Friends4Eric

DANGER - Public Access To Research

2012-01-10T16:08:00.000-08:00

I rely quite a bit on public access to research papers in order to better understand ALS and to bring you this blog, for what it's worth. The US Taxpayers, through NIH grants, fund quite a lot of the medical research that is done in the United States. If we paid for this research, we should be able to have access to the results (which, again, we already paid for).

However, a bill is being introduced to take that away. The bill is sponsored by Carolyn Maloney (D - NY) and Darrel Issa (R - CA). Ms. Maloney received the most individual political contributions of the medical publishing giant Elsevier in 2011. Mr. Issa is also on the contribution list. Once again we see that corporate money in politics does not favor the citizens. This is not a political blog so I will cease my digression.

Clearly this is a threat to public access to knowledge which the public already owns. This public knowledge benefits people like me and you as well as institutions such as schools. If you want to retain your rights to access that for which you already paid, action is needed. I urge you to contact your Congresscritter and urge him or her to kill HR 3699. You could also contact Congresswoman Maloney to express your opinion of this bill:

Twitter: @RepMaloney
@CarolynBMaloney

Phone: 202-225-7944

FAX: 202-225-4709

Email: Use this form

Don't let corporations steal from you and charge you for the favor.

Guest: Persevering On NP001

2012-01-07T23:03:00.000-08:00

A few days ago my friend, who goes by the handle Persevering on the TDI Forum, posted an evaluation of the PALS who have been self-reporting their experience with the Neuraltus Phase 2 trial of NP001 (which I have discussed here in the past). While the data looks exciting, I must caution that this isn't official data and makes some assumptions which, if wrong, could totally invalidate the evaluation. However, I have enough faith in Persevering to bring this to your attention. For those who don't have Patients Like Me accounts, I reproduce the graphs here.

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I have analyzed the NP001 phase 2 data from PLM to date.

I am aware of 37 PLM members who have participated in the trial and 34 who have entered sufficient data to track progress. This is roughly 1/3 of the listed full trial enrollment, and offers a great sample to predict actual trial results. The trial consists of 6 infusion cycles over 21 weeks (147 days), followed by 4 follow-up visits adding 16 more weeks. 13 have completed dosing. 11 will complete within 4 weeks, and all within 8 weeks.

In my thinking, since each infusion cycle is 4 weeks total, the first non-dosing follow up at week 25 (175 days) ends the dosing phase, and I have chosen to review data to day 175 in terms of FRS change. The variable of interest is FRS slope, and is very commonly used to evalauate efficacy for ALS clinical trials. For example, it was used in the recent report of Dexpramipexole phase 2 data, and was used for the official Lithium clinical trials in the US.

In my opinion it is possible to review reports of side effects for commonality to approximate those getting drug (either dose) versus placebo. I do not believe it is 100% accurate, and I also expect those getting a higher dose to have more or greater side effects, but it is not entirely possible to segregate the drug groups (high vs. low). Some may not be prone to side effects on drug and others could experience "nocebo" effects, so again this is not a true substitute for unblinding, which should occur later and allow a timely re-analysis of PLM data.

With that assumption/disclaimer, the summary statistics are:

(Green is improved FRS score, yellow is stable FRS down to -0.49/mo, and red is loss of FRS)

With side effects:

n = 20
Mean ALSFRS-r slope: 0.00
Standard Deviation ALSFRS-r slope: 1.24

Without side effects:

n = 14
Mean ALSFRS-r slope: -1.01
Standard Deviation ALSFRS-r slope: 0.68

Comparison: 100.4% mean improvement

2-tailed t-test p-value for difference = 0.0093

The most exciting outcome to me is that the difference in progression rate is very statistically significant (p<0.05), even with only 34 data points! This would be unprecedented for a phase 2 ALS clinical trial. For example, the recent exciting report regarding Dexpramipexole, with a 31% mean improvement versus placebo in the first 12 weeks had a p-value ~ 0.20, a value 4 times higher than acceptable to conclude drug is better than placebo, by convention (based on a sample size of 53).

There is rumor of an official NP001 trial efficacy review soon, based on all data available on January 24, 2012. Let's hope for statistical significance there as well, and potentially FDA accelerated approval, as occurs for cancer and HIV drugs.
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Thanks to Persevering for the work and for the guest-blog!

Oh, Holy Nerve...

2011-12-15T23:37:00.000-08:00

All I Want For Christmas Is My Phrenic Nerve

sung to the tune of:
http://www.youtube.com/watch?v=KyWiiDxbk-A

Everybody pauses and stares at me
My breath is gone as you can see
I don't know just who to blame for this catastrophe!
But my one wish on Christmas Eve is as plain as it can be!

All I want for Christmas
is my phrenic nerve,
my phrenic nerve,
see my phrenic nerve!

Gee, if I could only
have my phrenic nerve,
then I could wish you
"Merry Christmas."

It seems so long since I could say,
"Sister Susie sitting on a thistle!"
Gosh oh gee, how happy I'd be,
if I could only whistle (thhhh, thhhh)

All I want for Christmas
is my phrenic nerve,
my phrenic nerve,
see my phrenic nerve.

Gee, if I could only
have my phrenic nerve,
then I could wish you
"Merry Christmas!"

Happy Holidays to PALS around the world!

Nothing Vented Nothing Gained

2011-11-23T22:00:00.000-08:00

I have long been an advocate for PALS going on a vent. Many opt out for various reasons, one of which is, surprisingly, discouragement from medical professionals. Horror stories of cost and the difficulty of home care are common.

I beg to differ with that. Cost can indeed be an issue but with creative financing and the possibility of obtaining long-term care insurance before formal diagnosis, cost can be managed. In terms of home care, with a few simple rules adhered to, the risks of complications are minimal. Up until now I had only my own experience to use as proof of my contrarian view. It turns out I was correct all along.

In a study of over 100 PALS 78 were recommended for tracheotomy. 38 underwent the procedure. Of those, the one-year survival rate was approximately 80% (the same as lung transplant) and only one died from respiratory causes. As the study noted:

"Nowadays, starting [home venting] should no longer necessarily be considered as the beginning of the end for these patients. When the appropriate medical resources are in place and the patients wish to continue living, the old mentality of focusing only on palliative care which is still common in the management of this disease must make way for high technology and compassionate care."

Vents today are about the size of a grammar school student's backpack and very quiet. Assisted Communication Computers are covered by insurance and Medicare and are very easily converted to general-use Internet-capable computer systems. Web-based social media platforms give unprecedented communication and social access to today's PALS.

I have cheated The Reaper for 4 years now and others have for longer. In my view the old bastard can piss off until I am good and ready to go. My quality of life is what I make of it. Technology is my friend and has been for most of my life. As the esteemed Steve Saling says, "Until medicine arrives, technology is the cure."

I believe this and urge all PALS to use technology to win the battle against ALS until medicine provides the final victory.

Mutants Versus Mitos

2011-11-09T17:31:00.000-08:00

There is an excellent article over at the ALZ Forum written by the equally excellent Amber Dance. Rather than (poorly) paraphrase it, I have reproduced it here for your enjoyment. Please also follow the link to the original because the commentary following it is often as informative as the original article. I have highlighted certain portions in bold. After you have read the article I will discuss my opinions on why the bolded portions are interesting to me.
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4 November 2011. If you have wondered about the true importance of mitochondria in motor neuron disease, read on. Researchers from the Weill Medical College of Cornell University in New York corralled mutant superoxide dismutase 1 (mSOD1), a ubiquitous protein that causes amyotrophic lateral sclerosis (ALS), in these powerhouse organelles to prove that mSOD1 damages the mitochondria, and in turn, the cell and the body as a whole. In the November 2 Journal of Neuroscience, the researchers report that limiting the dismutase to the mitochondrial intermembrane space is sufficient to recapitulate much, but not all, of the ALS pathology caused by the SOD1 mutation, which causes a rare form of inherited ALS.

There is plenty of evidence that mitochondria play a part in the motor neuron degeneration that happens in ALS (reviewed in Hervias et al., 2006), but so do defects in many other areas such as RNA processing (see ARF related news story on Kwiatkowski et al., 2009 and Vance et al., 2009), the endoplasmic reticulum (see ARF related news story on Saxena et al., 2009) and Golgi (Urushitani et al., 2008), neighboring glia (reviewed in Ilieva et al., 2009), glutamate uptake (Rothstein et al., 1995), and axonal transport (see ARF related news story). The study authors, led by joint first authors Anissa Igoudjil and Jordi Magrané and senior author Giovanni Manfredi, sought to delineate the cause and outcomes of only the mitochondrial dysfunction. Researchers wondered whether malformed, underactive mitochondria cause some or much of the widespread pathology in ALS—or whether they are simply a symptom of a struggling cell. The current work confirms, as Manfredi’s team and others had also seen in cultured cells (Magrané et al., 2009; Cozzolino et al., 2009), that mSOD1 directly influences mitochondria for the worse, even if all else in the cell is normal.

The researchers designed a mouse model that makes the G93A mutant human SOD1 (an alanine for glycine at position 93), under control of the prion promoter. They linked the dismutase to the amino terminus of mitofilin, which targeted it to the inner mitochondrial membrane, facing the intermembrane space. The mitochondria of these mito-mSOD1 mice contained about the same amount of mSOD1 seen in mitochondria in the standard SOD1-G93A model with unrestricted mSOD1 targeting.

Mice with pan-cellular SOD1-G93A succumb to disease within a year. Male mice with mitochondrial mSOD1, in contrast, lived a nearly normal lifespan of 18 months, Manfredi said. Females suffered more severe disease, and their illness required they be sacrificed for ethical reasons by one year. That may be because the transgene landed in an estrogen-sensitive locus, not due to the mitochondrial mSOD1, Manfredi said. Males and females aged prematurely, hunching over and losing weight before their time. Compared to non-transgenic mice of either gender, females struggled with the motor coordination rotarod test when first examined, at three months of age, while males had near-normal coordination until six months. On a hang test for muscle strength, females performed worse than non-transgenics starting at three months, while males’ muscle weakness was not statistically significant.

When the researchers examined the mitochondria from the mito-mSOD1 mice under the electron microscope, they observed large, empty spaces, or vacuoles, in the normally densely packed organelles. In biochemistry experiments, mitochondria isolated from the brains of mito-mSOD1 mice were more sensitive to an uncoupling agent, failed to retain calcium ions, and had reduced activity of the respiratory enzyme cytochrome oxidase, as compared to mitochondria from non-transgenic mice. These data indicate that while the mitochondria with mutant SOD1 were functional, they were weakened and easily ran out of energy when stressed. Manfredi compared them to a four-cylinder engine firing on only three.

The effects of the mitochondrial mSOD1 extended beyond that organelle.
Compared to normal mice, fewer motor neurons populated the spinal cord of mito-mSOD1 mice, and they suffered a thinning of the motor cortex. The motor neuron loss was not as bad as in standard SOD1-G93A mice, the authors noted. In addition, one hallmark of ALS was decidedly missing: “What was surprising to us is, despite the fact that the mice lost a proportion of the spinal cord neurons and there was atrophy of skeletal muscle, we did not see denervation,” Manfredi said. He noted that just because neuromuscular junctions were intact, it does not mean they were healthy—the sickened neurons could still fail to send proper signals through the junction without completely detaching from it, explaining the poor rotarod performance.

The researchers concluded that mitochondrial mSOD1 is only responsible for part of ALS pathology. “It is now becoming clear that a combination of toxic effects are probably necessary to drive motor neuron disease onset and progression,” wrote Adrian Israelson of the University of San Diego, who was not involved in the study, in an e-mail to ARF.

Precisely how mSOD1 disables mitochondria is unknown. It might interact with proteins or other factors in the respiratory chain, Manfredi suggested, or it might promote the formation of free radicals. The new mito-mSOD1 mouse can help answer that question, commented Piera Pasinelli of Thomas Jefferson University in Philadelphia, Pennsylvania. “This is a powerful tool to really dissect the specific contribution for the mutant SOD1 in these organelles,” said Pasinelli, who also was not involved in the current paper.

One pathological event that is relevant to mSOD1 in mitochondria is production of reactive oxygen species, which generate other toxins, such as peroxynitrite, which can drive apoptosis, or programmed cell death. SOD chemically modifies other proteins in the presence of peroxynitrite. In the October 27 Journal of Biological Chemistry online, researchers from the University of Melbourne, Australia, propose a potential treatment for this mSOD1 effect. They discovered that a copper compound that scavenges peroxynitrite extended lifespan, and reduced inflammation, in a mouse model for ALS that expresses lower levels of SOD1-G93A than Manfredi’s mice. “They do not look at mitochondria directly, but it is possible that there is an effect of the drug at the mitochondrial level,” Manfredi wrote in an e-mail to ARF. In addition, Manfredi noted, this study reports for the first time that their low-expressing G93A mice also exhibit TAR DNA Binding Protein 43 (TDP-43) pathology, which up until now had not been seen in mSOD1 mice. TDP-43 accumulated as fragmented, abnormally phosphorylated protein in the spinal cord of these animals. The study was led by first author Cynthia Soon and senior authors Kevin Barnham and Qiao-Xin Li.—Amber Dance.

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...mitochondrial mSOD1 is only part of ALS pathology...
Previously I had discussed mutant or misfolded SOD1 being found in not just PALS with the genetic mutation but also those with the more common sporadic type. In another new study, it was shown that mSOD1 altered the shape and function of mitochondria prior to symptom onset. This is a very nice clue to a possible pathogenesis of ALS. Damaged mitochondria produce massive amounts of ROS and produce a fraction of the energy the cell requires of each mitochondria. Normally damaged mitochondria are destroyed and recycled by the cell but in ALS the recycling mechanism also appears damaged. Before going too far down this path I should remind readers that astrocytes carrying mSOD1 are sufficient to cause disease in healthy motor neurons. So the answer is never as simple as we would wish.

One pathological event that is relevant to mSOD1 in mitochondria is production of reactive oxygen species, which can drive apoptosis, or programmed cell death.
As discussed above, ROS causes damage to cellular machinery if it overwhelms the ability of the cell to fight it. The lack of energy output is a "bonus" in terms of cellular stress. Once this combination hits the Endoplasmic reticulum the cell is in serious trouble.

In addition, Manfredi noted, this study reports for the first time that their low-expressing G93A mice also exhibit TDP-43 pathology, accumulated as fragmented, abnormally phosphorylated protein in the spinal cord of these animals.
As I discussed in my previous post linked above, mSOD1 has been reported to interact with TDP43. The nature and implications of this interaction is very far from clear. A recent study showed that TDP43 binds to an inflammatory protein called NF-kb p65 in PALS but not controls (people without motor neuron disease) In the microglia, this causes upregulation of inflammatory factors in the CNS. Neuroinflammation is a major factor in progression of ALS.

This is a lot to digest, but are only a few of the clues to the etiology and pathology of ALS. They are like moths circling around a lightbulb that we cannot yet see. However, the more moths we see and the more precisely we can chart their paths, the more we can learn about the bulb. We now have many more moths, with much better understanding of their flight, than even a few years ago. The picture of the bulb is getting much clearer and brighter. One day soon we shall see the light.

Doggone It!

2011-10-30T23:47:00.000-07:00

As my readers might know, I have a PEG tube for feeding. I also have a little dog who is more like a 5-year-old in a dog suit. She is quite devious, even having learned how to stomp the foot lever that opens the lid on the trash can.

For the past few months, ever since I stopped using medical formula to correct the diabetic condition it created, I have been giving her a few tablespoons of my meals. Last Friday, I was working on some email while lunch flowed into me. Out of the corner of my eye I noticed some movement and realized it was the rolling stand from which the feeding bag was suspended.

I didn't feel the earthquake that must be responsible for the stand rocking back and forth and nothing else seemed to be moving (especially my computer which is suspended from the ceiling). A quick mental inventory revealed I wasn't on any drugs that I was aware of. Motor neuron disease doesn't involve hallucinations.

I didn't feel possessed...

Suddenly I felt a tug on the feeding tube and heard the tell-tale clicking of canine toenails on hardwood. That little thieving pooch was chewing the tube trying to get more of the clam chowder I had shared 30 minutes prior! I swear she knew that I couldn't do anything to stop her. But I also knew that, being 17 years old, she is a little hard of hearing. So rather than ring my call bell which she can hear and knows means trouble for her, I made my computer call in my caregiver on the sly.

Busted doggie!

PEACaboo

2011-10-15T20:02:00.000-07:00

Last month I wrote about the Steve Saling ALS Residence. Steve recently posted a video about the technology which is a large part of what makes the Residence so wonderful for PALS. Every PALS should demand a Residence in his/her local community.

Chair the Love

2011-10-12T01:04:00.000-07:00

Wondering about options for wheelchair-modified vans? My friend over at ALS Everyday Living has a very informative post on the subject. I urge my readers to hop over there and sign up for his updates.

Assaultrocytes

2011-10-03T18:58:00.000-07:00

In my post Prion, Garth! I had talked about mutant or misfolded SOD1 (mSOD1) spreading like a prion and infecting neighboring cells. A recently released study from Johns Hopkins shows for the first time in vivo that astrocytes expressing mutant mSOD1 damage the motor neurons they are supposed to protect. In the study, the authors transplanted SOD1G93A glial-restricted precursor cells—glial progenitors capable of differentiating into astrocytes—into the cervical spinal cord of rats to reveal how mutant astrocytes influence WT motor neurons and other cells types (microglia and astrocytes) in an in vivo setting. The G93A mutation of SOD1 is the most studied version of that particular genetic mutation responsible for many inherited (or familial) ALS cases.

This is the strongest evidence to date that "assaultrocytes" are primary culprits in ALS. It also further suggests that even some sporadic ALS can be caused by misfolded SOD1 which escapes proteasomal degradation and gets into the extracellular space. It also suggests that targeting mSOD1 and stem cell implantation of astrocytes can be viable treatment methods.

EDIT: Here is a more in-depth article by Amber Dance at the ALZ Forum.

Headlines

2011-10-01T00:55:00.000-07:00

First off, there is some wonderful news: Diaphragm pacing system receives FDA approval for use with ALS patients. This is a device which extends time until vent by electrically stimulating the diaphragm. Note that this will not replace a vent as the diaphragm muscle needs neurons to release acetylcholine to the muscle fibers in order for them to contract. However, I urge all PALS reading this to immediately begin talking with your neurologist about whether this would be right for you. Here is some good information regarding the DPS.

Next up is the recent news regarding the Neuralstem trial involving stem cells implanted in the spines of PALS. Readers can see a poster-style synopsis of current trial data here. The initial results are encouraging, and one patient has even shown improvement. The next step in the trial is cervical implantation where the cells will have the chance to impact the phrenic nerve (the "money" nerve that serves the diaphragm and breathing). There is still much to learn about this technique before it is available to but a few. Remember that this is still a safety trial. I would urge readers to consider the words of Neuralstem's CEO.

Prion, Garth

2011-09-20T20:20:00.000-07:00

in a previous post, I had discussed the possibility of misfolded SOD1 aggregating with TDP43 resulting in depletion of TDP43 from the nucleus which caused disruption of cellular processes and cell death. Further, misfolded SOD1 induces glial activation seen in ALS which poisons otherwise healthy neurons.

A new study explores the mechanism behind this prion-like behavior, and further indicates that extracellular misfolded SOD1 can be a cause of even sporadic ALS. It also points to a molecular target which could halt progression cold.

The study was done at the Brain Research Centre based at the University of British Columbia and the Vancouver Coastal Health Research Institute, in collaboration with researchers at the University of Alberta. The research was supported in part by Amorfix Life Sciences which has a "vaccine" against misfolded SOD1 already in development.

Now Is The Time

2011-09-01T17:32:00.000-07:00

I am a huge believer in staying at home while living with ALS, having done so for 4 years now. However, the financial stress is outrageous. I am personally bankrupt and have critically stressed the finances of my family. This is because there are no institutions which would accept me on a vent. Steve Saling, an architect with ALS, proactively designed a residence for people with advanced ALS and MS which utilizes technology to maximize their remaining independence and comfort. Steve currently resides there happily, and last year another PALS on a vent was rescued from a horrific institution and is now safely and happily living there. If I had a Saling Residence anywhere in this state I would have gone to live there instead. Please read the email message below.

Immediate Attention - If you've ever wanted to help, here's your chance. Please spread this to anyone and everyone you can. Please write your letters ASAP. See video here for inspiration: http://www.youtube.com/watch?v=KlQvcw3kQe4

We need your help in establishing a residential living center for those suffering from ALS or MS in Georgia - We need your letter no matter where you are, if we can provide a residence like this here, your state could be next!

We really need your help in generating the information requested below no later than September 15th. Forward this email to anyone you think can help. If we are unable to make a persuasive case for this facility it will not be approved and Georgia families (and everywhere) will be left to fend for themselves in supporting their loved ones afflicted with ALS/MS.

Thanks for your continued support.

Bill Saling

Immediate Attention-

We need your help in establishing a residential living center for those suffering from ALS or MS in Georgia

We are in the final stages of securing approval from the State of Georgia to build a skilled nursing facility that will focus on serving residents with neurological diseases or impairments to include an emphasis on providing care to MS and ALS residents. This state of the art facility will utilize technology to provide the maximum personal independence for each resident.

All of the necessary paperwork has been submitted and we are now being asked to provide additional written documentation by September 15, 2011 on the challenges currently being faced by those suffering from these illnesses.

We need letters from individuals and families outlining the difficulty they have had in securing residential skilled nursing care for patients with ALS or MS. We need letters from doctors and case workers showing the difficulty families have in Georgia trying to find suitable living accommodations for those living with ALS or MS. We need to hear from families who have had to go outside Georgia to find suitable care for their loved ones suffering from ALS or MS. It would be very helpful to hear from healthcare providers on the difficulties they face in finding suitable housing options for people living on a vent.

If we cannot convince the State of Georgia there is a pressing need for this type nursing center which is currently not being met by traditional nursing centers, it will not be approved.

Any letters of support, documentation or testimony should be addressed to:

Division of Health Planning, Department of Community Health

Please EMAIL me your letter as soon as possible. I need to receive them before September 15th, 2011, via my email at kherron@sas-ga.org - Please copy Bill Saling at b.saling@yahoo.com

Often Awesome

2011-08-23T12:52:00.000-07:00

Today the ALS Community lost yet another member. Tim LaFollette, Mr. Often Awesome, has returned Home. My heart is with his wife Kaylan.

While I initially hid my condition for over a year, Tim had the foresight and steel balls to create the Often Awesome video documentary series so that the entire world can see his decline as he battled this disease from start to finish. This is "Tuesdays With Morrie" on steroids -- a very intimate and detailed look into the horror and hope that is ALS. Not only did it show the effect on a young man cut down in the beginning of his prime, but it showed the devastating effect on family, friends, and community. One person may carry the disease, but many suffer irreversible collateral damage.

People have told me how brave I am. However, compared to Tim, I merely dabble in ALS. He had the A4V inherited version, the worst and most aggressive possible. Whenever I would feel down about my situation, I would think about Tim and how he dealt with even worse with a fortitude and grace I cannot contemplate. I would like to thank him for unknowingly lending me some of his strength.

I never met Tim personally, only having worked with him over Facebook on awareness and advocacy projects. When I heard the news this morning I shed exactly one tear. I then decided to more properly honor his memory by continuing to live with ALS as he did, on my own terms. I also intend to honor Tim by winning my battle and, like he did, help others win theirs.

Fuck ALS.

Common Cause?

2011-08-22T15:10:00.000-07:00

A sensational bit of news has begun spreading across the ALS Community: A common cause for all forms of ALS has been found!

But has it? Certainly it is a common process but is it really the cause?

The process involved is autophagy. One of the important jobs of autophagy is to break down and recycle misfolded (improperly constructed) proteins marked by another protein called ubiquitin. A proteasome then breaks down the protein into amino acids which are then used to build new proteins It's like tearing a house apart, timber by timber, and reconstructing another from the material. If this process is interrupted or incomplete then you have a pile of junk left laying around which is thought to impede the efficient operation of the cell. An example of this is the amyloid plaques that are thought to cause Alzheimer's. However, removal of those plaques did not affect disease progression.

ALS is now strongly considered to be a "non-cell-autonomous" disease. This means that something outside the cell is causing the disease. Some of the most persuasive evidence for this is a recent study involving cells known as astrocytes become toxic to the motor neurons. This happens in both the inherited form (familial or FALS) and the more common sporadic form (SALS). Previous readers will know about my interest in current research regarding neuroinflammation as a primary cause of ALS and other neurodegenerative disease. This is also a common cause from a variety of triggers. It is, however, upstream of the "cause" identified in the recent news.

The calcium influx from the excitotoxicity created by neuroinflammation damages the mitochondria. In fact, this is a primary event. It is known that the motor neurons "die-back" along the axon, and that mitochondria motility down the axon is one of the first problems in ALS and neuroinflammation models. Once the mitochondria are damaged and cannot be repaired/replaced, pretty much all bets are off inside the cell. The cell becomes starved for energy, the cellular machinery (such as proteasomes) begins to fail, and the mitochondria start producing apoptotic factors which leads to cell death. Normally this wouldn't be a problem as many of the cells in the human body die and are simply replaced (even brain cells). However, the motor neurons you are born with are the very same motor neurons you die with.

I therefore posit that this "common cause of ALS" is too downstream of the actual cause for treatment based solely on it to be effective in and of itself. It's like trying to stop a waterfall at the edge of the cliff rather than building a dam in the stream a mile further behind. I do believe that although this may not lead directly to a single effective treatment, it would nearly certainly be an important part of a "cocktail therapy". The major positive I take away from this is that it answers the question whether the SOD1 model is applicable to all forms of ALS.

Chatterbug

2011-08-05T16:57:00.000-07:00

Since I lost the ability to travel and talk, I use Instant Messaging to keep in touch with family and friends all over the world. Everybody seems to have their favorite client, be it MSN, Yahoo, AIM, or Google. Rather than try to force everyone to switch to a client program of my choosing, I installed all of the various programs and created accounts (I did force some to stop using Facebook chat because it doesn't play nicely with my system). This was fine and dandy, but now my boot load time was obnoxiously long and my computer's RAM was getting low, leading to performance issues. Luckily I had bumped my system up to 4GB in anticipation of my higher-than-normal demands.

This led me to search for an alternative, where I could combine most or all of my clients into one ("One client to rule them all, one client to find them..."). Prior to disease, most all my computer systems in the house ran Linux. On my personal laptop I used a program called Pidgin which talked to all the major IM services. The Windows port I found a little lacking and probably not a great fit for most users. A friend then suggested Trillian. I installed it, ran through the setup to fill in the login information for my various IM accounts, and launched the application. I was impressed with the sleek interface. All chat sessions are in one tabbed window. The settings are easy to use and customize. And my RAM usage dropped by about half a GB!

Trillian doesn't support all of the functionality of the native clients such as video/audio chat and sometimes the file transfer isn't available, but for regular text chat (including the overly-cute emoticons) it works great. If I need the other functions I just pop up the native client and close it when I'm done. To save boot time and RAM I disabled the natives from loading at boot. It also supports a Facebook connection but I found the newsfeed to be annoying; I prefer to leave Facebook on the web browser where it belongs. I would also caution about security: Your IM logins and conversations are not encrypted or secure and possibly subject to inspection by 3rd parties (also quite possible on the natives), so be aware that transmitting sensitive information over this is not advised.

If you are a chatterbug like me, I recommend using Trillian on your AAC computer. I would even recommend it for non-disabled people.

G-Whiz

2011-07-25T22:31:00.000-07:00

Holy dancing cow! Today I was playing with my Google account and finally set up a G-Mail account. I then noticed a "Call Phone" link that connected me to Google Voice. While this isn't new by any means, since it was free for USA domestic and Canada, I decided to install the web browser add-on. Within a few minutes I was placing phone calls to friends.

Imagine their surprise...

The default setup comes across as "CLIENT_ONLY" which might be ignored by people with Caller-ID (most of my calls went to voicemail at first). So a few more minutes later I had "upgraded" my Google Voice account with a brand new mobile phone number in my desired area-code and linked it to my house land-line so people can call me if I am offline. Calls to my Google Voice number which go to voicemail are placed in an inbox I can access via my Google Voice or email.

The voice quality on both ends was reported to be quite good. Calls were very easy for me to make. I cued up my opening lines so that as soon as the remote end answered I could hit "Speak" on my assisted communication device and identify myself. I had originally intended to use this in emergencies if I couldn't otherwise alert a caregiver (note that this is NOT suitable for dialing 9-1-1) but after my test calls went so well I decided that I have a "new" communication method for talking to my more patient friends. I had used Skype in the past, but Skype is only free for computer-to-computer calls, not to regular cell or land-line phones.

I was able to do all of this with my eye-tracking system with relative ease. If you have control over your eye-tracking assisted communication device and can install software, I recommend trying this out to see if it works for you.

UPDATE: Configuration instructions are in the Comments section.

Jury Duty

2011-07-21T14:59:00.000-07:00

As many of you know, I have two previous posts about a drug in trial called NP001 (see "Salty Dog" and "All Roads"). In the past few days ALSA released a statement about this trial. I thank ALSA for doing this service for pals in spreading the word about this trial.

Recent research seems to finally hold real promise of effective treatment for ALS, the realization of over a century of work. However, until we have the hard data all we have is promise and hope (which while powerful are still ineffective treatments for real disease). It is the responsibility of eligible PALS to become "jurors" in these trials and help us all to find the facts which can free us from the death sentence which Fate has issued.

Brainstorm Coming

2011-07-18T16:36:00.000-07:00

Some more very good news for PALS in the USA: Brainstorm is bringing it's stem cell clinical trial to the US! This technology, named NurOwn, uses a patient's own mesenchymal stem cells to produce little factories for neurotrophic factors (proteins that nourish and strengthen neurons). This would provide a constant and lifetime production of support for the neighboring neurons, a much more effective approach than drugs which are only present for a short time or may be reduced or blocked by the Blood-Brain-Barrier.

Note that this is not a replacement therapy, but rather one to help feed and protect existing neurons.

You can read about the trial protocol here. For recently diagnosed patients they will inject into muscles to try to take advantage of axonal uptake in the hope that this will preserve the axon and its attachment to the muscle (neuromuscular junction). Patients in later stages of disease will have an injection into the spine to treat the neurons' cell bodies directly.

All Roads

2011-07-07T15:06:00.000-07:00

It has been known for some time that chronic neuroinflammation is a primary driver of disease in ALS and its "cousins" Alzheimers, Parkinsons, etc. Many attempts have been made to address it by using anti-inflammation drugs without success. Recently a study was published using a "prodrug" in animal models of Alzheimer's and Huntington's diseases. In this study, the drug 2-(3,4-dimethoxybenzenesulfonylamino)-4-(3-nitrophenyl)-5-(piperidin-1-yl)methylthiazole (JM6) inhibited the action of KMO, which is involved in the metabolism of tryptophan. This causes tryptophan to metabolize into kynurenic acid (KYNA), a neuroprotective substance, instead of quinolinic acid (QUIN), a neurotoxic substance. This degradation of tryptophan is called the kynurenine pathway (KP). It is one of the major regulatory pathways of the immune response and is known to be active in neuroinflammation. In HD, AD, and PD (Parkinson) there is decreased KYNA and increased QUIN. In multiple studies, changing the KYNA/QUIN balance in favor of KYNA is neuroprotective via a variety of methods.

Of interest to the ALS Community is that the same imbalances are seen in ALS. Strong evidence suggests that dysregulation of the KP leads to the type of neuronal damage from chronic neuroinflammation seen in many neurodegenerative diseases. In vitro testing with rodent motor neuron cells revealed a functional KP, that degeneration increased with duration and magnitude of exposure of QUIN, and that KYNA was protective against damage to neurons. It is known that QUIN is an NMDA receptor agonist (activator) and that KYNA is an antagonist (inhibitor). NMDA receptor-mediated excitotoxicity via calcium (Ca+) influx is a known cause of motor neuron death in ALS. This means that inhibition of KMO (aka kynurenine 3-hydroxylase) should be beneficial in ALS as well. Fortunately, K3H/KMO has been characterized for some time. In a study done in 2000, KMO (referred to as K3H) was found to be inhibited by Cl- (chloride). Luckily for PALS, there is already a chlorine drug in trial. This drug creates Taurine Chloramine (TauCl) which modulates the pro-inflammatory response seen in ALS, and also appears capable of rerouting KP to a beneficial product rather than harmful.

From the above it appears that previous attempts at modulating neuroinflammation failed because they were targeting symptoms rather than underlying cause (like treating a headache with aspirin when the cause is a tumor). By boosting the body's endogenous TauCl production a clearly malfunctioning immune response can be guided to its secondary, nurturing, state. At the same time, multiple targets identified in ALS can be struck with a single weapon: Excitotoxic calcium influx from glutamate receptors (currently treated with little effect by Riluzole), mitochondrial distress (currently the target of other drugs in trial), and the neuroinflammation which is one of the main drivers of disease progression in ALS.

While all roads may lead to Rome, it appears that in neurodegenerative disease they may lead to KP moderation by chloramines.

Growing Grass

2011-06-05T19:47:00.000-07:00

A few weeks ago, Professor Stephen Hawking was quoted in The Guardian newspaper saying "there is no Heaven; it's a fairy tale." Shortly after, two radio "shock jocks" in the Houston market decided to take issue with Professor Hawking's words by belittling his condition and questioning his abilities. I won't repeat their attack, but it was immature and offensive to all people affected by ALS.

In response to their attack, a Facebook group was formed to boycott the radio personalities and the advertisers on their network of stations. The goal was formed to not just demand an apology but to make this a teachable moment by demanding that the parent company, Clear Channel, also air multiple PSAs. In addition, Clear Channel agreed to a 30-minute interview featuring Steve Perrin, the CEO of ALS-TDI. All of the boycott group's demands were met.

This marks a major event in awareness for ALS. An organized grassroots movement was formed via social network tools and used those tools to achieve a goal long-sought in the community. This is only the beginning, and a perfect example of the kind of the cooperative relationship we need to foster with media, local and national.

Cell Mates

2011-06-01T23:14:00.000-07:00

In 2006, mouse fibroblasts were successfully transformed from a fully differentiated state to a state of pluripotency. These cells were designated induced pluripotent stem cells (iPSC).Since that news, human cells were successfully transformed and techniques to increase the safety and efficiency of production have been found. Other techniques have been developed which can correct genetic defects in iPSCs with the eventual goal of repairing or replacing defective tissues.

iPSCs still have issues to be resolved such as:

certain methods of inducing pluripotency are tumorigenic

iPSCs appear to have "memory" of their original cell type

there is some data showing that iPSCs express certain proteins on their surface resulting in immune rejection even in cells donated from the host's own tissue

other complications such as efficiency (allowing sufficient numbers of cells to be generated within a clinically acceptable time at a clinically acceptable cost).

Some of these issues are already being addressed and quite frankly the pace of research has been astonishingly rapid. iPSCs are already being used to model disease and aid drug discovery. Due to the novelty of cell-based therapies and the fact that implanted cells are difficult or impossible to remove (unlike dosages of drugs which can be ceased in the event of adverse reaction), regulatory hurdles are necessarily high. However, as more trials are performed giving more data on safety these hurdles can be lowered somewhat and/or more easily surmounted. There are cell-based therapies already in or going through the regulatory process for trials using a variety of stem cell types. Not only do these prospective treatments face regulatory hurdles, they must also cross the Valley of Death of pharmaceutical research. Some researchers are finding ways of doing this on their own with intellectual property partnerships, and the NIH has been working to bridge the gap with new programs such as TRND.

This is a very exciting time for regenerative medicine.

FUS and ALS: What's the Connection?

2011-05-18T22:43:00.000-07:00

A very interesting article from the MDA. Discusses some exciting work regarding the role of FUS in ALS. The article also mentions TDP43 and a possible convergence in the pathologies of both.

The Cost of Breath

2011-05-06T14:57:00.000-07:00

Despite having a "fatal illness", with a little technology and someone to keep an eye on me for the inevitable adjustments, I can live until age draws the final curtain on the story of my life. My quality of life remains high regardless of my current certain physical limitations. There is nothing wrong with my mind: I am still as intellectually productive as ever.

Nothing would please me more than to earn my own keep (and I am not alone in this desire), but people classified as terminally ill don't appear to be considered viable members of the workforce. So I volunteer my time to raise awareness and try to understand relevant research, sharing what I learn with others (a part of my previous career and the genesis of this blog). I find this work fulfilling and it keeps my opinion of my quality of life quite high, focusing on accomplishment rather than loss. Those close to me can attest that I can get cranky between projects when I have nothing to do so I try to stay busy. As I am quadriplegic I must use a computer system that tracks my eye movement to approximate the use of a mouse. With this computer I write and respond to email and online chat offering technical advice and answering questions from other PALS, scour the Web for research information, create videos to promote awareness, created a website (with coding assistance from a friend far more skilled than I), and play with my home computer network among other projects.

The decision to vent or not is a highly personal one with many factors contributing to the decision. I chose to live on a vent for a few reasons. First, I had finally recently achieved real happiness in life and didn't want the dream-come-true to end so soon. Second, I saw some hope on the horizon with the state of research into the disease and possible ways to overcome it and I still hold this view more than ever. Last, and important to my perception of quality of life, I still had a contribution to make to the world and I have only grown more intense in that belief. I am simply not done living, with all which that experience entails.

But my every breath now comes at a price. Because I cannot move to assist myself I must have an able-bodied person within hearing distance of any alarms or signals from my equipment. The skill requirements aren't high and can be taught in a weekend, but nevertheless someone must be alert and on duty 24/7. Family is often preoccupied by the demands of daily living, volunteers are few and far between, and government assistance is non-existent for people in my condition. The one factor which should NOT be involved in deciding whether to live on a vent is the cost of attendants. Medicare will not provide for in-home attendants. There are even very few institutions which will take people on mechanical ventilation and hospice is not an option due to the vent being a life support device. With the enormous wealth floating around our for-profit healthcare system it is astounding that no insurance (not even my high-end corporate policy) will cover the cost of attendants. So my only option, given my desire to live, is to become a beggar on an offramp of the information superhighway. This is terribly humiliating to me.

Nerd Factor Five

2011-04-20T16:16:00.000-07:00

As an Information Technology professional I tend to accumulate equipment. I have a couple of old laptops lying around (some dating back to 1998). One of the slightly newer ones I connected to my TV via the external SVGA port (with an associated stereo sound cable connected to the headphone jack). Now I can stream Netflix and other online content to my big flatscreen TV while not using up the resources on my communication system. For independence I installed VNC which gives me full control over the remote machine. All I need is someone to power on the laptop and I am up and running.

Currently I am watching live surfing being streamed from Bells Beach, Australia. Think I'll crack a Foster's and enjoy!

More Press

2011-04-05T18:08:00.000-07:00

As many of you may already know, I was recently featured in an article in the Santa Cruz Sentinel. There was a lot of information to cover and I applaud Laura for getting it all in there.

I did want to clarify some points:
First (and least), I was the web group sysadmin for Lutris, building and maintaining the internal and external web infrastructure, and the I.T. manager for Mercedes-Benz Research & Development.
Second, regarding vents, my point was that due to the costs involved, many never have a choice. Some make a choice not to vent, and I respect that. However, due to the financial expense, for many the choice is made for them regardless of their desire. This deprives the world of many potentially productive and engaged people, and is an ongoing concern of mine.

Another Victory

2011-03-30T14:21:00.000-07:00

This is why we do it.

Olya in the Ukraine needed a biPAP which she couldn't possibly afford. She contacted ALS Guardian Angels. I chat with the ALSGA coordinator quite frequently, heard the story, and donated my old biPAP. ALSGA shipped it to Poland and Olya's friends got it to her from there.

Another PALS given more time alive by cooperation and action within the global PALS family. Although I appear in this story, it is not about me: It is about how we as PALS can change our own lives and the lives of each other. Without the new communications technologies now available (and the ability to use them) this could not have happened.

The following is an email trail following receipt of the biPAP and a technical issue resolved. Some of the discussions took place over real-time chat and so aren't shown here. Total time from request to receipt and use was less than a month.

--------------------------------------------------------------------------

From: Olya@.ru
To: @.com
Subject: I want to say thank you
Date: Thu, 31 Mar 2011 00:19:27 +0400

Hello, Lisa! I can't wait to share my happiness with you. Today I've used
the bipap for an hour or so for the first time and I felt excellent. Much
better than without it. I learned how to do settings. I find my mask to be
comfortable too. I feel deep relief now. I'm not scared any more not being
able to breath normally and sleepless nights are the past. I've attached a
picture of me while bipap therapy. Now I'm thinking back and understand
that is would not be possible without ALS GuardianAngels, Stu and your
priceless help. There were obstacles to ship the bipap and receive it, but
you were so patient and sympathetic to me and to all this process. I
sometimes can't believe it's true. When I tell people, that an American
organisation helped me with the bipap and tell them this story,they say:
"It's something unbeliveble, it's really hard to believe that miracles do
happen". You can't imagine how much your help means for me and my family.
I'm writing this and understand that I can't find right words to express
how grateful I am.I also want to tell Eric (the donar) that his donation
means '"surviving" for one more PALS (for me). That this is more than a
gift! That I will always be grateful to him and never forget it. I want
to cry out THANK YOU FOR EVERYTHING YOU ARE DOING FOR PALS! IT'S
PRICELESS! Happy Olya 29.03.2011, 17:18, "ALS GuardianAngels"
<@.com>:YAY, I am so relieved! Here is the companies
contact information:
Respironics Inc - 6 reviews - Place page
www.respironics.com - 1001 Murry Ridge Drive, Murrysville, PA - (724)
387-5200

From: olya@.ru
To: @.com
Subject: Re: Olya: Mission accomplished!
Date: Tue, 29 Mar 2011 15:09:30 +0400

Hello Lisa, It was voltage issue (the user guide info was right). My
husband bought another adapter and the bipap works with the new one.
Actually, at first we used an adapter too (an American one, as we have
American product and it does with the device), but the bipap didn't work
with it, but Ukrainian adapter is good.Thank you, Lisa, for your help,
anyway. I was really worried. But I still need the contact of a provider
in case something goes wrong in future.Model ð 1003986PCA1SN:3074661My
phone number +38 095 700-68-67 29.03.2011, 02:25, "ALS GuardianAngels"
<@.com>;:Also, please send me the model number and
serial number...any other information would be great. A detailed reply
about what is happening will also be helpful. Send me your phone number
again as well.

From: @.com
To: olya@.ru
Subject: RE: Olya: Mission accomplished!
Date: Mon, 28 Mar 2011 18:23:01 -0400

For now, bring it in to your doctor at your appointment...they may have
some advice. I'm hoping it's not a voltage issue between US and Ukraine
products...we looked into that and we were certain it wouldn't be an
issue. I can look for contact info, I already called them to see where
the device was originally made (needed that for Customs). I will call
them tomorrow as they are closed already today.

From: olya@.ru
To: @.com
Subject: Re: Olya: Mission accomplished!
Date: Tue, 29 Mar 2011 01:59:47 +0400

Picture is attached. This is what I see on the screen, when trying start
the bipap. 29.03.2011, 01:07, "ALS GuardianAngels"
<@.com>;:Olya, here is the user guide:
http://global.respironics.com/UserGuides/UserGuideBiPAPSynchrony.pdf Let
me know if this helps or not. Otherwise, I can definitely ask the Donor
if he has any suggestions.
From: olya@.ru
To: @.com
Subject: Re: Olya: Mission accomplished!
Date: Tue, 29 Mar 2011 00:51:09 +0400

Hello Lisa, We have just tried to start the bipap and failed. It does turn
on, but in several seconds long alarm sound and red solid and yewllow
solid turn on while system self test. I think we should adress the
provider, but we don't have one. Could you advice what to do? 28.03.2011,
17:58, "ALS GuardianAngels" <@.com>;:I just received
this wonderful update form Olya! Also, since Olya wished to thank the
donor I included him on this message. Olya, his name is Eric Valor...and
he's a wonderful man and PALS from Santa Cruz, California. Thank you
all, and Olya I look forward to more updates on how you are doing! -
LisaFrom: olya@.ru
To: @.com
Subject: Re: Need help to live with ALS
Date: Mon, 28 Mar 2011 16:53:01 +0400

Hello, Lisa! I have news. I've just received the bipap and the mask. I
didn't try it yet. I'm going to see a doctor tomorrow and she should do
all the settings. But I'm very excited I have the bipap. I will do my best
to get accustomed to it. There is a nice surprise. When I opened the box,
I found a humidifier there.I can't express how grateful I am to you and
Stu and the donor and to all the people who helped me to get it and of
course to God, who arranged my meeting ALS GuardianAngels. I'd love to
thank the donor who agreed to donate it to me. I hope you can deliver my
thanks to him. I am really very very excited. I can't believe everything
is done.I will write you how I am doing with the bipap. Olya

A Possible Cause

2011-03-21T16:38:00.000-07:00

For some time it appeared that the inclusions found in the cytosol of neurons in degenerative disease were causing the disease, likely due to disruption of movement of organelles and proteins up and down the axons. But evidence is now suggesting that may not be the case. With TDP-43, it appears that depletion of it from the nucleus is the cause of disease. With SOD1, an unknown toxic gain of function is still theorized. However, a recent study reported that mutant SOD1 interacts with TDP-43 where normal SOD1 did not. Conflicting previous studies have found and not found misfolded SOD1 inclusions in the motor neuron cytoplasm of sporadic ALS patients, though a study using novel antibodies specific for denatured SOD1 reported small inclusions in all tested SALS patients. SOD1 is a highly complex protein and such are easily misfolded. Usually this is no problem as either chaperones refold the protein or intracellular autophagy destroys the errant protein. But age and stress can cause autophagy to decrease in effectiveness, possibly leaving errant proteins in the cell where they can do damage. So assuming that mutant SOD1 is present either by genetic mutation or routine misfolding not corrected or cleared by the cell, and assuming interactions between mutant SOD1 and TDP-43 where TDP-43 is depleted from the nucleus, it could be held that mutant or misfolded SOD1 causes disease through depletion of nuclear TDP-43.

Activation of the glial cells (astrocytes, microglia, etc.) is a driving force in ALS progression. Experiments where mutant SOD1 was limited solely to the glia demonstrated the ability to drive disease on their own. In the case of inherited forms of ALS where particular mutated genes produce mutated forms of proteins throughout the body it is easy to imagine disease spreading rapidly once initiated. But what drives the more common sporadic forms? A clue might be found by looking at prion disease. In fact, a recent study shows that Huntington's Disease may very well spread this way, and it may be applicable to other neurodegenerative diseases. Indeed another study found that extracellular SOD1 can induce microglia to release pro-inflammatory cytokines and free radicals which promote motorneuron damage. A more recent study showed that introduced mutant SOD1 can induce disease. The biotech company Amorfix makes antibodies against extracellular mutant SOD1 and is now in trials to use these antibodies as a vaccine against ALS.

So with mutant or misfolded SOD1 we have multiple paths for disease as well as a likely pathway for spread of disease. Each of these questions are comparatively easy to test and seemingly easy to intercept in the extracellular space. I look forward to more studies to further illuminate these questions.

Public Service Announcement #2

2011-03-18T18:19:00.000-07:00

I have created another PSA to accompany my previous one. Please spread these links everywhere you can to increase awareness. Until we can get a serious advocate we must rely on each other.

Taze Me Bro!

2011-03-07T16:00:00.000-08:00

Rob Goldstein of the ALS Therapy Development Institute (ALS-TDI) talks to Dr. Seward Rutkove about his invention of device using Electrical Impedance Myography, which recently won the $1,000,000.00 Prize4Life award for biomarker development for ALS.

This is available as an mp3 stream. Very interesting discussion and well worth a listen.

Press Release

2011-02-18T16:48:00.000-08:00

This is a press release I created to help us get our story of struggle out to the media. Please cut and paste the text below and put your own contact information in the Contact: line then send to your local media with a cover letter explaining your own struggle and advocacy activities. With enough synchronous distributed local coverage we can generate national interest. If you can't cut and paste then email me and I will send you a copy.

YOU are the story. But together we can create the change we demand.

--------(cut and paste below)------------

People with ALS Changing Their Own World

Contact:

Much like the people in the Middle East, people here at home who are subject to another kind of tyranny are using social media such as Facebook, Twitter and Youtube to organize and spread the word about their condition. These people are known as PALS, or Person(s) with ALS.

ALS, commonly known as Lou Gehrig's Disease after the famous baseball player who died from it, is a progressive and incurable deterioration of the nerves controlling voluntary muscle movement. This leaves the person totally paralyzed and eventually unable to even breathe. Because the expected lifespan from diagnosis rarely exceeds five years, the population of living PALS is low and those living aren't able to make themselves into public figures.

Until now.

With the advent of social media, as well as the technology of mobile computers with eye-tracking input systems and text-to-speech synthesis, PALS are able to compete on an even footing in cyberspace with more physically capable people. Many of these PALS are in serious medical conditions such as near total paralysis and some on mechanical ventilation via tracheotomy. As the astrophysicist and PALS Stephen Hawking said, "My body may be crippled but my mind is free."

Unsatisfied with the level of advocacy and awareness generated by organizations with that as their claimed mission, PALS are doing it themselves and placing pressure on those representative organizations to change old operating procedures. Other organizations representing other medical conditions are very vocal and aggressive in public awareness (the foundation of funding and national priority for research) and this new group of PALS demand commensurate action from the organizations representing them.

Examples of the new paradigm are:

• an emergency Facebook movement to transfer one PALS from an abusive institutional care facility to an entirely new fully automated care facility (which was designed by another PALS who was also the first resident)
http://www.govostes.com/blog/?page_id=172
http://www.youtube.com/results?search_query=saling+als+residence+&aq=f

• the "Often Awesome" serial documentary of a PALS' life with ALS from diagnosis to current time
http://www.youtube.com/results?search_query=often+awesome+&aq=f

• various Facebook groups including a direct petition to the ALS Association
http://www.facebook.com/pages/Petition-Against-ALSA-National/139603146055424?ref=ts

• a movement to draft a Hollywood star as a spokesman
https://www.facebook.com/alsspokesman

• use of the popular video creation site xtranormal.com to craft and distribute their own Public Service Announcement
http://www.youtube.com/watch?v=NgNVvHbIIiI

Facebook as a corporation is aware of this group of PALS and recently invited a few to its Palo Alto, CA, headquarters to take part in a documentary being aired in March, 2011, on MTV. The documentary will be about how various groups have used Facebook to effect change.

Public Service Announcement

2011-02-11T15:08:00.000-08:00

This is a little video I put together. It was a bit of work to do with my optical tracking system. I need your help getting it distributed so please share via Facebook, Twitter, email, whatever.

Some may wonder why I didn't mention the ALS Association (ALSA). ALSA to this date refuses to mount a national PSA campaign like other more successful organizations, so I did my own. The two organizations I did mention I feel are more effective. But this is really about awareness so please help me and many others get the word out.

Thanks!

Be Yourself

2011-01-21T19:25:00.000-08:00

"I'm nobody! Who are you?"

The concept of "self" is critically important in the immune system. Each of our cells present a unique set of molecules on their outer walls which signal to our wandering immunity police that they belong ("your papers, please"). Any other cells not presenting the same combination are considered foreign invaders and are attacked ("your papers are not in order!"). This works great for resisting infection but is a major impediment to transplant surgery. Even "tissue matching" is inexact, requiring recipients to have their immune system forever after repressed in order to maintain the graft. Finding a way to allow for a graft of desirable foreign tissue but also maintain a robust immune system is a therefore a major goal.

A stem cell research grant by theCalifornia Institute of Regenerative Medicine has a quite novel approach: regenerating the thymus, the "police academy" where the immunity cells learn to recognize the body's own cells from foreign invaders. The thymus atrophies in adulthood, so regenerating it from stem cells from an appropriate HLA line might trick the immune system into accepting the graft with the same HLA type.

Quite a clever approach, and yet another reason that I am glad to have voted in favor of forming CIRM (ironically shortly before I was diagnosed with ALS).

Apollo 13

2011-01-17T21:34:00.000-08:00

"Houston, we have a problem."

Apparently you can't believe everything you read. Whether it is a problem of vanishing results, reliance on unrepeatable or outdated information, or the fact that not all publications are created equally, there seems to be a serious problem with relying on medical publications. While research papers provide valuable clues, only after those results are repeatedly verified can they reach the status of fact. And even that could change over time as the sample set grows beyond what is practical for a single study.

It seems that even rigorous science can fall prey to the human failing that people see what they want to see. This results in selective reporting as well as selective publication (rarely do negative results get submitted). And in the pharmaceutical industry there is the ever-present threat of monetary corruption. Note that this should not create a panic of Nihilism, but rather instill healthy skepticism and diminish false hope.

Axon-Axoff

2010-12-17T17:45:00.000-08:00

Why do axons go downhill? Gravity has nothing to do with it...

The linked study, though not specifically aimed at ALS, does seem to tie together a few "hot topics" in the pathology: axonopathy, oxidative damage, and mitochondrial dysfunction. With many plausible theories of damage, trying to link some together may provide more clues as to cause and/or (more importantly) ways to effectively treat the disease. Part of the tie to ALS in this study is the fact that mice bred to lack the SOD1 gene exhibit a similar disease process as mice bred with a copy of the malformed SOD1 gene which is a known cause of familial ALS. Reinserting the gene in the "knockout" mice, but only in the mitochondria, rescued the mice from disease.

Mitochondria are the power plants of the cells and as a consequence also produce molecules which can cause cellular damage (ROS, the "industrial waste" of cellular energy production). Anything which disrupts the ability to clear out this waste can cause damage to the cell. Damage to mitochondria impacts their ability to provide energy to the cell. Motor neurons have high energy requirements and due to their extremely long axons have mitochondria operating at large distance from the cell body. There are currently a few clinical trials going into Phase III aimed at mitochondrial support.

While the study doesn't provide an answer (except that this problem is "way beyond eating blueberries"), it does provide some important clues for further investigation.

More Baby Steps

2010-12-05T18:10:00.000-08:00

In June I posted a discussion about a prospective regenerative therapy. On December 1, I received a press release that the company developing this therapy has filed an IND with the FDA. This is a huge step forward for people suffering from motor neuron disease (especially late-stage PALS like myself). However, it is but the first baby step in the clinical trial journey. Let's hope that the FDA acts swiftly and positively on this IND.

Medical Tourism

2010-11-23T15:24:00.000-08:00

It's been over a month since my last post. A couple of interesting things have come over the transom but nothing really compelling for me to write about. Also I have been busy in other areas.

Something compelling did show up today. An article on Nature Magazine's website concerning the controversy around stem cell medical tourism and the difficulty in regulation. While stem cells offer tremendous potential, the science necessary to fully and safely exploit that potential is still in its infancy. However, because of the potential, the desperation of people afflicted with horrible disease, and the ability to conjure and proliferate medical buzzwords over the Internet, the unwary and uninformed are preyed upon by the immoral and unscrupulous.

As can be demonstrated by reading my previous entries, I am a firm believer in stem cell technology. I am anxious to participate in one or more procedures in the hope of regaining function. But the science needs a little more time to develop. Anyone offering or advocating a stem cell "therapy" is either lying or deluded. Several clinical trials are underway or will soon commence (some of which I have previously discussed). But for now, I urge the reader to save your money and preserve your health by not succumbing to the siren song of an exotic "miracle cure".

Stop the Pop

2010-10-16T14:26:00.000-07:00

Apoptosis is an important function in multicellular organisms such as people. It keeps cancer at bay and helps keep organs healthy and fresh. But when it occurs in cells that aren't replaced (like motor neurons) nasty things (like ALS) happen. A couple of clinical trials are currently ongoing to support the mitochondria to delay apoptosis (Knopp with dexpramipexole and Trophos with olesoxime). Recently, a study was published which took a rather more aggressive approach. The approach probably isn't appropriate as a therapeutic because it isn't cell-specific.

For a good explanation, please read Amber Dance's article over on the ALZ Forum. Ms. Dance is one of my favorite science writers and actually has some credentials to back up her analysis.

Stem Cell Update

2010-10-11T17:03:00.000-07:00

Today (10/12/2010), Geron began a Phase-I clinical trial using embryonic stem cells to treat spinal cord injury. While not directly applicable to ALS, a successful safety trial should open up approvals for similar subsequent trials utilizing human embryonic stem cells. Already there is favorable preliminary information coming from the Neuralstem trial (which uses fetal neural precursors, not embryonic stem cells) and several more are in the approval pipeline.

Meanwhile, in Israel, Brainstorm received approval to begin its trial for ALS. As discussed previously, Brainstorm engineers autologous cells to secrete neural growth factors and then implants them in muscle to promote axonal growth and nourish the cell body via axonal uptake. It's a novel approach which doesn't require risky surgery.

These are just a few very interesting things going on in research and clinical trials. But keep in mind that they are happening now.

National ALS Registry

2010-10-08T17:22:00.000-07:00

The United States National ALS Registry opened this month. There is an introductory page on the ALSA website, and a recorded webinar outlining the Registry can be replayed by clicking here. I believe it is the duty of each PALS to register so that finally accurate numbers can be known of the toll of ALS in the US. The oft-quoted "30,000" is a very rough estimate and in all likelihood much too few. This is an important tool too long missing from researchers' kits.

I registered yesterday. How about you?

Laser Focus

2010-09-26T16:39:00.000-07:00

For many years now, part of the fight against ALS has been focused on finding reliable biomarkers. This has proven difficult as there is so much variability in progression and phenotype. However, what if you had something better than a biomarker? How about direct observation of the motor neurons and the neuromuscular junctions.

This is a sales video of the type of device used (a confocal microendoscope). And here is a news video with the device being used in diagnosis of another condition.The ability to live-image, in-vivo, down to the individual cellular level is super cool and is nearly "Star Trek" in terms of nifty. Professor Richard Ribchester is the person leading the work.

This tool may be enormously helpful in studying neurodegeneration and in gauging efficacy of any experimental drugs or treatments.

Social Media

2010-09-09T16:56:00.000-07:00

In the past few months a group of ALS patients (PALS) and caregivers (CALS) have banded together via social media to support each other, spread awareness, educate themselves, and effect real change in their lives. This is more than blog posts and Facebook status updates but rather a concerted and united effort to fill some of the void in the research and treatment of their disease. Using email and messaging, individual projects have combined as a force-multiplier and are already beginning to see results. The ease of using and linking various social media technologies have allowed the infirm to reach out to and engage a global audience in a way and with an impact never before possible. They can do this because they are young, angry, and embrace technology to support and replace lost physical abilities. This movement represents a potential paradigm shift in the way ALS is perceived and dealt with.

The list of projects includes (but is certainly not limited to) my project to draft Hugh Laurie to be an ALS spokesman, Thomas Ohlson's Petition to ALSA National, the remarkable and unprecedented ongoing serial documentary following Timothy Lafollette from diagnosis to current time, and the recent various and coordinated efforts to rescue a quadriplegic PALS from an abusive nursing home situation (in which this blog also participated).

There are many other projects with various strategies, but all with the goal of increasing awareness, research funding, and support efforts. Where in the past these efforts would be singular, isolated, and have very limited impact, with the use of social media (Facebook, Twitter, blogs, online forums, email and messaging/chat systems) they are now being coordinated and their message distributed all over North America. As the number and scope of projects increase, there can only be a positive effect. If you have or know of a project to increase ALS awareness, please hook up with us via social media!

Wordsmith

2010-09-08T17:12:00.000-07:00

Since I am on a vent (tube stuck through neck into trachea, below vocal cords) and can no longer talk, I must throw my voice to another object. I therefore create a new word describing this amazing feat:

"Venterloquism"

This makes me and other similarly entubed PALS (along with our brothers and sisters in high cervical injury) Venterloquists. This is not to be confused with Ventriloquism which involves the creepy practice of people with Dissociative Identity Disorder manually sodomizing puppets for the purpose of entertainment. Venterloquism involves any of several methods of overcoming a cruel obstacle to communication.

Methods include the rudimentary Eyebrow Arch (induce your meatpuppet to say "yes" or "no"), The Ouiji (make your proxy point out letters and phrases on a board), and my personal favorite, The Hawking (making your words emanate from a nearby computer). Advanced and prepared Venterloquists can even use The Hawking to produce their actual voice for certain phrases!

Venterloquism is a growing skill set among a diverse population of participants. Please support your local Venterloquist!

911

2010-09-04T15:42:00.000-07:00

I need everyone reading these words to take a few minutes to read these words. This has nothing to do with politics. This is a genuine emergency call for another PALS in desperate need. If anyone is in the area I implore you to consider some volunteer work. Contact me for details if you are able to volunteer.

This is shocking and wrong and should be criminal.

RoIP

2010-08-31T15:20:00.000-07:00

Like VoIP (Voice over IP) for phones, the Internet also carries "Radio" over IP. I will be participating in an online radio show, The Global Voice with Susan Piontek. I will be joining ferocious advocate Michele Dupree of Carnival for PALS, Mike Miller, the founder of ROALS, and Mike Shannon of ALS-TDI. The show will air tomorrow, Wednesday, September 1, at 5pm PDT. This may be "today" for those of you who subscribe to this blog via email.

The subject will, of course, be ALS and I will be providing my view of things from the perspective of a PALS. This show will actually be Part 2 of last week's show which ran out of time as the subject has so many facets. That show is archived online at this link. Because I am on a vent and can't speak, I have prepared responses to some questions which were provided in advance. My wife, Claire, will read them live and I will edit this post on Thursday to include them (as well as a direct link to the archive). Listen live and either call in with questions or type into the simultaneous web chat. Maybe you'll hear me do my Stephen Hawking impersonation!

[edit]

The archived version of Part Two can now be found here.

My Q&A transcript follows below:

Q: Tell us about yourself and how ALS has changed your life?
A: At the time of diagnosis I was 36 years old, had a wonderful career in Information Technology and had just taken a position to manage the computer network infrastructure of the US research and development program for an automobile manufacturer. I had a little house on the shore where my wife and I could walk down the hill to celebrate our wedding anniversary by surfing together (also our first dating activity). I had everything I wanted and was extremely happy in my life. Then all of that was removed piece by piece. I am now quadriplegic, we are about to move to my parents' house, and I require a machine just to breathe. Fortunately the Internet is a great physical equalizer so I can continue my online life somewhat unchanged. Unfortunately, I now have plenty of time for Facebook.

Q: What would you like people to know about ALS; the disease, the current research, the expense?
A:Words will never be able to adequately express the pure horror that is ALS. You can feel pain but not move to avoid it. You can feel hunger and thirst but never consume to slake. Dignity is utterly destroyed. There is no other condition with the same combination of helplessness and misery. There is no risk factor or behavior which brings this curse, and not nearly enough is being done to end it. There are many fine people working to solve this but their work isn't supported enough and there aren't enough of them. PALS don't have time to wait. The technology is recently available to adequately study the problem so the only thing needed is money. As Dr. Stan Appel testified before Congress, "ALS isn't incurable, it's underfunded." The research is beginning to zero in on things that can make truly effective therapies and a few promising clinical trials are just starting or will soon. For the meantime, medicine has gotten quite good at dealing with the symptoms of ALS and Medicare pays for it. However, on the most crucial aspect only half measures are available. While ventilators and supplies are paid for, the people necessary to maintain the equipment, handle alarms, and assist with personal issues are not. Family members, when they exist, are destroyed from the combined physical and emotional strain. The cost for attendants is high and has bankrupted me. PALS can be productive in society with proper support and I am living proof. In addition to other activities I have begun to lobby ALSA to be more aggressive in public education and to persuade Congress to amend Medicare to pay for in-home vent care.

Q: What can people do to help?
A: The easiest way to help is to support an organization like TDI. But that is too passive. Our society likes to write a check, push a button, take a pill, then forget about the initial problem. That level of commitment doesn't cut it. In _addition_ to a financial contribution, more people need to follow the lead of the 3 Ms and agitate. Write a letter to ALSA demanding national television PSAs with a current A-list celebrity. Write a letter to your Congresscritter demanding changes to Medicare so PALS don't opt for death in the face of daunting costs (I have a year-long debate going with a friend who is facing ventilation). If you know of someone with ALS, keep that person's name in the local press. Write to the TV news networks demanding more coverage of this silent crisis. The more people who are aware of ALS, the more demand for a solution results in more action, more funding, and more participation from the industry. And use social media to reach out and coordinate activities. 10 voices are easy to ignore. 10,000 not so much. I and a group of PALS use social media every day to connect and coordinate. The services are free, very easy to set up, and have global reach. I have my blog and a Facebook page to recruit an A-list celebrity. If I can do this, someone with functional hands certainly can.

Salty Dog

2010-08-15T20:31:00.000-07:00

As discussed in a previous post, immune modulation appears to be a promising pathway to attack ALS. Recently, a company called Neuraltus has commenced a Phase I clinical trial of a substance they code-named NP001. This substance also works as an immunomodulator by reverting immune system cells from hostile to nurturing. For some time, chronic inflammation has been recognized as an important factor in ALS (though the cause remains elusive) and many attempts have been made to control it. This appears to be another promising method.

It can be deduced from the press release that NP001 manipulates the cytokines in the body which signal the various reactions to injury or infection. But what is NP001 and how does it work? Neuraltus isn't revealing the secret sauce so I went on a treasure hunt through PubMed.

One of the chronologically earliest results of searching on the Neuraltus founder Michael McGrath reveals that he has been investigating immunomodulation since 2002 (actually earlier, but this study serves as a good starting point which will become clear later). In 2004 he co-authored another paper investigating the immunomodulatory effects of WF10. WF10 is interesting because it down-regulates pro-inflammatory cytokines by reacting with hemoproteins to form hypochlorous acid which then reacts with taurine to form TauCl which inhibits the inflammatory cytokines. WF10 seems to also have some drawbacks so another, "gentler", chlorine ion donor is probably desirable.

In 2006 another paper was published, co-authored by Dr. McGrath and Dr. Robert G. Miller (the principle investigator in the NP001 trial) which investigated the role of defective macrophages in Sporadic ALS which expanded upon their 2005 paper. This research is doubly interesting as it looks directly at SALS as well as posits functional biomarkers which can be used to gauge drug efficacy instead of the clumsy ALSFRS (the NP001 trial lists this as a secondary outcome measure). A paper in 2009, again co-authored by Drs. McGrath and Miller, not only investigated immune activation in SALS but posits a cause. I hope to talk about that in future posts but for now I digress.

With the evidence for immune system involvement in ALS and the evidence that a chlorite-based drug can neutralize some of the cytokines that promote inflammation, it seems to make sense to investigate whether such a drug can address the neuroinflammation of ALS. I have an unconfirmed report that sodium chlorite is the active ingredient in NP001 (the chlorine ion donor). Also, according to this 2006 patent issued to Dr. McGrath, TCDO (WF10) and sodium chlorite are both considered for ALS treatment in dose-dependent manner.

I am intrigued and hopeful that this drug could have a positive impact in ALS. By reducing the amount of "attack" signals (cytokines), the "nurture" signals might help to end the damage caused by the neuroinflammation. Unfortunately my search for any of Neuraltus' preclinical (animal) research served a bagel so we have to wait for human results to evaluate beyond speculation. Of course, as always, remember that I am not a doctor or biochemist so take my words with a grain of salt (NaCl, sodium chloride, table salt.. get it? I apologize).

Shah Den Froi Duh

2010-07-30T16:57:00.000-07:00

There is a game show on ABC I enjoy called Wipeout. This is because I enjoy seeing people with a full set of NMJs get pummeled by padded machinery. It is the ultimate in schadenfreude television!

Poor SOD

2010-07-23T17:55:00.000-07:00

There has been a question whether SOD1 plays a part in sporadic ALS (SALS) as well as familial ALS (FALS), in which one of a large number of inherited defects in the SOD1 gene cause alterations (misfolding) of the SOD1 enzyme which it encodes. A recent study published in PLoS ONE suggests that misfolded SOD1 is present in all cases of ALS, not just in those involving genetic defect. Some previous studies have had similar results while others have not. Apparently this study used a fairly aggressive set of antibodies to detect inclusions (flaws) in the motor neurons which consisted of SOD1. Whether the misfolded SOD1 or the inclusions/aggregates that result are the cause of disease is still being questioned, although disease effects can be seen prior to visible aggregates forming.

Two things about this study I found interesting:

First, the study reported that the inclusions were found mostly in the axon hillock which makes me wonder if this can be related to the slowing of axonal transport which is a very early event in ALS.

Second, if you look at the diagram in the SOD1 link above, you can see that it is a rather tight and highly complicated enzyme to fold. A mutation may make it more difficult or impossible for a lysosome to break down. Lysosomes are rather important cellular components. The subject study indicates that the misfolded SOD1 found in the motor neurons co-localized with lysosomes, suggesting that the lysosomes were choking on the mutant enzymes. Lysosomal dysfunction has already been linked to several diseases, including neurological. It is known that lysosomal function degrades with age, and ALS is an age-related disease (both SALS and FALS begin after decades of otherwise normal life). At least one study is being conducted, attempting to address ALS by means of increasing lysosomal function.

Of course, this assumes a "neurocentric" view of the disease, where the pathogenesis is in the neuron itself. Recent research suggests this may not be the case, and that some upstream event triggers the cascade that leads to distress and death of the motor neurons. It is this "missing link" that continues to confound researchers.

Build A Cell

2010-07-14T18:17:00.000-07:00

Ever wanted to build your own pet cell piece by piece, feed it and defend it from hazards both external and internal? Well now you can! This engaging little game (built using Flash) entertains and educates simultaneously. While you are building your cell, each component's function is explained and demonstrated with practical applications. As your cell becomes increasingly more complex, so do the hazards come faster and more dangerous. Keep it fed, keep it producing energy and raw materials for growth and regeneration, and watch out for viruses!

The game teaches you cell biology and mechanics while you play. There is a bit about transpermia as the goal is to build the cell, train it up, and send it to another planet to ensure the survival of a species of rather clever and industrious platypuses...

Note that I have not made it through the end of the game because the action becomes too frenetic for my optical control system to control. My cell gets killed by virus attack. I try not to take it as an omen...

Baby Steps

2010-06-29T16:55:00.000-07:00

I recently came across a video of a talk given by Dr. Hans Keirstead, whose work I have mentioned in a previous post. In the video, posted June 29, 2009 (almost exactly a year ago), Dr. Keirstead showcases his research on a stem cell therapy for SMA. He shows how he was able to grow functional motor neurons (proving it by showing them innervating muscle fibers) and explaining the then-current status of a proposed human trial to replace damaged tissue.

The proposed trial is for infants who suffer from Type 1 SMA. SMA (Spinal Muscular Atrophy) occurs from a malfunctioning SMN gene and the Type 1 (infantile) version is rapidly fatal. Like with a form of ALS called PMA (Progressive Muscular Atrophy), the motor neurons between the spinal cord and muscles die leaving the person paralyzed. When the diaphragm muscle is eventually denervated the person dies of respiratory failure. Regenerative medicine offers a way to replace lost tissue and restore function. In lab and animal tests it appears Dr. Keirstead has been successful. now for the next step.

There seem to be good reasons to try this in SMA infants. I am going to be coldly blunt but I beg the reader to take a breath and stay with me. First, the infants are going to die very soon so the trial length is short; you will see quick benefit or have rapid access to post-mortem tissue (also the reason Neuralstem included late-stage ALS patients in its trial). Because of the infants small size, the grafted neurons don't have far to go to innervate muscle. In an adult such as myself motor neurons would have to grow a bit over a meter to reach fingers and toes. Even the phrenic nerve (the "money" nerve in neurodegenerative disease) would need to grow nearly half a meter to innervate my diaphragm muscle. Nerves grow slow so that could take as much as two years (for the more distal muscles). Infant bodies are still also in a rapid growth mode which may assist the grafts (mentioned in the Stanford study in a previous post). I could also guess that an immature immune system may be beneficial for anti-rejection purposes (pure speculation on my part). Time is in critically short supply in SMA (and ALS) so having short trial lengths is crucial. June 22, 2010 update on program progress.

Because SMA is so similar to ALS, if this trial goes well it would be huge news for PALS. In fact, ALS is the next disease in line for this treatment. With this program and the concurrent ongoing programs by Brainstorm, TCA, and Neuralstem either soon to be or currently in trial, I have great hope for regenerative medicine.

As always I invite responsible comments or questions.

Because Someone Has To

2010-06-15T18:36:00.000-07:00

A few years ago a report came out claiming some fantastic results involving Lithium's efficacy in ALS. The paper was published in a respectable journal. However, reaction was surprisingly cool. Because Lithium has been used for years in much higher doses for maintenance of bipolar disorder and was cheap and easy to get, many PALS started their own off-label "trial" which collected valuable data (unfortunately to the contrary of the results of the original study). This first in history patient-driven trial forced multiple professional clinics to stage real, placebo controlled, clinical trials (with results which matched the patient-driven trial).

Recently there has been interest in a natural bile acid which has anti-apoptotic effects, specifically in the mitochondria. There are two companies already in clinical trials with proprietary substances intended for mitochondrial support. Ursodeoxycholic Acid (UDCA) is found to be anti-apoptotic, easily crosses the blood-brain barrier, has an excellent safety profile, and is inexpensive and easy to obtain. A Phase 1 trial was already done which showed excellent safety for ALS patients. A few scattered PALS have been safely using UDCA and some anecdotal reports from S. Korea (using a version with a starch binder) have indicated efficacy. Unfortunately no clinic is interested in performing the trials necessary to fully investigate UDCA.

So I have created the second patient-driven clinical trial intended to provide some good data on the efficacy of UDCA as a treatment for ALS. While not a true clinical trial it should be a decent indicator.

I did this because the risk is low and the potential benefit high. I did this because doing nothing gets you nothing. I did this because someone has to.

Paradigm Shift

2010-06-12T15:41:00.000-07:00

I support ALSA because of their patient services programs. My life would be more difficult without them. But I strongly support ALSTDI because they take an engineering approach to finding a cure. Throughout my life I have learned that the engineering approach is the _only_ way to properly solve a complex technical problem. I encourage you to walk for ALSA but if you want to do more than bandaid a fatal disease, strongly support ALSTDI.

TDI is a paradigm shift in thinking not just about ALS but in addressing the translational research gap for orphan diseases altogether.

Insane in the Membrane

2010-05-27T17:49:00.000-07:00

I really love the Public Library of Science because they encourage and publish research articles in the Public domain. This gives a dilettante like myself access to current peer-reviewed medical research without emptying my bank account.

A couple of fascinating (if not immediately applicable) studies recently showed up in my search results. First was a study which researched how embryonic stem cells (ESCs) are not necessarily all created equal (good summary here). I rubbed that against this study which tracked how cells convert from Inner Cell Mass to ESCs. This is just basic research, so what? Well add this study from Stanford (mentioned in an earlier post) and that basic research gets more exciting. There is one company already developing methods to use placental stem cells for pharmaceutical purposes. Knowing how these cells change themselves, thereby facilitating in vitro manipulation, would be crucial.

The second study demonstrated making functional neurons out of astrocytes without first reverting them to a pluripotent state (as is done with skin cells to create induced pluripotent stem cells). Sounds great, except harvesting the astrocytes can be a bit tricky. While I consider that there are multitudes from whom whole lobes could be removed with no appreciable cognitive or behavioral impact, poking holes in the brain for experimental raw material probably isn't a good idea. And the study used retrovirus to deliver the genetic information, which for in vivo application could cause problems. (apologies for the inaccurate humor stretch)

While these studies don't appear to be immediately applicable to human disease (and regenerative medicine), they demonstrate how far knowledge has advanced at an extremely rapid pace. This continues to give me hope for an effective treatment very soon. While the word "soon" has been used for decades (resulting in much cynicism among PALS), the techniques explored above are extreme changes in paradigm. And as human trials with stem cell technology are already underway, the time from basic research to effective therapies is now being greatly compressed.

Stem Cell Update

2010-05-24T18:14:00.000-07:00

In a previous post I made mention of the Neuralstem clinical trial currently ongoing at Emory University. Recently, CNN ran a story on the trial which provided welcome news to the ALS community. Three implantations had been performed with no complications so far.

Today I received a press release which carried forward the good news. Based on the results so far with the first three, they are going ahead with a fourth with double the injections (both sides of the spine). This is great news as it is showing the procedure and product to be safe (the primary objective of this trial). It is still too early to determine any efficacy and the trial isn't designed to measure that anyway.

With each success the barriers are pushed back a little further. The success of the Neuralstem trial will pave the way for other trials.

Advocate

2010-05-19T22:03:00.000-07:00

Autism, Breast Cancer, Parkinson's, etc. all have internationally-recognized A-List celebrities advocating for them. As a consequence they have high public profiles with commensurate research funding levels. It is time that ALS joined the club.

Hugh Laurie (Dr. House, among many other roles) would be a perfect spokesman for ALS because he has personal knowledge of its effects. If Betty White can be "drafted" to host Saturday Night Live by a Facebook page, perhaps Hugh Laurie can be drafted to be a spokesman for ALS.

Off Topic

2010-05-13T15:12:00.000-07:00

(sort of)

I resisted posting this here because it is not in keeping with the mission of this blog (I originally posted it on my Facebook page - the more proper venue). However, due to numerous requests and delays in preparing my next intended entry, here goes:

My Strings Sing for Renaissance

The strings
To my Meat Marionette
Have been cut!
And so we
Round up the usual suspects.
As they are released
One by one
I realize that
Lying around in bed all day
Isn't as decadent as it sounds.

The floppy foot
Made a Goofy step
As it marched up the leg.
After the
Fall Season
I decided to have a seat.
Then I
Let my fingers do the walking
Until they took a hike.
I can't even
Give myself a hand.
And the creeping uneasiness
Took my breath away.

Unlike Mick
Time is not on my side
Although I seem to have more
Than ever before.
Now cyborg is as cyborg does
And I wait for
The bright near future
Where once again
Gravity is my friend.

© 2010 Eric N. Valor

Tread Lightly

2010-04-23T20:25:00.000-07:00

So here I am, minding my own business, when my mother brings her pooches over for a playdate with my two. No worries, I enjoy the sounds of rambunctious dropkick dogs scrambling around on hardwood floors. My mother brings one of hers over to my left side to say hello when my Yorkie jumps up on my right side and does a skidding slide across my abdomen and into my PEG tube.

POP!
gurgle gurgle gurgle

Mom and wife were talking and didn't take notice that this was a serious situation. Since I was not on the computer it took me a few moments to mouth what had happened. When my wife turned back the sheet the tube tumbled out. Now I have gastric goodies and some blood dripping down my side. To their credit neither of them fainted. I am lying there, angry, mentally adding up the cost of transportation and other out-of-pocket for replacement at the hospital.

Luckily we reached my doctor on his cellphone, rescuing him temporarily from gardening chores. He explained that the tube was held in place by a balloon on the end which had become semi-deflated and that we should just push it back in. Having already tried that with no success but much pain we were afraid it had started to heal closed in the 45 minutes it took to reach the doctor (a reality for tracheotomy). When we said that, his response was, "Did ya lube it first?"

A few globs of medical lubricant left over from a previous trache inspection procedure (tube down nose with camera; trying to forget) and it slips right back into my new second mouth. No worse for wear.

Important note: Tread lightly on the PEG.

Role Model

2010-04-04T19:14:00.000-07:00

A few days ago, Matt White, who lives with ALS, addressed the Butler NCAA basketball team prior to their Final Four victory over Michigan St. Normally I don't care about basketball (I am a hockey fan) but a Facebook friend posted the Youtube link above and I viewed it. The thing that struck me about Mr. White's address was his promotion of Sir Ernest Shackelton as a role model. If you don't know who he is or don't know his story, please take a moment to read the previous link (most notably the portion on the Trans-Antarctic Expedition).

Sir Ernest is a perfect role model for PALS because of his dogged determination, his cool ability to make rational choices in grim situations, and his use of those characteristics to survive a lethal predicament (multiple predicaments, actually). Not only did he survive but he ensured his men would as well. Contrast the experiences of Scott and, worse, Franklin. Even though Shackelton was forced to abandon his original goal, he achieved an even greater goal by surviving.

I would like to thank Mr. White for including Sir Ernest in his address and would like to concur. Even though PALS may be forced to abandon their goals, it is my hope that many can join me in "pulling a Shackelton" and doing what is necessary to survive an impossible situation.

CD40L and the MAB

2010-03-29T19:43:00.002-07:00

The ALS Therapy Development Institute is a non-profit biotech fully devoted to finding a treatment for ALS. A few years ago they undertook a genome-wide association study (GWAS) on the animal model of ALS (the G93A mouse).The results implicated the costimulatory pathway which links the innate and adaptive immune systems. In an attempt to address that pathway, TDI used a monoclonal antibody against CD40L. This decreased a specific T-Cell interaction which led to the body attacking the axons of the motor neurons. A very good description of the study can be found at the Alzheimer Research Forum (Alzheimers, Parkinsons, and ALS are selective neurodegenerative diseases so research in one can provide clues into the pathways of others).

This finding is interesting for a few reasons. For the first, it marks a shift in looking at ALS as a motor neuron disease to seeing it as some other dysfunction in which the neurons are injured. Second, while the treatment described isn't a "cure", it does point towards a significant pathway of disease management.

Another important point is the success reported by TDI. Since the development of the murine model of ALS numerous researchers have claimed varying degrees of success in preclinical work only to have the candidate substance fail in human trials. TDI undertook an internal study to figure out why and discovered numerous variabilities for which researchers must account when designing trials. TDI's mouse program is now recognized as the "gold standard" for that model. The fact that they can report measurable and repeatable results is significant.

Of course mice aren't men and this isn't a cure, but it does give quite a bit of hope that a truly effective treatment may be within reach.

[UPDATE 04-02-2010: TDI discusses this via MP3 podcast.]

[UPDATE 04-05-2010: The study is now available free of charge in PDF format. Very good of Nature Publishing Group to make this available to PALS and CALS!

Stem Cells for Dummies

2010-03-22T17:24:00.000-07:00

Stem Cells for Dummies is authored by Lawrence S.B. Goldstein, PhD. Dr. Goldstein also co-authored the legislation which created CIRM.

The book does, IMHO, a rather good job of presenting complex science in terms which laypeople can easily digest. It starts with a primer on biology as it applies to stem cells and a brief history of their discovery and initial uses. The differences between adult and embryonic cells is explored with frank discussion of the attributes and limitations. The role of these cells in the research and treatment of various diseases is discussed along with a review of the current state of the art (my previous post on stem cells deals with some cutting-edge techniques). There is a detailed section on the ethical and moral controversies surrounding this sensitive topic, and a section on common myths and misconceptions.

Stem Cells for Dummies is written from the scientist's viewpoint but takes effort to present in a neutral tone. It is written for anyone who wants to understand stem cell technology without requiring a PhD. Rather than spend weeks cuddling with Google and sifting through the inevitable dreck, drop $10 and receive a great resource from a recognized expert in either dead-tree or electronic form.

[disclaimer: I linked to Amazon for convenience and because I use their Kindle for PC application. If you can, support your local bookstores.]

Sausage-fest!

2010-03-21T20:09:00.000-07:00

Interesting things happen to one's body due to ALS. One of the most trivial effects I have noticed involves my fingers. I am quadriplegic so my hands spend all their time on a (relatively) flat surface. Grasping or any voluntary flexing of my fingers has been nothing but a memory for years. This allows the skin to tighten and smooth a bit.

You know those little wrinkles over your knuckles on each finger? I don't have any anymore! I noticed this during physical therapy a few weeks ago and wondered what these little keratin-tipped bony alien hotdogs were doing at the ends of my hands. Truly a sausage-fest.

Letter from Lou

2010-03-11T14:55:00.000-08:00

I recently received a handwritten letter from Lou Gehrig. Obviously it was not addressed to me as the people responsible for creating me had not yet themselves been created. But it does give an intimate glimpse into the life of a remarkable man (even without the disease his accomplishments are legendary).

I was struck by the proof of his equally legendary kindness and generosity, and hope to approach that in my own life as I struggle with fellow PALS to achieve the goal that eluded Lou.

Kindle for PC

2010-03-05T17:21:00.000-08:00

Back in November of 2009, Amazon released its Kindle for PC software. The program is free and available for Windows 7, XP, and Vista. A future version for Mac is promised.

While I have never used a physical Kindle (holding anything but my breath is no longer an option for me), the software appears to recapitulate most of the function of the device. The most important part for me (and for all advanced-stage PALS) is that it behaves very well with my optically-controlled assisted communication system. I use the ERICA from ERT. ERT was recently purchased by Dynavox but the K4PC should still work on that platform as well as the Tobii.

Downloading and installing is very simple. Once installed you need to register the "device" to your Amazon account (like the physical Kindle each registered software counts as one of the 5 devices on which you are allowed to share your purchases). If you don't have an Amazon account you will need to set one up (I recommend letting an assistant do the data entry here although I was able to do this myself). For those who already have a Kindle, you should see your previous purchases sync to the software. If this is your only device, new purchases from Amazon will appear within 30 seconds of purchase.

Each page has large, easy to read type and the size and spacing can be adjusted for comfort. To either side of the page are white arrows to turn the page. They only appear on mouse-over, and if you click even near them you will hit the target. They are spaced far enough away from the text that accidental page turn is almost impossible. If you close the application with a book open your place is saved automagically. Other bookmarks are easily set.

The software is considered beta at the time of writing this post but works very well for me. Updates are automatic but can be set to manual. For software not expressly written for handicapped users it satisfies some important requirements. I am very happy to be reading books again!

Stem Cells

2010-02-26T19:26:00.000-08:00

There has been a bit of action recently in terms of stem cells, with one human trial in MND which commenced this month and another which hopes to commence soon. There are a two ways for stem cells to be of benefit: Trophic support where the grafted cells support existing neurons by secreting nourishing (trophic) proteins such as GDNF and BDNF and regenerative where new replacement neurons are grown. Each approach has advantages and technical (biological) hurdles.

As I said, trophic is secretion of neurotrophic ("nerve-feeding") factors. It can also occur from the implanted cells just being a close friend to the diseased neurons. A benefit of trophic therapy is that the graft cells do not need to differentiate or grow. Cells modified to become GDNF "mini-pumps" have been shown to fully protect motor neurons in animal models of ALS. Unfortunately, however, in that study the protection did not extend to the axon. While the cell body was healthy, it made no contact with muscle which is functionally the same thing as the whole cell dying. In the trial underway in the United States, Neuralstem is using fetal stem cells. While they claim their product will differentiate into neurons and glials, they only claim to be pursuing a trophic therapy. In at least one animal trial, the implanted cells extended the life of the model (it is worth noting that due to variability in the model, the ten extra days could just be statistical noise). The cells were found to fully integrate into the host central nervous system. Another group, TCA Cellular Therapy is using autologous cells taken from the bone marrow. Both of these trials involve spinal implantation. A planned trial in Israel will also use autologous cells but will do the implantation in muscle to try axonal uptake.

Regenerative therapy has its own set of issues. While the ability for stem cells to become neurons has long been demonstrated, the new neurons still need to make proper axonal connections to muscle (spine -> muscle) and within the brain to other neurons (motor cortex -> spine). In 2006, a study by Johns-Hopkins achieved that in test animals. The process required not only implantation of prepared cells but also significant treatment on the muscular side of the connection (sharp readers may notice similarities to procedures discussed above). A much more recent study from Stanford showed that proper preparation of the stem cells is critical for proper behavior of the cells after implantation. The cells prepared with retinoic acid (as in the Johns-Hopkins study) failed to create proper connections whereas cells prepared by co-culture with stromal cells grew robustly and made proper connections from the motor cortex to the spinal cord, bypassing neurons from other cortexes (visual, etc.). Caveates of the Stanford study is that the work was done on very young animals (about a week old) so fully adult animals may present a different environment, and that requirements for cortex -> cord connections may be different from spine -> muscle.

On most of the studies above, the links are to press releases. This is done to indicate existence and to give limited information. Copyright prevents me from republishing any studies (except for the PLOS link which is intentionally placed in the Public Domain. The reader should also note that my technical training is in hardware and software, not wetware.

A Very Special Olympics

2010-02-19T15:53:00.000-08:00

People often ask, "How do you do this?" The simple answer is, I have no choice. There is only one alternative and that only interests me in terms of rhetoric not experience.

But there is a deeper answer. Anyone who knows me will tell you that I can be one stubborn cuss. My grandmother used to say that I would argue with a fence post. I have always lived on my terms (often to my detriment) and this presented challenges which I learned to overcome. My chosen profession (Information Technology) gave me unique and complex challenges every day.

Motor Neuron Disease is just another challenge. I see no reason why this one can't be overcome. MND tries to define you: how you look, how you act, how you live, and how you die. I have defined myself and am not about to change. Instead of MND defining me, I define it. It is hurdle to jump. It is a hill to ski. It is just another event in which I compete.

Like an Olympic athlete, technology gives me the equipment to compete. Assistive equipment allows me mobility, helps with personal tasks, and keeps me nearly as engaged with the external world as when I was healthy. And it keeps me alive.

As with Olympic athletes, I am part of a team. I have a personal team of family, caregivers and doctors without whom I could not succeed. These are my coaches, trainers, and equipment handlers.

I compete for them as well as for myself. And I am competing for the Gold.

That is why I do this: I intend to win.

I'm Not Dead Yet!

2010-02-12T20:03:00.000-08:00

It has been a long time since my last post. Blame the holidays a bit. But the blame lies in the website being hideously difficult for me to update. I had intended to use Blogspot as the "archive" but found it so much easier to edit that I looked for ways to automagically include it into a site in which I had no administrative access to the server. A clever use of the "object" tag (for those who are interested) permitted this.

I have some interesting news to report in future posts so please check back. I promise no more 4 month absences!

Thank you all for your support.

Radio Show

2010-02-12T15:45:00.000-08:00

11/02/2009

A few weeks ago my mother Joan participated in a half-hour radio interview with P.J. Ochlan of KGIL in Los Angeles. Since I can't talk I had prepared some points to cover. Mr. Ochlan opted to read them verbatim and they are shown below (followed by a link to the show which you can download and play with Windows Media Player or similar program):

While I have an immediate financial need, this opportunity should be also used to inform the public. If not for the short average survival the number of concurrent PALS would be much higher and more visible like cancer or alzheimers. The NIH funding for ALS research is 10% of that for other diseases like atherosclerosis which already have effective treatment and are not fatal.

It would be nice to have Medicare support for home caregivers. Necessary skills are minimal (basic trach care, personal care) but are the daily difference between life and death. This is already supported in most or all European nations.

I am still a useful human, trying to use my skills and training to continue to assist others while researching the applicable biology and physiology to better understand what is happening to me. The mental acuity of PALS is very rarely impacted.

It is now clear that ALS is a multi-system disease which means more than just neurons are involved. Research into ALS therefore can be applied to many other diseases.

The show can be downloaded here.

09/12-10/29/2009

2009-11-04T16:52:00.000-08:00

10/29/2009

happy birthday Internet! I am proud to have known you before the web became your most prominent feature.

10/06/2009

The site was down last night and this morning. We increased our allowed monthly bandwidth and it was created as a new account rather than credit to our existing. Once it was cleared up it took overnight for the servers to sync. Joan did a credible job as a DNS administrator!

10/01/2009

It's Hocktober! I'm excited to the point of levitation. Unfortunately this will be the first season I will not attend any games in person, but this is clearly the reason Philo Farnsworth invented TV!

Go Sharks!

09/23/2009

I wanted to thank everyone who has donated so far, and to reiterate that no amount is too small (even $5). I have been asked about the Paypal buttons. The first is a user-defined amount and the second is $25/month for 24 months. I also wanted everyone to know that I have left no stone unturned. I was diagnosed by the ALS teams at both UCSF (who follows me) and Mayo Clinic. I was even tested for an extremely rare bacteria possibly acquired during a surf trip in the South Pacific. I appreciate your concerns and your questions and am happy to share my knowledge and experience.

Thank you all again.

09/22/2009

Busy day. First, the Sentinel published a follow-up to the story last year, and yesterday a clinical trial I have been monitoring for two years finally got FDA approval. I have read the published pre-clinical animal studies and had the pleasure to converse with the CEO via email. i am not expecting a miracle but am anxious to see what happens regardless. Note that I am geographically unable to participate...

09/19/2009

Good news! I got picked up by the Huffington Post.

09/16/2009

we finally got the Paypal buttons up! It is quite a bit trickier to get that going (especially for a site like this) than one might think. Thanks to all of you who have already responded. Please spread the word. We should be able to populate the Photographs page tomorrow. I will sneak a few from my Facebook page...

09/12/2009

Hello and thank you for visiting. I will update here periodically to give an idea of what this experience is like, try to publicly answer questions thrown my way, and announce important new research in the quest for a treatment and/or cure. Older posts will be archived in the future as we change and improve the site.

Please check back often and don't hesitate to ask me a question; I spend a lot of time on research and enjoy sharing what I learn.