Friday, February 25, 2011

Round-Number Handbook of Physics for Medicine and Biology

The 4th edition of Intermediate Physics for Medicine and Biology contains a list of fundamental constants in Appendix O. Russ Hobbie and I got the values of these constants from a 2002 study, but the National Institute of Science and Technology (NIST) website we cite no longer exists. A new NIST website, http://physics.nist.gov/cuu/Constants/index.html, gives the most up-to-date values for these constants, often including many significant figures.

For some applications, knowing the electron mass to, say, nine significant figures is important. But in biology and medicine, most quantities are not known with such precision. If a number is known to one percent, that is impressive. When I teach biological and medical physics, I would much rather see my students have an approximate feel for the size of important constants, without having them bother to memorize more than one or two significant figures. To know that the speed of light is 299,792,458 m/s is nice, but what I really want them to remember (forever!) is that the speed of light is about 3 × 108 m/s. If they need more precision, they can look it up.

Edward Purcell, one of the great ones, published his “Round-Number Handbook of Physics” in the January 1983 issue of the American Journal of Physics. He presented a list of important physical constants, but only to one or two significant figures. It was meant not as a reference to look up precise values, but as a list of approximate values that every physicist should know without needing to consult a reference. Unfortunately, Purcell used cgs units, which are becoming more and more obsolete.

Below I present my version of a “Round-Number Handbook of Physics for Medicine and Biology”. I take the constants from Appendix O and approximate them as round numbers in (mostly) mks units. These are the numbers you should remember.

 c Speed of light 3 × 108 m/s e Elementary charge 1.6 × 10−19 C F Faraday constant 105 C/mole g Acceleration of gravity 10 m/s2 h Planck’s constant 2π × 10−34 J s ℏ Planck’s constant (reduced) 10−34 J s kB Boltzmann’s constant 1.4 × 10−23 J/K me Electron mass 9 × 10−31 kg mec2 Electron rest energy 0.5 MeV mp Proton mass 1.7 × 10−27 kg mpc2 Proton rest energy 1000 MeV NA Avogadro’s number 6 × 1023 1/mole re Classical radius of the electron 3 × 10−15 m R Gas constant 8 J/(mole K) 2 cal/(mole °C) ε0 Electrical permittivity 9 × 10−12 F/m 1/4πε0 Coulomb’s law constant 9 × 109 N m2/C2 σSB @font-face { font-family: "Cambria"; }@font-face { font-family: "Palatino"; }p.MsoNormal, li.MsoNormal, div.MsoNormal { margin: 0in 0in 0.0001pt; font-size: 12pt; font-family: "Times New Roman"; }div.Section1 { page: Section1; } Stefan-Boltzmann constant 6 × 10−8 W/(m2 K4) λC Compton wavelength of the electron 2.4 pm μB Bohr magneton 10−23 J/T μ0 Magnetic permeability 4π × 10−7 H/m μN Nuclear magneton 5 × 10−27 J/T

Friday, February 18, 2011

Tc-99m Production: Losing the Reactor

Periodically in this blog I have discussed the growing technetium-99m shortage that faces medical physics (see, for instance, here, here, here, and here). Russ Hobbie and I discuss technetium in the 4th edition of Intermediate Physics for Medicine and Biology.
The most widely used isotope is 99mTc. As its name suggests, it does not occur naturally on earth, since it has no stable isotopes … The isotope is produced in the hospital from the decay of its parent, 99Mo, which is a fission product of 235U and can be separated from about 75 other fission products. The 99Mo decays to 99mTc.
Interestingly, the 99mTc shortage here in the United States may be solved in part by our friends up north (or, for those of us living in the Detroit area, our friends down south; look at a map), the Canadians. You can learn more in an article on medicalphysicsweb.org (and I hope you are a regular reader of that very useful website).
Technetium-99m (Tc-99m) is the most widely used medical imaging isotope, employed in more than 30 million procedures worldwide each year. The isotope is created via decay of molybdenum-99 (Mo-99), which itself is produced in nuclear reactors. And herein lies the problem.

The nuclear reactor is needed to generate neutrons that bombard uranium-235 targets, with the resulting fission reaction producing Mo-99 around 6% of the time. This Mo-99 then decays into Tc-99m. Unfortunately, over 90% of the world’s Mo-99 is produced by just five ageing reactors, resulting in an extremely fragile supply chain - the vulnerability of which was highlighted recently when unexpected shutdowns and routine maintenance closures combined to create serious shortages.

But there are other ways to create Tc-99m, and ways that don’t require nuclear reactors or a uranium target—itself a cause for concern as most facilities currently process highly-enriched (weapons-grade) uranium. Instead, researchers are investigating production methods based on cyclotrons and linear accelerators. Such processes exploit nuclear reactions within targets of Mo-100, bypassing the need for uranium completely.

In a bid to advance such technologies, the government of Canada has invested \$35 million in four development programmes. The projects are headed up by: TRIUMF (Vancouver, BC); Canadian Light Source (Saskatoon, SK); Advanced Cyclotron Systems (Richmond, BC); and Prairie Isotope Production Enterprise (Winnipeg, MB) ….

In terms of practical implementation, the cyclotron-based method produces Tc-99m, which has a half-life of just six hours and must therefore be manufactured at or very near to clinical sites. This approach can, however, take advantage of a wide network of existing medical cyclotrons.

The electron accelerator approach creates Mo-99, which has a half-life of 66 hours and, as such, can be shipped. “One or two linacs could probably supply most of Canada,” Barnard said. This method also benefits from being more similar to, and thus able to exploit, the existing Tc-99m supply chain based on shipping of Mo-99.
The article was written by medicalphysicsweb’s editor, Tami Freeman, who has worked as a journalist for the Institute of Physics for the last dozen years, and who has a PhD in physics.

P.S. There is a nice article in the February issue of Physics Today about U.S. attempts to address the Tc-99m shortage (see the comments to this blog entry).

Friday, February 11, 2011

The Framingham Heart Study

The Framingham Heart Study is one of the oldest and most widely cited research studies in the history of medicine. Russ Hobbie and I mention the study briefly In Section 2.4 of the 4th edition of Intermediate Physics for Medicine and Biology, when discussing exponential decay.
Figure 2.8 shows the survival of patients with congestive heart failure for a period of nine years. The data are taken from the Framingham study [McKee et al. (1971)]; the death rate is constant during this period.
The data in Fig. 2.8 is from a paper with over 1400 citations in the scientific and medical literature: P. A. McKee, W. P. Castelli, P. M. McNamara, and W. B. Kannel (1971) “The Natural History of Congestive Heart Failure: The Framingham Study,” New England Journal of Medicine, Volume 285, Pages 1441–1446. The abstract to the paper states
The natural history of congestive heart failure was studied over a 16-year period in 5192 persons initially free of the disease. Over this period, overt evidence of congestive heart failure developed in 142 persons. In almost every five-year age group, from 30 to 62 years, the incidence rate was greater for men than for women. Although the usual etiologic precursors were found, the dominant one was clearly hypertension, which preceded failure in 75 per cent of the cases. Coronary heart disease was noted at an earlier examination in 39 per cent, but in 29 per cent of the cases it was accompanied by hypertension. Precursive rheumatic heart disease, noted in 21 per cent of cases of congestive heart failure, was accompanied by hypertension in 11 per cent. Despite modern management, congestive heart failure proved to be extremely lethal. The probability of dying within five years from onset of congestive heart failure was 62 per cent for men and 42 per cent for women.
 A Change of Heart: How the Framingham Study Helped Unravel the Mysteries of Cardiovascular Disease, by Levy and Brink.
In 2005, Daniel Levy and Susan Brink published A Change of Heart: How the Framingham Heart Study Helped Unravel the Mysteries of Cardiovascular Disease. The book is a fascinating history of this landmark study. Levy (the study’s current director) and Brink (formerly a writer for U.S. News and World Report) write
A turning point in our evolving understanding of heart disease was the establishment of the Framingham Heart Study in 1948. It was a large and ambitious community-based research project unlike anything that had been conducted before. It came at a time of growing awareness that cardiovascular disease was sweeping the country, even slowing down what should have been a steady rise in life expectancy. It was also a time, three years after the end of World War II, when resources from the national treasury, no longer needed for military purposes, could be used for research into the nation’s leading killer….

In light of this ignorance [of how to treat coronary disease], the U.S. government in 1948 made a twenty-year commitment to uncovering the root causes of heart disease. That scientific resolve was sponsored by the U.S. Public Health Service with half a million dollars of start-up funding from Congress. A cadre of physicians, scientists, government officials, and academics—many of whom knew each other from having served together at military hospitals during the war—selected a New England town in which to carry out this national scientific experiment. The Framingham Heart Study turned out to be instrumental in changing the attitudes, if not the behavior, of virtually every American, and it put the otherwise ordinary town of Farmingham, Massachusetts, on the map….

They [the Heart Study researchers] needed the 5209 men and women from Framingham at first, followed by 5124 of their sons and daughters, and now 3500 of their grandchildren who have donated their medical histories to science. It is ironic, perhaps, that this most respected—even beloved—piece of epidemiology centers on the heart, the organ that symbolically aches, breaks, longs, and loves like no other. It took a commitment from thousands of volunteers to make the study a success.
I found Chapter 5 (The People Who Changed America’s Heart: Voices from Framingham) to be particularly inspiring. For instance, they quote Evelyn Langley—housewife, mother, and PTA president—who played an early role in promoting the study among potential participants, and was a participant herself.
Langley’s heart still lies with the Study. “When they call me up and tell me it’s time to come in for an exam, I know I have that ritual to do,” she says. She has made the trip to the clinic twenty-seven times so far. “I am trying to give back to the Heart Clinic [Study] what they have given me. I always feel as if I am part of something bigger than myself. It’s not just for the people who live in this town. Many lives have been saved because of the Heart Study.”
You can learn more about the Framingham Heart Study at the study’s website: http://www.framinghamheartstudy.org. The study is currently funded by the National Heart, Lung, and Blood Institute (part of the National Institutes of Health) and Boston University. Let me finish with a fitting quote from the acknowledgments of A Change of Heart.
This book would not have been possible without the more than fifty years of dedication and commitment from three generations of Framingham Heart Study volunteers. We would like to thank them all for providing a gift to the world that has changed untold millions of lives.

Friday, February 4, 2011

Britton Chance (1913-2010)

Britton Chance died late last year. The website www.brittonchance.org states that
Britton Chance, M.D., Ph.D., D.Sc., for more than 50 years one of the giants of biochemistry and biophysics and a world leader in transforming theoretical science into useful biomedical and clinical applications, died on November 16, 2010, at age 97 in Philadelphia, PA. Dr. Chance had the rare distinction of being the recipient of a National Medal of Science (1974), a Gold Medal in the Olympics (1952, Sailing, Men’s 5.5 Meter Class), and a Certificate of Merit for his sensitive work during World War II.
His obituary in the New York Times describes his early work.
Over a lifetime of research, Dr. Chance focused on the observation and measurement of chemical reactions within cells, tissue and the body. But unlike most researchers, he also had expertise in mechanics, electronics and optics, and a great facility in instrument-building. His innovations helped transform theoretical science into biochemical and biophysical principles, the stuff of textbooks, and useful biomedical and clinical applications.

Early in his career he invented a tool, known as a stopped-flow apparatus, for measuring chemical reactions involving enzymes; it led to the establishment of a fundamental principle of enzyme kinetics, known as the enzyme-substrate complex.
Another obituary, in the December 17 issue of Science magazine, observed that
In his mid-70s, Chance (then emeritus) launched a new field of optical diagnostics that rests on the physics of light diffusion through scattering materials such as living tissue. He showed that scattered near-infrared light pulses could not only measure the dynamics of oxy- and deoxyhemoglobin levels in performing muscles, but also reveal and locate tumors and cancerous tissue in muscles and breast as well as injury in the brain. Because changing patterns of oxy- and deoxyhemoglobin in the brain reflect cognitive activity, the applications of this diagnostic approach widened to include assessing neuronal connectivity in premature babies.
Chance appears in the 4th edition of Intermediate Physics for Medicine and Biology because of his research on light diffusion. In Section 14.4 (Scattering and Absorption of Radiation), Russ Hobbie and I analyze the absorption and scattering coefficients of infrared light, and then give typical values that “are eyeballed from data from various tissues reported in the article by Yodh and Chance (1995),” with the reference being to Yodh, A. and B. Chance (1995) “Spectroscopy and Imaging with Diffusing Light,” Physics Today, March, Pages 34–40.

Then in Sec. 14.5 (The Diffusion Approximation to Photon Transport), we analyze pulsed measurements of infrared light.
A technique made possible by ultrashort light pulses from a laser is time-dependent diffusion. It allows determination of both [the scattering coefficient] and [the absorption coefficient]. A very short (150-ps) pulse of light strikes a small region on the surface of the tissue. A detector placed on the surface about 4 cm away records the multiply-scattered photons. A typical plot of the detected photon fluence rate is shown in Fig. 14.13.
Figure 14.13 is a figure from Patterson, M. S., B. Chance, and B. C. Wilson (1989) “Time Resolved Reflectance and Transmittance for the Noninvasive Measurement of Tissue Optical Properties,” Applied Optics, Volume 28, Pages 2331–2336, which has been cited over 1000 times in the scientific literature.

Finally, in Sec. 14.6 (Biological Applications of Infrared Scattering), we reproduce a figure from the Physics Today article by Yodh and Chance, which shows the absorption coefficient for water, oxyhemoglobin and deoxyhemoglobin.
The greater absorption of blue light in oxygenated hemoglobin makes oxygenated blood red…The wavelength 800 nm at which both forms of hemoglobin have the same absorption is called the isosbestic point. Measurements of oxygenation are made by comparing the absorption at two wavelengths on either side of this point.
This property of infrared absorption of light is the basis for pulse oximeters that measure oxygenation. Not all measurements of blood oxygen use pulsed light. Russ and I cite one of Chance’s papers that uses a continuous source: Liu, H., D. A. Boas, Y. Zhang, A. G. Yodh, and B. Chance (1995) “Determination of Optical Properties and Blood Oxygenation in Tissue Using Continuous NIR Light,” Physics in Medicine and Biology, Volume 40, Pages 1983–1993. A fourth of Chance’s paper that we include in our references is Sevick, E. M., B. Chance, J. Leigh, S. Nioka, and M. Maris (1991) “Quantitation of Time- and Frequency-Resolved Optical Spectra for the Determination of Tissue Oxygenation,” Analytical Biochemistry, Volume 195, Pages 330–351.

In 1987, Chance won the Biological Physics Prize (now known as the Max Delbruck Prize in Biological Physics) from the American Physical Society
for pioneering application of physical tools to the understanding of Biological phenomena. The early applications ranged from novel spectrometry that elucidated electron transfer processes in living systems to analog computation of nonlinear processes. Later contributions have been equally at the forefront.