I hinted earlier that my reduced frequency in blog posting had something to do with this conference I organized for a patient advocacy group last weekend.

I always have incredibly mixed feelings about working with Naevus 2000 France-Europe. I’ve seen them grow up from a fledgling group, because they got (re-)started at about the same time as the birth of my daughter with her very own giant congenital nevus. For those of you on the ball, you’ll see I was a bit redundant there, but there’s always that word “congenital” in there, no matter which way you scramble “nevus”, “giant”, and sometimes, “melanocytic”. She also has now about 200 “satellites” – randomly sized, smaller nevi that reveal themselves in the first few years of life.

My mixed feelings come from wanting too much, and not wanting to be involved with a patient advocacy group, all at the same time. It’s a little hard to explain.

(As an aside, my girl is perfectly gorgeous. Her mix of remaining nevi and surgical scars have not prevented her from being elected class delegate to her school council – everyone can get used to a kid who looks different, and she is not as handicapped as many others.)

Every year, I attend the general assembly of the group. Every year, I wish this could be a more professional organization. And at the same time, I like to be needed, although I also like to be in control of how much I respond to the neediness. I like not being just another mother-of-a-kid-with-a-worrisome-malformation. I am their only interface with researchers at all, and a rare translater for them for the multiple medical disciplines that can step in to take care of a child with a congenital giant nevus – pediatricians, dermatologists, plastic surgeons, and neurologists, for the most part.

Every other year on top of that, I take out my e-mail management system and scrounge up my contacts among French-speaking doctors and among researchers in pigment cell biology, and I convince some of them to come talk with this group of mostly parents, but some adult patients as well. Usually the association manages to organize alternative activities for the children. They’ve definitely gotten better at the infrastructure aspects of putting on a conference. The first conference I organized, I did everything – travel arrangements, hotel rooms, badges, an attractive programme – as a satellite symposium to the International Pigment Cell Conference in the Netherlands, and it was therefore in English and apart from the general assembly of the association. A good experience, but never again to that level of detail. I’ve learned since that it is possible to subcontract nearly everything for a price.

This was a year of drumming up contacts once more, and MC’ing their presentations to put them in context for the families. But as they say in French, the mayonnaise seems to be taking. (By stint of beating everyone enough?) A few surgeons and a very dedicated dermatologist and pigment cell researcher, and a couple of other researchers, are now regulars. They greet each other and the association president by their first names. They don’t slip away at the coffee break, but field questions well and beyond the call of duty.

Beyond that, I was very pleased this year that the requisite invitations to our sister organizations in other countries was accepted this year not just by one, but by two groups: Naevus Italia, a newer association in (you guessed it) Italy, and Nevus Outreach, a more experienced and larger-scale group in the U.S. I had been following the latter’s ventures for a number of years and have had the privilege of being on a sort of long-distance consulting and science/medicine brainstorming group for them the last couple of those years. The former’s president speaks a more than serviceable French, and the latter’s executive director was sufficiently courageous to prepare a speech in French phonetically. (It was very successful.)

Anyhow, the executive director and his daughter have been staying with us since last Friday. It’s vastly more entertaining to speak with them than it is to write my n’th grant, for which my kind collaborator-to-be has told me that I’m a “trooper”.

I mentioned to Mark that it had been a long time since I made a new friend, and how pleasant it was.

Before he figured out that I was referring to himself, he said, “Facebook friend or real friend?” Or maybe he had figured it out, but he’s quite the entertainer.

Real friend, of course. They’re even typing away quietly on their laptops so that I should get the grant done. So, with that, signing off for now.

Right now as I type, I am shuttling between laptop windows while nursing my foot, a cup of coffee at hand.

I am organizing my conference program from my bed (actually, from my kitchen right now) while I am waiting for the attendees of another conference to settle down and the next set of speakers to begin. A wonderful symposium in French, entitled the equivalent of Stem Cells and Cellular Medicine is underway in Paris, today. It is organized by the “Stem-Pôle” – a loose confederation of research groups in the Paris region interested in stem cell biology and therapy.

I just LOVE the possibility of attending a conference at a distance. I already had a good time doing so at an unearthly hour of the morning from the United States, but this is in a field of intense intellectual interest to me, so I am adoring the possibility to multitask in a new way.

The talks are going on live – the next session will be led among others by Nathalie CARTIER-LACAVE and Patrick AUBOURG, senior authors on the study I just got so excited about the other day – but the talks will also remain online and accessible afterwards. Patrick will start, also discussing gene therapy, naturally. They’ve been all over the French news lately – it must be nice to be among one’s peers again and not dealing with well-meaning but deadline-pressured reporters.

However, as for the last talk, the slides are not coming up simultaneously. Funny, it worked the first time. Ah, you must close then re-open the window.

And what a great way to not do the other paperwork, or to do it slowly…. Oh, sorry, I was at a conference!

Sometimes, it’s so appealing to become a passive entity.

Rather than resist the discomfort of my chronic knee problem, and a newly sprained foot on the same side, I’ll just stay in my pajamas and keep the foot propped on a pillow. I’ll go to the doctor, because I need to in order to obtain a pass to stay at home the next day or two (and have my salary still paid by social security), so I will get dressed. But it will be with the first clothes under my hand.

I’m responding to yet another NIH call for proposals, following the unsurprisingly ill-fated response to the (in)famous Challenge grants. Again, thank goodness for energetic U.S. collaborators who push, actively. I idly wonder what happens if I just drop the effort, don’t finish the forms. We wouldn’t get funded, but as we probably won’t anyhow, what does that change in the big picture?

Same thing for the December renewal of ethics committee approval for future use of human embryonic and fetal tissues. Am I not doing mostly molecular biology and bioinformatics analyses now, anyhow? And didn’t I want to move back into using the chicken embryo model system?

Saturday, I am organizing a six-hour symposium in Vichy, also infamous for a number of reasons, but actually a perfectly decent little 19th-century spa town in the foothills of the Auvergne volcanos. What happens if I don’t set up the afternoon structure, or confirm the room to the speakers? Will it really be less disorganized than usual, because of all sorts of unexpected events ranging from mayors wanting to speak to projectors blowing their bulbs?

Okay, okay. I do know the answers to these rhetorical questions, but they do spur the imagination. Let’s start with the shower and getting dressed. And another coffee, perhaps.

Much like the reflected glory of working in an institution with Nobel prize-winners, I am basking in the reflected glory of working at an institution that has more or less successfully applied gene therapy to alleviate the suffering of children with incurable genetic diseases. And they’re fighting the good fight, because sometimes, they win.

Luigi Naldini wrote, in his Perspective:

[This study is] the successful first clinical testing of an HIV-derived vector in hematopoietic stem cell (HSC)–based gene therapy. The procedure was used to treat a severe neurodegenerative disease, X-linked adrenoleukodystrophy (ALD), and the results indicate stable expression of a therapeutic gene in a substantial fraction of patients’ hematopoietic cells, as well as clinical benefits.

Why was it so necessary to use gene therapy as opposed to other cutting edge tools? First, the setting. In the words of the authors:

The ALD protein participates in the peroxisomal degradation of very-long-chain fatty acids (VLCFAs) in oligodendrocytes and microglia, and deficiency of this protein disrupts myelin maintenance by these cells. Affected boys enter a phase of active multifocal brain demyelination when they are 6 to 8 years old. Most die before reaching adolescence.

It makes one quail. Your little boy starts school, is perfectly normal, and then the nightmare begins… “In untreated ALD patients, the decline of performance and verbal functions is inevitably continuous and devastating during the first 2 years after the onset of inflammatory demyelinating lesions.”

Second, the only other possible treatment is to find an allogenic bone marrow donor. We all know how difficult and random that can be. After that, and if the lesions are not too advanced, the child has to survive the graft and it has to take, none of which are givens. Thus, successfully validated gene therapy is true hope for a previously hopeless situation.

The authors were very careful to not publish their results immediately but have been following their treated patients for the last two years. They have applied a technique to make sure that the treated cells of the immune system, which then infiltrate brain tissue and act as portable garbage removers of the VLCFAs, remain stable and display no warning signs that they could become cancerous. One of those signs could be that only one or a few engineered cells survive and multiply unduly.

They used a delightfully modern technique of high-throughput sequencing to make sure that there were lots of different sites of insertion of the therapeutic vector present in the circulating blood cells, and that that diversity did not diminish over time.

The treatment is at least as good as bone marrow transplantation in preventing additional degradation. In part of the brain of one of the patients, there was actually reversal, “a process that does not occur spontaneously in ALD.”

Two seven-year-old boys clearly benefited from this new technique. May there be many more.

Finally, the discussion concludes, rightly:

HSC gene therapy might also be considered as a therapeutic option for adult ALD patients who develop cerebral demyelination, for whom the mortality risk of allogeneic HCT is ~40%.

Hooray for Nathalie, Marina, Alain, Patrick and all their collaborators! Hooray for these two little boys and their families!

Update:

I hadn’t noticed, but Patrick Aubourg did (see session at 11:10), this editorial in Nature entitled, Gene therapy deserves a fresh chance. That about says it.
-
Cartier, N., Hacein-Bey-Abina, S., Bartholomae, C., Veres, G., Schmidt, M., Kutschera, I., Vidaud, M., Abel, U., Dal-Cortivo, L., Caccavelli, L., Mahlaoui, N., Kiermer, V., Mittelstaedt, D., Bellesme, C., Lahlou, N., Lefrere, F., Blanche, S., Audit, M., Payen, E., Leboulch, P., l’Homme, B., Bougneres, P., Von Kalle, C., Fischer, A., Cavazzana-Calvo, M., & Aubourg, P. (2009). Hematopoietic Stem Cell Gene Therapy with a Lentiviral Vector in X-Linked Adrenoleukodystrophy Science, 326 (5954), 818-823 DOI: 10.1126/science.1171242

Back in Paris from a brief stint in Marseille:

Funny, the difference 800 km makes. Everything is so much dimmer up north and continental.

The once-homeless and still clearly jobless fellow who sits at the corner of the escalator coming up into Montparnasse train station, has a bright smile and a handshake ready every day, at nearly any hour I head into the laboratory. I think he is Eastern European in origin, given his accent. The top of his pate shines from the top of the stairs that I take down to pass him and head to work. I wonder if he has ever taken the TGV*.

*(train a grande vitesse = high-speed trains leaving from all the major Paris stations)

The passage Vaugirard brings one efficiently through a city block and comes out facing a street that leads right into the ambulance emergency entrance to the Necker Children’s Hospital. I head in after lunch, after the flight back to Paris with my children. I missed the man who daily, mops the tiles of this semi-outdoor passageway, but it’s only normal as he has a schedule to follow. He’s an equally cheerful sort to the gentleman I described above, seemingly from the Caribbean but with a pure metropolitan French accent, also always ready with a handshake. Or a clasp, to be more precise. This is the working man’s clasp, a break from the mop. Vacation coming up? Had a good weekend? Bon courage!

When pigeons strut across my path along down there, as they are fat and happy from the crumbs scattered by people breaking off the ends of the baguettes they purchased at the chain bakery at the top of the stairs, I divert my path around theirs. I dislike making pigeons or sparrows expend extra energy, or adrenalin, or otherwise cause stress in their little birdbrains. Perhaps they will not sully my hand-clasping friend’s handiwork quite so quickly, if I don’t make them shit in fear? But the toddlers on their way to the creche along there are quite happy to make up for lost occasions.

No point to any of this musing, just noticing.

About two weeks ago, I started to be plagued with an inflammation of the membrane that encases the knee joint, called bursitis. The membrane secretes extra synovial fluid, and the pressure was indeed painful. I was struck by the amount of sympathy that this particular affliction elicited from my family and friends. (Thanks!). Since it keeps flaring up, an infiltration of cortisone into the joint this afternoon may calm things down for up to a month.

However, my expressions of pain in form of complaint are not really proportional to the pain itself. My complaints are verbal outlets to reduce the mental pressure that results from the frustration engendered by the pain. But the best way to describe pain itself is to elicit an empathetic reaction in the listener, by which they draw parallels with their own painful experiences and use their imagination to extrapolate.

Having tried a number of hands-on methods to learn about pain, all I can say is that the kind of pain induced really differs, but not how. It’s strange not to have the words to describe the the quality of feeling between them, but I can class them in order of least to most disagreeable ¹. When I look at the list, factors in the pain felt seem to be:

• Actual damage caused

• Novelty

• Chronicity

The British Pain Society among others has published a series of standard language translations of pain measurement scales for cognitively unimpaired adults.

The criteria being assessed are:

• Intensity (over time or not)

• Distress

• Relief upon treatment

A variety of other methods for assessing the same criteria in people who have problems using language are presented on a consecrated website called pain.com by Dr. Feldt.

As she points out, “Persons with dementia may not initiate conversations about pain or seek relief for pain because they have forgotten where they are, whom they should tell, or what event initially caused the pain.”

But they feel pain, and can be relieved from it with treatment. So verbal representation of pain and the attendant surprise or shock, is already distinct from the state itself.

A Checklist of Nonverbal Pain Behaviors (CNPI) is available here, and Dr. Feldt’s article from which it is derived is here

I wonder if, like for children, elderly people with dementia would actually find pain more distressing, and therefore more painful, when they can not draw on their memories of previous experiences of that particular kind of pain (eg. damage to the skin, or visceral pains of different sorts)? In addition, since they can express their feelings less well, they clearly don’t always get the reassurance and treatment they need.

A paper from the appropriately named journal, Pain, cites and presents additional evidence that the experience of pain can be somewhat analgesic for new encounters with pain: “Evaluation of pain severity depends on the context in which pain occurs.” One of the authors, Dan Ariely, has also written a very personal pamphlet describing his experience with burn pain and his subsequent step(s) back and analysis of its perception.

Ariely notes a number of interesting observations.

First, the altered perception of time, like for the pain itself, has to do with the level of shock – it’s a coping mechanism. Good for getting away from whatever caused the pain, but bad for the perception of how painful it was. What I called novelty, above.

Second, “pain that worsens over time is perceived to be more painful than pain that improves, or one that remains at the same level.” (cf citations therein). Related to what I called chronicity, and what the BPS termed “relief upon treatment”. Again, if the overall memory of the pain is something that gets progressively worse over time until the last experience of it, then one’s tolerance is reduced, the next time it happens. This makes me think somewhat of childbirth ². The fear of the pain is certainly part of the pain, and I came to that conclusion before I read any of Dr. Grantly Dick-Read ’s work. My first birth experience was already not horrific (although a touch of morphine when the forceps went in was welcome),so I was not dissuaged by the pain for a second delivery with really no painkillers. As it went better and faster than the first, I’d face another with even less anxiety (this does not suggest it’s underway, nor that I am dogmatic about avoiding painkillers for childbirth!). This willingness to face another delivery is contrary to some, but luckily, not most.

For the memory-impaired elderly person, perhaps the lost analgesic effect from not being able to draw on earlier painful experiences ³, is somewhat offset by not remembering that a chronic pain is objectively worse than a day earlier, or a month earlier? Or is there really such a thing as objective pain? Probably not. I’d have to experience renal colic to know if it is more or less painful than peritonitis. Pain is relative, and it’s really in the mind.

For children, I can attest from personal experience that their memory of an earlier painful event that did not improve, conditions their anxiety and therefore their perception of the next. My daughter had a number of skin reconstruction surgeries, and it was bandage-changing in the first couple weeks after each that was the most stressful and, presumably, painful. Like Ariely, she had to have iodine bath/shower sessions to unstick the first bandages, wash away the accumulated necrotic crud, and apply new ones. In later weeks, the glue from the bandages usually took off a superficial layer of the surrounding epidermis, to add injury to injury.

Nearly a decade later, when I came across one of the nurses who had participated in these sessions, she clearly remembered my daughter, her reactions, and my earnest efforts to make the bandage-changing as anxiety-free as possible. Also like Ariely, there were the nurses who allowed my daughter and myself “to have breaks and even, from time to time, remove some of (her) own bandages” and, especially early on, the ones who “gave [us] no control over the treatment process”. For the operations in the first year, letting her remove her own bandages was clearly not ideal. But quickly, I stepped in, realizing that if I could communicate any sense of control and expectation to my daughter, it was a comfort to both of us.

I should also add that my son is quite frightened of the pain of needles, to the point of tensing up so much that he’ll squeeze out blood upon an intramuscular injection ⁴.

Working at a children’s hospital, and frequenting collaborators at another specialized in cancer treatments, has shown me many examples of children who bear what seem to be excruciating conditions with a phenomenal amount of forebearance, because they are reassured. In this respect, not having a past reference point can be a boon.

So, to sum up all this, anxiety and the relationship of the ongoing experience to previous ones (based on memory), seem to be major factors in pain perception.

Footnotes

¹ Here are the owies that come to mind. There are probably a couple other minor ones.
- Epilation
- Superficial cuts and skin fissures
- Sunburn (I never let it get bad)
- Breast compression in mammograms
- Muscular fatigue from exercise
- Over-stretching
- Muscle aches from fever or lack of sleep
- Perineural fibrosis aka Morton’s neuroma
- Violent contusion (eg. falling, bike accident)
- Slamming a nailbed in a heavy metal frame of some sort or another
- Abscesses such as in the jaw, skin or breast
- Migraine
- Sciatica
- Burn (second degree)
- Sprains or cartilage issues (ripped meniscus or intervertebral disk issues, arthritis)
- Visceral pain such as childbirth, kidney infection, appendicitis
- Peritonitis (a whole other category despite being visceral)

² Childbirth, with its attendant possibilities of medical problems, is often brandished as an example of severe pain.

³ Older patients with visceral disease are more likely to present without pain

⁴ More recently, we’ve used topical analgesic like 1% lidocaine an hour ahead, under an occluding bandage, to great effect. A hint to other parents who find that the massively proven benefits of vaccinating their children outweigh the unsubstantiated inconvenients. But apparently, getting rid of the anxiety may be even better in eradicating pain than getting rid of the nerve transmission, though the assurance that the latter is effective may also reduce anxiety in a kind of positive feedback loop. A little harder to get rid of other kinds of anxiety.

This week’s Nature featured a Letter ¹ by Vecsey and colleagues entitled, Sleep deprivation impairs cAMP signalling in the hippocampus.

As an aside, a good title for the Good Paper Journal Club, were it not moribund from lack of time for people to keep it alive. And I see why this subject appealed to the editors, since it can appeal to all of us. Who among my readers is not sleep-deprived at some point or another?

I am another researcher experimenting on herself (how the sleep deprivation is acquired is another story, we’ll put it in Supplemental Methods, shall we?). How much short-term memory non-consolidation will I be able to tolerate until I actually forget to get up and pour more coffee? (Or: will I forget where I placed the mug?)

Caffeine is a non-specific phosphodiesterase (PDE) inhibitor. By inhibiting PDEs, caffeine prevents the PDE enzymes from being so quick about converting cyclic adenosine monophosphate back into its non-cyclic form.

In the other direction, epinephrine (of the famous epi pen) will activate other enzymes that push in the other direction, converting other derivatives back into cAMP.

In adrenalin rushes and caffeine highs, you are alert, and can have side effects such as heart palpitations. Having more cAMP around is a good way to rapidly relax bronchial (and uterine?) smooth muscle – hence, good for rapid relief for asthmatics, and curiously, as a vasoconstrictor, relieving Quincke’s edema or migraine, respectively.

Well, the article in question showed why brief sleep deprivation in a mouse model leads to difficulty in some memory tasks stored in the hippocampus. The lack of cAMP means the synapses, the major communication connections between neurons, don’t change in response to use, they way they should. In particular, it’s because there is too much of one of the PDEs around – it seems to be synthesized in response to the sleep deprivation – specifically, the PDE4A5 isoform of the PDE4 enzyme.

Treatment of mice with [broad, but also more specific] phosphodiesterase inhibitors rescued the sleep-deprivation-induced deficits in cAMP signalling, synaptic plasticity and hippocampus-dependent memory.

While the most specific PDE4A5 inhibitors are being developed to rescue synaptic plasticity and memory deficits produced by a brief period of sleep deprivation and enable the consolidation and persistence of memory, would you please brew me another strong, black cup of java?

Maybe that third cup will help me remember to save all my changes in both open spreadsheets when I close the program, and also to remember that the dialogue “Save changes?” is not the same as “Close the program?” when my itchy trigger finger on the mouse hovers over the “No” response.

If only I had a counter to see how many times I had to change windows, and go back and double-check, when flipping between the article, PubMed, and this post. I had better go try to terminate my test of the relevance of the sleep-deprivation mouse model to memory behavior of a scientific peer, this weekend.
—

¹ Nature 461, 1122-1125 (22 October 2009) doi:10.1038/nature08488

After the serious Lab Waste video by a local blogger whom we all know and love, here is The Safety Song:

Starring the world-famous Bokor Monster.

Courtesy of The Sounds of Science, from creative members of my alma mater.

A major plus for an American living in Western Europe is the proliferation of small, farmers’ style markets. While there are a few communities with such markets on the Western edge of the Atlantic, it’s not standard.

In France, the covered market has also become less standard over time, with the convenience of parking and packaging in what are known as “hypermarkets”. For the working scientist in the city, it can be very attractive to order all heavy things online to be delivered during a programmed two-hour window directly to your door.

However, nothing beats the local Market.

It’s possible to spend one’s Sunday morning revising a manuscript, look up at noon and realize you have nothing to feed your family at lunch, and dash down the street to the covered market.

The next time this happens to me, I will bring my own camera. It’s pittoresque à souhait – the seventeenth-century footpaths one can take perpendicular to the market road, the early twentieth-century meulières along the way, none of which are alas mine, and hedges and roadworks galore.

I was able to score the last one of these (resisting the particularly well-done, crunchy fried potatoes):

in favor of a couple of these:

and enough of these:

followed by decidedly non-pasteurized:

(only the one on the right, Abondance)

and, thanks to the wine-making family connections of my former student, some of this (actually it was from Domaine Maurice Gavignet, which I’d recommend):

And these to finish ¹.

I was going to actually wax poetic about the perfectly gorgeous and abundant orb-weaving spiders I met on the road, and their marvelous works of industry, and how they each seem to have a favorite leg to hook each segment of their web onto the support threads. But I’m afraid if I put up photos, that will put you off your appetite.

The French would never forgive me.

¹ Thanks to all the photographers for making their photos available with the CC license.

My first Ph.D. student successfully defended her thesis yesterday afternoon, completing the journey during which we took the above photo, years ago.

She did a great job.

I have all sorts of interesting feelings about this process that I’m not quite sure how to put into words, but pride is up there high on the list.

She’ll be back in November, hired by our cardiology colleagues to continue stocking DNA for a prospective research cohort into certain heart defects, and then will spread her wings and fly to a great lab in the U.S. for her postdoc.

I need to take stock, but perhaps the weekend will help with that.

Any other advisors feel a bit of “empty nest” syndrome? And relief?