maine, Massachusetts, Michigan, New Jersey, New Mexico, and New York. However, with more promising research emerging, other states medical marijuana programs need to follow suit and allow suffering patients the right to try and treat this horrible disease with cannabis if it can provide them with even a little bit of relief.
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    New clues to the origin and progression of multiple sclerosis

    Mapping of a certain group of cells, known as oligodendrocytes, in the central nervous system of a mouse model of multiple sclerosis (MS), shows that they might have a significant role in the development of the disease. The discovery can lead to new therapies targeted at other areas than just the immune system.

    Mapping of a certain group of cells, known as oligodendrocytes, in the central nervous system of a mouse model of multiple sclerosis (MS), shows that they might have a significant role in the development of the disease. The discovery can lead to new therapies targeted at other areas than just the immune system. The results are published in Nature Medicine by researchers at Karolinska Institutet in Sweden.

    2.5 million people around the world live with MS, with approximately 18,000 people in Sweden, and about 1,000 new cases annually. MS develops when the immune system's white blood cells attack the insulating fatty substance known as myelin that coats nerve fibres in the central nervous system. This interferes with the proper transmission of nerve electric signals and causes the symptoms of the disease. While it is unknown why the immune system attacks the myelin, a study by researchers at Karolinska Institutet shows that the cells that produce myelin, oligodendrocytes, might play an unexpected role. Oligodendrocytes are one of the most common types of cell in the brain and spinal cord.

    "Our study provides a new perspective on how multiple sclerosis might emerge and evolve" says Goncalo Castelo-Branco, associate professor at the Department of Medical Biochemistry and Biophysics, Karolinska Institutet. "Current treatments mainly focus on inhibiting the immune system. But we can now show that the target cells of the immune system in the brain and spinal cord, oligodendrocytes, acquire new properties during disease and might have a higher impact on the disease than previously thought."

    The researchers have shown that a subset of oligodendrocytes and their progenitor cells have much in common with the immune cells, in a mouse model of MS. Among other properties, they can take part in the clearing away of the myelin that is damaged by the disease, in a way that resembles how immune cells operate. Oligodendrocyte progenitor cells can also communicate with the immune cells and make them change their behaviour.

    "We also see that some genes that have been identified as those that cause a susceptibility to MS are active (expressed) in oligodendrocytes and their progenitors," says Ana Mendanha Falcao, joint first author of the study with David van Bruggen, both at the Department of Medical Biochemistry and Biophysics at Karolinska Institutet.

    "All in all, this suggests that these cells have a significant role to play either in the onset of the disease or in the disease process," says David van Bruggen.

    The study was conducted using the recently developed technique, single-cell RNA sequencing, which provides scientists with a snapshot of the genetic activity of single cells and therefore with a much more effective means of differentiating the properties of individual cells. This has made it possible for researchers to identify the various roles and functions of the different cells.

    Although the study was largely conducted on mice, some of the results have also been observed in human samples.

    "We will now continue with further studies to ascertain the part played by the oligodendrocytes and their progenitor cells in MS," says Goncalo Castelo-Branco. "Further knowledge can eventually lead the way to the development of new treatments for the disease."


    Environmental factors may trigger onset of multiple sclerosis

    A new study finds that certain environmental conditions like salt concentrations and temperature may precipitate structural changes that take place in myelin sheaths in the onset of multiple sclerosis (MS). Myelin sheaths are the 'insulating tape' surrounding axons; axons carry electrical impulses in neurons.

    A new Tel Aviv University study finds that certain environmental conditions may precipitate structural changes that take place in myelin sheaths in the onset of multiple sclerosis (MS). Myelin sheaths are the "insulating tape" surrounding axons; axons carry electrical impulses in neurons.

    The research demonstrates that myelin sheaths undergo structural transitions when triggered by changes in local environmental conditions, such as salt concentration (salinity) and temperature. These transitions, according to the study, render the body vulnerable to autoimmune attacks that can lead to MS.

    The research was led by Prof. Roy Beck of TAU's School of Physics and Astronomy and conducted by Rona Shaharabani, a doctoral student in Prof. Beck's lab, and Maor Ram-On, a doctoral student in Prof. Ronen Talmon's lab at the Technion Institute of Technology. It was published in the Proceedings of the National Academy of Sciences of the USA (PNAS).

    Earlier research by Prof. Beck revealed that changes in the structure of myelin sheaths are a factor in the development of MS.

    "Current therapeutic approaches have focused on the autoimmune response without identifying the culprit," says Prof. Beck. "We have found that under certain environmental conditions, such as elevated salinity and temperature, myelin sheaths protecting neurons undergo structural transitions consistent with pathological myelin structures in multiple sclerosis."

    Physiological conditions are regulated in the body itself, but temperature and salinity are subject to localized external changes. The results presented in the study suggest that even minor changes in these conditions may trigger multiple sclerosis.

    "The myelin sheaths undergo structural transitions at the molecular level when affected by different environmental conditions. These small modifications create structural instabilities that allow the immune system to attack neurons," says Shaharabani.

    The researchers used X-ray scattering and cryogenic transmission electron microscopy (cryo-TEM) to track and measure the myelin sheaths in healthy and diseased animal models. They found that healthy lamellar membranes spontaneously morphed into different pathological structures of nano-scale tubes called inverted hexagonal shapes.

    "These results highlight that local environmental conditions are critical for myelin function. These conditions should be considered as alternative possibilities for early diagnosis and as a means of avoiding the onset of demyelination," says Shaharabani. "Since we believe that these structural modifications result in myelin membrane vulnerability to the immune system attacks, it can help explain the causes of MS and perhaps pave the way for a treatment or a cure."

    "Since we now have a new biophysical understanding to investigate the degradation of myelin sheaths, we are following up on other candidates that can induce such structural transition. There are several molecular candidates, including specific proteins and other alterations in the myelin's fatty acids, that are relevant, which may unravel further insights to fight multiple sclerosis and related disorders," Shaharabani concludes.


    Solvents and smoking linked to increased risk of MS

    People who carry genes that make them more susceptible to developing multiple sclerosis (MS) are at much greater risk of developing the disease if they have been exposed to paint, varnish and other solvents, according to a new study from Karolinska Institutet published in the journal Neurology. If they have also been smokers, the risk of developing MS is multiplied.

    The study shows that people who have been exposed to paint or other solvents are 50 per cent more likely to develop MS than people with no exposure. People with exposure to solvents who also carry certain gene variants that make them more susceptible to MS are ten times as likely to develop the disease as people with no solvent exposure who do not carry the MS genes.

    Different risk factors

    People with exposure to solvents who carry the MS genes and in addition to that have been smokers are as much as 30 times more likely to develop MS, compared to those who have never smoked or been exposed to solvents and who do not have the genetic risk factors. How these different factors interact to create a much greater risk than they do on their own is not yet known.

    ”It’s possible that exposure to solvents and smoking may both involve lung inflammation and irritation that leads to an immune reaction in the lungs,” says lead author Anna Karin Hedstrom at the Institute of Environmental Medicine and the Department of Clinical Neuroscience, Karolinska Institutet.

    “How this cocktail of MS genes, organic solvents and smoking contributes so significantly to MS risk warrants investigation,” comments Gabriele C. DeLuca, MD, PhD, of the University of Oxford in the United Kingdom, in an accompanying editorial. “In the meantime, avoiding cigarette smoke and unnecessary exposure to organic solvents, particularly in combination with each other, would seem reasonable lifestyle changes people can take to reduce the risk of MS, especially in people with a family history of the disease.”

    Study included 5,000 people

    The study included more than 2,000 people who had recently been diagnosed with MS in Sweden and almost 3,000 people of the same age and sex without MS. Blood tests were used to determine which human leukocyte antigen gene variants the participants had. They were also asked about previous exposure to organic solvents, painting products or varnish and whether they had ever been a smoker. One limitation of the study is that it is possible that the participants may not have remembered correctly. Moreover, since it is an observational study no definitive conclusions can be drawn regarding causality.
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    Running with the wild horses in ketamine land
    Quote Originally Posted by mr peabody View Post

    CBD oil may prolong life for those suffering with ALS

    Based on some exciting new anecdotal evidence, the use of cannabis oil to treat ALS may actually prolong life in addition to relieving many of the diseases devastating day-to-day symptoms.
    This is a topic that is close to heart as my father passed from ALS years back.

    I am excited to possibly see some research between psychedelics and its neuro-regenerative properties pertaining to ALS. I plan to eventually dabble in research like this myself later in my career.
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    Low dose ibogaine therapy

    By Dr. Tom Grodski

    Parkinson’s disease, ALS and Alzheimer’s are chronic disorders with no known cure. Most neurodegenerative diseases require management with prescription medications that can have considerable side effects, which may cause a very poor quality of life for terminal sufferers. In turn, Ibogaine may be very beneficial to those with degenerative neurological diseases.

    Ibogaine is a naturally occurring psychoactive indole alkaloid derived from the roots of the African rain forest shrub Tabernanthe iboga. Ibogaine is part of the Apocynaceae family and traditionally used by the Bwiti, indigenous peoples of Western Africa; in low doses to combat fatigue, hunger and thirst.

    Ibogaine increases levels of glial cell line-derived neurotrophic factor (GDNF) in the brain, and this appears to have neuroprotective properties that promote the survival of both dopaminergic and motor neurons. GDNF can also cause sprouting of dopaminergic fibers and clinical improvement in experimental animal and human studies in which the test subjects had Parkinson’s Disease, with the resultant clinical improvement in symptoms. GDNF has been shown to have potent neurotrophic factor in both rodent and primate models of Parkinson’s disease.

    Direct brain infusion of GDNF into the brains of five Parkinson sufferers resulted in a 39% improvement in the off-medication motor sub-score of the Unite Parkinson’s Disease Rating Scale (UPDRS) and a 61% improvement in the activities of daily living sub score. Positron emission tomography (PET) scans of dopamine uptake showed a significant 28% increase in putamen dopamine storage after 18 months, indicating a direct effect of GDNF on dopamine function. Further, after one year, no serious clinical side effects were observed.

    The use of Iboga alkaloid extract or Ibogaine would provide a longer term and much less invasive method of GDNF administration than direct brain infusion. Thus, further research on Ibogaine and GDNF is certainly warranted. Ibogaine therapy may offer a non-invasive and low-toxicity method of treatment for sufferers of these disorders.
    Last edited by mr peabody; 01-12-2018 at 08:25.
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    MDMA shown to have a dramatic effect on Parkinson’s symptoms

    By David Concar

    MDMA is being hailed as the key to better treatments for the Parkinson’s disease, marking a complete turnaround from a few weeks ago when ecstasy was condemned for causing the disease.

    New animal studies have confirmed anecdotal reports that ecstasy can dramatically curb the uncontrollable arm and leg movements that plague so many people with Parkinson’s. But the finding may be of little immediate help to sufferers.

    The researchers are not calling for patients to be given legal supplies of ecstasy (MDMA). Instead, they want to look for related drugs with the same beneficial effects. And patients are being warned against trying MDMA for themselves. “It’s impure, illegal and dangerous,” says Robert Meadowcroft, policy director of Britain’s Parkinson’s Disease Society.

    Others are calling for further animal studies to establish the effective dose, followed by human trials. “People who are suffering should have the right to decide carefully for themselves whether or not to take MDMA,” says American drugs policy campaigner Rick Doblin. His organisation, MAPS, recently won approval from the Food and Drug Administration for a human trial of ecstasy for treating post-traumatic stress disorder.

    Regaining control

    The latest study was prompted by the experiences of a former stuntman, Tim Lawrence. He made headlines when he claimed in a BBC TV documentary that “E” enabled him to regain control of his body for hours at a time.

    Parkinson’s experts at the University of Manchester decided to test Lawrence’s claims. Concerns about the dangers of MDMA ruled out human trials, says team member Jonathan Brotchie, who now runs Manchester-based biotech company Motac. So the researchers turned to marmosets with a form of the disease.

    Parkinson’s is caused by a loss of the dopamine-producing cells in the brain. Symptoms include rigidity and a shuffling gait. Since the late 1960s doctors have treated it with L-dopa, a chemical precursor to dopamine that can “unfreeze” patients.

    The downside is that patients develop uncontrollable movements after taking L-dopa for a while. Their condition tends to oscillates between flailing limbs while on the drug and immobility off it.

    To mimic Parkinson’s, they gave six marmosets a chemical that kills dopamine neurons. Then, over the next few months, the monkeys had daily doses of L-dopa until they developed the usual side effect of uncontrolled movements. At this point the animals were given MDMA.

    Dramatic effects

    The effects were dramatic. Normally, monkeys on L-dopa move their arms and legs around in a repetitive and uncontrolled way virtually all the time. But in the six hours after a dose of MDMA, these movements happened no more than 15 per cent of the time. MDMA somehow reduces the debilitating side effects of L-dopa without blocking its beneficial effects.

    “The magnitude and quality of the effect took us by surprise,” says Brotchie, whose team’s findings were unveiled this week at the conference of the Society for Neuroscience in Florida. “It was always possible that Tim’s response to ecstasy was unusual.”

    The researchers suspect the finding reflects MDMA’s ability to stimulate the release of the neurotransmitter serotonin in the brain. That might make up for a lack of serotonin caused by taking L-dopa for prolonged periods, says Brotchie. However, there are fears that MDMA can damage serotonin-producing cells.

    And last month the journal Science published a paper claiming that MDMA can actually cause the type of damage to dopamine cells that can lead to Parkinson’s. But the evidence was far from conclusive.


    Stem Cell Transplants offer first-ever MS treatment that reverses disability

    Dr. Richard K. Burt performed the first hematopoietic stem cell transplant (HSCT) for a multiple sclerosis (MS) patient in the United States at Chicago’s Northwestern Memorial Hospital. Now Burt, Chief of the Division of Medicine-Immunotherapy and Autoimmune Diseases at Northwestern University’s Feinberg School of Medicine, is making headlines again.

    Burt and his colleagues published the results of their newest HSCT study earlier this week in the Journal of the American Medical Association. Their results show that HSCT could be the first MS therapy to reverse disability. Though the study group was small, the results have experts hopeful.

    For this trial, 151 patients underwent a stem cell transplant. First, their immune systems were tamped down using low-dose chemotherapy. Then, doctors used HSCT therapy, involving an infusion of the patients’ own stem cells, previously harvested from their blood, to reboot their immune systems. After a short stay in the hospital, the volunteers went about their normal lives, needing no “maintenance” drugs.

    Over the next several years, the volunteers were periodically given a series of tests to measure their disability. One test, known as the Expanded Disability Status Scale, or EDSS, measures cognition, coordination, and walking, among other things. Participants underwent MRI scans and completed questionnaires to measure their overall quality of life.

    The researchers found that at two years post-transplant half of the patients showed a marked improvement in disability. Of the patients who were followed for four years, more than 80 percent remained relapse-free.

    Since 1993, the FDA has approved 12 disease-modifying therapies to treat relapsing-remitting MS (RRMS). All are designed to suppress the immune system to one degree or another. These drugs cost about $5,000 per month and they must be taken indefinitely, since relapses will occur if the drugs are stopped. While patients now have many options to stave off disease progression, no DMT has been proven to reverse disability.

    HSCT costs about $125,000 per patient. “Although we haven’t done a cost analysis, given how expensive Tysabri is, and Fingolimod, since HSCT is a one-time treatment it should start paying for itself around 18 months,” Burt told Healthline.

    Who should have a stem cell transplant?

    “The caveat,” Burt conceded, “is this is not effective in progressive MS.” He pointed out the tendency among neurologists to try one DMT after another until the patient is out of options before offering HSCT. “But by then the patient has entered secondary progressive and most likely nothing will help.”

    “If you’re doing well on first-line therapies, interferons or Copaxone, good, that’s where you should stay,” Burt added. “But if you’re having frequent relapses, two or more a year despite those therapies … I think that’s the group that, rather than going to Tysabri or Fingolimod, should be given this therapy because it’s so much more beneficial. Plus, if you wait until you’ve had all those other [DMTs] then you increase the risk of this treatment.”

    Even after stopping the drug, patients who have taken natalizumab (Tysabri) continue to have an increased risk of primary multifocal leukoencephalopathy (PML) for many months. If they were to undergo HSCT during that time, the risk for this rare but serious brain infection carries over and would make the procedure more dangerous.

    "In their study," Burt pointed out, “we had no opportunistic infections, no PML, nothing, but my worry is, if you’ve had many years of prior treatment with Tysabri, and you’re [positive for John Cunningham virus], then you could get PML and people think it’s our transplant but it’s really all that prior Tysabri.”

    Getting her life back

    One of Burt’s trial patients, Roxane Beygi, spoke on a panel at the Vatican Adult Stem Cell Conference in 2013. In a video of the event, she describes her life before the study.

    Despite being on a DMT prior to the study, Beygi was relapsing regularly and could barely walk. She had trouble writing, brushing her teeth, and even performing simple tasks like drinking from a glass.

    “Since I had my transplant, my life changed completely,” said Beygi, speaking more than two years after treatment, “Before the transplant I had major fatigue where I couldn’t even get out of bed. … Now I get up at 6 ... and a lot of the time I’m studying and exercising until like 1 a.m.”

    Beygi ended her presentation by thanking Dr. Burt for giving her life back. She called him her “hero.”

    Although HSCT is currently only available in clinical trials and for “compassionate use” in certain cases, Burt is hopeful that more studies will lead the FDA to approve stem cell transplantation for MS.
    Last edited by mr peabody; 07-12-2018 at 10:25.
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    CBD and Parkinson’s Disease

    The endocannabinoid system and digestive imbalance play major roles in Parkinson's disease. Research on CBD, THC, and THCV has demonstrated that cannabis medicine may help to manage PD symptoms.

    Scientists at the University of Louisville School of Medicine in Kentucky have identified a previously unknown molecular target of cannabidiol (CBD), which may have significant therapeutic implications for Parkinson’s Disease (PD).

    A poster by Zhao-Hui Song and Alyssa S. Laun at the 2017 meeting of the International Cannabinoid Research Society in Montreal disclosed that CBD activates a G-coupled protein receptor called “GPR6” that is highly expressed in the basal ganglia region of the brain. GPR6 is considered an “orphan receptor” because researchers have yet to find the primary endogenous compound that binds to this receptor.

    It has been shown that a depletion of GPR6 causes an increase of dopamine, a critical neurotransmitter, in the brain. This finding suggests GPR6 could have a role in the treatment of Parkinson’s, a chronic, neurodegenerative disease that entails the progressive loss of dopaminergic (dopamine-producing) neurons and consequent impairment of motor control. By acting as an “inverse agonist” at the GPR6 receptor, CBD boosts dopamine levels in preclinical studies.

    Parkinson’s affects an estimated 10 million people worldwide, including one million Americans. It is the second most common neurological disorder (after Alzheimer’s Disease). Over 96 percent of those diagnosed with PD are over 50 years old with men being one-and-a-half times more likely to have PD than women. Uncontrolled PD significantly reduces the patient’s quality of life and can render a person unable to care for themselves, trapped in a body they cannot control.

    Dopamine depletion

    Parkinson’s Disease is most associated with compromised motor function after the loss of 60-80% of dopamine-producing neurons. As dopaminergic neurons become damaged or die and the brain is less able to produce adequate amounts of dopamine, patients may experience any one or combination of these classic PD motor symptoms: tremor of the hands, arms, legs or jaw; muscle rigidity or stiffness of the limbs and trunk; slowness of movement (bradykinesia); and /or impaired balance and coordination (postural instability).

    Additional symptoms include decreased facial expressions, dementia or confusion, fatigue, sleep disturbances, depression, constipation, cognitive changes, fear, anxiety, and urinary problems. Pesticide exposure and traumatic brain injury are linked to increased risk for PD. Paraquat, an herbicide sprayed by the DEA in anti-marijuana defoliant operations in the United States and other countries, resembles a toxicant MPTP [methyl-phenyl-tetrahydropyridien], which is used to simulate animal models of Parkinson’s for research purposes.

    Within the PD brain there are an inordinate number of Lewy bodies - intracellular aggregates of difficult to break down protein clusters - that cause dysfunction and demise of neurons. This pathological process results in difficulties with thinking, movement, mood and behavior. The excessive presence of Lewy bodies, coupled with the deterioration of dopaminergic neurons, are considered to be hallmarks of Parkinson’s. But mounting evidence suggests that these aberrations are actually advanced-stage manifestations of a slowly evolving pathology.

    It appears that non-motor symptoms occur for years before the disease progresses to the brain, and that PD is actually a multi-system disorder, not just a neurological ailment, which develops over a long period of time. According to the National Parkinson’s Foundation, motor symptoms of PD only begin to manifest when most of the brain’s dopamine-producing cells are already damaged.

    Patients whose PD is diagnosed at an early stage have a better chance of slowing disease progression. The most common approach to treating PD is with oral intake of L-dopa, the chemical precursor to dopamine. But in some patients, long-term use of L-dopa will exacerbate PD symptoms. Unfortunately, there is no cure – yet.

    Gut-brain axis

    What causes Parkinson’s? One theory traces the earliest signs of PD to the enteric nervous system (the gut), the medulla (the brainstem), and the olfactory bulb in the brain, which controls one’s sense of smell. New research shows that the quality of bacteria in the gut – the microbiome – is strongly implicated in the advancement of Parkinson’s, the severity of symptoms, and related mitochondrial dysfunction.

    Defined as “the collection of all the microorganisms living in association with the human body,” the microbiome consists of “a variety of microorganisms including eukaryotes, archaea, bacteria and viruses.” Bacteria, both good and bad, influence mood, gut motility, and brain health. There is a strong connection between the microbiome and the endocannabinoid system: Gut microbiota modulate intestinal endocannabinoid tone, and endocannabinoid signaling mediates communication between the central and the enteric nervous systems, which comprise the gut-brain axis.

    Viewed as “the second brain,” the enteric nervous system consists of a mesh-like web of neurons that covers the lining of the digestive tract – from mouth to anus and everything in between. The enteric nervous system generates neurotransmitters and nutrients, sends signals to the brain, and regulates gastrointestinal activity. It also plays a major role in inflammation.

    The mix of microorganisms that inhabit the gut and the integrity of the gut lining are fundamental to overall health and the ability of the gut-brain axis to function properly. If the lining of the gut is weak or unhealthy, it becomes more permeable and allows things to get into the blood supply that should not be there, negatively impacting the immune system. This is referred to as “leaky gut.” Factor in an overgrowth of harmful bacteria and a paucity of beneficial bacteria and you have a recipe for a health disaster.

    The importance of a beneficial bacteria in the gut and a well-balanced microbiome cannot be overstated. Bacterial overgrowth in the small intestine, for example, has been associated with worsening PD motor function. In a 2017 article in the European Journal of Pharmacology, titled “The gut-brain axis in Parkinson’s disease: Possibilities for food-based therapies,” Peres-Pardo et al examine the interplay between gut dysbiosis and Parkinson’s. The authors note that “PD pathogenesis may be caused or exacerbated by dysbiotic microbiota-induced inflammatory responses … in the intestine and the brain.”

    Mitochondria, microbiota and marijuana

    The microbiome also plays an important role in the health of our mitochondria, which are present in every cell in the brain and body (except red blood cells). Mitochondria function not only as the cell’s power plant; they also are involved in regulating cell repair and cell death. Dysfunction of the mitochondria, resulting in high levels of oxidative stress, is intrinsic to PD neurodegeneration. Microbes produce inflammatory chemicals in the gut that seep into the bloodstream and damage mitochondria, contributing to disease pathogenesis not only in PD but many neurological and metabolic disorders, including obesity, type-2 diabetes, and Alzheimer’s.

    The evidence that gut dysbiosis can foster the development of PD raises the possibility that those with the disease could benefit by manipulating their intestinal bacteria and improving their microbiome. Enhancing one’s diet with fermented foods and probiotic supplements may improve gut health and relieve constipation, while also reducing anxiety, depression and memory problems that afflict PD patients.

    Cannabis therapeutics may also help to manage PD symptoms and slow the progression of the disease. Acclaimed neurologist Sir William Gowers was the first to mention cannabis as a treatment for tremors in 1888. In his Manual of Diseases of the Nervous System, Grower noted that oral consumption of an “Indian hemp” extract quieted tremors temporarily, and after a year of chronic use the patient’s tremors nearly ceased.

    Modern scientific research supports the notion that cannabis could be beneficial in reducing inflammation and assuaging symptoms of PD, as well as mitigating disease progression to a degree. Federally-funded preclinical probes have documented the robust antioxidant and neuroprotective properties of CBD and THC with “particular application … in the treatment of neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease and HIV dementia.” Published in 1998, these findings formed the basis of a U.S. government patent on cannabinoids as antioxidants and neuroprotectants.

    Pot for Parkinson’s

    Although clinical studies focusing specifically on the use of plant cannabinoids to treat PD are limited (because of marijuana prohibition) and convey conflicting results, in aggregate they provide insight into how cannabis may aid those with Parkinson’s. Cannabidiol, THC, and especially THCV all showed sufficient therapeutic promise for PD in preclinical studies to warrant further investigation. Additional research might shed light on which plant cannabinoids, or combination thereof, is most appropriate for different stages of Parkinson’s.

    Anecdotal accounts from PD patients using artisanal cannabis preparations indicate that cannabinoid acids (present in unheated whole plant cannabis products) may reduce PD tremor and other motor symptoms. Raw cannabinoid acids (such as CBDA and THCA) are the chemical precursors to neutral, “activated” cannabinoids (CBD, THC). Cannabinoid acids become neutral cannabinoid compounds through a process called decarboxylation, where they lose their carboxyl group through aging or heat. Minimal research has focused on cannabinoid acids, but the evidence thus far suggests that THCA and CBDA have powerful therapeutic attributes, including anti-inflammatory, anti-nausea, anti-cancer, and anti-seizure properties. In a 2004 survey of cannabis use among patients at the Prague Movement Disorder Centre in the Czech Republic, 45 percent of respondents reported improvement in PD motor symptoms.

    Cannabis clinicians are finding that dosage regimens for medical marijuana patients with PD don’t conform to a one-size-fits-all approach. In her book Cannabis Revealed (2016), Dr. Bonni Goldstein discussed how varied a PD patient’s response to cannabis and cannabis therapeutics can be:

    “A number of my patients with PD have reported the benefits of using different methods of delivery and different cannabinoid profiles. Some patients have found relief of tremors with inhaled THC and other have not. A few patients have found relief with high doses of CBD-rich cannabis taken sublingually. Some patients are using a combination of CBD and THC … Trial and error is needed to find what cannabinoid profile and method will work best. Starting a low-dose and titrating up is recommended, particularly with THC-rich cannabis. Unfortunately, THCV-rich varieties are not readily available.”

    Juan Sanchez-Ramos M.D., PhD, a leader in the field of movement disorders and the Medical Director for the Parkinson Research Foundation, told Project CBD that he encourages his patients to begin with a 1:1 THC:CBD ratio product if they can get it. In a book chapter on “Cannabinoids for the Treatment of Movement Disorders,” he and coauthor Briony Catlow, PhD, describe the dosage protocol used for various research studies that provided statistically positive results and a dosing baseline for PD. This data was included in a summary of dosing regimens from various studies compiled by Dr. Ethan Russo:

    - 300 mg/day of CBD significantly improved quality of life but had no positive effect on the Unified Parkinson Disease Rating Scale. (Lotan I, 2014)

    - 0.5 g of smoked cannabis resulted in significant improvement in tremor and bradykinesia as well as sleep. (Venderov? K, 2004)

    - 150 mg of CBD oil titrated up over four weeks resulted in decreased psychotic symptoms. (Chagas MH, 2014)

    - 75-300 mg of oral CBD improved REM-behavior sleep disorder. (Zuardi AW, 2009)

    A threshold dose

    Of course, each patient is different, and cannabis therapeutics is personalized medicine. Generally speaking, an optimal therapeutic combination will include a synergistic mix of varying amounts of CBD and THC – although PD patients with sleep disturbances may benefit from a higher THC ratio at night.

    Dr. Russo offers cogent advice for patients with PD and other chronic conditions who are considering cannabis therapy. “In general,” he suggests, “2.5 mg of THC is a threshold dose for most patients without prior tolerance to its effects, while 5 mg is a dose that may be clinically effective at a single administration and is generally acceptable, and 10 mg is a prominent dose, that may be too high for na?ve and even some experienced subjects. These figures may be revised upward slightly if the preparation contains significant CBD content … It is always advisable to start at a very low dose and titrate upwards slowly.”

    Lifestyle Modifications for PD Patients

    It is important to treat the patient as a whole – mind, body and soul. The following are a few lifestyle modifications that may provide relief from PD symptoms and improve quality of life.

    - Do cardio aerobic exercise: This benefits the body in so many ways, including stimulating the production of one’s endocannabinoids, increasing oxygen in the blood supply, mitigating the negative impact of oxidative stress, and boosting the production of BDNF, a brain-protecting chemical found to be low in PD patients.

    - Eat more fruits and vegetables: The old saying “garbage in, garbage out” is so true. The majority of PD patients suffer from chronic constipation. A high fiber diet can be helpful in improving gut motility and facilitating daily bowel movements.

    - Get restful sleep: Not getting good sleep can undermine one’s immune function, cognition and quality of life. The importance of adequate restful sleep cannot be over emphasized.

    - Reduce protein intake – This may help reduce the accumulation of protein bodies that result in Lewy bodies that appear in the enteric nervous system and the central nervous system and increase the uptake of L-dopa.

    - Practice meditation, yoga or Tai Chi: The focus on the integration of movement and breath not only improve mobility but it also improves cognition and immunity. One study showed an increase in grey matter density in the areas of the brain associated with PD. Another showed that yoga improved balance, flexibility, posture and gait in PD patients. Research shows that tai chi can improve balance, gait, functional mobility, and overall well being.

    - Consume probiotic food and supplements: Probiotic foods — raw garlic, raw onions, bananas, asparagus, yams, sauerkraut, etc.— are a great source for the good bacteria in your large intestine. Augmenting your diet with probiotic supplements, especially after taking antibiotics, can support the immune system by helping to repopulate the upper digestive tract with beneficial bacteria. Consult your doctor regarding a recommendation for a quality probiotic.

    -Drink coffee: The risk of PD is considerably lower for men who consume coffee daily.
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    Ibogaine and neurodegenerative diseases

    Following is a summary on existing research looking at the influence of Ibogaine on glial cell line-derived neurotrophic factor (GDNF) levels in the brain, and the beneficial impact that an increase in this protein can have. While existing studies have examined these areas, few have identified a possible link between Ibogaine, GDNF expression and neurodegenerative diseases.

    Both Parkinsons disease and Motor neuron disease are chronic disorders with no known cure, and require management with drugs that can have considerable side effects, causing a very poor quality of life for terminal stage sufferers of these diseases. By contrast, a low dose regime of Ibogaine or Iboga alkaloid extract would be of low toxicity and free of serious side effects.

    GDNF has been shown to have potent neurotrophic factor in both rodent and primate models of Parkinsons disease. Direct brain infusion of GDNF into the brains of five Parkinson sufferers resulted in a 39% improvement in the off-medication motor sub-score of the Unite Parkinsons Disease Rating Scale (UPDRS) and a 61% improvement in the activities of daily living sub score. Positron emission tomography (PET) scans of dopamine uptake showed a significant 28% increase in putamen dopamine storage after 18 months, indicating a direct effect of GDNF on dopamine function. Furthermore, after one year, no serious clinical side effects were observed. The use of Iboga alkaloid extract or Ibogaine would provide a longer term and much less invasive method of GDNF administration than direct brain infusion. Thus, further research on Ibogaine and GDNF is certainly warranted.

    Regarding motor neuron disease (ALS), the research that has occurred in this area, such as gene transfer of neurotrophic factors, suggests its potential as a treatment for this disorder. Again, Ibogaine therapy may offer a straightforward, non-invasive, cheap, low-toxicity method of treatment for sufferers of this disease.

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    A biomarker for multiple sclerosis has been identified in humans by researchers at Purdue University and the Indiana University School of Medicine.
    Although just in preliminary testing, initial tests in humans have found that the substance acrolein, a waste product normally excreted by the body (shown here in green)
    can accumulate in some people and cause neurological problems by damaging the myelin (damaged myelin shown in red), which surrounds the nerve cell like insulation on a copper wire.

    Possible biomarker for Multiple Sclerosis identified

    A biomarker for multiple sclerosis that could be an early warning for the disease has shown promise in both human and animal testing.

    Researchers at Purdue University and the Indiana University School of Medicine found that acrolein, a molecule previously suspected as a metabolic waste product that accumulates in people with certain neurological disorders such as multiple sclerosis and Parkinson’s disease, could possibly be used to help diagnose MS.

    Multiple Sclerosis affects an estimated 2.3 million people worldwide, according to the National Multiple Sclerosis Society, and 1 million people in the United States have MS. The disease usually is diagnosed between the ages of 20 and 50, and affects twice as many women as men.

    Although there is no cure for MS, recent years have seen a flurry of activity around possible biomarkers and possible treatments.

    Dr. David Mattson, professor of neurology and the director of the Indiana University Multiple Sclerosis Center, says that if the results are validated, acrolein could also allow medical professionals to monitor the effectiveness of treatments.

    “We are in the process of trying to correlate acrolein levels with MS disease activity, which potentially would help us monitor disease activity with a blood test,” he says. “If this is validated, it would help us decide how aggressive to be with immunotherapy, whether a therapy is working or if there is a need to switch to a different therapy.”

    Acrolein is a byproduct of fat metabolism. Dr. Riyi Shi, a professor of neuroscience and biomedical engineering in Purdue University’s Department of Basic Medical Sciences, College of Veterinary Medicine and Weldon School of Biomedical Engineering, has found that an accumulation of the molecule is present in animal models of neurological diseases such as MS, Parkinson’s disease, or even spinal cord and brain injuries. Acrolein is thought to damage cells by disrupting the lipids, or fats, that protect nerve tissue, in a process called lipid peroxidation. Shi said that both blood and urine tests, or assays, have been able to measure acrolein levels in humans and in animal models.

    “The levels of this compound in urine and blood is correlated — the MS patients that had the highest level of acrolein in the blood also had the highest level in the urine,” he said.

    According to Shi, it is, therefore, possible that a high level of acrolein is indicative of more active MS, though low levels of acrolein do not rule out the possibility of having MS. Further study is needed to vailidate these initital observations.

    Shi says the study also suggests that acrolein is not just a potential biomarker of MS disease activity but could also be a target for therapies.

    “There are drugs already on the market that are known to be acrolein scavengers, and it is possible that one of these drugs could be repurposed as a possible therapy for MS,” Shi says. “But these drugs also have strong effects on other targets, so more study would need to be done to see if they have a therapeutic effect to eliminate acrolein at a safe level.”

    The two drugs in this catogory are hydralazine, used to treat high blood pressure and heart failure, and phenelzine, which is used to treat major depression.

    “Before attempting to repurpose these drugs to lower acrolein in MS patients, we plan to first confirm whether acrolein, indeed, correlates with disease activity in MS through a larger clinical study with more participants,” Mattson says. “Then we need to show that these drugs can, indeed, reduce acrolein levels in human MS patients."

    “If it turns out these agents can reduce acrolein levels in MS and offer benefit for the disease process in MS, then patients on these agents for the blood pressure or psychiatric indications would get two benefits for one.”

    Shi’s health research aligns with Purdue’s Giant Leaps celebration, which acknowledges the university’s global advancements in health, longevity and quality of life as part of Purdue’s 150th anniversary. This is one of the four themes of the yearlong celebration’s Ideas Festival, designed to showcase Purdue as an intellectual center solving real-world problems.
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    Ayahuasca and ALS

    Natural substances extracted from the ayahuasca plants have been found to possess unique restorative and strongly antioxidative properties on specific nerve cells in the brain and central nervous system controlling neurotransmission, muscle/motor activity, memory and coordination. This gives probable cause to the theory that ayahuasca could be an effective treatment for neurodegenerative diseases such as ALS, Alzheimers, and Parkinsons disease. Promising results as of date has also been obtained from studying the substance psilocybin, very closely related to the substances found in ayahuasca, naturally occuring in certain species of medicinal mushrooms consumed by the indigenous people where ayahuasca is also used.

    According to Dr. Juan Ramos, head of the neurological disease department at the South Florida university, USA, initial studies show that these substances stimulate the development of new cells in the areas of the brain controlling the above mentioned functions. If this could prove to be an eventual cure through complete restoration of damaged or destroyed cells remains to be seen, but initial results indicate this could potentially be the case. There is also a growing interest in exploring the cell regenerative properties of these plants within the spinal chord injury support communities. Should people with this background eventually try and find the results of this treatment useful, medical science would be bound to take note. Cancer researchers have also shown interest in B. Caapi, as its different alkaloids has shown to be effective against the growth of cancer cells.


    Ayahuasca could effectively be used in treatment of ALS and other motor neuron diseases based on the fact that studies suggest uniquely antioxidative effects that seem to protect brain/nerve cells, targeting motor neurons through a unique biochemical transport system, and that it and other molecularly similar substances, also naturally occurring, stimulate neurogenesis, the development of new brain/nerve cells, and the communicative capacity between these. In studies it has been found to reduce symptoms in Parkinsons patients; all neurodegenerative diseases share common ground, thus making it likely that something that improves a given neurological condition could also be beneficial to other conditions nearly related. Also based on credible personal accounts from people having used ayahuasca for symptom relief from their multiple sclerosis (the common ground of neurodegenerative diseases), documented in books about ayahuasca, and from descriptions of early stage minor improvement by those with various types of ALS now participating in the treatment project, already having used this medicine for a period of time. Studies also indicate the ability to normalize metabolism in mitochondria, crucial to motor neuron survival, and to regulate and decrease levels of excitotoxicity in the central nervous system.

    -Daniel Gustafsson

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    LSD and Parkinson's

    In a very real sense the circle is closing with respect to Albert Hofmann's hope, expressed at the time of his discovery of LSD. Because of its psychotomimetic action (ability to mimic certain mental illnesses), the drug might prove useful in their treatment. In fact, LSD has been employed to that end over the years by some psychiatrists, often with beneficial results.

    Recently, scientists at the School of Medicine of the University of California at Los Angeles have made some significant discoveries about the interaction of LSD with dopamine, one of the neurotransmitter agents in the brain, that may lead not only to a better understanding and eventual treatment of schizophrenia, the mental disorder to which the LSD "high" is a kind of temporary analogue, but even of such physically, rather than mentally, crippling disorders as Parkinson's disease. The investigators, Drs. Sidney Roberts and Kern von Hungen and Diane F. Hill, determined that adenyl cyclase, an enzyme in nervous tissue that is stimulated by naturally occurring neurotransmitter agents, is also stimulated by the action of LSD on receptors for one of these neurotransmitters, dopamine. In addition, LSD blocked the stimulatory actions of dopamine and other neurotransmitters such as serotonin and norepeninephrine. These are themselves structurally closely related to powerful plant growth hormones; dopamine, moreover, has also been identified with the giant saguaro cactus of Arizona and northern Mexico.

    Schizophrenia is thought to be a disease of dopamine hyperactivity; victims of Parkinson's disease, on the other hand, suffer from dopamine insufficiency, which is partially offset nowadays by the administration of a new drug, L-dopa, often in combination with Tofranil or some other amphetamine. The adenyl cyclase experiments enabled the UCLA team to show that dopamine receptors are present in the higher regions of the brain, which are concerned with the more complex experiences and thus are more likely to be the seat of alternate states of consciousness, or "hallucinations." Their work, report the UCLA investigators, makes it appear that the psychotic mimicking effects of LSD, first noted by Hofmann more than thirty years ago, may also be related to hyperactivity of brain dopamine systems. These insights have obvious implications for work on new drugs for schizophrenia on the one hand and Parkinson's disease on the other; recognition of their biochemical kinship was, of course, still far off in the distant future when Hofmann correctly predicted the ultimate benefits of LSD for brain research. Nor did he suspect at the time that "primitive" psychotherapy had been making effective use of a natural compound very like LSD for hundreds, perhaps thousands, of years.

    "Lysergic acid," Hofmann (1967) has explained, "is the foundation stone of the ergot alkaloids, the active principle of the fungus product ergot. Botanically speaking ergot is the sclerotia of the filamentous fungus Claviceps purpurea which grows on grasses, especially rye. The ears of rye that have been attacked by the fungus develop into long, dark pegs to form ergot. The chemical and pharmacological investigation of the ergot alkaloids has been a main field of research of the natural products division of the Sandoz laboratories since the discovery of ergotamine by A. Stoll in 1918. A variety of useful phannaceuticals have resulted from these investigations, which have been conducted over a number of decades. They find wide application in obstetrics, in internal medicine, in neurology and psychiatry.


    Wireless 'pacemaker for the brain' could offer new treatment for neurological disorders

    Device fine-tunes treatment by stimulating and and recording electric current in the brain at the same time.

    A new neurostimulator developed by engineers at the University of California, Berkeley, can listen to and stimulate electric current in the brain at the same time, potentially delivering fine-tuned treatments to patients with diseases like epilepsy and Parkinson's.

    The device, named the WAND, works like a "pacemaker for the brain," monitoring the brain's electrical activity and delivering electrical stimulation if it detects something amiss.

    These devices can be extremely effective at preventing debilitating tremors or seizures in patients with a variety of neurological conditions. But the electrical signatures that precede a seizure or tremor can be extremely subtle, and the frequency and strength of electrical stimulation required to prevent them is equally touchy. It can take years of small adjustments by doctors before the devices provide optimal treatment.

    WAND, which stands for wireless artifact-free neuromodulation device, is both wireless and autonomous, meaning that once it learns to recognize the signs of tremor or seizure, it can adjust the stimulation parameters on its own to prevent the unwanted movements. And because it is closed-loop -- meaning it can stimulate and record simultaneously -- it can adjust these parameters in real-time.

    "The process of finding the right therapy for a patient is extremely costly and can take years. Significant reduction in both cost and duration can potentially lead to greatly improved outcomes and accessibility," said Rikky Muller assistant professor of electrical engineering and computer sciences at Berkeley. "We want to enable the device to figure out what is the best way to stimulate for a given patient to give the best outcomes. And you can only do that by listening and recording the neural signatures."

    WAND can record electrical activity over 128 channels, or from 128 points in the brain, compared to eight channels in other closed-loop systems. To demonstrate the device, the team used WAND to recognize and delay specific arm movements in rhesus macaques. The device is described in a study that appeared today (Dec. 31) in Nature Biomedical Engineering.

    Ripples in a pond

    Simultaneously stimulating and recording electrical signals in the brain is much like trying to see small ripples in a pond while also splashing your feet -- the electrical signals from the brain are overwhelmed by the large pulses of electricity delivered by the stimulation.

    Currently, deep brain stimulators either stop recording while delivering the electrical stimulation, or record at a different part of the brain from where the stimulation is applied -- essentially measuring the small ripples at a different point in the pond from the splashing.

    "In order to deliver closed-loop stimulation-based therapies, which is a big goal for people treating Parkinson's and epilepsy and a variety of neurological disorders, it is very important to both perform neural recordings and stimulation simultaneously, which currently no single commercial device does," said former UC Berkeley postdoctoral associate Samantha Santacruz, who is now an assistant professor at the University of Texas in Austin.

    Researchers at Cortera Neurotechnologies, Inc., led by Rikky Muller, designed the WAND custom integrated circuits that can record the full signal from both the subtle brain waves and the strong electrical pulses. This chip design allows WAND to subtract the signal from the electrical pulses, resulting in a clean signal from the brain waves.

    Existing devices are tuned to record signals only from the smaller brain waves and are overwhelmed by the large stimulation pulses, making this type of signal reconstruction impossible.

    "Because we can actually stimulate and record in the same brain region, we know exactly what is happening when we are providing a therapy," Muller said.

    In collaboration with the lab of electrical engineering and computer science professor Jan Rabaey, the team built a platform device with wireless and closed-loop computational capabilities that can be programmed for use in a variety of research and clinical applications.

    In experiments lead by Santacruz while a postdoc at UC Berkeley, and by and electrical engineering and computer science professor Jose Carmena, subjects were taught to use a joystick to move a cursor to a specific location. After a training period, the WAND device was capable of detecting the neural signatures that arose as the subjects prepared to perform the motion, and then deliver electrical stimulation that delayed the motion.

    "While delaying reaction time is something that has been demonstrated before, this is, to our knowledge, the first time that it has been demonstrated in a closed-loop system based on a neurological recording only," Muller said.

    "In the future we aim to incorporate learning into our closed-loop platform to build intelligent devices that can figure out how to best treat you, and remove the doctor from having to constantly intervene in this process," said Muller said.
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    Ayahuasca component Harmine may be key in the fight against diabetes

    For centuries, some indigenous groups in South America have relied on a brew made from the parts of a local vine and a shrub. The effects of this drink, called ayahuasca, would begin with severe vomiting and diarrhea, but the real reason for drinking the tea were the hallucinations that followed. These visions were thought to uncover the secrets of the drinker’s poor health and point the way to a cure.

    Modern techniques have revealed that one of the compounds underlying these mystic experiences is the psychoactive drug harmine. What these first users of ayahuasca couldn’t have known was that, one day, this ingredient in their enlightening brew would be positioned as a key to treating diabetes.

    Such a cure is a long way off, but researchers took another step toward it when they combined naturally occurring harmine with a compound synthesized from scratch in a lab. Together, the pair can coax the insulin-producing pancreatic cells, called beta cells, into replicating at the fastest rates ever reported, according to findings published December 20 in Cell Metabolism.

    Type 1 diabetes arises when the body turns on these cells and destroys them. Type 2 diabetes develops when these same cells wear out and can no longer make insulin. Either effect is a point of no return because the beta cells we make in early life are the only ones we’ll ever have.

    If this pair of compounds eventually inches into the treatment toolbox, refreshing a faded cell population could become a reality and a possible treatment for diabetes. “Looking back 10 years or so, we questioned whether human beta cells could even be coaxed into dividing," says Justin Annes, assistant professor of medicine and endocrinology at Stanford University, who also works on beta cell proliferation, with a separate investigator group. “But what began as a fantasy has become aspiration, and perhaps in the coming years, will be a reality.”

    One stop on the trip to that reality was a 2015 study showing that harmine treatment of beta cells in a dish promoted their increase at a rate of about 2 percent per day. A promising beginning, says study author Andrew Stewart, scientific director of the Diabetes, Obesity, and Metabolism Institute at the Icahn School of Medicine at Mount Sinai, but a little too slow for someone who needs a replacement population.

    In this newest study, Stewart and his colleagues show that combining harmine with a synthetic inhibitor of another molecule kicks up the rate to 5–8 percent on average, and as high as 18 percent using some growth recipes. "The one–two punch of this chemical pair isn’t the only possible combination, and other groups also are working on various pairings," Stewart says. Annes and his colleagues have identified several compounds that hold similar promise for pushing insulin-producing cells to reproduce.

    “Basically, we’re all competing, but we all know each other so we share reagents and ideas,” says Stewart. “Different people have identified different drugs that make beta cells replicate.” His lab chose harmine because it’s the one they pulled out of their screening of 100,000 compounds in 2015, but “I don’t think harmine is especially better than any other one,” he says.

    In 2006, another group of researchers plucked harmine from a molecular haystack in a search for chemicals that interact with a protein associated with Down syndrome. Studies that followed showed harmine’s role in many body systems, including the gut and the brain, explaining in part the effects of ayahuasca on its earliest adopters.

    Harmine interferes with an enzyme called dual-specificity tyrosine-regulated kinase 1A, or DYRK1A. Like harmine, DYRK1A operates in a host of tissues. It helps, for one, in shaping the central nervous system during embryonic development. First identified because of its key involvement in Down syndrome, its routine duty is to add chemical tags to molecules to switch them on or off.

    The other molecule in the synergizing pair is an inhibitor of a group of proteins in the transforming growth factor-beta superfamily (TGFβSF). As with DYRK1A, these proteins are active in a large number of body processes, including cell proliferation.

    Stewart and his team homed in on TGFβSF and DYRK1A after probing the secrets of cells from benign pancreatic tumors called insulinomas. They reasoned that if they could pinpoint what made these tumors grow, they could co-opt that information to encourage growth of normal beta cells. Their exploration uncovered DYRK1A and TGFβSF-related targets.

    Inhibiting these molecules in human beta cells in a dish shuts down the cell regulators that usually keep the brakes on cancer’s out-of-control cell growth. Because harmine and TGFβSF inhibitor release this brake and DYRK1A and TGFβSF are active in many tissues, any treatment involving the pair of inhibitors must be closely targeted. “Certainly, we have a long way to go before these medications can be used in humans,” says Annes, calling the concern about cancer risk “reasonable.”

    Adding to that concern is that harmine affects other cell types, says Klaus Kaestner, professor of genetics and associate director of the Penn Diabetes Research Center at the University of Pennsylvania, who was not involved in the study. In 2016, his group reported that harmine triggers many types of hormone-producing cells to divide, including other cells in the pancreas.

    Stewart and his colleagues are sorting through a number of potential chemical tags that might help guide the inhibitors to the right location. "But for now," says Stewart, “we are Amazon and have a bunch of parcels, and we know that they’re for you, but we don’t know the address...”

    Type 1 diabetes poses another hurdle. Although the immune system targets and destroys these cells in this form of diabetes, a small pool of beta cells often remains, Stewart says. What’s unknown is if a new population grown from these cells would simply attract further immune destruction. Stewart says that if the harmine-TGFβSF inhibitor combination ever makes it to trials, the population it might initially suit best are those who have type 2 diabetes. Then the journey from a South American rainforest to a clinical treatment would be complete.


    CBD significantly reduces seizures in patients with severe epilepsy

    Cannabidiol (CBD), a compound derived from the cannabis plant that does not produce a “high” and has been an increasing focus of medical research, was shown in a new large-scale, randomized, controlled trial to significantly reduce the number of dangerous seizures in patients with a severe form of epilepsy called Lennox-Gastaut syndrome.

    In the new study comparing two doses of CBD to a placebo, the researchers reported a 41.9 percent reduction in “drop seizures” – a type of seizure that results in severe loss of muscle control and balance – in patients taking a 20 mg/kg/d CBD regimen, a 37.2 percent reduction in those on a 10 mg/kg/d CBD regimen, and a 17.2 percent reduction in a group given a placebo.

    The phase III trial was led by principal investigator and study first co-author Orrin Devinsky, MD, a professor of neurology, neurosurgery, and psychiatry at NYU School of Medicine and director of NYU Langone’s Comprehensive Epilepsy Center, and was published online May 17 in The New England Journal of Medicine.

    “This new study adds rigorous evidence of cannabidiol’s effectiveness in reducing seizure burden in a severe form of epilepsy and, importantly, is the first study of its kind to offer more information on proper dosing,” says Dr. Devinsky. “These are real medications with real side effects, and as providers we need to know all we can about a potential treatment in order to provide safe and effective care to our patients.”

    The study included an investigational liquid, oral formulation of CBD called Epidiolex. The product is manufactured by GW Pharmaceuticals, which operates in the U.S. as Greenwich Biosciences; GW Pharmaceuticals funded the clinical trial.

    Safety of two CBD doses studied

    Lennox-Gastaut syndrome is a rare and severe form of epilepsy characterized by frequent drop seizures and severe cognitive impairment. Six medications are approved to treat seizures in patients with the syndrome, but disabling seizures occur in most patients despite these treatments.

    Researchers enrolled 225 patients (age 2 to 55) with Lennox-Gastaut syndrome across 30 international sites in a randomized, double-blind, placebo-controlled trial to assess the efficacy and safety of two doses of CBD: Seventy-six patients received 20 mg/kg/d CBD, 73 received 10 mg/kg/d CBD, and 76 were given a placebo. All medications were divided into two doses per day for 14 weeks. The number of seizures were monitored beginning four weeks prior to the study for baseline assessment, then tracked throughout the 14-week study period and afterwards for a four-week safety check.

    Side effects occurred in 94 per of patients in the 20 mg CBD group, 84 percent in the 10 mg CBD group, and 72 percent of those taking placebo. Side effects were generally reported as mild or moderate in severity and those that occurred in more than 10 percent of patients included: sleepiness, decreased appetite, diarrhea, upper respiratory infection, fever, vomiting, nasopharyngitis, and status epilepticus. Fourteen patients taking CBD experienced dose-related, elevated liver enzymes that were reversible. Seven participants from the CBD group withdrew from the trial due to side effects compared to one participant in the placebo group.

    “This landmark study provides data and evidence that Epidiolex can be an effective and safe treatment for seizures seen in patients with Lennox Gastaut Syndrome, a very difficult to control epilepsy syndrome,” adds study co-first author, Anup Patel, MD, chief of Neurology at Nationwide Children’s Hospital.

    A study led by Dr. Devinsky published in last May’s New England Journal of Medicine showed a 39 percent drop in seizure frequency in patients with a different rare form of epilepsy, Dravet syndrome. Those findings represented the first large-scale, randomized clinical trial for the compound. Open label CBD studies led by Dr. Devinsky also have shown positive results for treatment-resistant epilepsies.

    In April, a U.S. Food and Drug Administration advisory panel unanimously voted to recommend approval of a new drug application for Epidiolex cannabidiol oral solution, following a meeting where researchers, including Dr. Devinsky, presented their findings. The FDA will decide whether to approve the medication in late June.

    “While the news gives hope for a new treatment option to the epilepsy community, more research remains imperative to better determine the effects of CBD and other similar cannabis-derived compounds on other forms of the disease and in more dosing regimens,” says Dr. Devinsky.


    UA clinical trial to repurpose ketamine for Parkinson’s patients

    The best-known treatment for Parkinson’s disease isn’t perfect. Named levodopa, the drug can treat the stiffness and slowness of movement associated with the debilitating disease.

    “The problem is levodopa works great for a few years — we call that the ‘honeymoon’ period — but then you start getting these side effects,” says Scott Sherman, MD, PhD, a neurologist at the University of Arizona College of Medicine – Tucson.

    Forty percent of patients on levodopa eventually will experience dyskinesia — uncontrollable and involuntary movements of the arms, legs, head or entire body. Severity can range from small, fidget-like motions to larger continuous bursts of movement.

    Unless patients stop levodopa treatment altogether, these movements do not go away.

    Now, UA researchers will repurpose ketamine, a drug currently used to treat pain and depression, to try to reduce and control these involuntary movements brought on by levodopa.

    Led by Dr. Sherman and Torsten Falk, PhD, a neuroscientist in the UA Department of Neurology, the two will launch a small phase I clinical trial this summer at the UA College of Medicine – Tucson. The trial is supported by a three-year $750,000 grant from the Arizona Biomedical Research Commission (ABRC).

    Drs. Sherman and Falk first got a glimpse of ketamine’s potential in Parkinson’s disease treatment more than five years ago.

    The two were using ketamine to relieve pain in five hospitalized patients with Parkinson’s disease. The treatment worked as expected, but the researchers noticed an unintended side effect: the patients’ uncontrolled movements while on levodopa were noticeably reduced. One patient experienced complete resolution of these movements for a period of several weeks.

    Intrigued, the researchers continued investigating and have since shown similar results in rodents with Parkinson’s disease.

    Ketamine has been known to raise blood pressure and cause a feeling of disassociation in humans.

    “Disassociation is a sort of ‘out-of-body’ experience,” Dr. Sherman explains. “When people describe it, they have told me that they feel like they are in fish bowl.”

    In the past, ketamine has been abused by partygoers for this psychedelic effect, but Dr. Sherman is hopeful these side effects will not affect the clinical trial.

    “We are going to monitor blood pressure closely to make sure it doesn’t get high,” he says. “And we know at what dosage ketamine causes this disassociation; we expect that the dosage needed in Parkinson’s disease will stay well below that level.”

    Using 10 patients, this first clinical trial will verify that Dr. Sherman’s hunch holds true — that ketamine is tolerable and effective for treating dyskinesia.

    In addition to supporting the clinical trial, grant funding from the ABRC will back a separate rodent study that examines exactly how ketamine affects the brain and reduces dyskinesia triggered by levodopa.

    “We want to find out exactly what ketamine is doing to have this effect,” Dr. Sherman explains.

    If the team achieves positive results in both the human and rodent studies, Drs. Sherman and Falk will be one step closer to their goal: establishing that ketamine can help patients with Parkinson’s disease.

    Dr. Sherman says, “Ketamine has been long overlooked. Now it could prove very useful for Parkinson’s patients.”
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    HERVs: Can Viruses in the Genome Cause Disease?

    Clinical trials that target human endogenous retroviruses to treat Multiple Sclerosis, ALS, and other ailments are underway, but many questions remain about how these sequences may disrupt our biology.

    In 2005, an HIV patient in an unusually difficult situation walked into a neuroimmunology clinic at Johns Hopkins University, where he was seen by the specialist Avindra Nath. The patient had not only immune deficiency resulting from HIV infection, but amyotrophic lateral sclerosis (ALS) as well, and the neurodegenerative disease was causing his condition to deteriorate rapidly. For several months, the patient had noticed his hands and feet becoming increasingly sore and weak, making tasks such as eating with utensils or opening a window all but impossible. When Nath saw him, the 29-year-old had difficulty climbing stairs and couldn’t get up from a seated position on the floor without assistance.

    The patient was initially reluctant to take a combination of anti-retroviral drugs to treat his HIV due to his rapidly progressing ALS symptoms, Nath recalls. “He said he would likely die from ALS before he died from HIV infection, so why take the anti-retrovirals?” But the doctor had read some clinical reports about other HIV-ALS patients’ ALS symptoms improving after a course of antiretrovirals, and Nath suggested he take them. The patient agreed and, like the other patients Nath had read about previously, rapidly began to feel better. When Nath saw him a year later, the patient no longer complained of weakness or muscle twitching, and his gait was normal. “This patient’s symptoms had totally reverted,” Nath tells The Scientist. “It’s one thing seeing it in the literature, but another thing to witness it yourself.”

    The experience piqued Nath’s interest in the potential role of viruses in ALS. Digging further into published research on the disease, he also found a handful of blood analyses indicating the activity of reverse transcriptase, an enzyme that converts the RNA genome of a retrovirus into DNA. But when scientists had looked for infectious retroviruses in those blood samples, they hadn’t found any. Nath reasoned that if the culprit wasn’t an exogenous virus, it could be one that’s already present in the human genome.

    Human endogenous retroviruses (HERVs) through the ages

    Over the course of evolution, several groups of ancient viruses colonized our ancestors’ genomes, leaving thousands of fragments of viral code in modern-day human DNA. The bulk of HERVs integrated during primate evolution. Subsequent mutations in these sequences have rendered older insertions nonfunctional, but some of the younger and more intact sequences from HERVs have been linked to disease.

    Around 8 percent of our genetic code stems from HERVs, the bulk of which integrated during primate evolution.

    - HERV-K viruses colonized the genomes of ancient primates as early as 55 million years ago (mya). Many of the youngest and most preserved elements, such as those in the HERV-K (HML-2) group, can produce viral proteins and have been linked to ALS.

    - The HERV-W group, which invaded the genome starting around 25 mya, was first detected in Multiple Sclerosis patients and named MS-associated retrovirus (MSRV) for its connection to the myelin-degenerating condition.

    - HERV-Fc, the youngest member of the HERV-F viruses, integrated into the genome more than 20 mya and has also been linked with Multiple Sclerosis.

    - HERV-L elements have been detected in all placental mammals, and are thought to have integrated between 100 million and 150 mya. They represent the oldest HERVs in the human genome, are not known to produce any proteins, and so far have not been linked to disease.

    Like many other animal species, humans carry viral remnants in their genomes, left behind from the integration of retrovirus sequences into the germline DNA of our ancestors over the course of millions of years. Today, these human endogenous retroviruses (HERVs) exist as 450,000 fragments of biological code, representing 39 major viral groups, broken up and scattered throughout the genome. Nath asked his colleague Jeffrey Rothstein, now the director of Johns Hopkins’s Robert Packard Center for ALS Research, for some samples of postmortem brain tissue of ALS patients, and began to search them for RNA transcripts of HERV sequences.

    The work yielded one match: HERV-K, the youngest group of viral insertions in humans. The transcripts were specifically associated with ALS, Nath and his colleagues found; they were not present in the brains of healthy individuals who died in accidents or in the brains of Parkinson’s patients.1 Since then, Nath, who now heads the Section of Infections of the Nervous System at the National Institutes of Health in Bethesda, Maryland, and others have been steadily accumulating evidence that these viral sequences are expressed in a subset—about 30 percent—of ALS patients.

    The vast majority of the HERV protein-coding sequences scattered across the genome have over time accumulated many mutations that render them inactive. That HERVs can cause damage to their hosts in modern times has long been dismissed as a fringe idea. Over the past three decades, however, research has implicated several of the younger, more intact HERV insertions in a range of diseases, including ALS, Multiple Sclerosis (MS), cancer, and schizophrenia.

    “Though they’ve mostly been ignored by the medical research community for quite a long time, they can actually have a large effect on the human body in more than one disease setting,” says Molly Hammell, a geneticist who studies HERVs at Cold Spring Harbor Laboratory in New York. Since this idea has come to light, some researchers have launched clinical studies to evaluate HERVs’ roles in diseases.

    Skeptics are still wary of the evidence that HERVs are involved in pathogenesis at all. Although there is a correlation, few studies address a possible causative role. “We know that they’re expressed,” says virologist George Kassiotis of the Francis Crick Institute in London, “but whether that expression really causes or really contributes todisease, that remains to be proven.”

    Rise of the Phoenix proteins

    In 1967, University College London virologist Robin Weiss noticed a viral envelope protein emerging not just from chicken cells that he had infected with a Rous sarcoma virus, which is known to cause cancer in poultry, but also in control cells that had not been exposed to the virus. Together with geneticist Jim Payne, the former director of the now-defunct Houghton Poultry Research Station in the UK, he conducted classical Mendelian cross-breeding experiments that pointed to the protein’s heritability, identifying the virus as avian leukosis sarcoma virus, an endogenous retrovirus in chicken genomes. “These things are inherited, just like Mendel’s peas,” says Weiss, noting that Peter Vogt of the Scripps Research Institute came to this conclusion around the same time.

    Initially, journals were reluctant to publish the result, says Weiss, who recently retired. At the time, reverse transcriptase—which made the concept of a retrovirus integrating into the genome plausible—wasn’t even known to exist yet. After the enzyme’s discovery in 1970, the idea that viral protein-coding genes could live in host DNA gained traction as additional endogenous retroviruses were found in mice and other animals. Many of these viruses proved to be active, giving rise to infectious viral particles capable of inserting new pieces of DNA into the animals’ genomes—and causing diseases, including cancer and autoimmune disorders.

    Since discovery of endogenous retroviruses in humans in the 1980s, there has been a contentious debate as to whether HERVs behave like endogenous retroviruses in animals. While scientists have established that most HERVs are dormant, some researchers believe that the youngest insertions of a HERV-K virus called the HML-2 virus, which invaded our lineage as recently as 670,000 years ago, can produce retroviral particles that infect other cells. In 2006, a group of French researchers succeeded in reconstructing the ancestral HML-2 virus in the lab based on a consensus sequence from all its snippets in the human genome. The resulting “Phoenix” element, as they called it, was capable of infecting other mammalian cells in culture. And in 2015, a team of Stanford University biologists captured electron micrographs of HML-2 viral particles—containing proteins and nucleic acids—budding off cultured human blastocysts,4 a phenomenon that researchers now think occurs naturally during development.

    To date, however, there is no in vivo evidence that such particles can infect other cells or result in new HERV-K insertions in the human genome. "In fact, Ralf Toenjes of Germany’s Paul Ehrlich Institute discovered in 1999 that two nearly intact insertions of HERV-K viruses have inactivating mutations, leading to a nonfunctional retrovirus,” he explains.

    Even if HERVs can’t assemble into infectious particles, they can still have a significant influence on human biology. For instance, many HERV sequences can be transcribed and even translated in human cells, with hundreds of HERV genes likely having the capacity to yield viral proteins, says Cornell University geneticist Cedric Feschotte. Some of these proteins may have taken on beneficial roles in humans. For instance, HERV-encoded syncytin 1 is produced in early development, and is thought by some researchers to function in the formation of the placenta. Moreover, humans appear to have co-opted many viral promoters to help drive the expression of our own genes.

    While Kassiotis doesn’t believe that HERV particles trigger disease, "in rare cases, the mere presence of HERVs in the genome can cause problems," he says. "For example, when normally silenced viral promoters lie upstream of an oncogene, and happen to be activated during cancer, they can sometimes contribute to accelerating the disease," explains Kassiotis.

    But other researchers are steadily accumulating evidence that our viral hitchhikers may be involved in much more than that—perhaps playing a direct role in the pathology of other ailments, in particular, ALS and MS.

    HERVs and neurological disease

    In 1985, Herve Perron, then a doctoral student at the University Hospital of Grenoble, France, came across a Nature paper that postulated a retroviral cause of MS. He decided to look for evidence of retroviruses in tissue samples from MS patients as part of his thesis. Sure enough, he found fragments of viral proteins in cultures grown from cells inside donors’ cerebrospinal fluid. In further experiments, he and others found the same viral particles in macrophages isolated from the blood of MS patients, but not in cells taken from control samples. Together with University College London’s Jeremy Garson, who had developed a technique to detect the RNA of unknown retroviruses, and other colleagues, Perron characterized the viral particle for the first time in 1997 and showed that the viral genetic code closely matched an endogenous family of retroviruses—the first hint that the element was endogenous. Perron called it the MS-associated retrovirus (MSRV), and it was later found to belong to a larger group named HERV-W.

    Parsing the HERV-disease link

    Current research suggests that viral hitchhikers in human DNA may play roles in cancer, inflammation, and neurodegenerative disorders. The mechanisms that underpin these connections between human endogenous retroviruses (HERVs) and disease are just beginning to emerge. Transcription of viral RNA can signal the presence of foreign DNA in cells, triggering defensive immune reactions. Scientists have also proposed that synthesis of the HERV envelope protein—which once enclosed the viral capsid of its retroviral ancestors—exerts pathogenic effects. In other contexts, such as certain cancers, researchers think that the disease state activates HERVs, rather than the other way around.

    (1) Activation of viral promoters: Ancient retroviral infections have left viral promoters throughout the human genome. Although our bodies have coopted many of them to drive the expression of our own genes, a lot of those promoters are kept silenced through epigenetic repression. Reactivation of these elements can result in abnormal expression of nearby oncogenes or tumor-suppressor genes.

    (2) Expression of viral genes: Under some circumstances, such as cancer, many regions of the genome that are normally silenced can awaken. This can activate the transcription of HERVs, causing viral RNA to accumulate in the cytoplasm. According to the “viral mimicry” theory, these molecules alert cellular RNA-sensing pathways to the viral material, triggering an immune response.

    (3) Translation of viral proteins: Some viral RNAs are translated into proteins, which can be secreted and travel to other cells. It’s unclear what effects these proteins have, but some researchers hypothesize they activate surface receptors and ultimately initiate immune reactions.

    Just as Weiss’s results had experienced 16 years earlier, these findings were met with a chilly reception. “People had the dogma that in humans, there are very few of such elements in the genome, and they are all junk DNA that is completely inactivated by mutations,” Perron recalls.

    But a series of studies has uncovered more associations between MS and HERV-W sequences as well as those of another viral group known as HERV-F. In the brains of deceased MS patients, for instance, researchers discovered fragments of viral proteins within the lesions that form in the central nervous system due to a loss of axonal myelin sheaths. And virologist Antonina Dolei of the University of Sassari in Italy and other researchers have uncovered a strong correlation between the blood levels of HERV-W RNA and the severity of MS symptoms: levels increase around the onset of the disease and as symptoms get worse, but decrease during remissions and under effective therapies. “The virus is present in the right place at the right times,” she says.

    "By now, researchers have a very well-argued case for an association,” says MS researcher Tove Christensen of Aarhus University in Denmark, “but we haven’t yet come to the point of showing that it’s actually causative.” Weiss is particularly skeptical of the idea of a cause-effect relationship. “I would say that maybe it’s the autoimmune activation that’s activating the virus, and not the virus that’s causing the autoimmune disease,” he says, though he adds that “the virus in turn may exacerbate the disease.”

    The idea that HERVs might play a role in MS was supported by the detection of a HERV-K virus in pathological tissue in ALS, as shown by Nath and others. "But a lot more work is needed to establish causation," Nath cautions. "Understanding the mechanisms at play is key not only for establishing its role in ALS,” he says, “but also for developing targeted therapy.”

    Mechanistic insights into HERVs

    In figuring out the possible mechanisms underlying HERV-disease connections, Nath says he thinks one of the most pressing questions is whether they’re capable of forming infectious retroviral particles. An infectious retrovirus would help explain the progressive nature of ALS symptoms, from motor extremities to the central nervous system. “If it’s not HERV-K being transmitted [from cell to cell], then there’s got to be some other factor that’s being transmitted to activate it,” he says.

    So far, there’s no evidence for this type of viral behavior in ALS or in MS. Rather, researchers have focused on HERV envelope proteins, because the homologous proteins in HIV are known to have neurotoxic effects. In 2015, Nath’s team created a transgenic mouse line in which the animals produced the envelope protein of HERV-K. The mice subsequently developed ALS-like symptoms, including spasticity, weakness, and muscle atrophy.

    How this occurred is a mystery. Nath hypothesizes that the HERV-K envelope protein can cause dysfunction in the nucleolus, the membraneless structure within the nucleus that hosts ribosome biogenesis. “And this messes up the entire protein synthesis machinery in the cell itself . . . that eventually leads to toxicity,” Nath speculates.

    MS researchers similarly suspect that the HERV-W envelope protein, which activates the immune-linked toll-like receptor 4 on microglia and macrophage cells, could drive the disease’s pathology. In fact, Perron is so convinced of its role that in 2006 he and others launched the Geneva-based biotech company GeNeuro to develop novel therapies based on antibodies that specifically target HERV envelope proteins. In a mouse model, Perron’s team found in 2013 that injecting the animals with the HERV-W envelope protein contributed to the development of motor defects and inflammation of the nervous system. "While not providing evidence of causation, the experiments showed that the protein is capable of initiating an autoimmune process that results in inflammation and tissue destruction in the central nervous system,” writes Robert Glanzman, the company’s chief medical officer, in an email.

    In subsequent experiments in murine and human cell cultures conducted by German researchers, the protein appeared to stifle the maturation process of oligodendroglial precursor cells, which would normally help repair degraded myelin sheaths. And in other research from the same group that has yet to be published, the envelope protein also inhibited microglia cells from scavenging myelin debris—another process critical to myelin repair—and stimulated them to secrete proinflammatory cytokines, Glanzman adds.
    HERV proteins in neurodegenerative disease

    The discovery of viral proteins in the eroded brains of MS and ALS patients has prompted researchers to investigate the role of HERVs in these diseases. Although this research is becoming more widespread, the mechanisms are still unclear and remain hypothetical.

    Multiple Sclerosis

    The HERV-W envelope protein binds toll-like receptor 4 on microglia, triggering the cells to secrete proinflammatory cytokines (1). At the same time, the protein also inhibits these cells from scavenging myelin debris (2), a mechanism important for rebuilding myelin sheaths that are damaged in MS, and prevents oligodendrocyte precursor cells (OPCs)—which normally help remyelinate damaged axons—from maturing (3). Combined, these two pathways create an inflammatory environment that contributes to the development of lesions in the brain, while also impairing the ability of local cells to repair the damage. Researchers haven’t yet discovered what triggers the production of HERV-W in the first place.


    Experiments in mice have shown that activation of the most recently integrated HERV in the human genome, known as HERV-K, in specific regions of the nervous system causes motor neuron deterioration. This could explain the neurodegeneration seen in ALS, although it is still unclear exactly how HERV-K is involved. Researchers speculate that the envelope protein of HERV-K causes disruption of the machinery in the nucleolus responsible for producing ribosomes, and this in turn results in cell death (1). This process is thought to spread from cell to cell—in accordance with the progressive deterioration seen in ALS—through factors that stimulate the production of the viral envelope protein, through the secretion of the protein (2), or possibly through the spread of HERV-K itself, though there is no evidence that the endogenous virus can behave in this way.

    The envelope protein is not the only way that HERVs can mess with the immune system. Even in the protein’s absence, excess HERV RNA and other HERV-derived nucleic acids can trigger the body’s immune response, alerting cellular sensors that detect cytoplasmic DNA, explains Feschotte, who receives funding from GeNeuro. And “when these sensors get overwhelmed, it triggers autoimmune reactions,” he says. “That’s very well characterized.”

    A key question that remains unanswered is why these disease processes would occur in only some people. The vast majority of HERV sequences are present in everyone. But people can carry variable numbers of particular HERV fragments, and a few HERV snippets are found only in some human genomes—both factors that can in theory contribute to individual susceptibility to HERV-driven pathologies.

    In addition, work by Christensen’s team at Aarhus University suggests that the host’s individual genetic makeup may come into play. In 2011, the researchers demonstrated a preponderance of certain single-nucleotide polymorphisms around a particular locus of HERV-Fc1, a member of the HERV-F group, on the X chromosome in MS patients, compared with healthy individuals. And other research suggests that environmental factors—such as Epstein-Barr virus, a common infection thought to play a role in MS—can activate the expression of HERV-W. Hammell and colleagues have found that the aggregation of the TDP-43 protein, an RNA- and DNA-binding protein known to accumulate in the vast majority of ALS patients, induces the expression of an endogenous retrovirus in Drosophila.

    Rush to the clinic

    Although the mechanisms remain murky, researchers are already eyeing HERVs as possible therapeutic targets for several diseases. Some researchers are now conducting trials with ALS and MS patients testing the antiretrovirals that have proven effective in preventing HIV’s reproduction and entry into the genome.

    The ALS patient Nath treated in 2005 inspired him to launch a small pilot study in which five individuals with both HIV and ALS each received a different combination of up to 16 antiretrovirals. Similar to his earlier observations, Nath noted that three patients experienced a reversal of motor symptoms associated with ALS, and the other two experienced a notable slowing of their ALS progression. However, Nath says, “it is quite possible that the antiretroviral had an effect on the ALS only because of downregulation of HIV.” He is now planning another study to investigate whether a combination retroviral therapy can affect the levels of HERV-K in the blood and cerebrospinal fluid of 20 ALS patients without HIV.

    Other diseases associated with HERVs

    There is copious research on the involvement of HERVs in ALS, MS, and cancer. But researchers have also identified tenuous links between the endogenous viruses and a handful of other conditions.

    1. Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), a neurological disorder characterized by progressive weakness and sensory disturbances in the legs and arms:

    - HERV-W envelope protein is found in the serum of some CIDP patients, and viral RNA is present in peripheral blood mono-nuclear cells.

    - The protein is also found in peripheral nerve lesions. In Schwann cells and immune cells of blood serum, the protein induces the secretion of proinflammatory factors.

    2. Schizophrenia and bipolar disorder

    - HERV-W RNA is present in the cerebrospinal fluid and brains of some deceased schizophrenia patients.

    - One particular HERV-K insertion serves as a genetic enhancer for the schizophrenia-linked gene PRODH.

    - Transcription of the HERV-W envelope (env) gene is elevated in bipolar disorder and schizophrenia compared with healthy controls.

    3. Type 1 diabetes

    - HERV-W envelope protein is detected in the blood serum of some type 1 diabetes patients, and its corresponding RNA is found in peripheral blood mononuclear cells.

    - Transgenic mice expressing the HERV-W env gene display hyperglycemia and decreased levels of insulin.

    4. Addiction

    - One specific variant of HERV-K, which is in close proximity to a gene involved in dopaminergic activity in the brain, is more common in drug addicts than in controls.

    Julian Gold, a virologist at Queen Mary University of London, is interested in using antiretrovirals to treat MS, but a 2014 pilot study of 20 MS patients proved disappointing: the antiretroviral drug raltegravir didn’t help reduce the number of new lesions, the most visible sign of myelin loss, that appeared in MRI scans of the patients’ brains.13 Gold thinks this is because he used a single drug, and not a combination therapy that is typically effective in HIV. In March, he concluded a separate trial in 40 ALS patients, this time using a combination therapy known as Triumeq. “The trial clearly shows that it’s safe and well tolerated,” says Gold, who is also director of Albion Centre, a public health-care facility in Sydney, Australia. The efficacy results are not yet published, but Gold says "the initial data make him optimistic about this approach in ameliorating symptoms in some MS patients."

    But Glanzman is skeptical, as he posits another reason for Gold’s disappointing MS trial—the use of an antiretroviral drug to target what Glanzman thinks is an inactive virus. "If the HERVs that have been linked to these diseases are incapable of replicating, trying to approach them with an antiviral treatment is not going to be effective,” says Glanzman. Instead, he and his GeNeuro colleagues are developing an envelope-targeting antibody called GnbAC1 that binds to a surface subunit of the envelope protein to block its interactions with toll-like receptor 4 carried by microglia and macrophage cells and has been recently shown to promote myelination in rat nerve cell cultures. Last March, the company concluded a Phase 2b trial with 270 MS patients in Europe that showed preliminary evidence of the drug’s effectiveness in treating the disease. In results that were presented at a conference on MS research in Berlin last fall, patients who got the antibody at the highest dose experienced 31 percent less shrinkage of cortical tissue, a hallmark of MS, compared with patients treated with placebo for six months. Treated patients also experienced a 63 percent reduction in the formation of “T1 black holes,” the brain lesions associated with the most severe damage to the central nervous system.

    It’s early days, Glanzman says, but so far the results look promising. “Now we have the clinical data to support that if you block the protein, you have beneficial effects.” The company is now following some of these patients to see if the changes observed in their brains translate to a clinical benefit; results are expected later this year.

    The company recently made an agreement to work together with Nath on treatments for ALS with a similar antibody approach, and is starting to work on other diseases that have been linked to HERVs. For instance, "unpublished research from GeNeuro suggests that HERV-derived proteins are toxic to the pancreases of mice," Glanzman says. After a study finding that 70 of 100 patients with type 1 diabetes had evidence of a HERV-W envelope protein in the pancreas, they initiated a one-year trial to see if an antibody against the HERV-W envelope protein is safe in type 1 diabetes patients. The company also plans to test HERV-targeting therapies to treat a condition known as chronic inflammatory demyelinating polyneuropathy as well as inflammatory psychosis, which encompasses some forms of schizophrenia and bipolar disorder.

    Other researchers have begun cancer trials that aim to improve immunotherapy treatments by epigenetically boosting the expression of HERVs to coax the immune system into killing the tumor cells. For example, George Washington University’s Katherine Chiappinelli recently showed that administering compounds that remove the methylation around HERV genes triggered the immune system to attack tumor cells in a mouse model of ovarian cancer. “The cancer cell thinks it has a virus, because it sees the viral RNA,” she explains, "triggering an immune response that helped the mice survive much longer than controls."

    Despite the growing link between HERVs and disease, and the positive results from early-stage trials, the idea that the viruses of the human genome can become destructive is still not widely accepted, Nath notes. “The way most of these things work is some people think it’s great science, some people are going to be skeptics, so it takes some time before other labs can reproduce your results,” he says. “Publishing one or two papers, it gets people excited about the field, but it takes much, much longer for people to accept the concept.”
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    Stoke Drug May Also Prevent Alzheimer’s

    Neuroscience News - January 15, 2019

    Summary: Researchers report a new drug being developed to treat stroke patients may also have neuroprotective properties against Alzheimer’s disease.

    Researchers from the UC SoCal have discovered that a drug currently being developed to treat stroke patients could also prevent Alzheimer’s disease. The study, published January 15 in the Journal of Experimental Medicine, shows that the genetically engineered protein 3K3A-APC protects the brains of mice with Alzheimer’s-like symptoms, reducing the buildup of toxic peptides and preventing memory loss.

    3K3A-APC is a genetically modified version of a human blood protein called activated protein C, which reduces inflammation and protects both neurons and the cells that line the walls of blood vessels from death and degeneration. 3K3A-APC has beneficial effects in various mouse models of disease, including traumatic brain injury and multiple sclerosis, and is currently being developed to treat stroke in humans, where it has been shown to be safe, well tolerated, and capable of reducing intracerebral bleeding.

    “Because of its neuroprotective, vasculoprotective, and anti-inflammatory activities in multiple models of neurological disorders, we investigated whether 3K3A-APC can also protect the brain from the toxic effects of amyloid-β toxin in a mouse model of Alzheimer’s disease,” says Berislav V. Zlokovic, Director of the Zilkha Neurogenetic Institute at the Keck School of Medicine, University of Southern California.

    The new paper to be published in Journal of Experimental Medicine shows that 3K3A-APC (right) greatly reduces
    the amount of amyloid-β (green) that accumulates in the brains of mice that develop Alzheimer’s-like symptoms,
    compared with no treatment (left).

    Toxic amyloid-β peptides accumulate in the brains of Alzheimer’s patients, leading to neurodegeneration and reduced blood flow within the brain. Zlokovic and colleagues found that 3K3A-APC significantly reduced the accumulation of amyloid-β in the brains of mice that usually produce large amounts of the toxic peptide. 3K3A-APC treatment prevented these mice from losing their memory and helped maintain normal cerebral blood flow. The drug also suppressed inflammation within the brain, another common feature of Alzheimer’s disease.

    Zlokovic and colleagues found that 3K3A-APC protects the brain by preventing nerve cells from producing an enzyme called BACE1 that is required to produce amyloid-β. Several different inhibitors of BACE1 have been tested in clinical trials for Alzheimer’s disease, but the new study suggests that using 3K3A-APC to block the production of BACE1 could be an alternative approach, particularly at early stages of the disease when amyloid-β has yet to accumulate to levels capable of permanently damaging the brain.

    About this neuroscience research article

    Source: Ben Short – Rockefeller University Press
    Publisher: Organized by
    Original Research: Abstract for “3K3A-activated protein C blocks amyloidogenic BACE1 pathway and improves functional outcome in mice” by Divna Lazic, Abhay P. Sagare, Angeliki M. Nikolakopoulou, John H. Griffin, Robert Vassar, and Berislav V. Zlokovic in Journal of Experimental Medicine. Published January 2019.
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    Psilocybin rebuilds neurotransmitters

    According to Juan R. Sanchez-Ramos, M.D., Ph.D., his thesis research has discovered using large doses of magic mushrooms (psilocybin) allows the (hippocampus and cerebellum for this study) brain to create new brain cells. Dr. Ramos is actively seeking alternatives from mainstream medicine to cure Neurodegenerative diseases, Huntington's Disease and Parkinson's Disease.

    What amazing news for Alzheimer's patients who suffer with a sloughing of brain cells causing a disruption and permanent loss of memory. This is also promising for people who suffer with depression because of the low serotonin levels. The magic mushrooms rebuild the neurotransmitters responsible for serotonin. Because at the root of many tragic massacres today are psychotropic (Prozac, Paxil, etc.) drugs with side effects like suicide, extreme depression and violence. It appears whenever a natural remedy is applied to alleviate a problem, it does not have these hazardous side effects.

    -Michael Erevna


    THC found to promote the removal of toxic clumps of amyloid beta protein in the brain thought to kickstart the progression of Alzheimer's disease

    The finding supports the results of previous studies that found evidence of the protective effects of cannabinoids, including THC, on patients with neurodegenerative disease.

    "Although other studies have offered evidence that cannabinoids might be neuroprotective against the symptoms of Alzheimer's, we believe our study is the first to demonstrate that cannabinoids affect both inflammation and amyloid beta accumulation in nerve cells," says one of the team, David Schubert from the Salk Institute for Biological Studies in California.

    Schubert and his colleagues tested the effects of THC on human neurons grown in the lab that mimic the effects of Alzheimer's disease.

    If you're not familiar with this special little compound, it's not only responsible for the majority of marijuana's psychological effects, including the high, thanks to its natural pain-relieving properties, it's also been touted as an effective treatment for the symptoms of everything from HIV and chemotherapy to chronic pain, post-traumatic stress disorder, and stroke.

    In fact, THC appears to be such an amazing medical agent, researchers are working on breeding genetically modified yeast that can produce it way more efficiently than it would be to make synthetic versions.

    The compound works by passing from the lungs to the bloodstream, where it attaches to two types of receptors, cannabinoid receptor (CB) 1 and 2, which are found on cell surfaces all over the body.

    In the brain, these receptors are most concentrated in neurons associated with pleasure, memory, thinking, coordination and time perception, and usually bind with a class of lipid molecules called endocannabinoids that are produced by the body during physical activity to promote cell-to-cell signaling in the brain.

    But THC can also bind to them in much the same way, and when they do, they start messing with your brain's ability to communicate with itself. The can be a good and a bad thing, because while you might forget something important or suddenly be incapable of swinging a baseball bat, you'll probably feel amazing, and want to eat all the snacks:

    Over the years, research has suggested that by binding to these receptors, THC could be having another effect on aging brains, because it appears to helps the body clear out the toxic accumulations, or plaques, of amyloid beta.

    No one's entirely sure what causes Alzheimer's disease, but it's thought to result from a build-up of two types of lesions: amyloid plaques and neurofibrillary tangles.

    Amyloid plaques sit between the neurons as dense clusters of beta-amyloid molecules, a sticky type of protein that easily clumps together, and neurofibrillary tangles are caused by defective tau proteins that clump up into a thick, insoluble mass in the neurons.

    It's not clear why these lesions begin to appear in the brain, but studies have linked inflammation in the brain tissue to the proliferation of plaques and neurofibrillary tangles. So if we can find something that eases brain inflammation while at the same time encourages the body to clear out these lesions, we could be on the way to finding the first effective treatment for Alzheimer's ever.

    Back in 2006, researchers at the Scripps Research Institute found that THC inhibits the formation of amyloid plaques by blocking the enzyme in the brain that produces them, and now Schubert and his team have demonstrated that it can also eliminate a dangerous inflammatory response from the nerve cells, ensuring their survival.

    "Inflammation within the brain is a major component of the damage associated with Alzheimer's disease, but it has always been assumed that this response was coming from immune-like cells in the brain, not the nerve cells themselves," says one of the team, Antonio Currais.

    "When we were able to identify the molecular basis of the inflammatory response to amyloid beta, it became clear that THC-like compounds that the nerve cells make themselves may be involved in protecting the cells from dying."

    It's exciting stuff, but it's so far only been demonstrated in neurons in the lab, so the next step will be for Schubert and his team to observe the link between THC and reduced inflammation and plaque build-up in a clinical trial. And they've reportedly already found a drug candidate called J147 that appears to have the same effects as THC, so this might be the way they can test the effects of THC without the government getting in the way.

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