Obesity. The Scourge of Modern Society

I must be cruel only to be kind, thus bad begins and worse remains behind. – Hamlet, William Shakespeare.

The afternoon had been brutal; temperatures melting the thermometers. A brownish glazed haze hung over like a limp dirty rag. The sky was obscured and the sun barged through with a bright circular, blinding orb; a view from a glaucoma eye. The streets were bare as the shimmering pavement cast its vistas of watery mirages.  I walked into a bar/cafe for a cold drink.

The bar was bustling with patrons. What caught my eye was the number of people draped over the stools on which they sat. Not a single seat fit the size of the seat. There were unambiguous folded-over curls of fat barely concealed by the clothes that were stretched at the seams.

Currently 73 million Americans are classified as obese and national spending on obesity related illnesses dwarfs illnesses related to alcohol and tobacco (the other civilization curses). It is estimated to cost $344 Billion by 2018 (ncbi data)

Obesity Data Adults and Children:

My mind goes ballistic when faced with these facts. No wonder we are where we are. The decline in health, the cost of healthcare not withstanding, we are doing it to ourselves. We indulge and want a pill. In fact a physician friend of mine remarked the other day, “I have a party to go to. It is at a such-and-such restaurant, you know the one where they have the delicious desserts with cheesecakes and truffles…” He paused and then said, “You know, I am going to take an extra Statin before I go.” Now granted he is a urologist and not quite that adept with issues of cardiology but also he does tip the scales when he drives his empty car through the highway weighing stations. He dresses in the extra-large and consumes the extra-large. There is very little, that has the smell of food, that passes him by without tickling his olfaction or gastric grumble.

I do remember him a decade ago though when he was the spitting image of a daytime TV star. But all that has been folded over and blanketed around by layers and layers of consumables.

What of this? My friend, an intelligent physician, never the less a human being at his basest, is also a victim of his own making. He blames it on stress, anxiety, divorce, work and family. He doesn’t ask my opinion, because I would say the same thing. “Too much food and too many excuses, buddy!”

Obesity Epidemic!

You pay a great deal too dear for what’s given freely. –A Winter’s Tale, William Shakespeare

Obesity is an epidemic. Yes! When 30% of the population is draping over their chairs, taking a pocketful of medications to keep themselves moving and wearing vertical stripes to streamline the misshapen body, then something is terribly wrong. One can easily blame the excess on excess. Wealth transgresses all elements of health until we reach the uber-rich where skinny is the name-of-the-game. And that “skinny” is not acquired from starving but from uber-neuro-stimulants, that only the elite can afford. But the addictive factor is the same. What struck me dumb was the chart that showed the Maltese were heavier then Americans. Say What? They are not wealthy, so what gives?

Le me not digress here too much. Let us look at the vile mechanistic prongs of desire; consumption and obesity.

Childhood Obesity:

This bodes dangerously on our society as a whole. Children are the Future. Preserve and Protect them!

Human Paleontology:

In the ancient days when Jean Auel’s Mammoth Hunters were still in the hunter-gatherer mode, only two fact-lets of life existed: Feast or Famine.

The human body had evolved though the virtues of its plastic genetics into allowing the (human) vessel to consume large quantities of food and store it in the form of “fat” for the lean days of “famine.” Not only was this mechanism true then, it is true today as well in the animal world. For instance the hibernating bears that forage during the seal-stalking season and then lie for months dormant while their bodies consume the fat slowly in their sleep. 

They are lean again after hibernation for more kills for survival. Now lets just imagine that in this land of bears if we were to have a “mega-seal-grocery store” open 24/7 for the bears to visit and satiate themselves. We would have… Obese bears barely able to carry their own weight of thousand pounds and they would probably not be able to stand on their hind-legs to scare anyone, except with their growl. (And then maybe we can spend on their health care also).

So from the metaphorical sublimity of thought to the facts on the physical ground today, one can see the obvious. We have 24/7 food available and there is no famine in at least the near-future, so the act of consumption has taken on a whole new direction. We have changed from “eat to live,” to “live to eat.”  We are devising more mechanisms to enjoy the abundant food in newer and newer ways. There are TV Chefs propounding one recipe after another making mountains out of butter and tall buildings out of chocolates. The constant barrage of this advertising campaign, out pours the juices of desire and lust into a mind filled with “wants.” One should ask, “Why does not the body not stop the consumption once it is satiated?”

Energy for the Organs: Glucose

Ah! here lies the rub of biological trappings in altered semantics. Food that is consumed is converted to glucose. As the liver does its wonderful and steady-paced work in this conversion called “Glucogenesis,” the glucose is liberated into the blood to reach its various destinations throughout the body for use. Remembering that the cells derive energy from glucose to commit to their functions: Liver; Assimilates and reprocesses food along with Glucogenesis, forming various clotting factors and creating enzymes, etc, Heart: Needs its energy requirements for pumping blood continuously for the human life-time with it’s over 2 Billion beats, Brain: In electrical transmission, dissemination of information within and storage of information, Muscles; to keep us moving, Bone; modulation to keep us from fracturing into a heap, Kidneys; for filtering the blood, good from the bad  and the Lungs; Work by exchanging gases: oxygen for carbon dioxide. So yes the glucose has all those places to visit to keep this wonderful organs to keep doing what they are supposed to do. The hormone responsible for delivering glucose to the cell and the muscles is Insulin. Once that process has been completed, the leftover glucose is converted into free fatty acids by the liver and stored as fat. Insulin is also instrumental in that lipid deliverance.

Energy for the Organs: Fatty Acids

It becomes obvious for all to see that excess of unutilized glucose would result in excess of stored fat. (Lipogenesis) That is exactly what happens. Additionally trans-fat consumption leads to a triglyceride blood-load, which flows through the liver and is converted into Fatty Acids for use as energy. Excess amounts return to the liver to be stored as fat. As more and more fat is stored in the liver and cause degeneration, free fatty acids roam the arborized jungle of the blood vessels. Excess of unconverted free fatty acids are also metabolized into LDL and VLDL. It is important to remember that fatty acids by themselves have very important functions in restoration of energy and since all the cellular walls are composed of phospholipids there is direct need for a constant supply of fatty acids for new-forming cells in the body and the brain.  (Thus removing the lipids artificially is also fraught with some concern: Some of the “Statin” side effects of muscle cramps, pain (Rhabdomyolysis) and memory loss are a result of this withdrawal.) A balance is needed.

“Fatty acids synthesized by the liver are converted to triglyceride and transported to the blood as VLDL In peripheral tissues, lipoprotein lipase digests part of the VLDL into LDL and free fatty acids, which are taken up for metabolism. This is done by the removal of the triglycerides contained in the VLDL. What is left of the VLDL absorbs cholesterol from other circulating lipoproteins, becoming LDLs. LDL is absorbed via LDL receptors. This provides a mechanism for absorption of LDL into the cell, and for its conversion into free fatty acids, cholesterol, and other components of LDL. The liver controls the concentration of cholesterol in the blood by removing LDL.”

Fatty Acids and Gene Control:

These are the fatty acids that my urologist friend was trying to minimize in his bloodstream.  Fatty acids are saturated  (if they have a double Hydrogen bond) or unsaturated and they too display Cis or Trans moiety (Left, Right tendencies) The proper fit for each fatty acid is needed for  function. (If the glove fits…) Fatty Acids store more than 6 times energy as compared to glycogen and the energy they release is via transportation into the mitochondria, where by beta oxidation and electron transport, energy is released and used by the cell. If my friend thought through the mechanistic triangle, he would easily see the irony of his actions.  And speaking of genetic mediation of the fatty acids, there is some data that suggests that about 12 SNPs (Single Nucleotide Polymorphism) on the ATGL (Adipose Triglyceride Lipase) gene is associated with the Free Fatty Acids, Triglycerides and Type 2 Diabetes. Any mutations will lead to disease probability outcomes. And we are not talking about the Apo gene collage which also play a part in the LDL management. (Time for your individual research, otherwise this Blog will reach gigantic proportions.)

Insulin Resistance:

What is interesting is that excess Insulin in the blood stream is among the signal generators transmitted by the brain for the need for glucose. Remembering that the software of the body resides in the brain. All things sensory and motor are driven by this three-pound marvel. So when the brain senses the excess relative/absolute Insulin it sends hunger pangs and borborygmias (growling stomach) and other alerts for hunter-gatherer mission. In obese people the system of alerts are falsely spiked. Here lies the conundrum; when there is excess free-fatty acids floating around and excess fat larding over in the various cellular compartments of the body, the brain is “blinded” to the insulin levels in the blood (which are trying to satisfy the cellular entry “deliverance”) but unable to send the “satiety” signals and therefore the constant hunger pangs continue even after a “Half-Pound cheeseburger, fries, milkshake and a piece of pie, have been consumed.

Organ Effects from Excess:

Excess free-fatty acids and glucose, all conspire to create damage to the various organs. The kidney filtration system suffers forcing dialysis, the blood vessels layered with clogging fat choke the delivery of blood, forcing the heart to beat extra hard and that tires the poor organ into congestive heart failure if not outright a heart-attack from the clogged arteries. The lung’s ventilatory volume is reduced due to the excess belly-fat that prevents full expansion leading to atelectasis. The eye suffers in vision due to retinal artery clogging and damage to the Rods and Cones within it. The brain suffers greatly because of diminished blood flow from the clogged arteries and also from the inactivity that commonly foreshadows obesity, thus names, places and memories get commingled and the thoughts are discombobulated. The liver gets laden with fat and ultimately scar tissue slides in to cause cirrhosis and even liver cancer, while the muscles of the body suffer from disuse and atrophy. So this majestic quintessence of dust, this like an angel turns into a disuse blubbering mass of protoplasm. (I am cruel only to be kind.)

High Fructose Corn Syrup (The devil in its details):

One more thing while I have the hacksaw with me. This High Fructose Corn Syrup, a chemical construct of such great harm, present in every soda, fast food dessert and drink, making all things taste sweet and addictive, is the devil in disguise. We should all take notice when a package states its presence and avoid the package. High Fructose Corn Syrup is pure fructose and pure unadulterated evil. The fructose has to be converted into glucose by the liver and weight for weight it delivers a significant punch. In fact there is data emerging that this “Syrup” has, because of its constant loading of the glucose in the bloodstream causes constant stimulation of the pancreas to liberate Insulin. This constancy leads to fatigue of the organ and ultimately dysfunction. Lab studies also show that High fructose corn syrup causes pancreas cells to proliferate and transform into cancer cells (By inducing Transketolase Flux) .  Quoting Dr. Liu:

“Carbohydrate metabolism via glycolysis and the tricarboxylic acid cycle is pivotal for cancer growth, and increased refined carbohydrate consumption adversely affects cancer survival.”

 And:

“Importantly, fructose and glucose metabolism are quite different; in comparison with glucose, fructose induces thiamine-dependent transketolase flux and is preferentially metabolized via the nonoxidative pentose phosphate pathway to synthesize nucleic acids and increase uric acid production. These findings show that cancer cells can readily metabolize fructose to increase proliferation.”

Insulin Growth Factor and Cancer:

One more thing while I am at it; Excess stimulatory influence of Insulin also stimulates the IGF (Insulin Growth Factor) The receptors for the IGF line themselves up on the surface of various cancer cells and coalesce with Insulin to stimulate the interior of the nucleus (of the cancer cell) to start manufacturing data for fattening, growth and proliferation. The stimulatory influences can be in the form of glucose, corn syrup or Free fatty acids. All three mentioned promoters have an effect on the pancreas to release Immuno-Reactive-Insulin (IRI) to counter the barrage.

Seyffert  et al.state unequivocally:

“Studies indicate that long-chain FFA, in physiological concentrations, can markedly stimulate insulin secretion by a direct effect on the pancreas. The results lend support to the concept of insulin as a hormone that is importantly involved in regulating the metabolism of all three principal classes of metabolic substrates and whose release is in turn regulated by all of them.”

The Pill & Blame Society:

Pills, pills and more pills! In this world where we are inclined to “fix” everything with a pill, There are an overabundance of “snake-oil” pills for you to consider. But consider does not mean consider for use. It means simply that they are harmful and lend themselves to you to perpetrate a fraud on your senses to achieve the desired goal without imposing limitation. No amount of blame on senses will rectify the problem. It is you and you are it, alone, against this beast called obesity. Please note and even though at the risk of repeating myself. No pill designed for weight reduction, will give you health. Period! There are no magic bullets, no potions, no apothecary concoctions that will minister to your need against obesity. There is but one and only one solution and that is limiting caloric intake. Simply: Eat Less!

Simple Dietary Math:

About 3000-3500 calories equate to ONE pound of excess weight. So if one reduces 300 calories a day (One less Twinkie) one would lose ONE pound of weight in 10 days. Simple math, not subject to conditions, questions or scrutiny!

Healthy 2000 Calorie Diet:

The average HEALTHY diet is one composed of 2000 calories a day. In fact data from rats and humans (if you insist) suggest that a 25% reduction in caloric intake leads to a 30% increase in lifespan. So what gives? Why are we trying to circumvent our lives by overeating? And there is very little but laughter that emerges from the Authors who have written countless books on “Special Diets.” They are literally laughing their way to the bank, while you contemplate. Remember it is the Intake (stored energy as in food) – (minus) Output  (Exercise/ work) = Weight Stability Loss or Gain.

Now that I may have set you on the path of research to confirm this truth, let me also say that the 2000 calorie diet that will drive you into the healthy 80s and 90s does not constitute bad foods. One cannot consider a 2000 calorie diet of “cookies and cream” and survive the hammer. Here some modicum of reasonableness needs to be addressed. Eat healthy and add “food-stuff” that is beneficial to you, for instance; broccoli, spinach, carrots, fish, some chicken, some fruit and sparingly (if you cannot give up red meats) a small steak. Limiting alcohol (Alcohol is a sugar and is metabolized into glucose rapidly) and EXERCISE. Ugh! You say now, but not when you are playing tennis, golf or skiing the Rockies, climbing mountain Kilimanjaro or for that matter swimming the English Channel in your 60s, 70s 80s or even 90s!

Obesity and Chronic Illnesses:

So no stones are left gathering moss; I’ll make this simple and direct: Cancer is directly linked to obesity! Obese people who are inactive and have slow colon-transit rates have a higher risk of colon cancer. Obesity is also linked to breast cancer, Prostate cancer and if one really thinks it through most chronic illnesses.

Speaking of Chronic Illness: The morbidity that ensues from obesity includes simple but crippling problems like Arthritis. The cause effect is simple. The joints were not designed by nature to bear ever increasing weights. The wear and tear leads to the canes, walkers and wheelchairs. Obesity is now being recognized as a “Metabolic Syndrome” that has dire consequences.

Metabolic Syndrome:

Emergence of the Metabolic Syndrome classified (ncbi):

“Metabolic syndrome is associated with many conditions and risk factors. The two most important risk factors are:

Extra weight around the middle of the body (central obesity). The body may be described as "apple-shaped."

Insulin resistance, in which the body cannot use insulin effectively. Insulin is needed to help control the amount of sugar in the body.

The disease-complex of Metabolic Syndrome is associated with atherosclerosis, Type II Diabetes, High Blood Pressure, Stroke, Heart Attack, fatty degeneration of the liver and Kidney disease.  New data from the National Cancer Institute suggest a higher risk of liver cancer related to Metabolic Syndrome.

Diabetes Type II. There is enough literature if reviewed would put a person into a state of starvation. Diabetes is a scourge of “advanced civilization” The over-abundance of glucose, stored fat and the inability of the pancreas to keep up with the demands leads to diabetes. Besides an overtaxed pancreas, there is true “blindness” to the circulating insulin by the free-fatty-acids in the blood stream which furthers the cause of having more glucose in the circulation and more unusable insulin that cannot optimally deliver glucose or FFAs within the cell for utility.

Once there was a hope, now vanished, to eradicate obesity with a “pill” called Leptin. No, Nada, Never going to happen! The only hope is that you give yourself a chance to live a healthy life.

There is only one hope if you wish to contemplate on the subject; If you wish to continue consuming large amounts of food: wait for the evolution to genetically modify us humans so we can concurrently metabolize excess – that could take another thousand years, or simply try to “push away from the table” method with “just a little hunger left in your stomach.”

Let me define Obesity once again: Any excess weight that elicits such complications as have hitherto been elucidated. Or for more practical matters: BMI below 30. Weight based on Actuarial Tables (the most accurate since they are associated with morbidity and mortality and the insurance companies assigns risk of capital based on that. The higher the risk the greater the premiums) is probably the most accurate for your own personal health-risk definition. If you can pinch an inch of your waist-line…

Excuses, excuses:

Life is full of excuses. We live under the stress of living. We live under the foreboding of death. We live in the dissonance of thought, of conflicts and upheavals. We live in the pejorative world where humans conspire to advance climbing to the top by “stepping-on” other humans. These are the travails of modern society. Ours is a future that can only be made better by knowing and taking responsibility for our own selves!

He that is good for making excuses is seldom good for anything else. -Benjamin Franklin

Eat Less! Exercise More! Laugh Often!

In nature there is no blemish but the mind: none can be called deformed but the unkind. – William Shakespeare.

References:

Liu, H et al. Fructose Induces Transketolase Flux to Promote Pancreatic Cancer Growth Cancer Res August 1, 2010 70; 6368

Groop, CL, et al. Glucose and Free Fatty Acid Metabolism in Non-insulin-dependent Diabetes Mellitus J. Clin. Invest. Volume 84, July 1989, 205-213

Ellsworth, D. L., et al. (1999) Coronary heart disease: at the interface of molecular genetics and preventive medicine. Am J Prev Med, 15(2), 122-133.

Felber JP, Ferrannini E, Golay A, Meyer HU, Theibaud D, Curchod B, Maeder E, Jequier E, DeFronzo RA. Role of lipid oxidation in pathogenesis of insulin resistance of obesity and type II diabetes. Diabetes. 1987 Nov;36(11):1341–1350

Seyffert WA, Jr, Madison LL. Physiologic effects of metabolic fuels on carbohydrate metabolism. I. Acute effect of elevation of plasma free fatty acids on hepatic glucose output, peripheral glucose utilization, serum insulin, and plasma glucagon levels. Diabetes. 1967 Nov;16(11):765–776

Lakka T, Laaksonen DE. Physical activity in prevention and treatment of the metabolic syndrome. Appl Physiol Nutr Metab. 2007;32(1):76-88

Tania M. Welzel et al. Metabolic syndrome increases the risk of primary liver cancer in the United States: A study in the SEER-medicare database. Hepatology  Volume 54, Issue 2, pages 463–471, August 2011

The ATGL gene is associated with free fatty acids, triglycerides, and type 2 diabetes. Diabetes. 2006 May ;55(5):1270-5.

Why?

It was sudden, abrupt and without preamble. It shut my thoughts down. These moments are rare and quite confounding to your inner equilibrium. The feeling is strange; time comes to a standstill, all else fades away except for what is. The sensation of a newborn’s tiny hands clasping the little finger of an adult, or seeing a stilled-lake-water reflecting the autumn tinged tops of the birch trees or the rising terrain glazed over with yellow and white wild flowers. These are moments of great magnitude when a question or statement or a visual arrests all mental cognitive domains of your brain.

Well that happened to me on this one innocent tweet. Yes, I said tweet. It read, “…If only I knew the questions to answers.”

Now what do you say to that? My reflexive nerve took over and I simply said, “gain more knowledge to ask the questions.” To a minor fractured fault that statement might be construed as correct but then there is a huge gash of credibility between what reality is and what the perceived goal of a quick answer would be. So I set out to somehow answer that wonderful, innocent and totally non-referential statement.

How do you ask the questions to answers that you know not of?  I think therefore, what I am about to say is my considered opinion. Why, in that tedious and irritating curious word, whose scent lingers after it is uttered, has such a boatload of undercurrents?

So let us start with a simple and well-informed question of why is the sky blue? Simple enough. The question is out there, blue from morning all the way till the evening. Blue for each of our eternities. It is blue. But the question is why? Ah there is meat in that one word, why!

It is physics after all that governs the color of the sky. The visual field is governed by a small spectrum of wavelengths. 

The blue light spectrum has a short wavelength while the red one is on the opposite side of the spectrum with a long wavelength. 

The shorter wavelength bounces of the suspended particulate matter (Martian Dust or Tinker Bell’s fairy dust if you prefer) and gets scattered thus coloring the sky blue. As the sun declines towards the horizon the red-color wavelength rides through but the angle of inclination of the blue wavelength cannot reach the eye due to its short wavelength, the red one does, hence those gorgeous red sunsets.

 The eye too, has  it’s own sets of rules based on the anatomy. The eye has cone-photoreceptors that are stimulated by the various wavelengths. Three main types of cone photoreceptors exist: The S (short, Wavelength= 400-500nm), M (Medium, Wavelength=530-600nm) and the L (Long, Wavelength=600-700nm). Previously they were termed as RGB for Red, Green and Blue, which is disputed currently. The stimulation of multiple cone-photoreceptors leads to a blending of the three main colors giving the person a wide spectrum of the rainbow. And there is of course one more major component to contend with and that is the brain. 

The Visual spectrum is received in the occipital lobe of the brain and then the electrical stimuli spread to the dorsum and the ventral aspects of the brain collating color information for interpretation. 

Just as different cone-photoreceptors need to be stimulated by the photons striking them, so must the right brain cells be stimulated electrically to display the perception. There are specific brain cells that are stimulated only by the respective color wavelength photon induced urgings from the retinal cells in the eye. So there you have it. That is why the sky is blue in the daytime and reddened in the evening.

Sunset

But you might ask, why then given this “blueness” of the sky, is the space black? After all the sky is the space and yet images from the space-shuttle and the Martian Rover seem to suggest a black void. 

Space the Black Void

That answer is simple if you follow the logic that there are no suspended, condensed particulate matter  (condensed as in: over the surface of the earth by the atmospheric pressures) in space. Hence the light does not scatter.

 Other theories suggest that the stars that are receding in an ever-expanding universe have a “Red-Shift” (moving away) from the observer so as not to register a stimulation of the cone-photoreceptor due to the distances( The distance in light-years is so removed that it does not allow for the action-potential to be initiated). And of course a third theory is since 97% of the  space is composed of “dark-matter” that this absorbs the visual spectra. All of these in isolation or combination is possible, but all remain  theoretical and thus all are valid for your interpretation. So go ahead find the proof!

Speaking of perception. What a wonderful set of orbs the eyes are, a set of gateways that another can look deep inside one’s soul.  The beautifully colored irises that make for blue, green, hazel and brown eyes give beauty to the beholder. So why are the eyes colored differently in different people?  (Asking the question again with a WHY)

The simplest answer is the genes made them that way (This is true unlike “my genes made me do it”).  However there are three known main genes that color the iris (EYCL1-2-3). What is now been determined that any set of parents with any given colored eyes can induce a magical different color in their offspring outside the ream of the Mendelian Constraint (Gregory Mendel). By that I mean, if both father and mother have brown eyes a blue eyed child might emerge. (The product of a milk-man , you say) Not necessarily. There are miRNA (Microinterfering RNA) that “interfere” with the genetic signals that are transduced to create the specific protein, which endows the specific color. These pesky miRNA are found everywhere in the genetic jungle. Additionally there are the Barbara McClintok’s famous “Jumping Genes” also known as Transposons that can through series of jumps within the chromosomal belt, land on a specific gene and modify its behavior or “expression.” The colors come at a price though. The hazel, blue and light green colored irises have a higher tendency to “Age-Related-Macular-Degeneration” and loss of vision along with a risk of choroidal melanomas while the “Brownies,” have a tendency towards cataract formation. Nature balances the rewards and punishment equally sometime. What the mind sees, sometime the eye cannot.  (http://jedismedicine.blogspot.com/2011/02/human-diversity-in-genes.html)

Speaking about mind. Well more like the curator of the mind, that is the brain. Why is there one brain and one heart and two lungs, two kidneys and one liver? And why pray does that happen? 

The answer to this complex question lies in the basic embryology. You knew I would say that, didn’t you? Joking aside, that is the truth. Lets look at the brain. It arises from the cephalic end of the neural tube. Grows three vesicles and the first and third vesicles sprout into two more giving us five vesicle formation around by the 35^th day of life. These five vesicles then form the basis of the brain structures with: midbrain, hindbrain, pons, cerebellum and the medulla oblongata.  Interesting to all this is at the time of the nerual tube formation and the first signals to start the activity of formation is given by a single instructor called the Sonic Hedgehog located on the left side of the notochord. 

Sonic Hedgehog

The Sonic Hedgehog binds to the “patched receptors” by inhibiting the patched inhibition of the “smoothened receptors,” which leads to the glial cells activation.

Sonic Hedgehog signalling

The brain as we know it or the Cerebral Cortex with all its “Grey Matter” is actually a later occurrence in-utero when the cell migration takes place.  There are three forms of migration, 

Radial Migration of neuronal cells

the Radial from sub-plate to the cortex, tangential and bipolar. The cells use the “rope” of the differentiated glial cells to climb to the top to replace the older cells and in so doing gain all the stored memories within to take on the job. It is like replacing a goalie in a soccer game. The departing goalie lets the new one know what is going on, who is on the up-and-up and who isn’t. Or in baseball terms a manager booted by the umpire turns his roster over to his vice-manager and then provides a few helpful hints from the hallway of the dug-out. Oh yes!

Brain development

At birth the infant’s brain has 100 billion neurons with 2,500 connections per neuron. As the baby grows and experiences the world some of these connections will be lost from disuse and others will be gained and at adolescence the connections (Synapses) per neuron are around 15,000.

 Lots of  Facebook, Twitter and Linkedin connections wouldn’t you say? The more connections the better armed we are with knowledge!

Synaptic Connection

Oh and if you didn’t ask, here is a bonus answer to a question that hangs in the air. Why do we forget? Simple: We don’t exercise the synaptic control of the connection by feeding it routinely with repetition and the connection is lost (withers) and so is the content of that connection. Thus the over-developed rut in the brain is the affliction of paranoia and the withered ruts are the lack of remembrances.

The skeptic in all of us will say, "But majority of the people in the universe are right-handed! So how does this left-handed nonsense work there. Elementary my dear Watson, the right handed people are Left-Brain dominant. aren't they? Right but what of those who are deaf-mute who correspond with sign language. What of them? They too young Watson utilize their right hand in signage more than let hand. Hmm, you wonder. Upon this bed of philosophy is a glazed surface of experiential and experimental credibility. Another interesting feature in this left-right issue is the molecule limonene that in its L-mode smells like an orange but the same molecule in its D-mode smells like a lemon. Now go figure! So changing the spin, changes function. The mind is confused but the heart is still into it. Isn't it?

Speaking of the one heart. Oh and what a divine piece of machinery it is. Ask the cardiologists and they will tell you the wonders of this rhythmic musculature that keeps the juice of life flowing. It springs, again speaking embryologically, from the two cardiac tubes that originates from the splanchnic mesoderm. 

Heart development

They merge to form a single cardiac tube that then the cardiac tube convolutes ventrally during the growth and forms five pouches that will form the basis of the atria, ventricles the aorta and the caval veins. (All of this happens through the genetic signals delivered at appropriate time in development, thus space-time is also governed by the DNA!) 

Heart Molding during development

For those needing more information, I will direct you to a signature article below: (2). Suffice it is to say that atria collect and the ventricles distribute the blood. A heart that beats an average of 72 per minute will have logged over 3 billion beats in a 80 year lifetime.

One more thing, remember, I said that the Sonic Hedgehog resides to the left of the notochord. The question is why. Why does it reside on the left side only? Is there a left sided conspiracy in the universe (apolitical)?

Interesting that you ask. Turns out, and this will surprise you. That almost all proteins are made up of levorotatory amino acids (L Amino-acids). Let me explain. There is something called chirality in every aspect of nature. The feature that is most often the cause of chirality in molecules is the presence of an asymmetric carbon atom. And to fulfill the limited lexicon for understanding, an optical isomer or mirror image of a L or D chiral substrate is termed as an “enantiomer”.

Enantiomers

 The proteins have it, the DNA has it and humans have it too in various degrees. And if you were a real stickler about it the atoms and their respective components have it too! So let me start by saying that nature is blossoming with left and right things. For example the nautilus sea shell cork-screws to the right – look at it sometimes and it follows the “golden-ratio” or Phi (Based on the Fibonacci numbers) Now looking back at proteins, as we know that enzymes are also chiral since they are basically preoteins. The enzymes behave like a glove-like cavity which is unique to fit/bind to its substrate. Thus a levo or left rotatory enzyme will have a hard time binding to a right-fitting substrate. (Its like the Democrats and the Republicans) That is why the RNA and DNA have a Dextro-rotatory chirality. The interaction between the amino acids and the RNA is governed by the Ribosome, which makes it a perfect fit/bind. 

So why then is the Sonic hedgehog sitting on the left side of the Henson’s node?  Because its counterpart gene called “activin receptor IIa” resides on the right side to guide the tissue proliferation, while the Sonic Hedgehog determines the “axonal guidance cues” and the “domains of the interneuron and motor neuron progenitors.” Oh nature, what a fabric of beauty it weaves.

Stopping now would leave an empty feeling inside the pit of my stomach and hopefully yours, if you are still there with me, that is. But nevertheless plugging along with this chirality mystery, let us dig deep into the atom and voila, 

we find that electrons have a left moiety and the muons, protons have a dextrorotatory vision. Even the W and Z bosons are majoring in the disciplines of left and right to keep the fate of the atom and the weak nuclear forces in balance.  A new study in Nature suggests that top quarks have an asymmetric force field counter to the Standard Physics Model. This could be the beginning of another beautiful confounding relationship between rethinking, theorizing and experimenting to understand the very edifice of life and the universe (6). Oh and speaking of the weak nuclear forces the W charge in the atom has a weak dextrorotatory alignment and this is associated with the “Nuclear Decay” as in, Radon Poisoning from the decay of Radioactive Radon and of course the lurking windfall dangers of storing huge quantities of spent nuclear fuels rods (plutonium) that have a constant but extremely long half-life of decay sitting somewhere deep underground the Rocky Mountains, waiting for a fissure or fault in the geological crust to bite us. Ouch! ( http://jedismedicine.blogspot.com/2011/04/radiation-and-humanity.html ) One last question here. Who discovered this left-right stuff anyway. Why of course the one and only Louis Pasteur, a chemist and a microbiologist by trait who confirmed the "germ theory" and was the first to make a vaccine for rabies and anthrax was also the person who discovered through crystallography the chirality of compounds. (enough trivia. lets move on...)

And a truly last point on this for now; Ever notice when going to the major museums, for instance the Louvre or the Metropolitan Museum of Art in NY, how many portrait paintings show the left side of the human face? Aha, got you. The rough estimates are 60:40. Humans are levorotatory inclined in deciphering beauty. Of course the “Golden Ratio” better be present in the facial structure for real “beauty” to be considered as “real beauty.” ( http://jedismedicine.blogspot.com/2010/01/leonardos-temple.html ) But truly take a sampling next time you visit. It will unnerve you, delight you and put you in the zone of circumspection. And if you look even closer at artifacts, they too are left-inclined slightly, majority of the times. Is that a human frailty based on our make up or is it something else? Another question emerges for you to inquire. Accepting an answer without question is akin to accepting the world is flat because that is as far as the eye can see. A conundrum that when answered by Galileo almost cost him his life in the inquisition. ( http://jedismedicine.blogspot.com/2010_08_01_archive.html )

I know, by now you are either cursing or on a path to questioning. But let it not rest in your minds that to question is a human freedom that can never be subjugated by another if we don’t allow it.  Whether on top of the mountain or diving deep in the sea, our thoughts and questions are ours and must remain so till the end. The answers we get from the “Whys” might surprise us into creating more synaptic threads of knowledge and understanding of how the world works.

 References:

1.Shonkoff, J.P., & Phillips, D.A. (Eds). (2000). From Neurons to Neighborhoods: The Science of Early Childhood Development National Academies’ Press.

2. Jiang X, Rowitch DH, Soriano P, McMahon AP, Sucov HM.. (2000). "Fate of the mammalian cardiac neural crest...". Development (Cambridge, England) 127 (8): 1607–16.

3. Charron F, Stein E, Jeong J, McMahon AP, Tessier-Lavigne M (April 2003). "The morphogen sonic hedgehog is an axonal chemoattractant that collaborates with netrin-1 in midline axon guidance". Cell 113 (1): 11–23

4. Dorus S, Anderson JR, Vallender EJ, et al. (2006). "Sonic Hedgehog, a key development gene, experienced intensified molecular evolution in primates". Hum. Mol. Genet. 15 (13): 2031–7.

5. McClintock, Barbara (1950) "The origin and behavior of mutable loci in maize". Proceedings of the National Academy of Sciences. 36:344–55

6. http://www.nature.com/news/2011/110723/full/news.2011.436.html?s=news_rss&utm_source=feedburner&utm_medium=twitter&utm_campaign=Feed%3A+news%2Frss%2Fmost_recent+%28NatureNews+-+Most+recent+articles%29

Freeze Dried Medicine

Statue of Asclepius

Somewhere along the road we came across a fork.  On one side was the conventional medicine climbing the slow and arduous ladder of scientific discovery and thoughtful action. To continue along that path was the considered opinions of the “experts;” that innovation would be slow and the potential to achieve huge dividends would be even slower in patient care. They advocated the other path; the one with faster methodology, quicker results and the hope of scaled returns. That was the chosen path. It was a brilliant piece of deductive understanding at the time to obtain huge dividends. As the rewards poured in, the entrenchment got deeper. Life was now being lived in the fast lane of “cause and effect.” The “cause” was arbitrarily determined as long as it fit the overall paradigm. The “effect” was glorified if it fit the causal premise. However if in contradistinction to the anticipated result, it was rendered, as craftily as possible, for overall impact to the reading physician in a mercenary statistical overtones, to confuse and obfuscate

Fresh Roses

From the many vagaries of numerical manipulations to the observed beliefs of a rigid scientific thought the forest of this data was massaged to render a fait accompli. Who could argue when the end result was an “improvement” in the wellbeing of patients? And yet as steadily as the beat of positive studies emerged from this abundance of derived literature, a slow drumbeat of contrary opinions began to surface. A clash of the contrarians and the protagonists was about to take place. But it did not.

What happened? Why did the fight vaporize? These are the questions worth exploring. Somewhere in that realm the protagonists realized that the fight would be lost. They came up with a formula to save and bolster the cache of their determinations. They came up with “Guidelines.” What were these “guidelines” and who determined them to be such? It turns out that these “Guidelines” were the considered determinations of the fast-lane society. They crafted a terminology called “Evidence Based Medicine.” What was the evidence and how did it serve medicine? This last question remains unanswered. But let me suggest that since medicine is a constantly evolving science and circumventing its practice to the simplicity of antiquated “evidence” is tantamount to making robots of the physicians and rendering their expertise and knowledge as moot. The “Art” that lies at the very heart of good medicine and practiced by the physician based on his or her judgment was rendered unworthy of any weight. Thus “Guidelines” were used to make consistent delivery of healthcare to the sick and remedy any possible weaknesses in the system. Did theses guidelines serve their purpose? That question may have been answered in many a mind as “no” yet it will take moving a mountain for the officials to declare it ineffective. For the present though there are many physicians who have bought into these crafty words and use it to echo their opinions under the “guidelines” scenario. So much so that the “Guidelines” are being used unfortunately as “mandates” by some. The luster and reach of this new magical beast is evaporating just as easily as driving a new car out of the parking lot.  As surely as the pendulum swings one way, the other side pulls and tugs at it.

Freeze Dried Roses

So in this robotic world of “Guidelines” and “Mandates” where does medicine fit in? Are the physicians simply there to quote the "evidentiary" statements from the proscribed “Guidelines” and express the percentages of success or failure without any empathic rendering of a personal nature to the patients? Did the experts not realize that medicine takes a little bit of the physician’s soul to heal the sick? Did they not graft into their thinking that without the emotional desire to heal the possibility of success in caring would suffer? Did they consider in their equation the thoughtful musings of many years of experience at all? The answer might be “Oh Yes of course!” and they would pepper it with, “That is why these are considered “Guidelines.” And yet the use and abuse of that word is in full display. Guidelines for physicians are similar to guidelines for teachers. No emotions: No impact. No desire to teach: its only a paycheck. No inspiration: No result! In fact write all you want in the annals of wisdom the dogma of “streamlined efficiency” and I will give you the perjured soul of Tantalis.

The other day some months ago a young student asked me of what I thought about medicine?

“Why do you ask?” I inquired.

“Oh, just your opinion?” he chimed.

“I think it is the greatest of all disciplines in all the fields of science.”

“You really believe that?” he asked with some incredulity.

“Yes, don’t you?”

“Well,” he said with a sigh, “ I thought there was a lot more that needed to be discovered. It turns out that all that remained is in the books. There is an algorithm for everything.”

“Yes but that is just current information.” I replied.

“Not really. If I punch in a diagnosis of colon cancer for a patient, the computer spits out all the required tests that need to be done and as I plug in that data the treatment is outlined.” He said with some dejection. “Where do I fit in. Am I just a keyboard puncher?”

I reflected on that for a while. This seemed like a heady statement from this intelligent youth.

“No the information is for your reference only. It is and will be your knowledge and experience that will guide you into helping your patient. Most of the time what the computer spits out will not be for the best for your patients and you will realize it as you develop your knowledge-base. And by the way we haven’t even unearthed the beginnings of the basics of what makes human life tick. That is a long ways away. Plenty of discoveries and inventions and innovations await you and the next generations to come. You just have to be on the lookout. It was not long ago when the medical field realized that the heterogeneity of cancer is governed not by the morphology of the cell but by the genetic riot within it. And also recently the questions about a stem cell as the precursor for all cancer are being raised because the field theory of cancer seems to be gaining some momentum. When single pathways cannot curb one cancer because discoveries of cross talk between disparate pathways within the cell continue to jangle the machinery that makes the cell double and grow. These are all recent phenomena. More of such low-hanging fruit is within grasp of anyone willing to take a swipe at it.”

He seemed pleased with my answer. His eyes opened wider with some thoughts running deep in his brain. His frown lines smoothed. There was hope for us after all.

In any field, individual thought renders the greatest success and equally the greatest failure is found when it is lacking. A Freeze-dried Medicine is an assembly-line of percentages bereft of the human element, one without richness of color and flavor and eventually good care.

The Doctor (painting by Luke Fildes)

Let us fatten medicine with the juices of tempered thought, of the warmth of individual care and with the luxury of individual experience. In an ideal world we would not equate medicine with money, so lets not. Let us foster individual responsibility for self-health and not resort to a “pill” for everything wrong with our universe. Let us all inspire the best in all of us. Let us encourage the true scientific reality and not devise methods that mimic real innovation. Let us once again be men and women of medicine and have individual thoughts and ideas. In the end it will be the best for us all.

References:

Henry E. Sigerist, A History of Medicine, Oxford University Press, 1987, p27-28

Albert R. Jonsen, The New Medicine and the Old Ethics, Harvard University Press, 1990, p122-123

Colon Cancer Energetics

Colon & Rectum

Statistics:

In the US, in 2011 141,200 people will be diagnosed with colon cancer. And about 49,380 will die from the disease. These are sobering statistics for the third most common cancer that afflicts people in the United States. Around the globe 610,000 deaths are attributed to colo-rectal cancer annually.

Location of Cancer:

72% are located in the Colon

28% in the Rectum

Biology:

96% of all colon cancers are adenocarcinomas. The growth of the cancer is a non-random linear progression. By that is meant it progresses from one state to another in serial uniformity. The process takes many years and by some calculations it can take between 10-15 years. These cellular dynamics indicate that there are plenty of opportunities to detect and protect people from this disease with early intervention.

Polyp into a Cancer

Interestingly the cellular dynamics that lead to colon cancer seem to have a genetic trigger. This trigger is usually present in the most terminal layer of the colon crypt cells. This genetic trigger mechanism can be a tumor suppressor gene or a proto-oncogene. Mutation of the tumor suppressor gene makes it unable to protect against an uncontrolled proliferation of cells as happens with the APC gene. The APC gene codes for a protein that is involved in restrained cellular growth of the cell. 

The APC gene is present on the long arm of Chromosome 5 at position 21-22 (5q21-22). 40% of people who carry the APC gene mutation and have Familial Adenomatous Polyposis Coli (FAP) have a100% chance of developing colon cancer by age 40.

Large Adenomatous Polyps

Since the process of cancer is linear, it requires other mutations to occur in the genetic structure of the precancerous cells before a full-blown cancer forms and these include DCC gene mutation, p53 mutation and others. If a single gene mutates without corresponding future mutations to move the story forward the net result can be a large adenomatous polyp (Stuck in the first gear – auto analogy) On the other hand if rapid sequential genetic mutations are written out on the DNA script, then a fairly small size cancerous tumor (sometime undetectable) can have disseminated metastases. Genes thus apply the breaks or press the accelerator in sequence and infrequently at the same time.

There is ample data in the medical literature that migrants assume risk of their destination. And studies of the  American Indians (AI) and Alaskan Natives (AN) living in Alaska have shown a 102/100,000 incidence of colon cancer versus 21/100,000 for AI/AN living in the Southwestern US.  So migratory patterns conforming to the destinations play a part in the risk factors. In other words the dietary habits, consumption of foods and exercise have a proximate bearing on the biological incidence.

Racial Disparities Incidence:

Race/ Ethnicity	Men %	Women %
Non-Hispanic White	56.8	41.9
Non-Hispanic Black	68.3	51.6
Asian American/Pacific	42.8	32.5
American Indian/Alaskan	43.2	34.4
Hispanic/Latino	49.2	36.8

Risk Factors: Overall:

1. Age: Individuals older than 50 years are at risk. The lifetime risk is 1 in 20 or 5%. Below the age of 50 the risk is 0.3%.
2. Sex: Men are 35%-40% are at higher risk then women including the fact that men have a higher predilection to rectal cancer then women.
3. Race: Blacks have a 20% higher risk then whites

Risk Factors: Non-Modifiable:

1. Heredity: Family History with first-degree-relative, (parent, child, sibling) has a2-3 times the risk then average. If the relative had colon cancer at a young age that risk increases to 3-6 times. And those patients who had cancer at age 60 yrs or younger have a higher risk of colon cancer in another part of their colon.
2. Lynch Syndrome (Non-Polyposis Colorectal cancer) 2-4% of cases. Lifetime risks of patients with Lynch Syndrome genetic mutation is around 66% in men and 45% in women and the median age is 42 and 47 years respectively.
3. FAP Syndrome due to APC gene has a100% risk by age 45.
4. BRCA1 and BRCA 2 gene mutations also tumor suppressor genes  are associated with a higher risk of colon cancer.
5. Chronic inflammatory diseases of the colon like Crohn’s Disease and Ulcerative Colitis are associated with a higher risk of developing colon cancer.

Risk Factors: Modifiable:

1. Diet: High Red meat content diet is associated with a higher risk. The suspected cause is Heterocyclic Amines (HCAs) that form as a result of high temperature cooking methods. Diets low in fruits and vegetables are also at a higher risk. (Exception=July 4^th)
2. Physical Activity: Sedentary lifestyle is associated with a higher risk, probably due to slower colon-transit-times. (Daily walks)
3. Consumption of Milk and Vitamin D/Calcium reduces the risk of Colon cancer. (A little white moustache)
4. Obesity: A high BMI over 30 especially with abdominal obesity has a higher association with colon cancer risk. (Push away from the table with a little hunger in your stomach)
5. Smoking: Smoking has a higher risk association with rectal cancer in both men and women. (Just say No)
6. Alcohol: Drinking 2-4 drinks a day is associated with a 23% higher risk of developing colon cancer. (Sober up)

Risk Prevention:

1. Aspirin: Daily intake of Aspirin lowers the risk of colon cancer. (An aspirin a day keeps the oncologist away)
2. Anti-inflammatory medications (NSAIDs) also reduce the risk via their inhibition of the COX-2 pathway.
3. Daily Exercise! (Just Do it)

Screening Procedures: (American Cancer Society)

Benefits from Screening:

There is a reduction of incidence of colon cancer by 3% in males and 2.3% females annually. This is significant because it shows the striking impact of screening. All physicians are reminded to encourage their patients aged 50-75 years to undergo screening tests. Given the patients other morbidity issues the appropriate screening test can be entertained and discussed. Soon with the availability of genetic testing in the stool samples the invasive procedures might not be utilized as much for initial screening. Quoting the Imperiale study, “The sensitivity of fecal DNA analysis and FOBT for all cancers and adenomas with high-grade dysplasia was 40.8% versus 14.1%, respectively. Specificity in subjects with negative finding on colonoscopy was 94.4% for fecal DNA and 95.3% for FOBT.”  Even though a joint force recommended the use of DNA testing as a screening tool, the frequency time interval was not established whether it be for every 5-year or 10-year  period. These tests however have to stand the rigors of time and further study based on some questions that have recently been raised.

Unfortunately as the incidence is declining in the age cohort between 50-75 years, it is rising in younger individuals between 20-49 years. This has been ascribed to various reasons including obesity, sedentary lifestyles in the young especially in this digital age and also to the prevalence of HPV.

Stage I

Stage II

Stage III

Stage IV

Stage and Survival:

It must be remembered that since colon cancer formation is a prolonged multistage phenomenon, it is silent through most of its infancy and early growth. Almost two-thirds of the life cycle of the cancer has been lived at the time of diagnosis without screening, therefore early detection is paramount in survival.

Polyp and its removal via Colonoscopy snare

 It is also well known that diagnosing and removing a polyp is tantamount to preventing cancer and thus life-saving by preventing cancer from forming in the first place. It is well established that early stages of any cancer has better prognosis and survival. The 1.1 million survivors with colo-rectal cancer can vouch for the preventative measures.

Colonoscopy

Early screening saves lives, thus preventative colorectal screening is the most compelling argument in medical care! (Cause and Effect)

References:

Role of well-done, grilled red meat, heterocyclic amines (HCAs) in the etiology of human cancer 
Rashmi Sinha, Nathaniel Rothman 
Cancer Letters - 1 September 1999 (Vol. 143, Issue 2, Pages 189-194)


Murphy G, Devesa SS, Cross AJ, Inskip PD, McGlynn KA, Cook MB. Sex disparities in colorectal cancer incidence by anatomic subsite, race and age. Int J Cancer. May 25 2010.

Perdue DG, Perkins C, Jackson-Thompson J, et al. Regional differences in colorectal cancer incidence, stage, and subsite among American Indians and Alaska Natives, 1999-2004. Cancer. Sep 1 2008;113(5 ) Suppl):1179-1190.

Siegel RL, Jemal A, Ward EM. Increase in incidence of colorectal cancer among young men and women in the United States. Cancer Epidemiol Biomarkers Prev. Jun 2009;18(6):1695-1698.

Levin B, Lieberman DA, McFarland B, et al. Screening and surveil- lance for the early detection of colorectal cancer and adenomatous Polyps, 2008: a joint guideline from the American Cancer Society, the US Multi-Society Task Force on Colorectal Cancer, and the American College of Radiology. CA Cancer J Clin. May-Jun 2008;58(3):130-160.

Kirkegaard H, Johnsen NF, Christensen J, Frederiksen K, Overvad K, Tjonneland A. Association of adherence to lifestyle recommendations and risk of colorectal cancer: a prospective Danish cohort study. BMJ. 2010;341:c5504.

Lynch HT, de la Chapelle A. Hereditary colorectal cancer. N Engl J Med. Mar 6 2003;348(10):919-932.

Murff HJ, Greevy RA, Syngal S. The comprehensiveness of family cancer history assessments in primary care. Community Genet. 2007;10(3):174-180.

Bernstein CN, Blanchard JF, Kliewer E, Wajda A. Cancer risk in patients with inflammatory bowel disease: a population-based study. Cancer. Feb 15 2001;91(4):854-862.

Eaden JA, Abrams KR, Mayberry JF. The risk of colorectal cancer in ulcerative colitis: a meta-analysis. Gut. Apr 2001;48(4):526-535

Wolin KY, Yan Y, Colditz GA, Lee IM. Physical activity and colon cancer prevention: a meta-analysis. Br J Cancer. Feb 24 2009;100(4):611-616.

Samad AK, Taylor RS, Marshall T, Chapman MA. A meta-analysis of the association of physical activity with reduced risk of colorectal cancer. Colorectal Dis. May 2005;7(3):204-213.

Wang Y, Jacobs EJ, Patel AV, et al. A prospective study of waist circumference and body mass index in relation to colorectal cancer incidence. Cancer Causes Control. Mar 6 2008

Chao A, Thun MJ, Connell CJ, et al. Meat consumption and risk of colorectal cancer. Jama. Jan 12 2005;293(2):172-182.

Jenab M, Bueno-de-Mesquita HB, Ferrari P, et al. Association between pre-diagnostic circulating vitamin D concentration and risk of colorectal cancer in European populations:a nested case-control study. BMJ. 2010;340:b5500.

Paskett ED, Reeves KW, Rohan TE, et al. Association between cigarette smoking and colorectal cancer in the Women’s Health Initiative. J Natl Cancer Inst. Nov 21 2007;99(22):1729-1735.

Rothwell PM, Wilson M, Elwin CE, et al. Long-term effect of aspirin on colorectal cancer incidence and mortality: 20-year follow-up of five randomised trials. Lancet. Oct 21 2010.

American Cancer Society. Cancer Prevention & Early Detection Facts & Figures 2010. Atlanta: American Cancer Society; 2010. Atlanta.

Imperiale TF, Ransohoff DF, Itzkowitz SH et al. Fecal DNA versus fecal occult blood for colorectal-cancer screening in an average risk population. N Engl J Med 2004; 351(26):2704-14.

Levin B, Lieberman DA, McFarland B et al. Screening and surveillance for the early detection of colorectal cancer and adenomatous polyps, 2008: a joint guideline from the American Cancer Society, the US Multi-Society Task Force on Colorectal Cancer, and the American College of Radiology. CA Cancer J Clin 2008; 58(3):130-60.