Saturday, September 27, 2008

Paul Newman


“We are such spendthrifts with our lives,” Mr. Newman once told a reporter. “The trick of living is to slip on and off the planet with the least fuss you can muster. I’m not running for sainthood. I just happen to think that in life we need to be a little like the farmer, who puts back into the soil what he takes out.” -- New York Times, September 27, 2008

Friday, September 26, 2008

It was a very good year

This photo -- of the outcroppings, the rocks, at Slate Creek in the Grand Canyon -- comes from one of TW's latest posts. He goes on to seamlessly pair image with verb:
but now
the days
grow short
i'm in
the autumn
of the year
and i think
of my life
as vintage wine
from fine
old kegs
from the brim
to the dregs
that poured
sweet and clear
it was a
very good year







Thursday, September 25, 2008

Tuesday, September 23, 2008

Translational Research: Gene therapy for chronic pain enters first human trial

University of Michigan Health System Newsroom

ANN ARBOR, Mich. —This week, University of Michigan scientists will begin a phase 1 clinical trial for the treatment of cancer-related pain, using a novel gene transfer vector injected into the skin to deliver a pain-relieving gene to the nervous system.

A gene transfer vector is an agent used to carry genes into cells. In this groundbreaking clinical trial, the investigators will use a vector created from herpes simplex virus (HSV) – the virus that causes cold sores – to deliver the gene for enkephalin, one of the body’s own natural pain relievers.

“In pre-clinical studies, we have found that HSV-mediated transfer of enkephalin can reduce chronic pain,” says David Fink, M.D., Robert Brear Professor and chair of the department of neurology at the U-M Medical School. Fink developed the vector with collaborators and will direct the study.

“After almost two decades of development and more than eight years of studies in animal models of pain, we have reached the point where we are ready to find out whether this approach will be effective in treating patients,” Fink says. The investigators are recruiting 12 patients with intractable pain from cancer to examine whether the vector can be used safely to deliver its cargo to sensory nerves.

The trial represents two firsts, says Fink: It is the first human trial of gene therapy for pain, and the first study to test a nonreplicating HSV-based vector to deliver a therapeutic gene to humans. Fink says the technique may hold promise for treating other types of chronic pain, including pain from nerve damage that occurs in many people with diabetes.

The HSV vector, genetically altered so it cannot reproduce, has a distinct advantage, Fink says: “Because HSV naturally travels to nerve cells from the skin, the HSV-based vector can be injected in the skin to target pain pathways in the nervous system.”

Gene therapy for pain

Chronic pain is an important clinical problem that, despite a wide array of therapeutic options, cannot be effectively treated in a substantial number of patients. Fink notes that one key problem in treating pain is that the targets of conventional pain-relieving medications tend to be widely distributed in the nervous system, so that “off target” side effects of the drugs often preclude the use of those drugs at fully effective doses.

“This provides the rationale for using gene transfer to treat pain,” Fink says. “We use the vector to deliver and express a chemical that breaks down very quickly in the body. The targeted delivery allows us to selectively interrupt the transmission of pain-related signals and thus reduce the perception of pain.”

Enkephalin is one member of the family of opioid peptides that are naturally produced in the body. Opioid peptides exert their pain-relieving effects by acting at the same receptor through which morphine and related opiate drugs achieve their pain-relieving effects. In this trial the enkephalin peptide, produced as a result of the gene transfer, will be released selectively in the spinal cord at a site involved in transmitting pain from the affected body part to the brain.

“We hope that this selective targeting will result in pain-relieving effects that cannot be achieved by systemic administration of opiate drugs, “ Fink says. “This trial is the first step in bringing the therapy into clinical use. A treatment is at least several years off.”

Preclinical studies led to human trial

The phase I clinical trial represents the culmination of studies performed by investigators working in the U-M laboratory co-directed by Fink and his wife, Marina Mata, M.D., also a professor of neurology at U-M, along with colleagues at the University of Pittsburgh led by Joseph Glorioso, Ph.D. In published studies, the researchers have demonstrated that HSV-mediated gene transfer is effective in rats with pain resulting from inflammation, nerve damage or spinal cord injury, and in mice with pain caused by cancer. The extensive preclinical data in animal models were reviewed by the Recombinant DNA Advisory Committee at the National Institutes of Health. The Food and Drug Administration approved an investigational new drug application for the therapy in February.

Funding for the preclinical studies was provided by the NIH, and related studies of the vector were funded by grants from the Department of Veterans Affairs and the Juvenile Diabetes Research Foundation. The human trial is supported by a research grant from Diamyd, Inc., a subsidiary of Diamyd Medical (DIAMB.ST), a publicly traded Swedish biotechnology company. Fink has no financial interest in or consulting relationship with Diamyd. He is an inventor on patents related to this work that are owned by the University of Pittsburgh and licensed to Diamyd. Susan Urba, M.D. and Frank Worden, M.D., medical oncologists at the U-M Comprehensive Cancer Center will serve as principal clinicians for the study, assisted by Suzette Walker, N.P., who will serve as study coordinator, and Heidi L’Esperance, who will serve as data manager.

Trial details

The investigators are seeking patients with intractable pain related to cancer that is unresponsive to maximally tolerated doses of conventional analgesic drugs. The vector will be delivered in 10 small injections into the skin, and will require an overnight stay in the Michigan Clinical Research Unit at U-M Hospital. For more information, contact the U-M Cancer AnswerLine, 800-865-1125, or visit:
www.med.umich.edu/engage/
www.cancer.med.umich.edu/research/clinical_trials.shtml
www.med.umich.edu/neurology

Monday, September 22, 2008

Stridor

One of the medical blogs I enjoy directed me to this story at a relatively new and entertaining blog, Ready To Deliver?

It made me remember the pride I felt at my recent highjinks in ICU. After four days on a ventilator, I was eager to be extubated. Finally, the tube came out and I eventually settled down in an effort to get some real sleep. That didn't happen because I had stridor and was put back on some sort of forced air do-dad.

As I would simultaneously tire and drift off, the oxygen saturation numbers would kick off a loud, obnoxious alarm -- and bring to my bedside a stream of medical types, all yelling at me to breathe, and other ridiculous verbal commands.

So, as my heart pounded from the sudden light, noise, and movement, the next thing my nurse would insist upon? "Retired Educator, you have got to relax and get some sleep!"

Yes. This went on for what seemed like forever but could only have been about 8 hours. The various doctors who wandered in assured me that the ersatz tube could be gotten rid of the next day, and that I should just relax and get some sleep -- surely I was exhausted!

ALARM-ALARM-ALARM-ALARM!

I decided that all tubes, except the foley, for which I was, in truth, quite grateful, would have to go... The i.v. was fine, too -- didn't hurt, didn't keep me awake, and didn't ALARM.

I was polite enough to discuss it with my nurse. She must have thought the discussion to be purely philosophical -- until I detached and yanked everything on my face, and handed it to her while she was still sputtering rules, regulations, and orders.

Respiratory Therapy decided not to go to war over my show of initiative, and the regular alarm proved much easier to sleep through. The alarms cannot be turned off -- but they were set at their least sensitive. And so I finally fell into a natural sleep...

Until my nurse showed up to put in another nasogastric tube. My reach had exceeded my grasp! I gather that most people who yank things out while in ICU are confused and agitated, have to be restrained -- both chemically and physically. So it must have been a weird site to my surgeon when he walked in and found me studiously attempting to help in the reinsertion of the n/g.

I don't know why. I mean, I explained it clearly enough: I meant to just pull out the breathing tube but accidently pulled out the feeding tube as well [goofy grin].

The Trinity of These Days


I am in denial.

Can vancomycin or cefepime, or a combination thereof, cause severe depression? Is it true that there is always a first time?

The day after I was home from the hospital, I decided to tell Fred about the growing and severe pain in my *left* shoulder, ending the admission with the happy understanding that in no way could it be related to infection of any sort.

His response was to say": "That is what I am talking about... We need to talk... I have been trying to have this conversation for a long time... What are we going to do when you get even worse? I can't take care of you. And who is going to take care of me?"

There was yelling and crying, on my part; Stalking off, on his.

And no one has discussed the pain in my shoulder. The *left* one. No, that's not true. He told me to tell my VIPMD, who did seem to take me seriously -- maybe.
After having pooh-poohed the symptoms of fever, pain, and fatigue for over a year that led, finally, to the discovery of a septic joint, I guess he must take me seriously. God forbid that I should simply inspire his attention. God forbid that simply my complaint should carry the day.

But instead of looking into it, he spun off into never-never-land, where shoulder pain devolves into... something to chart, something to watch, something to bury under the weight and mass of our present troubles.

I cannot reach across my body with that arm, cannot raise it above shoulder height. It throbs with no provocation, and hurts sharply with movement. And -- oh! -- does it get moved -- given that my right shoulder is, well, missing. I am extremely grateful to know that there is no infection -- an impossibility since I am on IV antibiotics -- and that the problem is probably "mechanical." The prosthesis must be loose.

(Yes, both shoulders were replaced. Along with a hip... which is doing marvelously. The other hip is pinned. One ankle is plated and screwed, as is the right elbow.)

The night that Fred and I had this most recent irrational (that is, rational to an *impossible* degree) spat, I relieved him of IV drug duty, although I had to wait two days for an extension to my PICC ports to be provided so that my right hand could reach the tubing. He had been ranting about having places to be, people to see, and the difficulty of doing so while tied to my antibiotic regimen. I believe I referenced his social schedule with a heavily ironic tone before promising to make the changes necessary to free up his dance card.

He said it was good to see me taking some "responsibility" for myself.

"But where does by far the bulk, the whole ambulance load, of pain really come from?"

Okay, so I have been waiting years to have some remote reason for quoting Salinger's Seymour, An Introduction -- this quote, in particular. That he references the pain of artists is no deterent to my citation. I am an artist. I am! Okay, already! Shut up, you.

Salinger is an indulgence that I am so sad to have outgrown. Or do I flatter myself?

Denial, depression, pain -- the trinity of this post. A touch of self-pity.

He woke me around 3 am because I was moaning in my sleep, rocking back and forth. Noon now, it is time to try for sleep once again, and to put all this to rest. Strict instructions shall be given to ignore any and all moans, any and all movements.

Denial, depression, pain -- the plan is to sleep off this shameful state, this wailing weakness.

As for the remnants of self-pity? It is a waking task, to take on that delusion. You've seen me tackle it before... and with such success, too. Hence the word "remnant."

Oops, time to flush my line and hook up to antibiotic number two...

A Jacques Brel Morning


CHANSON SANS PAROLES

J'aurais aimé ma belle
T'écrire une chanson
Sur cette mélodie
Rencontrée une nuit
J'aurais aimé ma belle
Rien qu'au point d'Alençon
T'écrire un long poème
T'écrire un long " je t'aime "

Je t'aurais dit " amour "
Je t'aurais dit " toujours "
Mais de mille façons
Mais par mille détours
Je t'aurais dit " partons "
Je t'aurais dit " brûlons
Brûlons de jour en jour
De saisons en saisons "

Mais le temps que s'allume
L'idée sur le papier
Le temps de prendre une plume
Le temps de la tailler
Mais le temps de me dire
Comment vais-je l'écrire
Et le temps est venu
Où tu ne m'aimais plus