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Same players, different game: AMPA receptor regulation in oligodendrocyte progenitors
Lindsay M De Biase & Dwight E Bergles
Journal name: Nature Neuroscience
Volume: 14, Pages: 1358–1360 Year published: 2011
DOI: 10.1038/nn.2965
Published online 26 October 2011
Neurons form synapses with oligodendrocyte precursor cells (OPCs) that may control their maturation and myelination. Key signaling molecules regulating glutamate receptors at neuronal synapses also act in OPCs, but to opposite effect.
Many Older Americans Have Mild Memory Loss
Study Shows Global Rate of Mild Cognitive Impairment Is Similar to U.S. Rate
By Charlene Laino
WebMD Medical News Reviewed by Laura J. Martin, MD
July 22, 2011 (Paris) -- Mild memory loss is relatively common, affecting between 10% and 20% of older adults in the U.S., new data suggest.
In addition to getting older, a new study shows that diabetes, stroke, and obesity increase the likelihood of mild memory loss. The ApoE4 gene, which has been linked to Alzheimer's, was also associated with mild cognitive impairment (MCI), the medical term for early memory loss.
Research has shown that people with MCI are at increased risk of developing Alzheimer's disease within a few years. But not everyone who gets a diagnosis of MCI goes on to develop Alzheimer's. Some factors that may cause MCI to progress to Alzheimer's are depression, anxiety, and other medical conditions.
MCI involves problems with memory or other brain functions that are noticeable to the affected person and those around him, but not serious enough to interfere with daily life.
MCI: The U.S. View
In the U.S. study about 7% per year developed MCI, says Ronald Peterson, MD, PhD, professor of neurology at the Mayo Clinic College of Medicine in Rochester, Minn. He studied more than 1,600 people aged 70 to 89 who had no memory problems at the beginning of the study.
Also, 10% of people per year who developed MCI went on to develop Alzheimer's dementia , he says.
But the patients were only followed for about four years, Peterson says. "Based on the data we have, we would expect about 80% to convert from MCI to dementia if they were followed longer, for 10 years," he tells WebMD.
MCI: The Global View
In addition to the U.S. study, researchers at the MCI symposium presented data on more than 30,000 people aged 65 and older from Germany, Great Britain, Sweden, France, and Australia.
MCI was more common in Australia than in the other countries, affecting over 35% of people, but that's probably because the researchers used a less stringent definition of the condition, Peterson says.
If the same definition were used as in the other countries, the frequency was closer to 10%, he says.
These findings were presented at a medical conference. They should be considered preliminary as they have not yet undergone the "peer review" process, in which outside experts scrutinize the data prior to publication in a medical journal.
SOURCES:Alzheimer's Association International Conference 2011, Paris, July 16-21, 2011.Ronald Peterson, MD, PhD, professor of neurology, Mayo Clinic College of Medicine, Rochester, Minn.Henry Brodaty, MD, DSc, professor of aging and mental health, University of New South Wales, Sydney.
© 2011 WebMD, LLC. All rights reserved.
Zooming in on AMPA receptor regulation by CaMKII
Author: Victor Derkach1
Journal name: Nature Neuroscience
Volume: 14
Pages: 674–675
Year published: 2011
DOI: doi:10.1038/nn.2852
Published online 25 May 2011
Abstract: Insights into the molecular mechanism of synaptic plasticity suggest that AMPA receptor phosphorylation by CaMKII accelerates channel opening and that TARPs preserve this regulation despite the presence of a GluA2 subunit.
One option that has not been discussed lately is the merger of Cortex with another small company that has the money and no pipeline. Maybe this has not been discussed because such another small company does not exist. But, it seems clear from Neuro's data that the model of BP bringing all new compounds through to release will not be the model for the future.
Its pretty simple - because the company communication is so poor and so sparce, there is always someone waiting for the slightest piece of good news to dump their holdings. It is the only time that there is any volume.
I wish Hu were planning to visit Irvine instead of Chicago...
It does not look like the financing is complete since there are so many blanks, including the name of the exclusive placement agent. It also looks like they have not determined how many shares (+ warrants) will be sold, and have reserved the right to not raise the full $3M. It appears that they are just getting ready to raise the money if they choose to at some point in the future. The optimist might guess that there is good news pending and that the company wants the option to sell some shares when the share price is higher. The pesimist might just believe that they are just planning to grub more cash by selling shares because they have no other option, and the $3M is all they think they can raise with the number of shares available for sale.
The link is on the Cortex Investor page, or you can just look up the sec reports directly. Here is the link:
http://www.sec.gov/cgi-bin/browse-edgar?action=getcompany&CIK=0000849636&owner=exclude&count=40
Interesting. Either the company expects the share price to go up based on some pending announcement, or they are selling the available shares (& warrants) for $3M. So the mystery continues, and we can firmly conclude that the share price will either go up or down...
Yes, we should all obviously get back on our meds... Personally, I'm not at all surprised in their needing some time to go through the data set. It seems like it would be a pretty complex set to analyze, especially with the small number of subjects. They would want to do more than just look at event frequency, and may want to try to separate the types of SA events, look at other systemic effects on the sleep cycle, and check any number of suspected correlations.
I know Neuro did not agree with my interpretation of Mark's comments, but my mind immediately factored in a week or two after receipt of 'The Data' before anything would be released. If it were me, I would want to be really careful about the release of any conclusions from this study that could over- or under- state the efficaciousness of the compound, or the impact of any side effects.
Just my 2 cents worth - or was that 2 shares worth?
A quick question to help out my old memory... In the Cortex website under product pipeline, Servier is shown as performing all HI phase 3 tials with any Cortex compound(s). I thought the relationship with Servier was completely severed. Any new investor who sees this chart would infer that Cortex had sold all rights to AD to Servier. Could someone please clear this up for me?
Thanks!
Neuro, I agree that they must disclose the results as soon as they are understood. In this case I interpretted his statement as more or less meaning that the last subject will have completed by the end of October. I figured there would be some delay between when the last subject completed to when they would have something coherent to release.
By the way, I would be very surprised if they did not see any signal in the SA study, as they saw very strong evidence of an effect on SA in one or both of the RD studies. In fact, I thought that they would have been better off showing an effect in opioid induced SA alone, rather than looking at the larger population of SA sufferers.
Alert,
I expect $0.17 on good news, $0.15 on bad news, and $0.16 on ambiguous news...
In Blade's email response from Mark Varney he said,"We remain on target to have data by the end of October for the sleep apnea." Getting the data by the end of October is not the same as making a public announcement by the end of October. I can't remember exactly how he phrased it before, but I think it was along the line of the study being completed by the end of October. I'd expect the announcement a week or two later.
http://au.news.yahoo.com/a/-/latest/8068581/brain-has-extra-second-learning-power/
Brain Has Extra 'Second-Learning' Power
By Danny Rose, AAP October 5, 2010, 12:02 am
Australian and American scientists have found a previously unknown and alternate pathway by which memories are stored in the brain, allowing so-called "second-learning".
The discovery challenges the orthodox view on how the brain handles its core functions of memory and learning, said molecular neuroscientist Dr Bryce Vissel from Sydney's Garvan Institute.
The research also revealed a promising new target for drugs or therapy that could one day help people with Alzheimer's disease, and other brain impairment, to boost their cognition and learn new skills.
"Up till now, memory has long been thought to involve a molecule on nerve cells called the NMDA receptor in the hippocampus (a region of the brain)," Dr Vissel told AAP on Monday.
"The NMDA receptor was previously thought to be important not only for forming new memories, but was thought to be essential for all memory formation.
"... The way we have been thinking about this is fundamentally correct, however, it is not always true - there is an angle that has been completely missed."
What was missed was the role played by calcium permeable AMPA receptors, an alternate process now known to handle memory storage during events which are novel but not totally unique experiences.
Dr Vissel, working along with fellow experts at the University of California Los Angeles, conducted a series of experiments in mice that showed how disabling the brain's NMDA receptor did not always block the ability to learn as would have been previously thought.
They found evidence of the alternate AMPA processes kicking in and allowing the mice to learn completely new things in cases where it had already learned the general "rules" of its environment.
"This is `second-learning` involving a completely different mechanism of learning in the brain," Dr Vissel said.
"... in some circumstances of learning, you don't need to use the NMDA receptors at all, the system that has been until now thought to be essential for all learning.
"This is a fundamental discovery of a new mechanism underlying how memories can be formed."
The discovery is also significant when viewed alongside growing scientific evidence showing the important role NMDA receptors play in the progression of Alzheimer's disease.
Dr Vissel said new anti-Alzheimer's drugs, which boost the role played by AMPA receptors, could be developed along with new "iterative, repetitive" teaching programs that could help people with brain impairment learn new skills.
"For a typical Alzheimer's patient ... you could start to teach them a set of rules about how to live, which doesn't depend on the NMDA receptor," Dr Vissel said.
"The point is there is an alternative mechanism of learning that can be exploited."
The research is published on Tuesday in the journal Plos ONE.
The lurking lawyers (there are always lawyers lurking...) can correct me, but I believe that the information must be related to the divulging of a Cortex trade secret (it could be technical or it could be plans, strategy, or something else not technical) or another party's information that they are obligated to protect. To be a Cortex trade secret, the information must be such that divulging it would likely harm Cortex's competitive position.
http://au.news.yahoo.com/a/-/latest/7573434/brain-can-rewire-itself-scientists/
---------------
Brain can rewire itself: scientists
By Danny Rose, AAP July 13, 2010, 12:02 am
Australian scientists say the brain has an under-appreciated ability to "rewire itself", and work is now under way to use this as a therapy after it is injured.
The Hobart-based Menzies Research Institute has been investigating how the brain responds to trauma, particularly what occurs within the cerebral cortex or the outer layer of grey matter.
"Our data suggests that the cerebral cortex ... is capable of significant remodelling following injury," said Menzies' senior research fellow Dr Tracey Dickson.
Dr Dickson and fellow researchers focused on the activity of two types of neurons in the cortex - pyramidal neurons and interneurons - and their very different reactions to trauma.
Menzies PhD student Catherine Blizzard said the pyramidal neurons were seen to regenerate "into the injury site whereas interneurons reorganised their processes away from the injury site to undamaged areas".
"Interestingly, our studies demonstrate that neurons ... have an unappreciated capacity for remodelling away from the actual injury, and that these neurons are attempting to rewire the brain following an injury," Ms Blizzard said.
"These distinct responses exhibited by different neurons, provide insight into the potential of the mature brain for plasticity or remodelling."
Their findings were published recently in the international neuroscience journal Cerebral Cortex.
The research is now focused on trying to identify ways in which the healing response could be boosted, creating a new therapy to treat brain injury.
About one in 45 Australians - mostly men - have an acquired brain injury from causes including traffic accidents, assault, sporting injury or infection.
TZA inversely tracks by 3x the Russell 2000 Index. The Russell 2000 Index was down 1.03% to 660.03 today.
Emenem & GFP,
I remember that during the RD study they showed evidence of either prevention or recovery of opioid induced sleep apnea. If I recall correctly, the evidence was very strong. Isn't this an indication of likely efficacy in central sleep apnea? CORX also presented some addional data showing improvement in muscle tone that was hypothesized might improve obstructive sleep apnea.
So, I believe that the belief is that it will impact central sleep apnea, and that there is a chance that it will improve obstructive sleep apnea. I assumed that the tight selection criteria for the SA study was aimed at trying to assure that many or most of the participants suffered from at some form or partially from central sleep apnea.
GFP seems to have a much better memory (or notes) than me and can probably remind us of the details from the RD presentations.
Thanks.
Study questions widely-used ADHD drugs
By Danny Rose, AAP February 18, 2010, 12:02 am
An Australian study has revealed a "significant lack of effect" of conventional drugs used to treat ADHD, a finding that surprised at least one of its researchers.
Professor Lou Landau was co-author of the WA-based research which investigated the effectiveness of drugs now widely used to treat Attention Deficit Hyperactivity Disorder (ADHD) in children.
The principal medical adviser to the West Australian Department of Health said he did not expect such a strongly negative result.
"Yes, we weren't anticipating that significant effect," Prof Landau told AAP on Wednesday.
"... or the significant lack of effect of the medication."
Prof Landau and fellow researchers pulled data from the nation's long-term Raine Study to assess the health, and other, outcomes of 131 children with ADHD among more than 2,800 Australian families.
It showed how those using conventional ADHD drugs, such as Ritalin and dexamphetamine, had significantly poorer educational outcomes than children with ADHD not using the stimulants.
The drugs were also linked to a "trend toward slightly higher depression scores", the study found, along with a potentially long-term risk factor for heart disease.
Children using ADHD drugs were found to have elevated diastolic blood pressure - which is the minimum pressure in the arteries when the heart is at rest.
Prof Landau said this side effect was known though it was previously thought to occur in children "while on the medication and it drops down when you stop".
"That was the difference that this study showed ... it was having an effect on the blood vessels that persisted," he said.
When it came to educational performance, children on ADHD drugs were shown to be significantly worse off than those with unmedicated or no longer medicated ADHD.
This effect was present even after researchers accounted for the fact that ADHD children with the worst symptoms were most likely to be prescribed the drugs.
"In children with ADHD, ever receiving stimulant medication was found to increase the odds of being identified as performing below age-level by a classroom teacher by a factor of 10.5 times," the study found.
Overall, there was "little long-term benefit of stimulant medication" for ADHD children, the study concluded.
They had roughly the same behavioural and attention problems "regardless of medication use", it said, though "where an effect was noticed, this was in the direction of symptoms worsening with the use of ADHD medication".
The results of the population-based study would need to be confirmed with randomised trial, Prof Landau said, but it did show how parents should not automatically opt for a drug-based treatment for their ADHD child.
"That management is a partnership between the parents, teachers and their doctor," Prof Landau said.
"It has to make sure (ADHD children) are healthy, have educational support and social support and then, in some cases, there may be a role for medication.
"But before making that decision one has to consider the potential short-term benefits against potential risks and possibly not a major change in the long term."
Prof Landau is a co-author of the "Raine ADHD Study: Long-term outcomes associated with stimulant medication in the treatment of ADHD in children" report.
The report was released by the WA government on Wednesday.
http://au.news.yahoo.com/a/-/latest/6818922/study-questions-widely-used-adhd-drugs/
gfp,
Looking at the recently released 3Q balance statement, Cortex had ~$4M at the end of September. Shouldn't this give them more time than we have been estimating? The $300K debt is probably the annual licensing fee to Univ. of Alberta for inlicensing RD, and payment of this can likely keep being put-off.
ADHD drugs and psychotic episodes linked
AAP
October 13, 2009, 5:59 am
At least 30 children have had psychotic episodes and wanted to kill themselves while taking drugs for attention deficit hyperactivity disorder (ADHD), according to reports.
Documents from the Therapeutic Goods Administration outline the figures, Sydney's Daily Telegraph says.
One seven-year-old boy became so depressed while taking Ritalin in 2008 that he tried to commit suicide while an eight-year-old hallucinated that spiders were crawling up his skin after taking ADHD drugs.
The newspaper also reports that the overall number of serious reactions to ADHD drugs has doubled to 827 in the last three years.
However, the true extent of side-effects being experienced may be hidden because of doctors and parents under-reporting the impact.
Experts in children's health say there is a clear link between ADHD drugs and psychotic episodes in children, with boys said to be worse affected than girls.
http://au.news.yahoo.com/a/-/latest/6209580/adhd-drugs-and-psychotic-episodes-linked/
Dew,
23 November is a lot longer than 14 days from last Friday. Shouldn't we be viewing this possible dilution as Plan C (or D or...), that is, doesn't the timing of the meeting at a point where they are projected to be very low or out of money mean that it is just a back-up plan to be used only if the other options fail? If the scheduled meeting date were much sooner, I would be more worried. My observation is that the Cortex management has been burnt enough to realize they need to keep all of their options open.
Thanks.
I have 200K shares with an average cost of over $1. I will vote No if I still own the shares at the time of the vote.
I think my biggest mistake was not selling everything and running when Stoll mentioned the 6 foot box of data. The alarm bells sounded loudly at the time. Even though I've never dealt with the FDA, I cannot imagine when it is ever appropriate to send that much data to anyone to support a decision. In my work, if I can't justify a position in a less than 100 page report (with all supporting data available for inspection, if requested), I'm dead.
I recall Stoll saying at some point when he was discussing the near miss at partnering ADHD that the company was surprised that there was more interest by potential partners in neurodegenerative use for CX717 (perhaps not CX717 alone) than in ADHD. This combined with the obvious desire of the FDA for Cortex to persue a higher morbidity indication than ADHD for the first use of an Ampakine, I believe is the most obvious spot to question management decision making. There was clearly an opportunity to partner for AD, though I'm sure the $ were less than they wanted at the time. The biggest 'mistake' as I see it, is the failure to fully understand the FDA requirements for getting CX717 approved for further testing. They and their high paid consultants definately missed the boat here. I have no idea whether better communication with the FDA was possible (the FDA was very over-loaded at the time), but I hope that they didn't quit pressing for more information during the long period for the assembly of the 6 foot box of data.
OT: Bigworld,
Thanks for the suggestion. I picked up some QID and SPXU last Friday, and am surprised that the markets are still moving up. HL and GDX have done well, but I wonder if we'll see a substantial pull-back there, too.
OT: bigworld, I agree with your general assessment, but I think your timeline might be a bit compressed. I'm concerned that inflation may be held off by the still falling real estate values, and the underlying fear of the potential impact of the securitized commercial real estate loans. I am also unable to predict the actions of an administration desperate to pass a slate of social legislation that depends on economic perceptions. There may be more big ups and downs before we enter the big slide and high inflation.
That said, which short ETFs do you like - QID, DXD, SDS, SPXU?
Thanks,
Karl
OT: Thank you bigworld. I have been holding off with about 30% to see what will happen, but at some point I need to quit cutting bait. Maybe the timing will be right to also invest my massive COR profits when I break even as the COR pps goes over $0.90!
Dew,
COR has some new warrants that are exercisable at $0.34 after a specified date. What happens to these if the company is sold before that date at a price above $0.34? I think the answer to this question could impact the transaction date if the company is sold.
Thanks,
Karl
OT: Bigworld, Tregaron,
We've had some drop in gold and oil, and the VIX & VXO have moved up considerably. Do you think the fall will continue, or is this a good time to buy. A couple of my holdings, HL and HES, have fallen significantly (nothing new there...) and look to be pretty good deals. My track record the last 2 to 3 years is sooooo bad that I can't tell a good deal from a scam anymore. My guess is that they could fall more, but with everyone jittery over the certain future inflation, these might see some support at these levels. Any thoughts?
Thanks!
OT: bigworld,
I have been adding HL and am thinking of adding CDE instead of GDX because of their bigger falls over the past year, which may mean a better recovery. HL seems to be a good deal now at $2.50 a share - but then so did COR!
Oil might also be good to pick up on this dip. I'm also buying HES, which took a pretty big hit this last week, and may be a fairly safe place to put extra cash.
Neuro,
Thanks for the response.
As for Indian companies I was thinking that with the patent law changes in 2005 and the following mass associations of Indian companies with western companies, that there would be some desire from several to buy or partner with Cortex. Ranbaxy has a focus on respiratory disease, which might mean they are interested in RD.
As far as Latin America goes, EMS in Brazil has done original work with benzodiazepines, and seems to have a reasonable development program. They might be interested in acquiring rights to ampakines to broaden their areas of emphasis.
Personally, I think many companies around the world would be happy to pick up Cortex, or license the rights to develop ampakines in specific therapeutic areas - if the price is right. I guess it is just the difference in opinion on what the right price is that is keeping things stalled....
Neuro,
There has been continued discussion on potential acquirers and partners of Cortex, with several US and a few European companies frequently mentioned. But I have not seen any mention of other potential foreign suitors. There are some Indian, Latin American, and especially Asian companies who it seems would greatly benefit in acquiring the ampakine platforms, and even an early stage development lab in the US. Some of the bigger Japanese companies that already have a global development presence would seem to be potential candidates - for example both Takeda and Eisai have neurological development programs.
Any thoughts?
Thanks,
Karl
iggs, I don't recall the company ever having less 6 months of cash on hand. But, yes they were talking about in-licensing, for which this board roundly complained. They followed through, and did the in-licensing for RD with the Univ. of Alberta (not the type of in-licensing that the folks posting had considered) and the scolding morphed to praise.
I don't know what they are up to any more than anyone else, but my observation is that they generally do what they say they will - we just misinterpret what they say.
bigworld, corwatcher,
I thought I'd point out a couple of additional things to consider in your assessments.
First, part of the decision on whether to select a 15 year or 30 year mortgage is the spread between the interest rates. Today you can get 30 loans at very nearly the same rate as a 15 year loan. Historically this is unusual.
Second, if inflation is going to go as high as some suggest, then rents will also skyrocket, whereas a mortgage payment will stay constant. If you have a secure job, your pay will likely also experience inflation, so while your house may be worth far less in old dollars, it may be very cheap for you to pay it off in future dollars.
I kind of expected the Fed to encourage inflation the last couple of years when the mortgage problems started to appear - what is an easier way to get mortages above water? Sure your house may be worth a whole lot less than you paid for it, but if the dollar declines even more, the mortage would still be above water.
dominate, thanks for the posting. Does anyone know what the "...previously announced pending acquisition of a drug that already has approval in Europea." refers to?
Neuro,
It looks like you were right and I was wrong in their ability to complete the study - at least with enough margin with out more time and/or money. But, since they bought time and money with the workforce reduction, the question is, do they now have enough of both to finish the trial?
GFP,
Remember that Cortex has already reported that CX717 positively reduced opiate induced SA from observations in the RD studies.
Emenem,
I know that you have expressed continued skepticism of ampakine effectiveness in SA. I still disagree with the significance of your concerns, even if ampakines promote alertness at the dosages required for effective treatment of SA. First, I would not be surprised to find that the effective dosage is very variable from individual to individual. This would be no different than for many, many other drugs in a huge range of indications - omeprasole, Adderal, Paxil, warfarin, asprin, benadryl, etc., etc., etc. Secondly, the human body can be quite adaptive, especially if there is a strong motive. Not wearing a CPAP mask would be a pretty strong motive for me, and probably for most people to give the drug a chance. To support this, remember in our last exchange on this subject I mentioned that caffeine now (now that I am an old guy...) kept me from falling asleep because of all the stimulant effects. I wondered if I could get used to even these very uncomfortable sensations when trying to fall asleep. So, an hour or so every night before going to bed I drank caffeinated stuff (tea, coffee, soda). For the first few days, I had trouble falling asleep, though I never stayed awake for more than an hour or so. But, after only a few days, even though I still had the caffeine induced symptoms, I could fall asleep pretty quickly. That is pretty crappy antidotal evidence, and maybe I was only building up some kind of resistance to the caffeine, but why wouldn't something similar be true for an ampakine? I'd like to volunteer to find out!
Just my opinion.
Finally, don't get me wrong - I'm as unhappy with my investment in COR as the next guy. I think that the company has been fending off buyout offers that any of us would be happy to accept, but because of the depth of their underwater options, they have been unwilling to consider them. It is unclear to me what would happen if a company would come out with a buyout offer presented to the shareholders, but COR would likely use it as an opportunity to sell more shares and continue to swing for the fences. I just hope that some DH finally makes contact!
GFP,
I still disagree with you on the difficulty of conducting a PIII RD trial. I think you are just considering the difficulty in gaining statistical significance in rescue usage for severe RD. It seems to me that establishing effectivity in preventative usage is pretty straight forward, and at worst just involves a larger sample size. The crash carts would still have Narcan. I would expect the ampakine usage in RD Rescue to be incremental, and occur after approval for preventative usage. But, if you never have a patient in a depressed respiratory state when they are preventatively treated, then you would significantly reduce your rescue market anyway.