Laminate this

I have never had fasciculations or weird muscle behavior in my rear neck muscle, the one that keeps the head up, but I have had them for several days this week. Does this freak me? Oh yes, it does. It's a sign of getting ready to die. No thank you.

We saw 'Minority Report,' for the first time, on DVD last night. This ALS thingy begins to become increasingly urgent and bizarre. It's like science fiction. Soon I am going to try powerful drugs. I'm not getting a new set of eyes and hiding in an ice bath, but it feels like that.

I'm going to print this, laminate it, and attach it to my key ring. Just in case:

I'm not drunk; I'm disabled. I'm not retarded; I can understand what you say. (Flip card, please)

I am not drunk or retarded. I have a disability that makes it difficult for me to walk and talk. But I am very intelligent and I can understand what you say. If you will be patient, I can communicate with you. My doctor is Dr. XXXX XXXXXXXXX, (000) 000-0000.

Pants update: I washed the Levi's on hot and dried them on hot, twice. The new ones (32W 36L) fit without a belt. The two I got a few weeks back can kinda stay up without a belt, but they feel more secure with one. Satisfactory. The pile of old jeans with holes in the knees can now stand down from duty. With respect, they are shown to the right.


Social Security update: I am in the process of completing my Social Security benefits application. I finally called the local office to complete the one I started online in November. The nice man sent me some forms to fill out. Yes, I know it's been over a year since my diagnosis and I should have done this in the first month. But I did what I wanted to. Call me lazy; It's true.

My daughter got her first pair of ruby slippers. See picture at right. They were a hand-off from a friend who outgrew them.


Here are a couple of URLs describing long-term beta-lactam treatment. All of these drugs should act on GTP1, per the 1/6/05 piece in Nature. The first URL mentions use of ceftriaxone for three weeks.

The second URL mentions use of amoxycilan for 26 weeks. No neurological problems are mentioned in either case, as far as I can tell from skimming.

So it looks increasingly like the risks I face are the standard ones, diarrhea, colitis, or the Jarisch-Herxheimer reaction, if indeed I do turn out to have Lyme.

I bought a hand dynamometer on eBay the other day, for testing my grip strength. Hopefully it will arrive before we start the Ceftriaxone Wednesday. Also, I ordered probiotics over the internet yesterday. A friend of my local neurologist's has had success with probitoics (friendly bacteria found in the body naturally). Based on what he says here, I may be able to go to a fancy health food store and walk out with what I want:

I use Garden of Life (Company) "Primal Defense" Probiotic formula (90 caplets to a bottle). It also can be taken in powder form. Both need to be refrigerated. It should be in a refrigerator section of the health food store and then in your refrigerator at home. It is a culture of 14 probiotic sources and is delicate. Once swallowed, it lasts 72 hours but needs to be replenished daily. These days I take only one per day but postop I took 3 at night & 3 in the morning. Most lactobacillus products will help digestion but do not much more. This one is strong and diverse enough to block many opportunistic bacterial invasions following the disabling of an immune system by massive antibiotics and/or excessive radiation.

9:07 AM: I just got back from a local health food store with the exact brand of probiotics the guy mentioned. I downed three caplets right away. And the bottle is in my refrigerator. Yay!

I also just ordered some glyconutrients. It may be just way to sell you expensive sugar, but it at least has plausibility. Unlike homeopathy. But it looks like I'm going to be getting that for free. Which is what it seems to be worth.

11:27 AM: Every single time, I think I am going to make a sort quip and be gone, but it usually turns into a tome. So after I scored the probiotics and ordered the glyconutrients, I went to pick up my prescription of the obscenely expensive, barely effective drug riluzole, which usually costs me $15, and the lady said, "Wow, this is really expensive," to which I said, "Yeah, but my insurance covers that." Then she asked me for $8.23. Or at least I thought she did. What she really said was $823.59. Still thinking there had been some price break from $15 to $8, I said "But it's usually $15." She checked again, and said that my prescription had been rejected by a third party. I asked her for a printout, and she gave me one. It does not even say what third party. If this had happened a year ago I would have been super-stressed right now, angry, jittery, sweating, hot. As it is, I could almost not care less. I know that riluzole doesn't help people, and I plan to start ceftriaxone, acupuncture, probiotics (started!), glyconutrients, and homeopathy this week. But I did send an email and leave a voicemail for the useless ALS clinic, as well as leave a voicemail with my employer, in case they are the third party. I have recently begun making payments to them to pick up my part of the insurance, so I assume my status has changed in some way. Or maybe it is because my employer was purchased by a larger company, which switched us over to an equivalent, but new, health plan. I bet that's it. The pharmacy is probably running the pill deal off of the old policy, which is kaput now. Whatever; riluzole is useless.

She was being nice and just doing her job, but she also asked me to sign off that I had read the privacy policy. This is the policy where you must agree that they will violate your privacy. I had to ask her twice for a copy of the policy before she understood. She looked around and had trouble finding it. I may have been the first person to ever ask to read it.

3:53 PM: Yep, the change in plans was the problem. Now I have the pills. Under the new, improved plan my co-pay goes up from $15 to $50. I'd say this drug is worth about $27.95.

9:18 PM: Just got both kids to bed. Phew! Did I forget to mention that I got my first accupuncture today? The needles are so tiny it's hard to detect them. Acupuncture has some plausibility, and quite a history. And it can't hurt to listen to Joni Mitchell.

FARK

My limp when I walk is something you would notice. But at higher speeds it is less apparent.

Off to the right you see the prototype of the new B&V rocket under construction. I'll explain that some other day.

So with a name like FARK.com, and topic categories that include things like Boobies, Dumbass, Sick and Weeners (among more standard ones such as NewsFlash), you might think that the members there are a bunch of immature, scornful guys. Especially after you notice the animated GIF in the corner showing the extremely-endowed "SbB girls." Wrong. I posted a link to my So You're Going To Die! transcript there, and some FARK member called MelLuvsDMB bought me a $25 membership. No kidding. I found a picture of her on the web. The picture is in the second row down, on the right. Thanks Mel! When I logged into the site, there were a flood of supportive messages. Some from women, and some from guys who aren't jerks. And there was no abuse factor. Wow!

I got a lot of praise for being strong and having the right attitude. I'm not sure I deserve credit for this, as I consider myself lucky to have been born naturally irrepressible.

Now you are wondering why I promoted the site to FARK. Two reasons. One, I am interested to learn from experience how the internet culture works, and how communities are built. And two, I have gotten a lot of useful information and ideas from complete strangers who've read this blog, and, given what folks have said, it has sometimes gone both ways.

I encountered FARK when reading some random blogger's post about what happened to his hits when he FARK'd an image of skimpily clad model. One hundred and fifty thousand extra hits. My FARK adventure netted maybe one thousand times fewer extra hits, but I feel even more cozy about my fellow human beings than I did before. Thanks, people!

Sputum update: This is a medical blog, so avert your eyes unless you want the sputum report.... Uh, the gram of bronchial phlegm I noticed two mornings ago morning had by yesterday morning increased to a teaspoon. This happens just once a day, but it is obviously increasing. I would be tempted to call my GP and ask if I should start taking the poultry antibiotics now stored in my closet. But this is the weekend. And I suppose I could call him Monday and start them then, but see I have this plan to receive a massive infusion of powerful antibiotics on Wednesday. So, hmm....

Infusion plan

My speech slurring is increasing, and is noticable to strangers now, though none have commented on it, nor have the kids. The awkwardness walking continues to increase.

Ninety percent of parenting is talking, and it really concerns me to think of losing my ability to speak. A lot.

Currently the plan is that I go to the infusion center at a local hospital for the first ceftriaxone injection. They put a needle in me that stays in me for the whole course of the treatment, which to start with will be seven days. I don't want my kids seeing the persistent needle, and I don't want it being jostled or torn by my clumsiness, so I am going to ask if they can put it up close to my armpit. The first day's adventure should take about three hours.

Then the next day the infusion nurse will come and teach is how to do the injection at home. That will eat two hours. We only have two days a week when both the kids are simultaneously in preschool and daycare, and my lovely wife will be sacrificing much of that time for this effort, rather than doing her professional work.

Meanwhile I am also interested in pursuing the acupuncture, probiotics, and glyconutrients. The acupuncture appointment has been made for Monday Jan. 31. I still have not ordered the probiotics and glyconutrients. Lazy dog. Maybe I can get some probiotics first thing Monday and start slamming them right through to Wednesday. I want to have good flora going into the procedure, and a way to restore them after. And what the heck, during. But this drug ought to kill off every good bug I have in me.

One thing my neurologist has made extra clear is that if the drug gives me diarrhea, I must stop immediately.

A friend who might have Lyme disease, or might not, wrote me about his experience with antibiotics, educating me about something called the Herxheimer reaction:

> Here's what happened to me. I was about 7 months
> into my "attack", and still undiagnosed. My Lyme
> test was negative, my neuro said maybe MS, but
> probably not. I had done research on minocycline,
> and found that if it was MS, then minocycline was
> having good results as a means to stop its progress.
> My neuro wanted nothing to do with trying this, so
> I found an "alternative" doctor, who was quite open
> to experimenting, and he gave me a minocycline
> scrip. Day 1, nothing. Day 2, nothing. Day 3,
> woke up feeling like I'd been hit by a truck. Day 4
> the light bulb went on over my head; I'd remembered
> reading about the Herxheimer reaction with Lyme
> patients, but I really wasn't expecting it, so had
> sort of forgotten it.
>
> I felt crappy for about 8 or 9 days, then started
> feeling better. Within a week, I had an appointment
> with a Lyme specialist, and he said that yes, that
> could have been a Herxheimer reaction, and he
> switched me from minocycline to tetracycline. I
> reported this back to my alternative doctor, and
> then we both agreed to let the Lyme specialist
> manage my meds for the next year or so. So I've
> been on antibiotics for about a year now (from
> minocycline to tetracycline to biaxin and, in the
> past month, back to minocycline). Still
> symptomatic, still slowly getting better, and yes, I
> know that that might just be coincidence.
>
> But as for you, well, if you feel like you've been
> hit by a truck, you'll know why. Note that
> Jarisch-Herxheimer reactions last longer for Lyme
> (maybe a week, sometimes longer) than they do for
> syphilis (only 24 hours or so), which your neuro
> might not know. But even if you don't have a J-H
> reaction, you still might have Lyme. So by all
> means find a specialist!

Socks off

In case I didn't mention it, the banister I put up is a roaring success. I also need to paint those window frames where we had the contractor repair the ropes in the sash system.

I love having projects to do all the time. Good thing we bought a nice, older house.

Also, stand by for a radically-new spec for the B&V rocket. I have prepared an epoxy-coated corkwood plug for the end of the reaction chamber. If that doesn't get your blood pumping, I don't know what will.

I may just be on the point of beating this cough, as I think that the cold itself is gone. But I know I have felt that way previously, right before the cough kicked into high gear. We Shall See.

A friend was telling us yesterday about how their kids were waking them up four times a night with issues like "My socks fell off," and how they finally got them to stop by saying that Mommy and Daddy need sleep too, and if you wake up, we're not coming. I didn't get a chance to ask her how they prevent the kids from coming to them. Our son had been good about not waking us up for about a week, by the time he heard that story. Last night he came in and said his socks had fallen off. The little girl cries out several times in the night, and my lovely wife goes to calm her down. My lovely wife does this despite having a cold and her throat hurting. I think the girl is doing it just because she is sick, and may have molars coming in too.

Drip

I was downstairs in the garage last night spraying the instant chalkboard black onto the decorative knobs and the spots where I have epoxied them onto the ends of the new curtain rod. I heard a dripping sound as I turned off the light to go.

"Uh-oh," said my brain.

I turned the light back on and saw water dripping down from between the joists and onto the old dusty rug that is down there to catch paint drips. My son was upstairs taking a bath and running the water.

Man of action, I cruised upstairs, determined to turn off the main water supply to the house. Then I noted that the dishwasher was on, and that got me to thinking that the leak was localized from the drain of the bathtub. This was wrong thinking by the way, as it could have been from the water supply to the tub.

When I got upstairs I saw one holy mess of water on the bathroom floor, but I surmised that it had come from the splashing of the boy, not from some leak. I turned off his water and told him and his mom that it had to stay off, because there was a leak. I pulled the plug to start the tub draining. This did not cause me to reflect on my earlier error in thinking that the leak must be from the tub drain.

Then I went downstairs to have a look at the pipes, and realized that I was a lucky dog. The leak was coming out between two floorboards, and definitely not from the nearby pipes. Somehow, the lake my son had created in the bathroom had gotten down through the floor.

My theory is that it went under the door flashing and the carpet just a bit, found a crack between floorboards, and did what nature demands of water.

Today I hope to find time to remove the flashing, inspect under the carpet, squirt in some caulking if needed, and perhaps form some kind of seal between the flashing and bathroom floor so that the water cannot leak out next time.

Because, despite whatever stern lecture I give, there will be a next time.

Saw the doctor about the cough
I went to see the GP yesterday, due to my cold and cough. He listened to my lungs and seemed to think they were all right. He gave me some free samples of Nasonex. My lovely wife swears by it. It has helped our son with his allergies. My lovely wife thinks that I may have allergies that make me more susceptible to colds. The GP said that my nasal passages look like they have a cold, not allergies. Although on the previous visit he did say that my nasals looked somewhat allergy stressed (white tissue, as opposed to red). Because a friend of ours who has been through chemo twice gets an annual nasal injection of steroids, I was instructed by my lovely wife to ask about that. The GP said that while it does reduce your vulnerability to allergies, it also weakens your immune system. So it's a wash. The weight continues to be up: 136.5 in pants and shirt with no shoes or keys. And the blood pressure is good too: 118/76. Pleasant surprise: My self-measured inhale volume was 4500 mL, twice last night, despite the cough and cold. That's the best since 12/30/04. Go figure.

Pants update
I don't like the new, thin denim in the 501 Levis, I don't like that they chose to make it hard for you to buy them, and I don't like the supersizing either. But yesterday in the store my lovely wife and I encountered a whole wall of them. I found three in my size. Add that to the two new ones I already have, and you come up with the magic number of five. I'm washing them on hot and drying them on high, in hopes of shrinking them. So for the next few years anyway, you'll generally see me in jeans. Nonetheless, I'll always be planning my defection to khakis or something else.

11:26 AM -- In other good news, the chiropractor, who I have not seen in several months, perhaps six or eight, reports that the scoliosis (bending) of my spine toward the right side (the stronger side) is no more pronounced than it was last time she saw me. She says the disks are somewhat rotated, and the ribs on the right protrude a bit at the spine.

The roofers are up there making things better. I noticed some faint water damage and called them. They did good work last time, and I expect that they will this time, too. The house will be protected, even if I kick off rapidamente.

In other news, with the application of a little black paint to coat the screws, and putting the rod in place with decorate end knobs, my portion of the curtain-rod project is officially complete. This is what we call a Yay-Daddy! moment. Now, on to painting the new cabinet for the kitchen...


It's the people at the ALS clinic who will try to bring me down with their sober assessment of just how messed up I am and how much functionality I have lost. I have tried to prepare my wife for this by telling her that it's not what they say that matters, but rather what I can still do and how I still feel. I can still do a lot and I still feel happy and optimistic. Rock on, Jacksonhole.

6:29 PM: I just got off the phone with my local neurologist who I relate to so well. He called. He says the fear of developing bacterial resistance is not such a big one in my case since I do not have an infection. Then again (and let's just agree that the body is a mysterious thing), you can make an argument against anything ... and I've always understood that many bad germs (e.g. pneumococus) are present in the body at all times, just waiting for their chance to blossom. So I might be developing antibiotic-resistant pneumococus bacilli and a few years from now when I get pneumonia, they'll be resistant. Maybe.

He said the major risk is diarrhea, and if I start to get that, we have to stop the ceftriaxone.

So far the plan looks like this: I will get the first dose intravenously at a hospital, in case of allergic shock, then be trained to self-inject using a syringe. Supposedly insurance will cover this approach.

We also talked about down-regulation, and he stated that if this ceftriaxone had a down-regulation effect on GLT1, that would be a major neurologic complication which should be reported in the side-effects, and he said it's not.

So the plan would be to go with a full seven-day course and then assess regarding future dosing schedule, if any.

Remember, those cell cultures and those rodents showed improvement within 48 hours. We're going to use grip strength as our measure.

Isolate and stupefy

My cough continues, though no burning sensation yet. This blog IS for tracking my medical condition, so it is without shame that I mention the gross detail that there has been a tiny bit of productivity to some of the coughs. Maybe a bacterial infection setting in? Going to see the doctor this afternoon. Aside from the cough, I have been feeling great for the past two or three days. Maybe psychological, maybe physical. Maybe it's the people praying for me. I'll take it!

The coughing woke me up this morning, but fortunately I had obtained enough sleep. This morning, for the first time, one of the yawn-stretch muscle cramps (right calf) persisted, and made me limp, more than usual, getting out of bed. It's still there, though I am working it out by pressing the foot against a crate under this desk.

I while back I drafted an essay explaining my thoughts on the election, the war in Iraq, the struggle against terrorism, American culture, history, and everything else I could think of. I sent it to a few friends, who offered lots of helpful feedback. Then I put it in the molding bin. It's still there, molding, but I thought I would bring you one of the thoughts I've often had about American culture and the role of the New Right.

First of all, let me say that many systems evolve naturally and spontaneously without any master conspiracy. And what I am about to describe falls in that category.

The first effect is isolation. Due to our history, geography, and economy, Americans live in small, single-family units, often at great distances from their own families of origin. In many parts of the world, people live in multi-generation households, with extended family (aunts, uncles, siblings, cousins) quite nearby. There are major irritations to living this way (as no doubt Bushra can tell you), and I don't want to live that way with my relatives. But there are undeniably major advantages. Bushra, or one of her selfless and giving younger siblings, could do laundry for everyone, while I cook dinner. Many hands make light work.

Americans are isolated, through a process often called atomization. We are not the only ones so affected¹, but we may be the most severely-atomized large culture in history.

You've heard of "divide and conquer." The isolation is the "divide" part. It's perpetuated and reinforced by itself. As our economy and infrastructure increasingly encourages individualism, the economic and lifestyle options for people increasingly require atomization. Automobiles and highways are just one example, now perhaps a bit dated.

Yes, I know that this trend also effects Europe and other developed areas, but we Americans are particularly susceptible to it given our collective ethos of rugged Western individualism (we are all cowboys to a certain extent).

The "conquer" part is that we're all so busy coping with our own deficit of time and money (Kids! Mortgage! Car payment! Work! Sleep?) and pursuit of the various luxuries we have been convinced that we need, that community and political involvement is very low on our list of priorities, and usually entirely absent. We're conditioned to pick up on what is easy and abandon what is hard, and we're more prone to adopt simple, entertaining and satisfying social beliefs and political positions.

The same in true in Europe, of course. But it has not snowballed out of control the way it has in America. There are a couple of reasons. To observe one, we can return to the Rugged Individualist ethos once again, and consider that the average American considers joining with and getting support from others as weakness -- not "standing tall." Working with others smells Communist, too.

The other part of the "conquer" is that the Republican party since 1980 has tacitly devoted itself to destroying the quality of education in this country, while publicly declaring its love for education. In kind, they have encouraged destruction of quality news sources, and enabled the suffusion of ignorance-promoting media from Fox News to the morally degrading content that they make so much political hay from opposing.

The Republican party itself did not always stand for turning America into a Third World plutocracy. The party used to be lead by sophisticated, rich, greedy, elitist patriots dedicated to their country, and principles of liberty and responsibility. If you are an educated, open-minded Republican voter and you are still reading this post, you most likely are a contemporary manifestation of that earlier, civil, Republican Party, and I'd like you to wake up, look around you, and recognize the destructive forces who have remade your party into an engine of insult.

Ronald Reagan personified the attack on intellectualism. Anti-intellectualism had always been a thread in American culture, but Reagan wove it into a shirt that still torments us. We entered a self-reinforcing cycle in which uneducated, malcontent, impoverished people who consider themselves to be the real, genuine, honest Americans vote Republican -- and thus against education and the benefits of community. And a new generation of Republican voters is born.

Certainly, not all Republican voters are ignorant. Many sophisticates are supporters because they are wealthy and greedy. Still others have other reasons. But the bulk of Republican support comes from a well of ignorance and privation that leads to a desire to lash out. The targets may change from year to year (foreigners, racial minorities, gays, the ACLU, over-regulation, greedy doctors, big government, pagans, Hollywood, the rich) ... but the real damage is done to education and community bonds. The result is more ignorance and resentment, and more Republican voters.

I don't believe that the New Right set out to do this with a master plan, but each time an election comes up, from local to national, they obtain the most Republican voters by being venal.

I say "Republican voters" in a qualified way, because Americans are not Republicans by nature. They are honest, hardworking people who truly want to care about others. And the New Right may quickly find itself to be the target of all the anger they have infused into our society.

Or not. Perhaps we will never recover.

The initial conditions and vectors which lead one complex system (such an an ecological system, or a culture) to spiral down into a hole, while another flourishes and remains healthy, can be quite subtle. Infinitesimal. The famed Butterfly Effect.

While Europe is quite similar to the U.S. in many ways, it is also quite different, in that they would never have elected or even considered a vile thug like George W. Bush to be their leader. I believe that there was vote-rigging in Florida and Ohio in 2004, but it only worked because nearly 50 percent of Americans did vote for Bush. In Europe that would never happen. The rigging required would be obvious, and there would be a revolution.

And they would not sit passively while their educational systems were destroyed, much less assist in the demolition.

Some Butterfly Effect must have made the difference in the history of American culture and European culture. It is not necessary for my thesis to identify correctly what that was. But my guess is that the idea of America was founded by those who departed Europe, who wanted to escape, and who then again rejected a European system in the American Revolution. Add to that the huge frontier, settling new lands, and (despite all the evidence of cooperation in our history) we find ourselves slightly more willing to think of ourselves as rugged individualists, and to distrust other people.

I have faith that this is not the only America that is possible. I love America, and none of you should count her out.




__________________________________________________________
1
Yes, I used 'affected.' Actually!

And yes, this is another post that I thought would be a short quip. It got out of control.

Lucky

Yes I know I have lost functionality in the past few months, become more clumsy and slurred, and yes it alarms me. But yesterday my two-year-old daughter told me she wanted to push her baby doll in the stroller to the park (which is about four blocks away). And as I accompanied her, it struck me how lucky I am, not just to have such a wonderful daughter, but also to have had ALS for over a year and yet still be able to walk with her to the park, including the parts where I carry her and the stroller across the street. We had a good time at the park. On the way back, she bundled the baby doll in its quilt and carried it along, kissing it on the top of the head every now and then. "I'm cuddling her," she said. On the last block my daughter wanted to be carried, so I carried her and the stroller (she carried baby doll), for a block. And yes it was a strain on my arm and yes I did have to walk very carefully so that my left toe did not catch up on something. But I did it. Soon she will be too big to carry, but soon she'll be able to cross the street while holding hands.

Lucky man.

There was an article in yesterday's S.F. Chronicle which mentioned this blog.

My cold is taking the usual course but I am not miserable yet. I will see the doctor, perhaps even today. And I have the antibiotics for chickens in my closet.

As to Iraq, expect the U.S. to bug out in 2005, beginning the process after the Jan. 30 elections. The super-tough New Right will turn tail and run, with lots of hand-waving about how we can't solve all the problems in the world, and how the Iraqis have to sort their own problems out. As the blood seeps under the closed door the phrase will be that we can't "turn Iraq into Sweden." As a fractured cauldron of theocratic terrorist training camps blossoms, expect the dialog to be about how the liberals made this happen because they're so disloyal.

Baggage

Once when we were in college we were running the dorm during the summer to host a conference of some kind. We had been told not to help anyone with their bags. A woman arrived with her daughter of perhaps seven and presented us her bags, saying without preamble: "My daughter has a fatal, incurable disease called XXX..." (I don't remember what it was) "...and so I think we deserve that you will carry our bags upstairs." She seemed annoyed.

I was then, and still am, a radical in many ways, and so I remained seated, and just looked at her. One of the other, more dutiful students (I think it was a girl), hopped up and carried the woman's bags.

"I know she was mean," said the dutiful one later, "but that poor kid."

Knowing what I know now, even after my ALS experience, if you made me 20 again, I still wouldn't carry that woman's bags an inch. Not one inch.

I have a real, involuntary cough now, but it has not gotten to the burning or hurting stage yet.

Curtains

I am being attacked by cold germs, my sinuses are stuffy and there is some initial coughing.

It does put me in a bit of a weird experiential state. And as a result of my progression, I am feeling both more selfish and more selfless.

So come close my child, let me whisper you this: If you are going to use that instant chalkboard spray paint on a smooth metal surface, it will easily abrade off, but if you coat it with a polyurethane from the stain section of your paint store, it will be fine, though it will add just a hint of gloss, which you can only see up close.

Olney

The point of this article on Olney, the director of the UCSF ALS clinic who has recently been diagnosed with the disease, is to point out how noble he is for participating in a placebo study he designed.

But the parts that strike me are these:

In any case, it appears that Olney will not be among the long-time survivors, according to Lomen-Hoerth. She said he probably has only a matter of months to live.

[...]

Olney said his case appears to be on the fast-moving end of the spectrum, characterizing it as more rapid than average, albeit not the most rapid case he has seen.

When I look at my own case, and consider that I was diagnosed over a year ago, and through all that time could still walk and talk and use my hands and work on the house and play with my kids, I think what an astounding blessing it has been. Not that I can expect to progress slowly and live long, because recent events and the clumsiness of my own tongue belie that, but rather, that I had that magical year at all. And it fills me with an anger, an angry insistence that whatever functionality I yet have left in me must not be squandered or taken for granted.

Each day is precious. Those of you who do not have ALS, but who are instead fated to be run down by buses and ambulances and Oscar Meyer weiner-mobiles, accept intellectually that every day is precious. But those of us with ALS feel it, or ought to feel it, every minute.

I dug out three dandelions from the lawn yesterday. I put up a curtain rod. I played with my kids.

This week I met two people through this blog who have ALS. They are the first two, ever. There is a Yahoo group, and there are other forums, including local meetings, where people with ALS can be met. But meeting folks with ALS through the blog is valuable to me, because I assume (perhaps wrongly) that they do not find my sarcasm and irreverence offensive. There are a lot of very sincere, but very innocent, people out there with ALS, and I feel separated from them because I am such a weirdo, and many of them are not.

Hoo-ah

Let us give thanks to the European Space Agency (with help from NASA) for the excellent peek at Titan.

And, as usual, great work Mars rovers team!

Effect vs. Affect, round two

Servant's comments reminded me of a couple of lines from a poem I wrote years ago:

words are periscopes
submarines collide

Thanks for checking with your professor, amanda, but her first sentence addressed common usage, and as we know, my readers are exceptional. ;-) Seriously though, in this section she appears to support my stance:

When you mean "to bring about the result" (instead of to influence), "effect" is the verb: He effected the change (He brought it about--he didn't just influence it)

Effect is the verb for bringing about a result. While there is apparent conflict between her first and last sentences, it is only in the area of whether these words are used commonly or in specialty discourse. Since she specifically addresses effect as a noun and affect as a verb, it is does not bear on the point, since I am addressing the case where both are verbs.

This example, however, I must differ with.

The weather affected the availability of tomatoes in our stores. (influenced; verb)-- frequent usage

At least using Merriam Webster, we conclude that she means the weather cultivated, feigned, tended toward, or frequented the availability of tomatoes. That makes no sense, and in this case I think it is correct to use "effect" in that the weather caused to come into being a shortage of tomatoes.

Given that I had to insert the word "shortage" into the example, this supports the idea that we are all using the words incorrectly much of the time. The verb "effect" comes with requirements that we often fail to meet. Probably it's better to say that the weather influenced the availability of tomatoes, or better yet, led to a tomato shortage.

CJ is correct in her comment that language is a pliable, evolving structure. Lamarkian. It's odd that I appear to be in the "proper usage" camp on this issue, as my stance has always been to tell the language prudes to get bent. My vehemence here is actually a counterpunch against the language prudes. You can use "affect" to say that the ear influences the body if you like, just don't by thunder tell me that the dictionary proves you are right, and I am wrong to use "effect." The dictionary backs me up. Don't tread on me.

This So Fresh and So Clean, Clean post is hilarious.

Stretch cramp

When I awake in bed I stretch, often with a yawn. It's involuntary, you probably do it too, and normally it's a healthy thing. However, for me, it usually results in a cramp, and a feeling of damage to my muscles. If my legs are curled, it hurts the thighs. If they're straight, it hurts the calves. I conjecture that this is the major way my leg muscles deteriorate. I don't dwell on the negative, but I imagine that if some day I am unable to get out of bed and stand up, this will be the reason. I don't know if there are drugs which can inhibit yawning and stretching, but you'd have to think that they'd be awfully nasty compounds that you wouldn't want to take.

Ear seeds

I have tiny seeds taped to my ears as I write this, and the ears are still hurting from the pinching. Getting hit, or tapped, with the cardboard tube didn't hurt at all, but when she pinched the joint of my left thumb, my thumb twitched a bit.

I hope the Silicon Valley vibe of the iPod earbuds I'm wearing doesn't conflict with the traditional medicine of the tiny taped seeds, but I wanted to listen to the news, and unfortunately they are broadcasting the confirmation hearings of that odious Dr. Rice.

Although I must say that I think Velvet Underground performing "heroin" is not the right Chi for me at this time. Good song. But so sad the concept.

The acupuncturist's English was better than I expected, but I realized as I was driving home that I had wanted a detailed speculative consultation involving lots of rapid back-and-forth discussion. My wife knows an acupuncturist, so I think I will go to that person for the consultation and the actual sticking. Today's doctor gave me a discount from her usual $88 fee to $40, because, I think, she didn't stick me.

What I did learn, and you will have to excuse me but this will be a blend of what I thought I was told and my own interpretation, and therefore probably wholly inaccurate...

The ear is analogous to a baby, head down in it's mother's womb, about to be born. The parts of the ear correspond to the parts of the body, and by manipulating the ear we can effect¹ the body. The earlobe represents the head, the edges of the ear represent the arms, the top edge the legs, and inner parts of the ear the lungs and heart. By stimulating these parts of the ear with pinching and pressing as well as, presumably, acupuncture, we can stimulate and heal the corresponding parts of the body.

My theory regarding the seeds taped to the ears is that seeds contain vital energy and compounds; they are the start of life. By taping them to the ears (it was important to press them until they hurt), we transfer that new life energy to the corresponding parts of the body. Using much the same logic, modern Western medicine has begun to focus on embryonic stem cells for healing and rejuvenating properties.

The head apparently contains tendons which effect the rest of the body. By tapping on the head with a knuckle or hard brush needles, we stimulate and heal those parts of the body.

I was advised to tape the seeds to my ear each day. On the first day I should squeeze the ears, until they hurt, three times. On the second day twenty times, then three the next day, and so on in alternation.

The questions she asked me were whether I was cold, whether I was hungry, and whether I'd been coughing.

I was told to relax. This was really the main message. Not worry. And this I can say I will be able to do. The not worrying part and the relaxing part have been my practice for years.

Also, stay out of the sun. She looked at my freckles. This raised my hackles a bit because many years ago I ran into a very bad doctor who called my freckles "sun damage." I had the reaction then that he could get bent. I decided to forgive the acupuncturist and we moved on.

I was assigned 30 minutes of daily visualization work: The wheel of energy flowing from the head to the hands and then back to the other hand, in a circle. The flow of energy (or something) from the head down the legs to the foot and then flowing away, not coming back. I was also told to visualize the organs behind the three centers of my Chi (clavicle join, upper abdomen, lower abdomen), and picture healthy lungs and heart, healthy stomach and kidneys, healthy bladder. See the body as a flower or (I think she added this for the Western mind), as a street with traffic flowing smoothly. See good water in the kidneys.

Don't drink or eat cold things. Drink a glass of warm water each day, avoid being hungry or overly full, put your feet and hands in warm water for 30 minutes each day. Then, after the warm water, spend 30 minutes pressing the hands and feet on something hard that has an edge. If you find a spot that hurts, press more there.

I was advised to slowly tap myself on the head for five or 10 minutes each day, gently clap my hands together for another five or 10, as well as give myself a five-minute ear massage. I am supposed to massage my own hands and arms, and hit all major parts of my body with a wand or tube for a few minutes each day.

Pinch your fingers and your radius and ulna firmly each day.

Also, spend five or 10 minutes each day chewing nothing. Gently chomp the teeth together.

Lemon tea.

When you walk, go slowly and easily. Don't rush.

Relax.

The relax part I can do, but add up all the time I am supposed to spend and I think we come to over 110 minutes. I just do not have that kind of time. So I'll have to catch my visualization on the fly, and consider the shower as the warm hand and foot bathing. I can do a little clapping, tapping, and tooth clicking from time to time as I think of it. But I have barely remembered to do the isometric neck exercise I was given by the chiropractor. And it is almost all I can do to remember to hang my feet over the edge of the mattress and press each one up into the mattress 20 or 30 times before bed. I came up with this by myself and I like to think it is strengthening my ability to lift my left foot. That's an important thing when you have ALS. since many people suffer from "foot drop" and wind up tripping over things like rugs and Legos.

I'm glad I went to the acupuncturist. At the very least it gave me something to write about.

I'm going to spawn my own school of ear stimulation that involves stroking and rubbing, but no pinching or crushing. Ow!



__________________________________________________________
1
Effect
Function: transitive verb

1 : to cause to come into being
2 a : to bring about often by surmounting obstacles : ACCOMPLISH b : to put into operation
synonym see PERFORM
usage The confusion of the verbs affect and effect is not only quite common but has a long history. Effect was used in place of 2affect as early as 1494 and in place of 3affect as early as 1652. If you think you want to use the verb effect but are not certain, check the definitions in this dictionary. The noun affect is sometimes mistakenly used for effect. Except when your topic is psychology, you will seldom need the noun affect.

Affect
Function: verb

1 archaic : to aim at
2 a archaic : to have affection for b : to be given to : FANCY
3 : to make a display of liking or using : CULTIVATE
4 : to put on a pretense of : FEIGN
5 : to tend toward
6 : FREQUENT
intransitive senses, obsolete : INCLINE 2
synonym see ASSUME
usage see EFFECT

Movie reviews

Actually no, despite being a Cate Blanchett fan, I haven't seen "The Aviator" yet. We're like cave dwellers. We don't get out much.

I bought "My Life" with Michael Keaton and Nicole Kidman. It's about a guy given less than a year to live who makes videos for his unborn son. Normally I wouldn't buy this kind of tripe but I did happen to be looking at the $6 DVD section and I did happen to have a fatal, incurable disease and I do happen to be making a video project for my kids to watch after I die. So, I bought it and watched it. I guess I'd grade it as a straight C. At least they did have the sense to kill him off in the end, not cure him with happiness. Don't go out and get it. All the actors were squandered, especially Kidman, and Keaton is no great prize. The movie suffers from what I call Script Obstacles, meaning that a character is given artificial emotional issues in order to create some kind of tension. So in this one they decide that Keaton is a workaholic who avoids emotion and buries his childhood anger. Now granted, there are plenty of people like that. But watching the movie is like reading Blue's Clues: Should Blue just be sad, or should she help clean up the milk? The moral lesson is so obvious. I'd much rather watch a movie about a sensitive, emotionally and spiritually advanced guy who is dying his freaking ass off. Something sophisticated, not typical Hollywood drivel. I'll send this one on to the troops. What with the theme of dying before you get to see your kid born, it ought to freak them right out.

I also bought "Sex, Lies and Videotape," which goes to show you how out of touch with current events I have been for, oh, 16 years or so, since when videotape itself was a fairly new, trendy, titillating concept. Now we use digital video, but I'd still never seen this film before. It starts out with a guy having sex with his wife's sister. Do you suppose there'll be a happy ending? ... Wow, the danged thing was over before it started. I guess that's an independent film for ya. Not bad. Happy ending? Maybe, sorta. We won't know.

Blame

When you are diagnosed with ALS and you start asking what you might have encountered or fallen victim to that precipitated it in you, they tell you that you are not to blame. "Nothing you did caused this," they said at the unimpressive ALS clinic. As if I were blaming myself. That's an answer to a question I didn't ask. Since the experts don't know what causes it, there is no harm in patients trying to piece together patterns. And since my rapid progression in November and December (which I hope is stabilizing now, though I don't know), I have reviewed the blog to remind myself of things that happened in that period that I might blame. Yes, I know it's possible, or even likely, that the progression was going to happen no matter what. Here are the suspects I came up with, things that changed during that period:

• painting the cabinet parts in the garage


• Astelin


• Claritin D12


• taking some pills with food instead of all on empty stomach


• daily morning hike to preschool replaced by midday walks to video store


• MRI December 9


• ginseng

All of these factors have reverted to pre-decline standing, except for taking pills with food as indicated.

Solving a non-problem

My daughter, who is two, is able to blow bubbles using bubble juice and a wand. But it's not easy for her. This is the kind of bubble-juice container that can be tipped and dropped without spilling the juice out. Necessary features of this design are that the wand is inserted through a slot, and there is only a small amount of juice at the bottom of the container. Part of the problem my daughter has is technique. She holds the wand closer to the middle than she should, which reduces the length that she can insert, and she jiggles the wand in and out in an apparent attempt to prime it better. These techniques have the result that she often draws the wand out with no juice in the circular orifice. I tried to show her how to hold the wand by the end, and insert as far as it goes, but she immediately resorted to her tried and true method. It has, after all, resulted in several bubbles for her. She's only two, so she can be forgiven. But many adults take this same approach when using computers. Only they cuss more. I recently helped someone who is setting up a new Macintosh after years of using PCs. I had told her to just plug the ethernet cable into the back of the machine and she'd be golden as far as network goes. She called me a couple of days later and said that she'd been talking with the broadband provider (who let me just presume is a PC expert) and the Mac still could not see the internet. Worse yet, the Mac didn't seem to have Internet Explorer. I asked her to find that thing that looks like a compass (Safari) and click on it.

"OK, now it's showing me a page from Apple computer."

"Now try CNN.com."

"That worked."

"OK good, so you do have internet."

"But it kept telling me I didn't."

"What told you?"

"The Mac."

"What part of the Mac?"

"The network setup."

"OK, but you didn't need to set up the network. You were solving a problem that didn't exist."

She seemed annoyed.

Most aspects of a PC require hours of frustrating circular hassling, and so a good PC person (myself included) arms themself with a series of setup routines, a diagnostic mind, and patience.

In this case though, my friend was choking up on the wand and jiggling it. The attempt to make things work prevented things from working.

Then we were all getting in the car and my son asked me why the red lights that are exposed when the door opens did not work. I went into lots of theorizing about it. I explained when I thought the lights should work, and the scenarios under which other drivers would need to see them. We put effort into trying to figure it out, tested what happened when they key was in. Then I finally realized that the "lights" were merely reflectors. Once again, trying to solve a problem that didn't exist.

Then when I drove out to help my friend with the new Mac, she was completely gracious, and never blamed me or the machine, and we got a lot accomplished.

In other news, I'm pretty sure I can no longer juggle. I tried it today with oranges in the back yard. The reaction time of the left hand appears to be just too slow. I can still juggle two balls in the right hand, though.

Breathing room

I had this dream a few nights ago. In the dream I was testing my breathing, which is the primary indicator of how soon you're gonna kick off when you have ALS. Buy the farm. Screw the pooch. Check out. Die. And in the dream my breathing was getting stronger. I filled my lungs up as far as they would go, and then, by accessing some extra set of muscles, some other gear, I was able to draw in even more air. I enjoyed that feeling, in the dream. But in reality my self-measured inhalation volume is only 4300 mL, and remains in that range despite my lungs being clear. I just tested it, now. The decline from what used to be 5000+ is indicative of nerve and muscle loss to the breathing apparatus. What are ya gonna do?

My thanks go to two friends who recommended acupuncture. It may not help, but anything that seems plausible to me and does not involve a lot of time or money, is welcome. Yoga involves a lot of time. Or, let's put it this way: Since I am not a yoga person, every moment seems like a chore to me. Now don't go tellin' me that's the exact obstacle I need to surmount in order to break on through to the other side ... I am not a yoga person. And although I am spiritual in a way that does not need explanation or justification, I am also very much not a religion person. Maybe you can say my religion is my life; I can't go to church and lock away my goodness there.

Another thing I have lost, along with running and jumping, is my ability to be funny in person. I hope I'm not one of those annoying people who tries to be funny all the time, but judging by the fact that people sometimes think I am too serious and intense, I'll assume I am not. Anyway, I often see the humor in things and often talk about what I think is funny. Or do or say things that make people laugh. A major part of good humor, I think, is the ability to keep a straight face, so that the funny part comes as a surprise to your victims. I crack people up. Sometimes. If they're smart. And not mean. These days however, the disinhibition I previously wrote about (the nervous system loses control over expression of emotion ... leading people with ALS into uncontrolled fits of laughing or crying), has taken it's toll. Often, when I have something funny to say to my wife, I start grinning and laughing so much that I can't say what I was thinking. She can't even understand me, much less fall for the joke.

I used to be a master of poker face and smooth delivery. It's not totally gone, and I still get off a good one from time to time. But it's like losing part of yourself.

In the living years

Do you hear that song? It's about telling people what you feel, here and now. I have been practicing that a lot since my diagnosis, but had gotten into the habit many years before that. I make contact with people to tell them how much I appreciate them, or complete some dangling thread of conversation from twenty years ago. Or apologize.

So yesterday I did it again. In the computer store. I told the owner how excellent his staff are. These are people who have saved me much time and money by explaining things to me about my computers. Yesterday I learned that you can daisy-chain any firewire devices that have two ports, so a hub is not necessary. I also got a replacement for my keyboard, which I spilled water on that morning. In all my years of using computers, I have spilled water on keyboards many times, but this is the first time I killed the keyboard. Usually I turn the board upside down right away, and let the water drain down from the electronics. But yesterday I did not notice, until some time later, the small splash that had gotten in.

So when I was down there getting a new board and learning that I did not need to spend extra money on a device I thought I wanted (a common theme with them ... they're not just fatuous butt-faces trying to sell you things), I told the owner how excellent his staff are. He seemed proud, and thanked me. Yes, I think he's a Christian. So what, he has a right to take it any way he wants. The guy ringing me up also thanked me.

"Well you ..." I said, "...you're, uh, you're welcome."

pants in crisis!

So the Levi's 501s I have known and loved over the years have been modernized to the point that I can no longer wear them. This is a big deal, because since some time in the year 2000, they became the only pants I wore. Programmers are sometimes whipped like dogs and treated like dirt (though well paid!), and I decided at one point that since I felt like I was dying for my project, the least I could do was wear comfortable clothing.

But now the number on the label is a lie ... the pants are actually about four inches wider around the waist (yes, I am familiar with the difference between preshrunk and regular), and they have changed the fabric to this thinner version of denim which I despise. You might counsel me to just buy a smaller waist size. But then, what am I looking at, a 28w 36L? I doubt they even make that size. And I hate the new thin fabric.

So, now that corporate marketing pricks have destroyed one of the all-time classic American products, the question becomes: What pants should I wear? I am thinking about switching to Docker-style khakis. Please, people, if you have any suggestions, let me know. Because I plan to wear these pants seven days a weeks, 365 days a year.

One year since diagnosis

It's been one year since my diagnosis. Yesterday I installed a banister on our stairs. And I can still walk up and down those stairs. So I'm still here. Somewhat spanked, but still here. Nyah!

Apple

There is something instinctually rewarding about letting your little kids eat your food. Yesterday I was just about to finish my lunch with an apple when my two-year-old daughter came up and asked for a bite. She kept taking bites, and stood there with her warm little hands firmly over my hand, and ate about half the apple. I felt like the luckiest person in the world.

Argh!

My son continues to wake us up in the middle of the night, often more than once. It is grinding on me. I feel tired all day. We've tried everything to get him to stop. Usually it seems to indicate a worry he has about something. We thought it was the worry that we would put him in some kindergarten without him having any chance to prepare or adjust. We addressed that and he stopped the wake-ups. Now he's resumed again. It's hard.

Neon

I adore my 1995 Neon, which is going on ten years old and has never had an engine or transmission problem, no major problems at all, only minor things like blinkers and cables.

But it is all manual: manual transmission, mirrors, windows, steering, everything. And I have ALS and have noticed myself getting weaker and more clumsy. It is not yet a problem with driving the Neon, but it soon could be. And so it is with some sadness that I have decided to junk the Neon and get a car with power steering, automatic transmission, and power mirrors and locks. Oh, and a radio and air conditioning.

My lovely wife agrees. It's not as though I do a lot of driving, but having two cars does come in handy when she takes the kids somewhere in the other car and I have errands to run.

I despise the idea of buying a new car when I have one which works so well and does not come with a payment. So maybe I should look for a quality used car? Or ... buy a new car and then if I kick off or become unable to drive in two or three years, My lovely wife can sell the Ford and use the new car?

You may be wondering why I don't make the new car the family car and drive the Ford. Well, I hate the Ford.

Thanks for the suggestions folks. Well, I favor the Passat. As far as I am concerned, it's the best looking thing on the road, and in terms of looks, the rest of the cars are just cars, SUVs (transportation for fat people), or cartoon-luxury jokes like the Jaguar and the BMW-Mercedes-Lexus nexus. For solid, luxurious and stylish, I look no farther than the Passat. And it seems well-engineered and dependable. If I got a new car, though, it would have to be a Subaru, because we are walking-distance from to the maintenance facility for the Subaru. But if I get a used car, and not under warranty, then it could be anything, as there are a couple of decent repair shops near here.

berkeleygal, a sporty green Miata? A Mini Cooper? A BMW Roadster? Those are chick cars. OK, except the roadster, which guys who are trying to show off drive. So chicks and pricks. Those cars are strictly chicks and pricks.

Favorite MRIs

Here are some of my favorite MRI images. Some of them show the amyotrophic lateral sclerosis that is supposed to kill me. Some of them don't. But it is fun looking at the inside of your own brain.

The ceftriaxone plan

I went to see the local neurologist yesterday, and the plan we came up with was that once a month I would have three days of injections of Ceftriaxone, also known as Rocephin, at two grams per day.

I would like to thank Scott, with whom I was corresponding about Lyme disease, for being the first to alert me to the beta-Lactam study. Thanks also go to ALife, for providing the Nature article, and to Robert Fenton, for his excellent comments and concerns.

What Robert said was:

#1. The body is remarkably well adapted to down regulating genes that have turned on in excess. I would think that it will be difficult to adjust dosing to activate the promoter just enough to produce a healthy amount of GLT1 without the cell trying to immediately down regulate it. Further, would the patient experience the "law of diminishing returns" such as Parkinson's patients experience.

#2. Ceftriaxone has a very long bio half life. So much so that dosing is almost exclusively q24, and sometimes q12. Would a more stable dosing be required? Further, renal damage would become a concern at some point as well. Not to mention the implications of microbial resistance.....

This is the sort of thing I have read about, and knew about, but which did not occur to me as I was planning to jump with both feet into beta-Lactam antibiotics. Robert administered the smelling salts.

So after I got my parking receipt validated, I sat in the neurologist's waiting room and again read the study. A few things jumped out at me:

-- The mice, rat and human cell cultures responded to the drug within 48 hours, and the effect persisted for at least seven days.

-- The increase in GLT1 expression could be observed in normal rats given the drug, even after three months.

-- In mice engineered to be deficient in SOD1 and thus experience motor neuron loss (a.k.a "ALS mice"), "ceftriaxone treatment significantly delayed loss of muscle strength and body weight," as well as extending life span. This effect was observed within seven days after treatment.

-- (By the way, the study also showed no benefit from minocycline, so I expect the human clinical trial now underway to yield no positive result.)

-- The dosage given to the cell cultures was "comparable to the known central nervous system levels attainable with therapy for meningitis."

You might wonder why the "ALS mice" still died despite their increased expression of GLT1. They only lived about eight percent longer than usual (132 days versus 122). Putting on my rosy glasses, my response is that "ALS mice" are genetically engineered to become messed up. But the human cause is not solely genetic, and so mice and humans may experience different fates under ceftriaxone treatment. I like to think that the mice are doomed to fail, but humans are not.

I took seriously Robert's concern about the body down-regulating the gene expression. However, I was heartened that after three months, the rodents were still expressing at high levels.

The risks are down-regulation, strain on the liver, allergy development, and microbial resistance.

Given that the cell cultures responded within 48 hours and that the effect persisted for seven days, I thought that maybe it would be appropriate to go on ceftriaxone for only three days a month, in order to create a flushing effect, a period in which the motor neurons could clear out excess glutamate. If the effects persisted for seven days, then I would experience the flushing for 10 out of 30 days, or a third of the time. Who knows what benefit might accrue from my motor neurons having normal glutamate transport one third of the time? Maybe complete halt to progression. Hopefully the limited exposure would reduce the chance of Robert's concerns emerging as realities.

I loved making the decision on the fly in the waiting room. I have always trusted my hunches and strategic thinking (yes, especially when my hunch is that I do not have a good idea). I also enjoy debugging complex computer and software problems. And what could be more invigorating than trying to solve a wetware problem where your own life is at stake? So the waiting-room decision was a thrill.

An additional thought I had about the down-regulation threat was whether there might be normal people without ALS who use ceftriaxone on an ongoing basis. It stands to reason that if their bodies down-regulated in the presence of the over-expression, they must at some point experience motor neuron impairment. But we haven't heard of that. Which doesn't mean it doesn't happen.

But first the doc wanted to see if the sleeping hand I have experienced in the right hand each night for a week (except for last night and the night before) was carpal tunnel syndrome. He thought it would be. He has a very simple test using small electrode pads that he says is very reliable. My results were perfectly normal. So I don't have carpal tunnel. I like that result because it means that I can add the limb tingling to the ambiguous Lyme panel results to begin to imply that I have an atypical set of symptoms. I believe that I do have ALS, but I view ALS as a symptom, not a cause. So if my symptom set is atypical, then I hold out hope that my progression will be as well, and that my treatment and cure will be too.

The doc and I talked about my ceftriaxone plan, and he agreed. He looked up the dosage for meningitis and worked from that. By the way, my weight is holding steady at 136.5 pounds in pants and shirt but no shoes, so figure 135 pounds. He decided on two grams of ceftriaxone injected in half-doses twice a day for three days of each month. Originally he was going to do seven days, but I talked him down to three.



Now, the first time the ceftriaxone is injected, there is a chance that I will have an allergic reaction to it. It's potentially fatal. I can say, however, that I've had penicillin and amoxicillin with no allergic reaction, and they're both beta-Lactams like ceftriaxone. Anyway, he wants to inject me with the first dose, and observe me for 20 minutes. They'll have a needle of adrenaline ready and presumably schelp my spastic body across the street to the emergency room if I should have an adverse reaction. I'll be in good hands, or at least among good people.

I said that the conservative thing to do might be to wait until the first human trial is completed. But just between you and me, given the rapid progress that the ALS made in November and December, and still seems to be making (my walking gait and speech are incrementally getting worse), I'm not sure I'll be around in the three years or more it takes to complete a human trail. Or I may have lost a lot of functionality. I feel like the time is right for me to become a guinea pig, be my own human trial, get on the forefront.

The doc affirmed my thinking. You've got the worst disease there is, he said, anything you can do that isn't harmful is a good idea. I don't think it's the worst disease (can anyone say glioma?) but it is pretty bad.

You have to admit that this plan is pretty cool, in terms of the mental movie. He's dying, see, so they come up with an experiment to save him with a drug, but nobody's ever done it before. He could go down in like, the medical textbooks, or he could wind up as, like, a cadaver. Ain't it cool?

In the course of the conversation, the doc, who is a very smart cookie himself, was talking about a friend of his who is very smart. Then the doc made an interstitial remark that he placed this friend in the same "pantheon" as I am in. And he went on. I made a note of that. It's nice to know I'm in the pantheon.

The able office assistance also called me her "favorite patient" in front of the new office assistant and another patient who was, presumably, fighting back tears.

Our objective measure of the efficacy of the ceftriaxone treatment will be the same as that used on the rodents: grip strength. The doc has a thing called a grip dynamometer. I'm going to get one. He had me squeeze it three times, as hard as I could, with each hand. Using the right hand, I got it up to 100. The doc says the best he can do is 94, but he's significantly older than I am. With the left hand the best I could do was 38.

In the rodents, grip strength actually improved. I don't want to practice the test to the extent that I improve my grip through mere muscle exercise. So I think maybe I'll limit myself to testing it once a week.

But wait -- it gets more complicated. When I went to the pharmacy with the prescription, the pharmacist said that my company's drug plan does not cover injectables. The cost to me for one kit would be $520.

However there is the possibility that if the doctor administers the drug, the cost may be covered under the "physician's benefit." That means that they cover what the doctor does to you in the office. So I called the able office assistant and she said that on Monday she will have the new office assistant call my insurer and see if we can get it covered that way.

Those of you in other industrialized countries are no doubt recoiling in horror. Well, this is America. Sick people with no money are thrown overboard.

If it becomes the case that the drug will be covered on the condition that the doctor injects it, I won't mind paying a 10-minute visit to him three days of the month. And he'll be able to test my grip strength.

The Roche Labs manual's section on ceftriaxone ("Rocephin") says that in the case of meningitis, the ceftriaxone can be injected once a day, or in equally-divided doses at twelve hour intervals. In the case that he has to inject me, I will suggest to him that we use one injection a day, instead of two half doses. However, he has said that he is worried that two grams all at once is too much.

Since the antibiotic will tend to kill my internal flora, making, for example, death by diarrhea a possibility, I plan to load up on "probiotics" (oral supplements of the body's natural bacteria), both before and after the injections.

If you read all of this, claim your prize at the door.

Ad astra

My son and I flew his first successful rocket a few days ago. It's powered by a mixture of vinegar and baking soda. The air rocket never took off, and the water rocket went all of two feet. But the vinegar rocket soared to 25 feet, despite some fuel mixture problems. I think we can easily get it to 100 feet.

Soon after the flight I began thinking of designing a new fueling and launch system. The current rocket relies on you turning it over to empty a bay of (dry) baking soda into the vinegar, then placing it down on the ground and stepping back. The pressure of expanding gas builds, and the cork pops and the rocket flies up. But our baking soda did not all dump out into the vinegar, because the tube that held it was damp, causing the powder to clump.

And I got to thinking that modern radio-controlled servos should be capable of remotely triggering the mixture. Ideally, both fuel elements would be liquids, which would enable a gravity-release mechanism to enhance their mixing.

I just performed a crucial test in the kitchen: I mixed vinegar with baking soda powder and it fizzed, and I had my baseline. Then I first mixed the baking soda into water, then dumped it into the vinegar, and it fizzed even more! This test was important for me, because I did not know what would happen to the baking soda when mixed with water, if it might lose its strength.

So picture this: The rocket contains two internal bays for holding liquids. The fueling gaskets are stiff rubbery tubes that puncture the airframe of the rocket. It requires mechanical force to insert the fueling, uh, pitot and fill the internal bays. The bays can be emptied by force of gravity once the servos open the tubes leading into the reaction chamber of the rocket. This all sound very complicated, but it's not. No, I'm not going to make a drawing for you. The boy and the dad fuel the rocket, then step back and flip the switch that sends the signal to the servos in the rocket. The fuels come down and mix, the pressure builds, the cork pops out, and the rocket soars. Yay! Dad can even attach an altimeter that deploys a parachute.

The dad enjoys himself immensely while the boy wanders off and plays on the swings?

Secret of FIRE!

Now you too can master the secret of fire!

Girl power

Janelle in Plano was kind enough to post a link to this story. I have copied the entire text of it here, because I know how these Yahoo news links tend to break after a while....

Girl saved tourists thanks to school lesson
Mon Jan 3,12:18 AM ET

LONDON (Reuters) - A 10-year-old British girl saved 100 other tourists from the Asian tsunami having warned them a giant mass of water was on its way after learning about the phenomenon weeks earlier at school.

"I was on the beach and the water started to go funny," Tilly Smith told the Sun at the weekend from Phuket, Thailand.

"There were bubbles and the tide went out all of a sudden. I recognised what was happening and had a feeling there was going to be a tsunami. I told mummy."

While other holidaymakers stood and stared as the disappearing waters left boats and fish stranded on the sands, Tilly recognised the danger signs because she had done a school project on giant waves caused by underwater earthquakes.

Quick action by Tilly's mother and Thai hotel staff meant Maikhao beach was quickly cleared, just minutes before a huge wave crashed ashore. The beach was one of the few on the Thai island of Phuket where no-one was killed.

Her teacher, Andrew Kearney, paid tribute to his quick-thinking student.

"Tilly is a very bright, level-headed girl ... it is an incredible coincidence that our class were learning about this type of tsunami just two weeks before Christmas," he told the newspaper.

On Sunday, the Foreign Office said 40 Britons were confirmed dead from the December 26 tsunami which claimed some 130,000 victims. The toll is expected to rise.

The Nature letter

OK, here is the paper that appeared in Nature. I have read and understood the paper, but I have not proof-read this post, and I apologize for the formatting, and that some of the scientific notation did not translate (e.g. the 'plus-or-minus' sign). I have pasted the figures in almost at random. Use at your own risk.

letters to nature
NATURE |VOL 433 | 6 JANUARY 2005 |www.nature.com/nature
© 2005 Nature Publishing Group

..............................................................
b-Lactam antibiotics offer
neuroprotection by increasing
glutamate transporter expression

Jeffrey D. Rothstein1,2, Sarjubhai Patel1, Melissa R. Regan1,
Christine Haenggeli1, Yanhua H. Huang2, Dwight E. Bergles2, Lin Jin1,
Margaret Dykes Hoberg1, Svetlana Vidensky1, Dorothy S. Chung1,
Shuy Vang Toan1, Lucie I. Bruijn3, Zao-zhong Su4, Pankaj Gupta4
& Paul B. Fisher4
1Department of Neurology, 2Department of Neuroscience, Johns Hopkins
University, Baltimore, Maryland 21287, USA
3The ALS Association, Palm Harbor, Florida 34685, USA
4Columbia University Medical Center, College of Physicians and Surgeons,
Department of Pathology, Neurosurgery and Urology, New York, New York 10032,
USA
............................................................................................................................................................................
Glutamate is the principal excitatory neurotransmitter in the
nervous system. Inactivation of synaptic glutamate is handled by
the glutamate transporter GLT1 (also known as EAAT2; refs 1, 2),
the physiologically dominant astroglial protein. In spite of its
critical importance in normal and abnormal synaptic activity, no
practical pharmaceutical can positively modulate this protein.
Animal studies show that the protein is important for normal
excitatory synaptic transmission, while its dysfunction is implicated
in acute and chronic neurological disorders, including
amyotrophic lateral sclerosis (ALS)3, stroke4, brain tumours5
and epilepsy6. Using a blinded screen of 1,040 FDA-approved
drugs and nutritionals, we discovered that many b-lactam antibiotics
are potent stimulators of GLT1 expression. Furthermore,
this action appears to be mediated through increased transcription
of the GLT1 gene7. b-Lactams and various semi-synthetic
derivatives are potent antibiotics that act to inhibit bacterial
synthetic pathways8. When delivered to animals, the b-lactam
ceftriaxone increased both brain expression of GLT1 and its
biochemical and functional activity. Glutamate transporters
are important in preventing glutamate neurotoxicity1,9–11.
Ceftriaxone was neuroprotective in vitro when used in models
of ischaemic injury and motor neuron degeneration, both based
in part on glutamate toxicity11.When used in an animal model of
the fatal disease ALS, the drug delayed loss of neurons and muscle
strength, and increased mouse survival. Thus these studies
provide a class of potential neurotherapeutics that act to modulate
the expression of glutamate neurotransmitter transporters
via gene activation.

Figure 1 Screen of 1,040 FDA-approved drugs revealsb-lactam antibiotics as inducers
of GLT1 protein expression. a, Rodent lumbar spinal cord cultures. b, Sample raw data
slot blot of GLT1 protein in triplicate, including untreated tissue control, dibutyryl cyclic
AMP positive control (dbcAMP), DMSO drug vehicle control, and various drugs (all shown
here at 10mM). c, Screening results for 1,040 sample compounds. Bar height reflects
increased GLT1 protein expression relative to vehicle-treated controls. d, b-Lactam
antibiotics were highly represented among the most potent compounds. e, Dose response
analysis for ceftriaxone, revealing EC50 of 3.5mM for GLT1 expression.



To identify compounds capable of increasing rodent GLT1
expression, a structurally diverse library of 1,040 FDA-approved
drugs and nutritionals were individually added to organotypic
spinal cord slice cultures prepared from postnatal day 9 rats
(Fig. 1a). This approach mimics the cellular metabolism and cell–
cell interactions present in vivo. All assays were conducted in a
blinded fashion, and each drug (100mM, added biweekly) was
studied in duplicate or triplicate (10–15 tissue samples per drug).
After 5–7 days of drug treatment, tissue was harvested and immunoblotted
for expression for GLT1 protein using GLT1 anti-peptide
antibodies (Fig. 1b). Dibutyryl cyclic AMP, a GLT1 gene activator,
served as a positive control (Fig. 1b), while 0.1% DMSO controlled
for drug solubilizer. Approximately 50–60 drugs per week were
investigated. GLT1 protein was analysed by semiquantitative, semiautomated
densitometry. Replicate variability was less than 10%.
Over 20 compounds were capable of increasing GLT1 protein
expression by more than twofold compared to untreated controls
(Fig. 1c). Analysis of the top 2% of all hits revealed that a single class
of compounds,b-lactam antibiotics, was overly represented. Fifteen
different b-lactam antibiotics, including penicillin and its derivatives,
as well as cephalosporin antibiotics, were highly active in
stimulating GLT1 protein expression (Fig. 1d). Increased expression
could be seen as early as 48 h after drug treatment. Validation of
the most active drugs was confirmed by repeat treatment of
spinal cord cultures with 10–100mM drug. The EC50 for increasing
GLT1 expression by a representative cephalosporin, ceftriaxone,
was 3.5mM (Fig. 1e), which is comparable to the known central
nervous system (CNS) levels attainable with therapy for meningitis
(0.3–6mM)12,13. Non-b-lactam antibiotics included in the screen
had no effect on GLT1 protein expression, including kanamycin,
fluconazole, minocycline, polymyxin and doxycycline.
To better understand the mechanism of action, the effect of the
drugs on the GLT1 promoter was examined in cell lines from astrocytes and non-neuronal tissues.

Figure 2 Promoter reporter analysis.b-Lactams activate human GLT1 promoter. a, In
human fetal astrocytes transfected with the GLT1 promoter/luciferase reporter,b-lactam
antibiotics at 0.1mM (black), 1mM (red) and 10mM (green), markedly activate the GLT1
promoter in a dose dependent manner, while controls such as glutamate and glycine have
no effect. Dibutyryl cyclic AMP is a known GLT1 promoter activator. b, Closer analysis of
cephalosporin antibiotics reveals consistent activation (10mM) by many, but not all,
structural variants, while vancomycin had no effect. Data
shown as mean+s.e.m.




A 2.5-kilobase (kb) fragment
of the human GLT1 promoter linked to firefly luciferase was
transfected into human fetal astrocytes7, and used to screen the
active compounds identified above. Similar results were also
obtained using stable cell lines of human fetal astrocytes or COS7
cells transfected with a 2.7-kb GLT1 promoter fragment linked to
both enhanced green fluorescent protein (eGFP) complementary
DNA and firefly luciferase cDNA. As shown in Fig. 2a, the human
GLT1 promoter fragment was significantly activated by ceftriaxone,
amoxicillin and dibutyryl cyclic AMP, but not by the antibiotic
vancomycin, amino acids glutamate and glycine, or the vehicle,
DMSO. These effects were dose dependent, seen as early as 48 h after
drug administration, and persisted for at least 7 days in vitro
(Fig. 2a). Additional analysis of various cephalosporins (10mM)
and b -lactams revealed prominent activity among the various
agents (Fig. 2b), although the parent structure, cephalosporin C,
was inactive in astroglial cell lines. No b-lactams were found that
inhibited promoter activation.
As these compounds were capable of activating the promoter at
concentrations known to be attainable in brain after parenteral
administration (for example, 10–150mM)14, we further explored the
in vivo biological activity of ceftriaxone in normal rats. After five to
seven days of ceftriaxone therapy (200 mg per kg, i.p. daily, n 1/4 5),
animals were killed and brain tissue collected. Antibiotic treatment
led to a threefold increase in GLT1 protein expression, and active
splice variant GLT1b (ref. 15), as determined by semiquantitative
immunoblots from hippocampus and spinal cord (Fig. 3a, b). This
increase was persistent, and could also be observed after 3 months of
treatment (n 1/4 10). Conversely, the other molecular subtypes of
glutamate transporters, including the astroglial protein GLASTand
the neuronal glutamate transporters EAAC1 and EAAT4, were
unchanged after ceftriaxone administration (Fig. 3a, b).
GLT1 promoter activation was also observed in vivo (Fig. 3c, left
panel). Chronic treatment of GLT1-BAC-eGFP promoter reporter
mice with ceftriaxone produced an obvious increase in reporter
expression in astroglial soma and processes throughout the hippocampal
CA1 neuropil (Fig. 3c, right panel). Notably, in this brain
region neuronal expression of the gene was not induced by drug
(Fig. 3c, right panel). The effects of ceftriaxone appeared to be
relatively specific, as the constitutive proteins actin (Fig. 3a) and
superoxide dismutase 1 (SOD1, not shown), neuronal specific
proteins neurofilament L and synaptophysin, and the astroglial
protein glial fibrillary acid protein (GFAP), were unaffected by
ceftriaxone therapy. Treatment with non-b -lactam antibiotics
including vancomycin and minocycline had no effect on brain
GLT1 levels.
Glutamate transporters are preferentially localized to astroglial
membranes, although in some cases, increased protein expression is
not always mirrored by concomitant membrane localization and
functional activity16. However, cephalosporin therapy did increase
biochemical glutamate transport, as measured by L-[3H]glutamate
uptake into cortical membrane (Fig. 3d) or spinal cord (not shown)
homogenates prepared from adult animals treated intraperitoneally
for 7 days with drug. Similarly, after 7-day treatment, ceftriaxone
increased GLT1-mediated L-[3H]-glutamate transport in a dose
dependent fashion in cultured spinal cord slices (Fig. 3d). The
increase in cell surface GLT1 was confirmed with cell membrane
impermeant biotinylation reagent (Fig. 3e). Biotinylated GLT1 was
increased on plasma membranes from mixed cortical neuron/
astroglial cultures treated for 7 days with ceftriaxone. Finally,
glutamate-transporter-associated currents tended to be larger in
hippocampal astrocytes following 4–7 days of treatment of postnatal
rat pups with ceftriaxone (Supplementary Data). Thus, in vitro
and in vivo administration of ceftriaxone led to a threefold increase
in protein levels and a comparable increase in GLT-1 specific
biochemical and electrophysiological transport. Penicillin treatment
also increased biochemical transport (Fig. 3d), although its
brain penetration is less, presumably accounting for the lower level
of activity. Vancomycin was inactive in these functional assays.
Glutamate receptor antagonism has been extensively explored in
acute and chronic neuroprotection, but no therapies exist to
modulate glutamate-mediated injury via transporters. Genetic
overexpression of transporters in transgenic mice and in engineered
cell lines suggest that increasing the density of transporter in
astroglia can be neuroprotective17. The level of neuroprotection
may depend on the magnitude of overexpression. To determine if
b-lactam antibiotics, ceftriaxone in particular, could be neuroprotective,
we tested the compound in a series of in vitro and
in vivo models. Treatment of cultured neurons with a low oxygen,
low glucose condition, known as oxygen glucose deprivation
(OGD), models the neuronal injury that can occur in ischaemic
injury. In this model, one hour of OGD was lethal to cultured
neurons, with toxicity known to involve excess glutamate18. However,
when cultures are preconditioned 24 h before the lethal
condition with transient OGD (5 min), there is a dramatic and
robust resistance of neurons to cell death. This neuroprotection,
referred to as ischaemic pre-conditioning, is due in part to increased
expression of GLT1 (ref. 18), although some studies suggest these
transporters could contribute to ischaemic injury2. As shown in
Fig. 4a, baseline neuronal death in the cultures was 14% (no
treatment column, NT). Ceftriaxone (1mM), when added for 48 h
to cultures, did not increase the baseline cell death (NTþceftriaxone),
but increased GLT1 protein levels (.25%; not shown) and transport.
Cultures subject to 1 h OGD, without preconditioning,
increased neuronal death to 50%. Ischaemic preconditioning
OGD (5min) applied 24 h before a one-hour OGD prevented
neuronal injury. Importantly, 1mM ceftriaxone (or the b-lactam cefuroxime, not shown), when added 48 h before 1 h OGD, was also
protective, reducing the percentage of neuronal cell death from 50%
to 20%—similar to ischaemic tolerance neuroprotection. Thus blactam
pre-treatment appeared to prevent neuronal death in
ischaemic tolerance.
Chronic blockade of glutamate transport in spinal cord organotypic
cultures, with the non-specific transporter inhibitor threo-bhydroxyaspartate
(THA) or DL-threo-b -benzyloxyaspartate
(TBOA)11 leads to chronic increase in extracellular glutamate
and subsequent slow death of motor neurons. To determine if
ceftriaxone-induced GLT1 overexpression could be neuroprotective,
we examined motor neuron degeneration in the organotypic
spinal cord model. Organotypic cultures were prepared from
lumbar spinal cords of 8–9-day-old rodent pups11. No drugs were
added for the first 7 days following culture preparation. Then
ceftriaxone (1–100mM) was added with media changes, and after
7 more days, THA or TBOA were added at a concentration
of 100m M, which produces chronic death of motor neurons.
After 2–4 weeks, cultures were immunostained for neurofilament
to quantify large ventral horn motor neurons. As shown in Fig. 4b,
ceftriaxone treatment prevented motor neuron loss in a dose
dependent manner. Similar neuroprotective results were seen with
penicillin (not shown). As an additional control, organotypic spinal
cord cultures prepared from GLT1-null mice were not protected
from THA toxicity by ceftriaxone pre-treatment (Fig. 4b). Vancomycin
was not protective.
To determine if ceftriaxone could alter neurodegeneration in a
disease model that involves altered expression of glutamate transporters,
we treated G93A SOD1 mice with drug. Studies have
documented a contributory role for excess glutamate in this
model, including neuroprotection by glutamate receptor blockade11,19
–21. Modest GLT1 overexpression can alter disease progression17.
Guo et al17 reported that a 1.5–2.3 fold increase in Nmyc
labelled human GLT1 expression in G93A SOD1 mice delayed
disease onset as measured by grip strength (,14 days), but had no
effect on other onset parameters such as weight loss and paralysis
(3 days), and had no effect on survival. Initiating drug treatment in
this animal model around the time of clinical disease onset at, for
example, loss of strength, most closely matches the use of human
therapy, and could be more therapeutically relevant22. G93A SOD1
mice were treated daily with ceftriaxone (200 mg kg21 i.p.) starting
at 12 weeks of age—approximately the time of clinical disease onset.
Drug-treated animals (n 1/4 20) and saline-injected controls
(n 1/4 20) were monitored daily for survival, and weekly for grip
strength and body weight22,23. As shown in Fig. 4c, d, ceftriaxone
treatment significantly delayed loss of muscle strength and body
weight. This effect was observed within 7 days after treatment, and
persisted for 4–6 weeks. By 19 weeks of age, the strength preservation
was lost. In a similar manner, the drug also increased overall
survival of the mice by 10 days (ceftriaxone treated, 132 ^ 2 days
(all data with errors show mean ^ s.e.m.); saline control,
122 ^ 2 days; log rank, x2 1/4 7.8, P . 0.005; Wilcoxon x2 1/4 7.5,
P . 0.006) (Fig. 4e). This effect is typical of drugs given relatively
late in the life of G93A SOD1 mice, when the first clinical signs of
disease are evident, and thus even a small effect may have clinical
significance. When the same dose of drug was administered somewhat
earlier, at 6 weeks of age, survival was also increased (ceftriaxone
treated, 135 ^ 2 days, n 1/4 20; saline treated 122 ^ 1.9 days,
n 1/4 20), although not significantly better than late delivery at
90 days of age. The lack of greater efficacy when given earlier
would be consistent with the observation that the loss of GLT1
expression does not begin to occur until around 90 days in this
model.

Figure 3 b-Lactam induces transporter promoter activation and protein expression in vivo.
a, b, Ceftriaxone (black bar) induces expression of GLT1 and GLT1b protein, in
hippocampus (Hipp) and spinal cord (sp. cord) (a, western blot) compared to saline control
(a, control (con); b, red bar). Expression of the glutamate transporters GLAST, EAAC1 and
EAAT4 were unaffected. c, Increased in vivo activation of the GLT1 promoter (c, left
panels, low power light microscopy; scale bar, 200mm), using GLT1 BAC-eGFP promoter
reporter mice, in hippocampal CA1 astrocytes (asterisks; c, right panel, confocal
microscopy; scale bar, 50mm) and neuropil but not CA1 neurons (arrows) from drugtreated
mice, compared to untreated control mice. d, Ceftriaxone and penicillin
administration increased 3H-glutamate transport in cortex homogenates from drugtreated
mice (left panel) and treated spinal cord cultures (right panel). *P , 0.05
compared to untreated control. e, Immunoblots of total (T), intracellular (I) and biotinylated
fractions (M) of mixed neuron/glial cortical cultures treated for 7 days with ceftriaxone (cef,
100mM). Molecular weight markers in kDa. In b, d, data are mean+s.e.m.



To determine if ceftriaxone altered cellular neurodegeneration
in vivo, G93A mice were treated with ceftriaxone starting at 70 days
of age. Two weeks of drug therapy lead to a significant prevention of
motor neuron loss (Fig. 4h, i) and reduction of hypercellular gliosis
compared to saline-treated control G93A mice. GLT1 expression
decreases around the onset of clinical disease24, yet ceftriaxone
administration was able to increase endogenous GLT1 expression
significantly in spinal cords from the chronically treated mice
(Fig. 4f–h). The neuroprotection seen in this study was not likely
to be due to the normal antibiotic properties of the drug, because
ALS mice are not septic and do not have lung infections at 12–16 weeks of age—when prominent muscle strength effects were
seen. In addition, the use of other CNS-penetrating antibiotics
when given at this late stage (12 weeks old) do not prevent loss of
muscle strength (for example, minocycline; L.I.B. and J.D.R.,
unpublished observations).
b-Lactam antibiotics, first identified with the discovery of penicillin
in 1928, are now the most widely used antibiotics, and are one
of the most important modern pharmaceuticals8.Notably, they have
no substantial toxic CNS actions at normal antibacterial doses. Our
studies document a new property of these antibiotics, and demonstrate
that b-lactams can activate the gene for a neurotransmitter
transporter. This is, to our knowledge, the first evidence of stimulatory
pharmaceutical modulation of the glutamate transporter,
and provides a new pathway for drug discovery and manipulation of
glutamate transmission in disease. The mechanism of this overexpression
appears to be activation of the genetic promoter for
GLT1, although the pathway for promoter activation is as yet
unknown.

Figure 4 In vitro and in vivo neuroprotection by ceftriaxone. a, Oxygen glucose deprivation
(OGD) of cultured cortical neurons was neurotoxic, but OGD preconditioning or ceftriaxone
pre-treatment (1mM) was protective compared to no treatment (NT). b, Ceftriaxone (Cef)
treatment of spinal cord cultures prevented threo-hydroxyaspartate (THA)-induced motor
neuron loss but not in GLT1-null mouse (GLT1 2 /2) tissue. *P , 0.05 or **P , 0.01
versus untreated control. c–e, In G93A SOD1 ALS mice, ceftriaxone initiated at disease
onset (red) delayed loss of muscle strength (c) and body weight (d) compared to saline
treatment (black); ceftriaxone initiated at disease onset also increased survival (e). Spinal
cord GLT1 protein levels (f, g) and tissue expression (h) were markedly elevated in
ceftriaxone (Cef)-treated ALS mice compared to saline (Sal)-treated ALS mice and
untreated wild-type (WT) mice. Molecular weight markers in kDa. Two weeks of drug
treatment (Cef) delayed loss of lumbar spinal motor neurons (h, i) compared to saline
treatment in haematoxylin and eosin (H&E) stained tissue. Scale bar, 50mm. For panels c,
d and e, n 1/4 20 saline, n 1/4 20 ceftriaxone group. *P , 0.05 versus ceftriaxone. Data in
a, b, g, i, are mean þ s.e.m.; data in c, d, are mean ^ s.e.m.



----
Methods
Screening assay and protein expression
Organotypic cultures were prepared from postnatal day 9 rat lumbar spinal cords11. Slice
cultures were maintained on Millicell-CM 30-mm inserts (5 slices per insert; Millipore,
PICM 03050) in 35-mm six-well plates (Falcon no. 3046) containing 1 ml growth media,
without antibiotics, and maintained in a humidified atmosphere of 5% CO2. After 7 days
in vitro, cultures were treated with the NINDS Custom Collection (MicroSource
Discovery) drugs at a concentration of 100mM for 7 days.Media and drugs were changed
biweekly. GLT1 was quantified by slot blot (5mg protein per slot). Protein concentration in
tissue sonicates was determined using Coomassie Plus protein assay (Pierce no. 1856210).
GLT1, GLAST, EAAC1 and EAAT4 protein were detected using primary rabbit polyclonal
rat anti-carboxy-terminal GLT-1 antibody followed by chemiluminescence (SuperSignal
West Pico Chemiluminescent Substrate (Pierce no. 34080) detection (BioRad VersaDoc,
Quantity One Discovery Series software,v4.3.0)). Twenty-one compounds were selected
for retesting at 10–100mM to confirm hits (.300% of control). These compounds were
also screened in a six-point dilution series with a maximum concentration of 300mM.
These dilutions were created from freshly prepared 10mM stocks in DMSO.
Concentrations required to achieve 50% of the maximally achievable effect for each
compound (EC50) were calculated using SigmaPlot (Ver 9; Systat).
Human GLT1 promoter reporter assay
GLT1 promoter activity was studied in normal human fetal astrocytes seeded at
1 £ 105 cells per 35-mm plate. Twenty-four hours after seeding, cells received the indicated
compound at a final concentration of 1–10mM or were left untreated (control). Fortyeight
hours later, the cells were transfected (calcium phosphate precipitation method7)
with a pGL3/GLT1 luciferase reporter construct (5mg) plus a pSVb-galactosidase
construct (1mg). In some cases, human fetal astrocytes or COS7 cell lines transfected with
the GLT1 promoter (2.7 kb) luciferase/eGFP construct were used. After an additional 48 h,
cell lysates were prepared and luciferase activity was determined using the Luciferase Assay
System Kit (Promega, E1501) and luminescence determined using a luminometer (Turner
Designs, TD20/20)7. Data presented is the average of three independent plates ^ s.d.
GLT1 activity and immunoblotting
Levels of GLT1 protein were quantified by immunoblots3. Functional glutamate transport
was measured by accumulation of 3H-glutamate in spinal cord slice or crude cortical
synaptosomal membranes25. Measurement of total glutamate uptake actually reflects the
combined physiological activity of all transporter subtypes. GLT1 protein is uniquely
sensitive to transport inhibition by dihydrokainate (DHK). To estimate the contribution
of GLT1 to transport, aliquots of tissue homogenates were also incubated with 300mM
DHK. Non-specific uptake was determined in the presence of 300mM threo-bhydroxyaspartate
(THA), at 0 8C and in sodium-free homogenates.
Generation of GLT1 BAC eGFP transgenic mouse
The BAC transgenic mice were generated as described previously26 with a shuttle vector
provided by N. Heintz. The BAC clone included approximately 45 kb upstream of the first
GLT1 exon, the full GLT1 coding region (123 kb) and 24 kb downstream of the last exon.
EGFP cDNA was inserted into the GLT1 start codon.
Oxygen glucose deprivation/ischaemic preconditioning
Primary corticalmixed neuronal-glial cell cultures were prepared from rodent fetal cortex
(gestation day 14–16 CD1 mice) using the paradigm of ischaemic preconditioning18.
Motor neuron toxicity
Neuroprotection in spinal cord organotypic cultures prepared from postnatal day 8–9
wild-type rat or GLT1-null mouse tissue was performed as described previously11.
Ceftriaxone was added for 5–7 days before the addition of 100mM THA or DL-threo-bbenzyloxyaspartate,
(TBOA) 100mM. Surviving motor neurons were counted 2–3 weeks
later by staining for phosphorylated neurofilaments (SMI-32).
G93A SOD1 mouse—disease onset and survival
Male transgenicmice expressing the human G93A SOD1 (B6SJL-TgN(SOD1-G93A)1Gur,
high expressor) were bred with background-matched B6SJL wild-type females (Jackson
Laboratories). The progeny were genotyped and used for subsequent studies. Experiments
were conducted at Psychogenics (Hawthorne, New York) in accordance with protocols
approved by the Johns Hopkins Animal Care and Use Committee. Mice were assessed by
daily observation for survival, and by weekly weighing and testing of grip strength starting
at 12 weeks of age22,23. All experiments were performed blinded with coded syringes for
injection.
Histology and motor neuron counts
Mice were perfused via cardiac infusion with 4% buffered paraformaldehyde and spinal
cord post fixed with the same solution. The lumbar enlargement was collected, paraffin
embedded, and serially sectioned at 14mm, for a total of 140 sections. Every seventh
section was stained with haematoxylin and eosin, and examined at 20 £ for motor neuron
identification and counting22. Images were acquired using the Zeiss LSM 510 Meta
confocal microscope (argon laser setting at 488 nm) with the operator blinded to
treatment groups. All images were captured with the same gain, offset, pinhole diameter
(2.53 Airy units), and scan speed (12.8ms with scan averaging set to 2). Z-series images
were collected at 1.03mm intervals.
Statistics
Quantitative differences between in vitro and in vivo drug effects were analysed by analysis
of variance (ANOVA) or Students t-test. Survival analysis was performed by Kaplan-Meier
analysis. Software for statistics included Statview, and JMP 5.1 (SAS Software).
Received 11 July; accepted 4 November 2004; doi:10.1038/nature03180.
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Supplementary Information accompanies the paper on www.nature.com/nature.
Acknowledgements We are grateful to J. Lee and C. Cocci for technical assistance; K. Tanaka for
GLT1-null mice; C. Leahy for ALS mouse studies; and J. Heemskerk for initiating the project,
discussions and encouragement. G93A SOD1 mice were provided by Project ALS. The work was
supported by the NIH, the Muscular Dystrophy Association and The Robert Packard Center for
ALS Research at Johns Hopkins.
Competing interests statement The authors declare competing financial interests: details
accompany the paper on www.nature.com/nature.
Correspondence and requests for materials should be addressed to J.D.R. (jrothste@jhmi.edu).
..............................................................
Nucleolar proteome dynamics
Jens S. Andersen1†, Yun W. Lam2†, Anthony K. L. Leung2*, Shao-En Ong1,
Carol E. Lyon2, Angus I. Lamond2 & Matthias Mann1
1Department of Biochemistry and Molecular Biology, Campusvej 55, DK-5230
Odense M, Denmark
2Wellcome Trust Biocentre, MSI/WTB Complex, University of Dundee, Dundee
DD1 4HN, UK
* Present address: Center for Cancer Research, Department of Biology, Massachusetts Institute of
Technology, Cambridge, Massachusetts 02139, USA
† These authors contributed equally to this work
............................................................................................................................................................................
The nucleolus is a key organelle that coordinates the synthesis
and assembly of ribosomal subunits and forms in the nucleus
around the repeated ribosomal gene clusters. Because the production
of ribosomes is a major metabolic activity, the function
of the nucleolus is tightly linked to cell growth and proliferation,
and recent data suggest that the nucleolus also plays an important
role in cell-cycle regulation, senescence and stress responses1–4.
Here, using mass-spectrometry-based organellar proteomics and
stable isotope labelling5, we perform a quantitative analysis of
the proteome of human nucleoli. In vivo fluorescent imaging
techniques are directly compared to endogenous protein changes
measured by proteomics. We characterize the flux of 489
endogenous nucleolar proteins in response to three different
metabolic inhibitors that each affect nucleolar morphology.
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