Sunday, June 26, 2011

The Li-Fraumeni Cocktail

Nanakarobi Yaoki (七転び八起き)

His eyes looked weary. The frown lines etched on his forehead were deep from single-minded despair. The shallowness of his temple had been gouged by the fear and worry of life. Life had not been kind to this unassuming kind and gentle soul. While he had traipsed through the early years with an uncommon benevolence that nature gifts to some – a total freedom to worry. The cruel trick behind those moments of frivolity was the test yet to come. He had been inured into this nature’s conspiratorial web. He looked upon it as a challenge, while his friends empathized with him of his bravery, courage and strength to fight. Ah yes, life was blooming every where but for him and yet there he was in his green striped pajamas and a plain white tee shirt, oblivious and reluctant to take a step back.

It must have been five years ago when he first located the lump on his chest. He ignored it as most often people do. But then the progressive thrust of this vile appearance could not be ignored. He sought attention of a competent physician and the rest was a history full of “shades of grey in the large canvas of black and white,” as he put it eloquently.

What really happened to this gentle soul from the Far East? That became the soul and cry of many a physician and nurse who encountered him. Why does one have to bear the burden of many?

To go back further into the deep recesses of medical thought, it appears that there was a switch in his genetic system that had been switched to an “on” position. So the question was, “Who or what.,’ had set this off. And there in lies the mystery of genetics, known to many through the insight of a monk named Gregory Mendel.

Now what happened in our good man was a change in a portion of his DNA that corresponds to the site that protects such issues from occurring. In other word, in the portion more richly if simply and aptly termed TP53.
Chromosome 17 (Red line at 013.1 site of TP53)


To most TP53 may mean little, but to the cancer community of physicians it is considered the “Guardian of the Genome.”  It preserves the stability of the DNA by preventing mutation. This conservational ability grants it the title of “the master watchman.” Any stray, uncalled for or unnecessary genetic mutation that can harm an individual is reviewed by the TP53 gene and if found wanting the cell replication will be stopped and the cell will undergo a “suicide” program or apoptosis (Programmed cell death). Thus this small 20-kilobase length gene present on short arm of Chromosome 17 (17p13.1) location has great responsibility in preserving human kind health. This is also a “Tumor Suppressor Gene.”


TP53 can bring in a cadre of helper proteins that initiate DNA repair to try to fix a DNA mutational anomaly by arresting the cell cycle growth arrest at the G1/S phase. This allows time for the proteins to come in and do remediation. If however there is too much DNA mutational burden present, it simply chucks it to the “rubble heap” of the “suicide pile.”


What provokes the TP53 gene, are stresses that cause DNA damage. These include Ultraviolet, radiation damage, other chemicals, viruses, Oxidative stressors, even Transposons related Oncogene over-expressions and other mutagens. This provocation causes the TP53 to release p53 protein that goes to work in protection and preservation. The primary effect in the damaged or stressed cell is, the accumulation of the p53 followed by or simultaneously, conformational changes in the protein itself via phosphorylation to become active.
Cell Signaling Pathways and Apoptosis


Since two copies of the TP53 are required for normal cellular preservation, a loss of one copy (i.e. knocked off the one short arm (p) of the two-short-arms of chromosome 17 will cause dysregulatory influence on the cellular behavior of that individual with resultant cancers forming in early adulthood.

Almost 50% of human cancers have mutation and or deletions of the TP53 gene. This may constitute the “chicken or the egg” issue but other then in a hereditary mode it is the “chicken.” (Assuming you agree that the egg came first.)
p53 stained cells (in brown) in malignant Astrocytoma (brain tumor)


Two methods employed to restore p53 in the system have led to different results. Just by increasing the p53 amounts in the environment of the malignancy has resulted in “premature aging”. (this methodology is obviously not the right one). However the other mechanism is to restore the functionality of the existing or endogenous p53 and that holds promise.

Not until 1993 when the Journal Science published a paper touting p53 as the “molecule of the year” was this a known entity in the geneticist world. This article was on the heals of a published paper in the journal Nature Genetics in 1992 by Wafik El-Deiry, MD PhD 
Wafik El-Deiry, MD, PhD.


and Bert Vogelstein, MD 
Bert Vogelstein, MD


then at Johns Hopkins University. These brilliant scientists first determined the consensus sequence of the binding site of the p53 (produced by a baculovirus produced human p53) to the DNA TP53 via immunoprecipitation methodology.

Even though the mechanism of this disease became known not until 1992, it was through two other equally brilliant physician scientists Frederick Pei Li and Joseph F. Fraumeni, Jr., 
Joseph F. Fraumeni, Jr MD


who discovered this disease entity. Their criteria were simple. This composite syndrome of soft tissue sarcoma, bone sarcoma, acute myeloid leukemia, breast cancer, adreno-cortical carcinomas and brain tumors occurring in a patient probably had a common genetic link. Their screening methods were simple; any individual before the age of 45 with sarcoma with first degree relative  (less than 45 years of age) with cancer and any family relative of similar age with cancer or at any age with sarcoma. This disorder was aptly termed as the “Li-Fraumeni Syndrome” in respect for the discoverers. It is an autosomal dominant hereditary genetic disorder. The damage to the TP53 gene cancer can occur through out the 20-kilobase location as evidenced below:
SNPs (Single Nucleotide Polymorphism(s)) leading to Li-Fraumeni syndrome include:



"This gene encodes tumor protein p53, which responds to diverse cellular stresses to regulate target genes that induce cell cycle arrest, apoptosis, senescence, DNA repair, or changes in metabolism. p53 protein is expressed at low level in normal cells and at a high level in a variety of transformed cell lines, where it's believed to contribute to transformation and malignancy. p53 is a DNA-binding protein containing transcription activation, DNA-binding, and oligomerization domains. It is postulated to bind to a p53-binding site and activate expression of downstream genes that inhibit growth and/or invasion, and thus function as a tumor suppressor. Mutants of p53 that frequently occur in a number of different human cancers fail to bind the consensus DNA binding site, and hence cause the loss of tumor suppressor activity. Alterations of this gene occur not only as somatic mutations in human malignancies, but also as germline mutations in some cancer-prone families with Li-Fraumeni syndrome. Multiple p53 variants due to alternative promoters and multiple alternative splicing have been found. These variants encode distinct isoforms, which can regulate p53 transcriptional activity." (NCBI)


Now as the sun was rising from behind the curtains that were flailing helplessly to the gentle breeze from the air conditioner, he picked at his breakfast, a soft-boiled egg and a single slice of bread. The difficulty was all too apparent for anyone to see. This was his third battle. He had arrived at it with a measure of defiance and fortitude. Yet lying there weak and unable to hold together the very nuance of his existence, the idea of “chucking it all,: seemed very real. His eyes glanced at the photographs of his family members filling the long thin rectangular table against the far wall. “Should I subject them to this?” was the question on his mind.

“How’re you doin?” The young resident walked into the room and asked without much preamble.
“Ok.” He replied weakly as he eyed the entrant.
“Well, I have some good news for you.” He looked expectantly at his patient and not getting a response, he continued, “ Yesterday’s PET scan fails to show any residual evidence of the breast cancer.”
His patient just nods.
“I would hope you would be more elated that that.”
“Yeah, I am,” his patient replies with a shrug of his shoulders.
“You should be able to go home tomorrow.” The resident states with his hand in his pockets, then remembering additional information he stops and turns back, “Also tonight we will have a conference by your bedside, it would help if your wife was here. Around 5’O’clock?” The resident recedes out into the hallway.
“What? Why?” He mutters to himself. “Conference?” He shrugs his shoulders and goes back into the land of dejected thought.  Crypted communication are the norm in the fast paced medical world. But he does not want to delve into any of this. His mind is burdened by more weighty issues.

It is around 4:45PM and he can see the buildup of a lot of youngish intern/resident crowd outside his room. Most seem excited and energized, some are looking at their smart phone screens while others are allowing their gaze to wander around. He sees all this and his mind starts to wander at the prospects of this “conference.”

“Mr. T,” as he is called by most of the staff, begins the resident in charge, “has successfully conquered his third malignancy. As some of you know, he had a soft tissue sarcoma on his left chest, which was removed and radiated twelve years ago. He then had a bout with AML and following a bone marrow transplant, he remains disease free from that and this time he had the left sided mammary carcinoma.” The resident pauses to make sure he has everyone’s attention, “we originally surmised that the breast cancer was in some way radiation induced since the site was on the same side as the soft tissue sarcoma, but one of the intern has through diligent research and testing discovered the real problem behind Mr. T’s dilemma.” Now all eyes are on him except one female intern who coyly keeps her eyes rooted to the floor.  She is possibly the referred-to intern, shy in her humility.

“Anybody?” The Resident asks. The crowd remains mute while Mr. T looks expectantly to understand the significance of this gathering and this discovery.
“We believe Mr. T has LF-1!” There is a minor emphasis on the letters LF.
“Ah!” a gasp escapes a few in the crowd.

“Right, so Mr. T, what we are saying is that you have a flaw in your genetic system that allows bad cells to escape and become cancerous.” The resident takes both his hands out of his pockets and explains creating shapes only his mind can fathom.  Mr. T’s wife looks dejected after the explanation and so does her husband. The resident finally looks at his patient and understanding to some extent the husband and wife’s dilemma, chimes, “You see, Mr. T you will be a frequent visitor at this facility for observation. The risk of another cancer is real but with close observation we can mitigate that and arrest the disease. This may not sound as good news to you just yet but you will hopefully not have to fight malignancies when they have spread and early detection will result in better eradication through close follow up.”

The silence fills in behind the words and but for a few coughs and a sneeze the echo of the couple’s fears ring loud and true. Just then the slightly bent figure of an older man walks in. The hush is deafening.

“So did you explain to Mr. T and the lovely Mrs. T the issues we discussed this morning?” The man asks the resident.

“Yes sir!” the resident answers. This professor has generated more literature and earned more accolades then anyone in the university is in the minds of many, a walking encyclopedia. Yes he is entitled to that respect.

“So Mr. T,” The professor begins slowly, “What we are faced with is a warning from your genetic system that tells us that there is a mechanism that is misaligned and that we have to keep a close watch on you to prevent it from hurting you. Your surveillance, as we call it, will become a routine for you. It will encumber you, may be, one visit per every six months and as we do with some executives of large corporations you will undergo some screening tests that will all be accomplished on the same day. The dates will be in accordance with your convenience. All what I have said is considered prevention!” The professor stresses on the word and leaves a moment of quiet before he continues, “It is fortunate that we were able to discover this anomaly. It is of great help for you.”

Mr. T has a brief smile on his face. This explanation is so much more confidence inspiring. He face relaxes and his burden seems to ease somewhat. His brows are relaxed and his eyes still in questioning slits are more open in receiving the light of this information. He grabs his wife’s hand and startles her momentarily. His spine is now straight and there is conviction in his eye. The cataract of despair has been washed away. He says; “ Nanakarobi Yaoki.”

The assembled physicians and would be physicians all have quizzical looks.
“It means, Fall down seven, Stand up eight.” Mr. T interprets for the group.

And there in those words lies courage!

References:

1. el-Deiry WS, Kern SE, Pietenpol JA,Kinsler KW, Vogelstein B. Definition of a consensus binding site for p53. Nat Genet. 1992 Apr;1(1):45-9.

2. Li FP, Fraumeni JF (October 1969). "Soft-tissue sarcomas, breast cancer, and other neoplasms. A familial syndrome?". Ann. Intern. Med. 71 (4): 747–52

3. Koshland DE (December 1993). "Molecule of the year". Science 262 (5142): 1953.

4. Hollstein M, Sidransky D, Vogelstein B, Harris CC (1991). "p53 mutations in human cancers". Science 253 (5015): 49–53.

5. Clemens A. Schmitt; Fridman, JS; Yang, M; Baranov, E; Hoffman, RM; Lowe, SW (April 2002). "Dissecting p53 tumor suppressor functions in vivo". Cancer Cell 1 (3): 289–298.

Saturday, June 25, 2011

A New World Unfolds



As the morning steals the night
A peaceful thought is born
The barren landscape of yesterday
Recedes slowly into oblivion

The wisdom battles the wit
As reason extols it's virtue
Concepts arise as scaffolds
Amidst landscape once forlorn

Clarity abounds near muddy shores
The day gets busy with plans
Ventures all consuming
New thoughts become grand

The victories in the mind
Are now victories on the playing fields
Old wounds get scarred over
Replaced by distant memories

A new day is born
A new idea takes hold
A new thought awakens
A new world unfolds

Saturday, June 18, 2011

"Thus Conscience does make Cowards of us all…"


The sea of tranquility oft times is roiled by the deep fissures between moral and unethical thought. From the Calvinistic “battleground” where human thoughts clash with the Kingdom’s imperative to the theological reasoning enjoined to do good and avoid evil, life is lived on the fringe. And yet what pricks the bubble of existence is this seat of universality or Emmanuel Kant’s “Categorical imperative.

Conscience is pithy, Einstein’s “Inner voice,” or Schopenhauer’s “mirror to the will.” It makes us resent our inaction but then equally congratulates us for it. It allows us the freedom of thought yet corrals us within safe bounds that prevents chaos due to deviation from societal normative values.  Conscience is a traitor to selfish desires and also the seat of a harmonious existence. It is a contradiction!

It is this contradiction that Shakespeare had in mind that prompted his Hamlet to say, “Thus conscience does make cowards of us all.” He was after all referring to the mystery of death and the conscience of doing right over wrong to avoid the gates of hell. It is that very motive and that very morality that forces the physician from a militancy of action into servility. For the conscience that pricks and awakens one at night at the thought of another human being’s misery, is that very voice that also prevents the physician from glorifying the self.

What has happened medicine, is the vortex created by the volatile world of business and politics that has trampled upon the nobility of the most glorious of all professions. This profession made noble through the ages for helping life and steering away the curse of illness from another being has been vilified and victimized by society at large today.

Not a day goes by that the medical profession is not de-conditioned and tramped over. There are accusations of fraud, impropriety, public health risks all borne of the health care industry. The finger points and a man or woman in a white coat with a stethoscope represents the “face”. The physician is no longer the healer of what ails the person but the causative agent of what ails people and the society. Once the angel of life, he is now considered the devil himself. The media regales in it, the politicians devour it for every meal to press forward with their agenda, the layperson caught in the middle of this drift follows the trail of the written and spoken word, unable to separate the wheat from the chaff. Oh! but for that banner of truth to free us all from the shackles of this malaise and drudgery.

Meanwhile using the pulpit of this destructive force, the powers use means to control and coerce through regulatory fiat the very practice of medicine. The litmus test of good medicine is based on its value at being cheap. The innovation is desired but not utilized for the masses. Under the spotlight of bright fiscal scrutiny, life is being demeaned and death is being regaled. It is a 180-degrees from when only yesterday life was rejoiced. Today age is being rendered as a curse and therefore quickly and expeditiously to be curtailed. The very trumpets that heralded every new discovery and each new success in the medical field are silent. Where have, “the rational principles congruent with nature and the universe” that the Roman Emperor Marcus Aurelius once touted, gone?

Something has gone haywire and yet the physician continues to toil. He works harder cares for more and is meted out with angry eyes and harsh words. His conscience pricks and he silences his own voice, for his oath must never be in jeopardy – above all do no harm. By expressing anger and militancy he risks the transgression across the “nobility-line.” He remains muted. He remains quiet and suffers from the perjury of the assembled. He has perforce embraced cowardice for fear of that transgression within his own conscience.

So are we as physicians cowards after all? Yes, and it is not a maybe! By coward do I mean handcuffed by our Conscience from exposing the great lie in a battlefield against the entrenched selective bias? Yes! By coward, do I mean that we want everyone to know the perils around the corner of the fake “yellow-brick-road” ahead but find ourselves stifled? Yes! By Conscience do I mean our innate desires as physicians to care for the sick and the unhealthy without the distractions that abound? Yes! Can anything be done? I think the answer to that is most certainly, yes! For now the physician psyche is glued to the delusional of when the natural reasoning is eventually restored the process of healing will finally take place. Nothing in this conversion of politics, business, fakery and fiat leads me to believe that, that will ever happen given the current format. Not until the conscience and cowardice are sewn together will the physician voice be heard. Until then we might as will bow to the king, “The king is dead, long live the king!” But maybe, just maybe, there is hope, and then again hope is just another dirty four-letter word for inaction.

The single photon that escapes the darkness carries potential. That beam of light is the physician’s voice and it is being expressed. The pitch and volume is extremely low but it has been increasing. The squelch is diminishing and the clear expressions are arriving at the muddy shores. These lone voices are slowly emerging in the vast universe of the Internet. One day in not too distant a future the combined force of this displeasure will be expressed in unity and the evil that surrounds and occupies the periphery will cede control back to the rightful owners of this noble profession. And once again we as physicians will be able to discuss the matters of health, heal and comfort the sick and do for our communities what we do best without the distractions of fiscally mediated intrusions. As John Ralston Saul said, “... consumers risk turning over their conscience to the technical experts,” he was early by a few years. Ah! There, behind that great mountain is our Shangri-La. We just have to find it again.

Legions of characters surround this profession not only to gape at it in wonderment but also to partake in the bounty of its goods. They see potential for themselves and their companies. They advocate, promulgate and create various ventures to make the art of the practice cheaper but their eyes are always on their own bottom line. The snake-oil salesmen are at it again in pinstripes and slick hair. There are traps upon traps hidden within this mosaic called medical practice. The physician who now has been relegated as a ”provider,” must find clues and artfully avoid these pitfalls. All these distractions are there to prevent him from realizing that he can control his own destiny. And all this smoke is not from fire but  a nebulous vapor amplified by mirrors as distraction. Ultimately saner minds and calmer demeanors will prevail in this most noble of all professions. One day soon when the epitaph has been written and the ashes have been wept over, the phoenix of this nobility will rise again. I am confident!

Thursday, June 16, 2011

EXERCISE for health, longevity and your mind!!

EXERCISE !!

Exercise!

Exercise!

Extension of Life might just be in your muscles! Quality of life might just be in your brain!

The New Dawn of media hype, blogs, tweets and Facebook links that tout sculpting your body has arrived with bushels of resolutions, top amongst them is “I will exercise! to show-off in the speedo? "--- Don't Please! I mean do exercise but that speedo part keep it in front of a mirror if you must.

Okay maybe here might be some incentives for you.

  1. Exercise overall tones your body, sculpts your muscles and lubricates your joints and prevents the bone softening that come with age.
    1. The facts are simple. Use them or lose them. Muscles like the brain need to be fed with some repetitive resistance to develop memory. Just like the brain when it is fed with knowledge it grows in intelligence and wherewithal.
    2. Exercising the muscle leads to increasing the IGF-1Receptors that help store the glycogen within the muscle cells for use as energy. The higher the IGF-1R expressed by the muscle the less the Insulin floating around. Thus exercise leads to utilization of the consumed foods converted into sugars to be stored for use by the muscles. This leads to less sugar in the blood for insulin spikes.
    3. Excess sugar floating in the blood stream is converted into fat and stored in the adipose tissue. So the larger the storage the fatter the person. This ultimately leads to resistance to insulin and Voila Type II Diabetes mellitus happens. There is a feed-forward-loop mechanism where accumulation of fat leads to more lipogenesis (fat production). It is like liking chocolate and then becoming a chocoholic. The initial desire if not curbed will lead to a perpetual desire. 
    4. Of course the more unconverted sugars in the blood stream, the more filtration by the kidney and more sugar spills in the urine to the point that kidney damage results, ultimately leading to dialysis.
    5. And if that was not enough more sugars in the blood stream floating through the eyes leads to impairment of vision.
    6. And last but not least (since this is a simple primer) Excess sugars convert to triglycerides and those fatty molecules lining the arteries leads them to become rigid which leads to high blood pressure leading ultimately to strokes, heart attacks and other maladies that are not fitting for any bloggersdom.
    7. About the brain. Well there are ample studies that have replicated the fact that exercise increases blood-flow to the brain. You know heart pumps faster thus increasing the blood-flow-rate and the result is more nourishment to the brain. Remember the brain resides atop the body in most people whose hormones are not in play (a little joke). Anyway the more nourishment the better the cells live and thrive. It definitely beats the alternative doesn't it: To be sitting in a lounge chair trying to remember your own name! Data show that exercise reduces dementia! Oh yes it does! Believe me and if you don't heed to this piece of information then well, at age 80 or sooner you won't need to worry about it at all.
    8. Excess fructose/corn syrup that food industry desires to add to most foods and drinks cause an excess fat deposition in the liver which I am positive the liver does not like. You can experiment at your own peril. My suggestion look at the food label and then decide to ingest - simple.

Exercise and the Heart: Speaking about the heart, and there is a lot to be said about "heart." Suffice it is to say, exercise of those gloppy-gooey icky things that can stick to the inside of the arteries will stick and sometime in the future when the need is great and the blood supply constricted from reaching its source or a sudden collective rupture of the endothelium (inner artery lining) causing a cascade of platelet clumping will cause a lot of pain. A few pictures will roil your mind, cause chaos in your brain and hopefully get you off the couch.

Atherosclerotic Artery Section

Calcified Coronary Artery
XRay view of calcified arteries
Mayo Representation of atherosclerosis


  1. Moderate Exercise and Endurance: Results in a IGF-1R expression in the heart muscle too which leads to allowance for cardiac myocyte (heart cell) hypertrophy (Or physical exercise leads to a tougher heart) So in a sedentary individual there is limited if any IGF-1R protein presence and faced with “fight-or-flight” scenario such as a muscle-bound coming at you with a sledge hammer, the heart would not be able to expand to function at peak capacity for the potential induced stress and thus might outrace itself into an arrythmia (irregular heart-beat which can cause sudden-death). That is why athletes have a resting heart rate much lower than non-athletes. On the other hand a compromise is needed. One cannot overdo exercise either. Too little and a bad diet and too much exercise can induce some coronary damage via "dystrophic calcification." (Calcification through damage;  calcium deposit in the heart (coronary) arteries leads to them being rigid and ultimately narrowed enough to limit blood supply for the induced physical stress.)
  2. Exercise and Cancer:
    1. If a sculpted “cool” body does not grab your attention let me try another approach that I know will get the point across:               Cancer Cell
    1. Exercise leads to a lower death rate from Colon cancer. 
    2. Exercise induces IGF-1R expression in patients with a specific type of Triple Negative Breast Cancer where those patient who had a higher expression of IGF-1R in their cells had a higher survival rate then those without. So exercise did make a difference in their survival and well-being.
    3. Women who exercised regularly had lowered risk of developing breast cancer. Exercise was preventative!
    4. Women who had breast cancer had a higher chance of increasing their overall survival and potential cure.
    5. Exercise is also implicated in reducing the risk of lung cancer in current or former women smokers.
    6. Exercise with diet rich in vegetables, fruits are also implicated in reducing the risk of Prostate Cancer in Men


  1. Exercise and Brain Function: This will not come as any surprise to anyone, but exercise induces the flow of neuro-chemicals in the brain, which lead to a feeling of well-being. These chemicals are called “Endorphins.” The feeling of well-being leads to a positive outlook on life and changes the approach to life.
    1. Decision Making is on a moment-to-moment basis. We make decision at every level, at every turn of the screw and at every fork in the road. We survive through life living with the results of those decisions. Might it not be a good reason to make all decisions when we have a full score of endorphins circulating in our brains? Remember Charles Dickens, he would walk the streets of London and those walks gave him the ideation of the Classics and the temper to toil writing such works as "Oliver Twist" and "A Christmas Carol."
MRI of the Brain 
Was there something you were waiting for that I forgot to mention? Oh yes: "Just Do It."

Okay, so get off the couch, turn the TV off, put away the 3D glasses, put your sweats on and roll with the endorphins.

Wish you all a happy healthy and endorphin-rich-proper-decision-making-rest of  2011!

References:
  1. 1. Insulin-Like Growth Factor I Receptor Signalin is required for exercise induced Cardiac Hypertrophy, Jaetaek Kim et.al; Molecular Endocrinology 22 (11):2532-2543.
  2. 2. Enhanced muscle insulin receptor autophosphorylation with short-term aerobic exercise training, J.F. Youngren et. al: Am J Physiol Endocrinol Metab (2001) 280: E528-33.
  3. 3. Impact of physical activity on cancer recurrence and survival in patients with stage III colon cancer: findings from CALGB 89803, Meyerhardt JA et al. J Clin Oncol 2006 Aug1; 24(22): 3535-41 (Dana Farber Institute, Boston, MA)
  4. 4. Tao MH, Shu XO, Ruan ZX, et al: Association of overweight with breast cancer survival. Am J Epidemiol 163:101-107, 2006.
  5.  5. Bianchini F, Kaaks R, Vainio H: Weight control and physical activity in cancer prevention. Obes Rev 3:5-8, 2002
  6. 6. Del Giudice ME, Fantus IG, Ezzat S, et al: Insulin and related factors in premenopausal breast cancer risk. Breast Cancer Res Treat 47:111-120, 1998
  7. 7. Holmes MD, Chen WY, Feskanich D, et al: Physical activity and survival after breast cancer diagnosis. JAMA 293:2479-2486, 2005.
  8. 8. The Association of Physical Activity with Lung Cancer Incidence in a cohort of Older Women: The Iowa Women’s Health Study. Sinner,P et. al. Cancer Epidemiol Biomarkers Prev 2006;15(12):2359–64.
  9. 9. Evidence of Inhibitory effect of Diet and Exercise on Prostate Cancer Cell Growth. Tymchuck, CN et.al. Journal of Urology Vol 166 (3): Pages 1185-1189, September 2001

Friday, June 10, 2011

The New Norm and the Future


IT was in a train where I first observed this behavior. It appeared bizarre and rather unfriendly. Five youngsters dressed down to their level of chic with cut-offs and ripped jeans, huddled together with arms and legs slung over each other and their eyes glued to their phone screens. They looked like spaghetti in a bowl – a slithering morphing piece of humanity. I must admit it was curious but also profoundly shattering of my mental construct of public human behavior. They were all equally involved in their own little worlds connected and yet not. The only link they seem to have with each other was the limited physical contact between an arm a leg or a torso. A laughter here and a snicker followed by a whoop was the detail of their linguistic communication.

The change is here. We see the new generation make their mark on the world. In their teens they are adept in the world of connected online communications. They speak a language that is, well, different. There are abbreviations made up of letters and numerals and where invoking pleasure a colon, dash and a bracket suffice. But they are at peace with this new world. They are creating it and it is a joy to watch. Through this sea change they are modifying the habits of all other generation representatives and it is one of these individuals with the foresight into the connectivity concept that a computer program has netted over $30 Billion. Their net is being cast and the world is their oyster.

Society is transforming before our very eyes. It is in a state of flux as it always has and this time is no different.  From the free-wheeling easy-street, fast-love, lawless generation of the 60s that now governs, this new generation waits to seek its advantage in society of the future. The only difference is that the manifestation is different, ideas borne of a varied culture and a different mindset. So what will be the legacy of this generation? Where do we see ourselves in the next decade or two? Answering these questions with any degree of certainty is tainted with a large dose of wrongness. Predicting the future within such volatility is fraught with error. A minor change can lead to a different world, or as physicists will tell you, maybe a whole different universe. The strange Attractor is in play as it always has been. Future changes in small increments, but for that unrealized minor element, that can change all. The new generation is about to lead and we should have an idea where to, shouldn’t we? Is it possible?

It is January 5th 2015. The sun has made it up above the blanket of snow that covers the bushes and the street in front of the house. All is quiet. The street was once bustling with activity, now most people get up and sit in front of their computers and do their daily office work. A few still drive in the morning braving the elements into their scaled-down headquarters to hold videoconference with clients. The youth of 2011 has matured into the 20 something that live in the escapist world of game playing. Schools are a computer created edifice for distant learning. Education is doled out to a growing majority via 1 and 0. The enucleated family seems to be bridging the gaps once again. Structured universities of the past are large warehouses for research and development, sponsored by the corporate giants. Advancement in science is taking place at break-neck speed.


On February 10th 2020. The afternoon sun is bearing down the heat amidst the cold frigid air. The streets are busy once again, only now the mode of transportation is different. The vehicles are hovercraft. Magnetic levitation has been solved without the need for super-cooling and individual transportation with vehicles designed as small cubes race around in perfect harmony avoiding each other through sonar and infra-red technology as they dash to their destinations. Propulsion still remains energy dependent and liquid gas from North America make up the largest suppliers.  A thirty-year old Eric walks in his ergonomically designed shoes that prevent injury to the ankles and knees in his future. All rotational, torsional and shear forces related to walking have been circumvented. The most common sport of the day is “laser-tagging” with a twist. Only now the victim bears a permanent scar of being tagged and thus becomes less desirable to the opposing sex. The youth has upped the ante and want to claim their rightful place in the “survival-of-the-fittest.”
 
March 15th 2030 evening brings with it the violent storms of the spring season. But the reinforced glass dome-shaped houses are resilient to the elements. The contours prevent any damage to the inhabitants within. A 2-hour warning sounds for any oncoming weather related event and the inhabitants seek shelter as their hovercraft slide conveniently into roadside shelters on cue without input from the rider. Overhead a streak of an entrail with periodic plumes of frozen moisture reflect the plasma driven aircraft that zip across the continent in less then two hours at blinding speed, rising into space and falling back into the atmosphere near their destination. Energy problems seem to have been solved with “fusion-energy.” Small packs, the size of an encyclopedia can transform a laser-tagging field like the Baseball fields of years gone by from night into day. 


The “Fusion-energy” is derived from a combination of Magnetic fusion 

merged with an Inertial Confinement Fusion technique, 

where laser-driven implosion of a small pellet of fusion fuel simultaneously converge on a tiny target, intensely heating the outside and squeezing the fuel into the center of the pellet. The inertia of the implosion traps the fuel for a billionth of a second at ten-million-degree temperatures and densities far greater than solid matter. The intense heat and pressure force the fuel to fuse, much like inside a star. The fused fuel remains for delivery in a small but intensely confined magnetic field created in the miniaturized “tokamak” (a donut-shaped enclosed environment).
Tokamak

 Soccer seems to be making a comeback in sports with a twist. The game is played with new partially levitating shoes and a soccer ball that morphs from round to elliptical in, in-fight. The goal posts are twenty-feet in the air and guarded by the plasma propelled rocket boots of the goalkeeper. Baseball still enjoys its place in the culture but it is played with wooden bats once again and under a glass dome that can be used for overhead displays for replay. The umpiring is done by infra-red and computer algorithms. Meanwhile the work place is transformed into a 24/7 model where all transactions are made via holographic images created by a smart-phone type device. All data is computer driven and coders are in high demand.


 “Glaminar” is the largest home-building company in the land and has million+ employees. The employees are distinguishable by their stark-white tight-fitting uniforms. Quantum computing and protein storage is the norm in this data-abundant-driven-society.

The April 20th 2040 twilight is colored over by the rich brightness of the “foo-flames” that are geo-positioned in the sky and light the streets everywhere. The sun sets but the light remains. People gather in small parks to spend time with each other. Little girls and boys chatting away, running after each other while their elders look upon them with comfort and love. The society is once again transformed from the hard-hitting generation to the one looking for solace and comfort of the flesh. The elderly live out their century in comfort without aches and pains.
Nanobots capturing cancer cells


 Cancer has been circumvented. Each person is injected with a nano-material that looks for any aberrant cell destined to become cancer and destroys it. 
Nanobot primed with proteins

These nano-bots are 50-70 nanometers and made of polymers attached to a protein that connects to the precancerous cell. The protein is commingled with a siRNA (small interfering RNA) which deactivates the altered DNA, shutting down the gene activated protein production in the precancerous cell thus destroying it.
Nanobots in the Blood Stream


 Hearts and other organs repair themselves with ease, if damage is detected, selected stem cells are activated by the nano-bots and repair is done without any physical knowledge of the individual. These stem cells are derived from the individual’s infancy and kept in “Stem-farms” later conjugated with the nano-bots. 
Actual photomicrograph of pluripotent stem cells


The Hayflick Limit has been rendered moot with the telomere lengthening medications that prevent aging significantly and also circumvent early death.


 The mitochondria (energy producing structures within cells) are constantly washed and their load of super Oxygen radicals are eliminated by the  “Super-Oxide-Desmutase” secreted by the nano-bots.
Nanoparticles in the tissues

 Man has conspired to alter the basic mechanism of nature and seems to be winning. The population of the world has reached the 12 billion mark and while food remains widely available for demand, production via means of genetics and replication technology has helped overtake starvation. The currency of the world is in “Credits.” Credits are obtained by work performed. Crime still exists in smaller and smaller pockets and criminals are scanned for genetic behavior, finding which they are treated for that behavior with nano-particulate therapy. The success rate of this technology is still at 50%. Incarceration is in glass-domed prisons that oversee playgrounds and parks. Meanwhile the citizens cannot see within due to reflective technology. This experiment is to show the prisoners what they are missing and that “real” change in behavior would allow them back into society. Individualism is the key to progress in this society. New breakthroughs occur from garages and small cubicles on a daily basis. The governments are concerned only with providing infrastructure and protecting individual rights. The US Constitution is a global document used as a source of inspiration for all other nations.


It is May 25th 2050 night when the “first-landers” communicate from near the outer space,


 just beyond the Kuiper Belt and much before the Oort Cloud,


 that they have established a colony and a first generation of humanoids (human DNA merged with machine via the Von Neumann concept) has been born in a land of plentiful resources. Pluto is a distant cousin. They have named this planetary astronomical object as Earth II in typical human fashion. Reports from the far-away land are encouraging. The first generation has survived 1/100,000th of the planetary year. The weather is humanoid created since all live beneath the surface. There, the resources are mined and food is planted or replicated via the replication machines brought from earth. Life is different, but it is life. The evolving generation of humanoids are precise, productive hard-working and community-based individuals. The total population of Earth II is a mere 200.

…to be continued…


      
 

Thursday, June 2, 2011

A Response to Atul Gawande

And since you know you cannot see yourself;
so well as by reflection, I, your glass,
will modestly discover yourself,
that of yourself which you yet know not of. ~ William Shakespeare

You know how some words immediately leap an image into your minds eye? Just like that! One word and the image comes tumbling down. I say, Rose and you the reader immediately grasp the essence of what I am saying. The word invokes the image, the fragrance and sometimes even an event associated with it. Well then let me say Cowboy. What comes to mind in your head?

Wild Bill Hickok?  Poor James Butler Hickok died at the tender age of 39 years with a lead shot in the back of his head. He was a gambler, Marksman and a gunfighter.

Sundance Kid? Well Harry Alonzo Longabaugh was a robber and member of the Wild Bunch gang and committed suicide when surrounded by the posse at age 42 years.

Okay one more and then we will get to the real story. Jesse James? Young Jesse Woodson James alas got some lead in the back of his head also at an even more tender age of 35 years. He was an outlaw, a bank and train robber and member of a Clement Gang.

So what did these people have in common besides the obvious? You might have guessed it they were all Cowboys!

So the other day I read a commencement address given by none other than the “Checklist” fame guy Atul Gawande MD and it made sense to consider the Cowboys and Indians story once again. Atul is certainly not like Geronimo or Chief Sitting Bull or even Chief Crazy Horse, even though his parents hail from India.

Now what was Atul preaching to the young, impressionable newly minted Harvard Medical School graduates? Ah but that brings us to the crux of this story.

Are the independent thinking doctors now to be labeled “Cowboys” for outside the box thinking. And does Atul want to take that rarity of independent thought away and render them to the heap of little Indians without a Chief? A weighty question, don’t you think?

The concept did arise in my mind when he went on to say that doctors no longer have the luxury of practicing the art of medicine. Well, he did not in so many words but definitely his words implied to that effect. For he preached that medicine will now be guided by the largesse of evidence based guidelines and that doctors may become irrelevant as decision makers except in a team spirit. The first part of that statement any hard-working, sleep-deprived physician will find issues with, but the second part implies that doctors don’t get along with each other and don’t seek each others opinions –that they do!

Atul then goes on to say that doctors of the future will have to rely on other paramedical personnel for proper case management. Atul the docs certainly rely on all possible means to heal their patients today, especially when they need supportive help from other disciplines. But that is not what you are talking about is it? You meant, and I don’t want to put words in your mouth, that the proper decision making for patient care would be rendered with much more alacrity by nurses, Social Health Care Workers and the “Panels that will determine the need for any care?” Don’t you? Have you bought into the new science of “Global Societal Struggle and Health Care Rationing?”

Well Dr. Gawande if what you propose is to pass, according to your progressive agenda, then far be it for me to force you to consider the foundational basis of medicine that harks back to the days of people like, Marie Curie, Edward Jenner, Louis Pasteur, William Harvey and the like. Whose names will join with that illustrious group?  Medicine has not sprung from little Indians thinking as a “Borg Collective.” If it were, then and maybe only then, I might consider some advancement in science that could plod along in an advanced society, but even then it would be no match for the surprise, adeptness and intellectual leap of a single Captain Kirk! No not these little Indians, Pit Crews as you call them, they are being taught to mimic what is preached in the gospel written by the writers and the dreamers of progressive social coherence and they will merrily belch along to keep things simmering for a long, long time.

Oh, my dear man, what happened to you after borrowing the Checklist concept from the aviation industry ("The Checklist Manifesto") and making a name for your self, you have resorted to telling young and plastic minds in medicine that they must be reasonable in their thoughts when they practice. And by reasonable, you mean, make use of the template and lose their inherent wisdom? It reminds me of a quote by George Bernard Shaw, “The reasonable man adapts himself to the world; the unreasonable one persists in trying to adapt ... Therefore all progress depends on the unreasonable man”

Oh by the way, I did like three of your Five Rules from 2005. (1)

Rule #1.
Ask an unscripted question. Or speak to strangers – in other words communicate with our patients. Great!
Rule #2
Don’t Whine. Even you must whine at times to let off steam. Maybe not. Maybe you are perfect.
Rule #3:
Count Something. Maybe good advice but all you are counting is sponges left in someone’s belly, rather then counting the Ns in a study using statistical manipulation to prove the improbable.
Rule #4:
Write Something. I wholly endorse this one. Bravo!
Rule #5
Change. Early adoption. Also a very important step for a scientist and someone energized to do the very best for his or her patient.

Even though the Five Rules in 2005 gave me some goose-pumps,  your entire 2011 monologue delivered at the Harvard Medial School Commencement Address covered me in a rash of bleeding blisters. (2)

Five Quotes from Atul Gwande’s Speech to Harvard Medical School in May 2011:

1. “We train, hire, and pay doctors to be cowboys. But it’s pit crews people need, the ability to implement at scale, the ability to get colleagues along the entire chain of care functioning like pit crews for patients.”

So what happened to that man that claimed such simple powerful ideas and morphed himself into advocating doctors to become “Pit Crews”

2. “I was part of the reason my children didn’t have enough teachers. We all are in medicine.”
Using political rhetoric of money for education, knowing full well that creativity, inspiration and devotion in teachers are not motivated by money and excellence in schools is NOT as a result of funding! You seem to want to anneal together the “knee bone” with the “breast bone.”

3. “We are now witnessing a global societal struggle to assure universal delivery of our know-how.”
There is a lot of nobility in that statement, and universal delivery of our know-hows are certainly needed in impoverished lands. Believe it or not the United States spends millions if not billions of dollars in medical supplies overseas. There are scores of Missionaries that carry out their selfless brave work in impoverished areas to their own detriment.

4. “They are symptoms of a deeper condition—which is the reality that medicine’s complexity has exceeded our individual capabilities as doctors.”
I don’t know about you, but the human body, its physiology and pathology has not changed much. Knowledge has increased but you can carry that in your iPhone, Blackberry or other device. It is the interpretation of the information that a doctor excels in and not the excessive content of information. So I don’t think our capabilities have been exceeded yet.

5. “Even the cowboys, it turns out, function like pit crews now.”  Corralling a disease also requires many disciplines, yet each person has an opinion to express and each opinion must carry its own weight.

In the end, I don’t think doctors act with the same irrational, impulsive grandiosity as the “Real Cowboys” of the years past. Most doctors are concerned, focused, disciplined and hard-working as they always have been. They do not gamble with any person’s life. So much so that it takes a piece of them when they lose a life. But you call the previous generation of doctors as "cowboys" and end up adding notoriety to them while simultaneously denigrating the spirit of what they do. I am sorry for that.

Oh my, how the incline in your ascent has perched you into the hypoxic stratosphere of non-limbic thinking. Yes Atul you have achieved success but remember it lasts only for 15 minutes until some one else comes up with another catchy “template.” Even though you have crossed the finish line ahead of others in this marathon, please do not cast an eye on those behind and consider them as a faceless, homogenized mass of protoplasm worthy only of collective thought. They each have a name, a face and a brain worthy to be in that illustrious of places where Sir William Osler and Jonas Edward Salk reside.

I must be cruel only to be kind;
Thus bad begins, and worse remains behind. ~ William Shakespeare


Read more

1. http://www.leighbureau.com/speakers/AGawande/essays/Harvard.pdf

2. http://www.newyorker.com/online/blogs/newsdesk/2011/05/atul-gawande-harvard-medical-school-commencement-address.html#ixzz1O55qqZcU