A randomized clinical trial of coenzyme Q10 and GPI-1485 in early Parkinson disease — The NINDS NET-PD Investigators 68 (1): 20 — Neurology

On the subject of Guilford Pharmaceutical drugs that I’ve worked on, the second NIND NET-PD trial has been published, a futility design that included GPI-1485.

A randomized clinical trial of coenzyme Q10 and GPI-1485 in early Parkinson disease — The NINDS NET-PD Investigators 68 (1): 20 — Neurology: “Coenzyme Q10 and GPI-1485 may warrant further study in Parkinson disease, although the data are inconsistent. ”

This trial was independently conducted by NINDS. We supplied the drug. Their results in untreated patients were consistent with our own 2 year long study of patients who were already on dopamine agonist monotherapy. There are important lessons to be learned from these studies about the challenges of designing studies to test disease modifying drugs in Parkinson’s Disease and other neurodegenerative diseases.

Aetna to End Payment for a Drug in Colonoscopies – New York Times

Of interest:

Aetna to End Payment for a Drug in Colonoscopies – New York Times: “Aetna, one of the nation’s largest private health plan managers, is the latest insurer to clamp down on the use of a powerful anesthetic during an increasingly common form of colon cancer screening.”

This insurer’s reaction to the use of anesthesiologists to administer propofol for colonoscopy is of interest to me because of my work with AQUAVAN over the years. At Guilford Pharmaceuticals (and then MGI Pharma after their acquisiton of Guilford) I directed the first in man study of AQUAVAN and worked on trials on and off through the recent NDA filing. AQUAVAN, as a prodrug of propofol, is not expected to require the same FDA mandate for administration by an anesthesiolgist that propofol does.

AQUAVAN is a prodrug of propofol, extending its action enough to make it a better sedative and a less powerful anesthetic. It’s an interesting, perhaps unique example of how making a drug worse for one use makes it more suitable for another.

This Times article doesn’t mention the alternatives like AQUAVAN or midazolam, but with pressures like this on physicians from insurers and pressures from patients for comfort during procedures, I expect that AQUAVAN will find its niche as a sedative for procedures. Eisai is now in the process of acquiring MGI, so AQUAVAN’s future now rests with them.

Nikon P5000 Again

The Patch of Sun

It’s actually hard for me to believe how much mental energy I’ve devoted to deciding whether or not to capture images with the Nikon P5000 compact digital. On the one hand I can have it everywhere, all the time. On the other hand, the image quality just doesn’t compare to either the Leica / chromogenic BW film system or the Nikon D300. On the other hand, I’m less serious with the P5000. I don’t evaluate exposure or work subjects the way I do with the serious cameras.

When issues are so undecidable, I tend to believe that the goals are unclear. These various image capture systems result in entirely different results for which I have not set relative values. The single dimension that they vary on is portability, Decision theory would dictate that I chose based on that dimension and accept the varied results as the outcome of deciding on the basis of whether I can carry the kit.

CRO Industry Outlook

Investor’s Business Daily: Upturn In Biotech Spending Drives Covance’s Growth: “Growth in the CRO sector is driven by biopharmaceutical research, development spending and a robust biotech funding environment, which hit $20.1 billion last year.”

As large pharmaceutical companies struggle with their cost structures they turn increasingly to outsourcing. Development stage biotechs often choose not to build their own infrastructure from the start to avoid the fixed costs. It’s driving CRO growth, where I currently work.

Against the Slats

Against the Slats, originally uploaded by jjvornov.

I just finished reading Seth Godin’s small book “The Dip”. And a very small book it is. His thesis, if you haven’t read the book, is simply that success general follows a pattern of initial results followed by a long “dip” of challenges and fewer rewards that can lead to great results. If you can get through “The Dip”, you graduate into a rarified class of the best where scarcity leads to disproporational returns.

The book helped me see my work career in a perspective that I had never taken before. While I enjoy clinical and scientific work immensely, there have times- years long sometimes- that have been stressful and seemingly without reward. Yet because of them I stand in a somewhat privileged place in my profession, having more that 20 years of research experience in Neuroscience, having worked with outstanding colleagues at outstanding institutions.

Somehow in the last year or two, I’ve taken on the challenge of digital color landscape photography. While I was pleased with images I created two years ago with the Olympus E-1 and excited about images with the D80 a year ago, I now have knowledge and tools at my disposal to create images that I could not have achieved then. The Archive pages in Flickr are a nice way to review progress over time.My “eye” or stye has not changed much, nor has my choice of subject matter. But I now can evaluate the light in a scene and think about how the camera sensor will respond. I’ve now started to think ahead to how I will deal with image problems in post-processing.

I have enough experience with “The Dip” to know that I’m in an exciting early phase where knowledge is not that hard to come by. I only have 295 photos up on Flickr, so every image I process is a significant learning experience. At some point the tools will be familiar enough that they will fade to the background and I’ll be faced with the slower improvement that comes with perfect practice.

However, I do have one strong disagreement with Godin’s approach. For the sake of the thesis, he presupposes that this path of progress is a linear journey with a clear destination from the outset- to be the best in the world. My life experience has taught me that one never knows where the path will lead. Thus it’s most important to focus on one’s immediate choices and continue to grow in skills and experience. I wasn’t planning on working for a global CRO as a therapeutic area leader, but here I am. I built a skill set and it suits this companies needs now.

While the contrasting patterns of slats and shadows were what drew me to capture the image, it’s the purple shadow vs. green wood that interested me as I brought it up though Capture NX and Photoshop. I took this with the Nikon D300 and the 105mm VR Micro. These details are a nice break from the wider landscapes I’ve been capturing with the 12-24mm f/4 DX and the 24mm f/2.8D.

But all I was trying to do was create an image that spoke more elequoently of the surprising beauty to be found in the wood of the porch outside of my kitchen here in suburban Baltimore. Certainly I’ve adopted a strategy of collecting images and improving my skills to generate a portfolio of a dozen or so strong images. I have no idea what my lie beyond that relatively short term goal.

Creating an Image

The Sky Reflected

I captured some images this afternoon. I thought it would be nice to give my Nikon 105mm f/2.8 Micro VR a workout as I haven’t used it much since I bought it a few months ago. Image harvesting was tough because most of the larger scenes had too wide of an intensity range to get the kind of image I want to work with these days. And it was a bit too cold and blustery to go and get the tripod to play with putting multiple exposures together. But there was a bucket in the shade with these leaves soaking in rainwater on top. Since I think the image is a nice representation of what I’ve been trying to acheive over the last few days, I thought it would be worthwhile to document the post processing workflow.

Since I still can’t use Aperture, the RAW files are copied into a reference folder on the image hard drive. I’m browsing in Capture NX, which is a bad idea, but I don’t want to open Bridge as yet another program. Capture NX just shows the embedded JPEGs and takes a few seconds to render the NEF into a full resolution image on screen. So I’m selecting promising images and and opening the NEFs to evaluate focus. I picked this one out of the series because of the composition, reflection of the sky and the grid-like pattern at the center.

Here’s the out of camera conversion, Picture Control: Vivid

Out of Camera NEF Conversion

Once I’ve selected one to work on, I modify overall exposure, white and black points and color cast with Capture NX as I believe that these manipulations are best done on the full 14 bit RAW file. I also use the U-Point color point adjusments to create the right relative values in the image. If the problem is uneven lighting on one side of the image or the other I’ll fix it with a gradient, like using a graduated filter. Capture NX’s control of gradients is very nice- easier than in Photoshop for me.

Here’s the image after adjustment with Capture NX:
Capture NX Version

After saving the image as a 16 bit TIFF, I open it in Photoshop. My first step is to optimize tonality using George DeWolfe’s method of desaturating and creating a curve that places the values so that they create a good monochrome image. Color gets in the way, so you desaturate, adjust the color, then add it back in.

BW Photoshope

And with the color added back in by hiding the desaturated version:

Adjusted Color

This was frequently where I stopped processing in the past, but as you can see from the image at the top, I’ve done more selective control of tone and saturation using techniques I’ve been picking up from Vincent Versace’s book, now including some of the Nik Color Efex filters.

20 Minute Body Weight Conditioning

Ascent Heart Rate

On Sunday I wrote about how I tried to do a 20 minute interval session with my usual strength training routine, failing to get my heart rate into a cardiac training zone. I ended up going on to an 8 sec work / 12 sec rest indoor training session on the bike.

After a bit more research couresy of Hillfit again, I did my usual Pilates routine followed by a body weight conditioning effort for 20 minutes. All while wearing my heart rate monitor, the record of which is above. The first half is the Pilates and it’s clear that over 20 minutes my heart rate stayed under what I have marked as Zone 1, my recovery area. In the second half I did 10 cycles of a 2 minute circuit: pushups, squats, lunges, jumping jacks. My rate rose into Zone 3 and bounced around there depending on how continous my effort was. It was challenging both from a strength and a cardiac perspective.

I’m now pretty convinced that this kind of 20 minute workout can provide a strong training stimulus, although it won’t build endurance for long efforts. From my simple exploration so far, it seems that moving body weight is the key. Only the body’s prime mover muscles will develop enough power to provide the cardiovascular stimulus. Effort has to be continuous, or at least rest has to be incomplete to push heart rate toward lactate threshold.

2007 Training Summary

207 Hours in 2007

Last Febuary, needing a new heart rate monitor, I invested in a Garmin Forerunner 305. It’s an oversized watch unit with a built in GPS unit, wireless heart rate monitor and, with a bicycle accessory, cadence sensor. I chose it because it was flexible for running or cycling and, most importantly, because I would finally be able to track workouts on the computer.

While Garmin had finally started supporting the Mac with it’s software, I ended up using Ascent from Montebello Software. Based on appearances, I presume that Ascent is a Cocoa based program that integrates with Microsoft TerraServer and Virtual Earth for mapping. While the maps and the workout data displays are nice, what I find most useful is the journal function

Since Feburary, I know I’ve lost a few hours of recording because a dead battery in the Garmin. And when I do my 15-20 minute Pilates stretch and core strength routine, I can’t wear the monitor. Weight training and any swimming haven’t gotten recorded either. So I’m tracking running and cycling for the most part.

Since the Journal tracks by day, week, month and year, today I finish the first calendar year with the system. Since I didn’t have the unit during January, I’ll need to extrapolate the missing data.

During 2007 I totaled 207 hours of activity. That’s about 19 hours a month or a bit less than 5 hours a week. Of course there was a good bit of variability with months ranging from 22 hours in April to a low of 14 hours in August. During the year I realized that time was a constraint- family, vacations and business travel making many days unavailable for exercise. One of my adaptations was to use those weeks as rest weeks and pile up extra activity in the week before if possible.

It’s clear that I could do better simply by being more consistant on easy days. I can also be a bit smarter about matching time to intensity. For example, when I have a couple of weeks during the summer with limited travel, I can use the flexibility of my schedule to move to lower intensity, longer duration workouts. During the tough travel times, I can do consistent days that are shorter, but higher intensity. Overall, though it’s unlikely that I’ll be able to push total training time above 250 hours.

Am I more Fit This Year Than Last?

When I set up this new weblog, I made my categories into goals. My fitness goal was simply to be more fit this year than last. I didn’t set objective criteria at the time, but there are a few that emerged. Of course, there’s weight. Today I was at 156.5 pounds. Last year, I was at 160.5, so there’s an objective improvement. As well, I’ve taken about an inch and a half off my waistline, so my fat loss may have been more that the 4 pounds of total weight. Psychologically, my stress level is low and I’ve had fewer colds and viruses this year than in years past.

I’ve tracked fitness somewhat using field testing as suggested by Chris Carmichael. My 12 minute Cooper Fitness Test, my running test has improved from 1.125 miles last August to 1.38 miles last month. Based on the standard calculations, that means that my VO2 Max has improved from 29 to 34, a 17% improvement. I haven’t had a long enough interval to judge my progress on the Carmichael 3 mile maximal effort cycling test, but based on my riding speeds, I expect that I’m faster there. I’m doing base miles at speeds of 13 to 14 mph this year rather than 11 to 12 that I was doing early last year.

Sadly, I’ve just managed to get myself into the average category for age. I’m not a naturally gifted endurance athelete and for years my exercise was always just recreational- hiking or long cycling. I have no trouble training to go long, I just can’t go fast. So while I’m clearly responding to training stimuli, I likely lack the genetic capability to ride or run really fast because of my limitations in oxygen use efficiency.

But knowing that my clear limiter is VO2Max and not strength or endurance gives me a focus for training this year. I’d like to see to what extent I can use last year as a platform to get another 10 to 20% gain by this time next year. If I take off another 6 pounds and put on some more lean weight, my strength to weight ratio should be better and performance should improve.

In the end, I’m deeply grateful to be able to be working on my athleticism as I enter my 50’s rather than dealing with the onset of chronic illness of aging.

Trying 8 Second Intervals

On the local bicycle club mailing list I saw this link to an interesting report on very short intervals. There are links to the thesis there, so one can review the data itself. The investigators first examined the physiological effects of very short, high intensity intervals, comparing first 8 s work followed by 12 s rest vs 24 s work and 36 s rest. There was little difference physiologically, but the 8/12 sequence was preferred by the subjects. In the following 15 week training study the 8 second / 12 second 20 minute interval training was compared to a 40 min standard cardio workout at 60% of VO2 peak..

For some reason I was very interested in trying it. This morning I put on the heart rate monitor and tried to use my strength exercise as the stimulus- working hard with light weight for 8 seconds, resting for 12 and going continuously for 20 minutes. It didn’t work at all, because as I always find with continuous circuit training I feel the effort, but my heart rate never gets very high even though I’m working hard. I get to audible breathing, but I remain in at a low level of aerobic exertion based on heart rate.

Not wanting to give up, I gave it 20 minutes on the bike. I picked a resistance on the trainer that felt like work for 8 seconds followed by “just turning the pedals over” for 12 seconds. And the workout was quite intense. It’s seems like it’s quite self regulating to get one working very quickly just above lactate threshold. The rest periods are no where near long enough to recover and and the work periods I kept to short of painful, since I was going to be doing this for 20 minutes. Over about 10 minutes then, my heartrate stair-stepped up to about LTHR and slowly moved moved beyond it in the second 10 minutes.

I think it’s a nice way to build intensity on a trainer while stressing the aerobic system primarily. I could see pushing the workout over time to longer than 20 minutes, since I felt a modest amount of fatigue after the workout. I’ll see how ready I am tomorrow, which is the true test of workout intensity, but tonight my guess is that it’s a moderate, not a hard workout and I probably could do it again tomorrow.