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Friday, June 27, 2008

Sergeant York's School House

During World War I, the U.S. Department of War invited Robert Yerkes and his colleagues to develop and implement a series of tests examining the intellectual abilities of its soldiers. The tests known as the Army Alpha and Beta Tests constituted the first empirical aptitude and ability studies carried out with sample sizes (over 1 million participants) sufficient for rigorous statistical analysis. They uncovered appalling deficiencies in the education of Americans. The worrisome results jolted the country. Federal and state governments began to confront the challenges of offering an education to the broad populace that would meet the needs of a rapidly developing industrial nation. The test results eventually inspired the G.I. Bill of 1944.

The fabled World War I hero Sergeant Alvin C. York did not need sophisticated statistical analysis to recognize the shortcomings of education in his world. He owned a farm in East Tennessee and knew the problem first hand. After military service, he spent much energy and a large part of his own assets to found a secondary school for the children of Fentress County. The Alvin C. York Institute was founded in 1927. Classes began in 1929. Though much progress has been made since, great need remains. The Tennessee Economic Council on Women reports that 59 % of the women living in Fentress County graduated from high school in 2000. That is about 15 % fewer than in the nation, according to a recent National Women's Law Center report. Only 6 % graduated from a four-year college.

The Institute was eventually incorporated into the public school system. In 1980, the original building was deemed too expensive to repair. The old facilities were closed and new ones were built on the premises. Now the old building is slated to be torn down. It is registered in the National Register of Historic Places. Members of the York family and friends of the Institute are attempting to raise funds for its preservation.

The Tennessean's Rachel Stults reports in her article entitled "Family, preservationists rally to save York's dream" published Apr. 22, 2008, that the building's years may soon be counted. Restoration would cost a daunting $ 5-10 million. Neither the state nor the county government are prepared to provide this large sum for a project that does not seem to help address persistent urgent needs. Can there be a rationale for investing 10 million dollars in a dilapidated building far from any economic hub of note?

The answer is yes. Tennessee's countryside is beautiful. Costs of living are low. It is a perfect location for industries that do not need to be near metropolitan areas, yet want a seat in the U.S. Internet-oriented services and e-commerce come to mind. Such high technology-oriented enterprises commonly hesitate to settle in rural areas, because the local work force does not have the expertise they seek. Like any high school in this state, today's Alvin C. York Institute already attempts to seed the knowledge for such jobs. A learning center for computer sciences in secondary education would greatly enhance the effort. The center could lend OLPC to those who cannot afford a computer. The little machines are also known as XO computers. They constitute cost effective, robust and powerful slim clients. I wrote about them in my post on this site on December 7, 2007, and am writing this post on one.

Instruction in the use of computers would help the children to develop the understanding and the skills needed to embrace the world wide web and elicit interest in internet careers. The preparedness for college would improve. The center's seat in the building that Alvin C. York conceived to bring opportunity to his people through education would represent a beacon of hope for those who live in rural America and feel left behind by the innovations of the 21st century. It would demonstrate that York's dream can be fulfilled. The symbolism is priceless.




Monday, June 23, 2008

The Brain: A Giant Self-Medicating Gland

The use of psychoactive drugs is older than humanity. Primates have been observed to deliberately feast on fermenting fruit rich with alcohol. The debate over the benefits and perils of treating mental disorders with psychoactive drugs has been unrelenting and passionate among patients, physicians and scientists. Alternative treatments promising improvement are hotly disputed. Two recent articles in The New York Times highlight the substantial public attention paid to these issues.

The first one, published online Apr. 15, 2008, was written by Richard Friedman M.D., a concerned physician who worries about the presently unknown health effects of life-long medication beginning at an age when our brain still develops. The prescription of anti-depressants to youngsters diagnosed with adolescent depression is used as an example. Brain and mind may develop differently with the constant exposure to these drugs. The body will be burdened with a foreign compound for a life time. The author argues convincingly that more research is needed to examine the long-term effects of the chronic exposure to psychoactive drugs. This concise, informed, and sensitive contribution initiated comments from 360 readers.

The second article, published online Jun. 16, 2008, is a post by Tara Parker-Pope describing therapies for Attention Deficit Hyperactivity Disorder alternative to conventional drug treatments. The article has attracted 160 comments to date. Prudence is advised when examining the options discussed in this post. The assessment of recently developed treatments is wrought with difficulty. The time for gathering experience with a novel therapy is commonly too short to allow a valid comparison with the risk/benefit analyses of established therapies supported by large bodies of data.

It is important to emphasize that any type of intervention will influence the biochemical make-up of the brain. The nerve cells in the brain produce psychoactive substances and modify their production at all times. The nerve cells excrete chemical substances known as neurotransmitters to communicate with each other. Neurotransmitters affect the behavior of nerve cells immediately. The predominant excitatory neurotransmitter is glutamate. Glutamate bound to specific receptors on the cell body surface stimulates the production of electrical signals known as action potentials. Action potentials travel along the nerve cell's outgoing arbor, i.e. its axon, and exact the release of neurotransmitters at its contacts with other nerve cells known as synapses. Gamma-aminobutyric acid, by contrast, inhibits the production of action potentials. Acetylcholine, norepinephrine, dopamine, and serotonin may influence neural behavior more persistently and are also known as neuromodulators, playing crucial roles in psychiatric disorders. Opiates constitute the purest type of neuromodulator, because they do not act as neurotransmitters. Eventually, it is important to understand that some neurotransmitters can excite or inhibit nerve cells, depending on the type of receptor they bind to.

Compared to neurotransmitters and neuromodulators, however, hormones exert the longest lasting effects on the brain. When I was a student I participated in research on the Siberian hamster Phodopus sungorus of Siberia in the laboratory of Professor Gerhard Heldmaier (Rafael and others, 1985). These amazing creatures are only the size of a mouse. Yet, they cope with the frigid temperatures of Siberian winters. They grow a thick white coat for the winter and can rely on paws padded with dense fur even on the palms. But, the key to the hamsters' survival is the brown body fat, known as brown adipose tissue or BAT for short, that they build up before snow fall sets in. The hamsters are crepuscular, that is they are most active during the twilight hours of the day. As the light grows more orange and the days grow shorter, the hamsters forage more intensely for food, almost double their body weight, and their physiology changes. Come Winter, the hamsters can resist deep freezer temperatures as low as -70 °C for many hours without any harm, using their brown body fat to maintain body temperature. When the brown fat is depleted, they begin to shiver and die in short time. By contrast, animals unconditioned during the autumn would perish already at -30 °C.

The hormone melatonin is thought to play a crucial role in the hamsters' seasonal behavioral and physiological changes. Nerve cells in the brain's pineal gland secrete this hormone into the blood stream. The cells are light sensitive and increase hormone production, when the animals are more exposed to long wavelength-rich autumn light and extended nights. Heldmaier and others (1981) observed that hamsters that were artificially maintained at long daylight hours in the autumn, developed only mild cold resistance. However, their sensitivity to melatonin was enhanced. Chronic administration of melatonin increased cold resistance in these animals. By contrast, short daylight-adapted hamsters showed the anticipated increase in cold resistance and no sensitivity to melatonin treatment. Summer- and winter-adapted hamsters are shown in the video below.


Melatonin does not only govern the Siberian hamster's life. It plays a crucial role in the bouts of depression that people living above the polar circle confront during the long and dark winters. The control of nerve cell function through a substance that nerve cells produce in response to environmental changes constitutes a powerful demonstration of experience-dependent brain self-administration.

Normally, the nerve cells in our brain are well poised to maintain control over the diverse processes that keep our brain's biochemistry in balance. However, genetic predisposition, developmental mishaps, and traumatic experience may sway that balance toward extremes beyond control. We may be able to bounce back by just taking time out, re-balancing our brain and calming our mind. If our own coping mechanisms do not suffice, we need professional help.

Psychotherapies have proven effective for some. Yet, success seems subtle. Time is needed to produce measurable results. By contrast, drugs targeting specific neurotransmitters are known to restore functionality quickly and robustly. An overwhelming number of comments from affected people sent to The New York Times supports this contention. But, there is no reason to believe that substances purified from natural products should be a priori more beneficial than pharmaceuticals synthesized in laboratories, solely because the former originate in nature. Only thorough research and experience will tell which drugs produce positive results regardless of provenance.

Drug therapies entail one drawback. The substances are administered systemically. That is, they are injected or ingested and absorbed by the whole body, although their intended targets may only consist of small regions of the brain. Other organs may be susceptible to the drugs. notably, the walls of the intestines contain more nerve cells than the brain. The intestinal nerve cells possess receptors similar to those found on brain nerve cells and may respond to the drugs with adverse effects on digestive function.

Moreover, drugs accumulate in the liver. Foreign chemical compounds are made water-soluble by oxidative liver enzymes. The increased concentration of the drugs may induce detrimental hyperactivity of these enzymes. The load that the metabolites add to the kidneys, where they are excreted with the urine, may damage kidney tissue. The risks mount, when medication begins early in life. But as Dr. Friedman so validly pointed out in his article, we simply do not know at present what the precise consequences of the life-long exposure to psychotherapeutics will be.

Therapies that are targeted only to the brain regions involved in the disorder would reduce the risk of adverse effects. Psychotherapeutic drugs are designed to target specific receptors on nerve cells and modify the molecular pathways that are particularly involved in a specific disorder. However, their action could be directed to specific brain regions only, if they were infused directly into the tissue, requiring a craniotomy.

By contrast, biofeedback-based therapies may improve nerve cell function locally without invasive intervention. Cognitive therapies can be considered as providing biofeedback, if they concentrate on the behavioral manifestations of the disorder and address specific symptoms. Conscientious modification of behavior may re-adjust the biochemical balance of the involved brain regions and this re-adjustment may conversely improve the behavior. Other therapies involving biofeedback consist of learning to play a musical instrument or a sport. These methods challenge sensory and motor skills. They demand focus and render immediate sensory feedback. With practice, brain function and skill improve concomitantly.

Neurofeedback, e.g. BrainMaster, is a technologically more sophisticated extension of the behavioral interventions described above. Electrical brain waves are recorded from the scalp with button electrodes. The power of these brain waves is used to inform the participants whether they are making progress in the desired direction. The measurements can be displayed in dynamic graphs on computer screens or integrated into computer games. I have written about such electroencephalographic techniques and the experience I had with equipment manufactured by J&J Engineering in my post published on this site on May 24, 2008. The brain waves of interest are known as alpha waves. Their profound role in mental focus can be explored with Mind ball popular in science museums.

Neurofeedback is an emerging technology and several comments to Parker-Pope's article lament its shortcomings with frustration. The applications using this technology must be sufficiently flexible to accommodate the very specific needs of the participants. Costly, time-consuming experimentation may be needed to find effective parameters in each instance. Moreover, the recordings of the minuscule surface potentials from the scalp are sensitive and easily compromised. Thick hair diminishes conductance and attenuates the strength of the recordings. Firm contact between the electrodes and the scalp needs to be established with sufficient amounts of conductance paste that must not dry out during the session. The impedance of the electrodes needs to be held stable to produce accurate and reproducible measurements of brain wave power. Thus, participants need to be fully cooperative and must be careful not to pull on the recording wires. Failing at any step may render the whole session useless.

References



Revised: 01/30/2012

Sunday, June 22, 2008

Morat: Triumph of Free Will

“The idea of America endures. Our destiny remains our choice.  And tonight, more than two centuries later, it’s because of our people that our future is hopeful, our journey goes forward, and the state of our union is strong.”
President Barack H. Obama in his State of Union Address, Jan. 25, 2011 (added on the following day).

Today, Jun. 22, in 1476, the Swiss Confederation won a decisive battle against Charles II, Duke of Burgundy, known as the Bold. This account of the event is mainly based on the Freiburger Geschichtsblaetter, vol. 60 (1976). A good summary is available on the web here. A formidable depiction of the battle can be found here. Charles II was a highly educated feudal lord with a penchant for war as a tool to fulfill his territorial ambitions. This renaissance ruler oversaw a wide swath of land across Western Europe from the shores of the North Sea to the shores of the Mediterranean. The wealthy Swiss cities on the Eastern borders of his realm infringed upon his zone of influence and also promised a good additional source of income for his treasury. From adolescence, the Duke was unrelenting in his effort to keep the wealthy cities of the low lands on the North Sea under his control. A campaign to subdue wealthy Swiss cities was an eastward extension of this policy.

In January 1476, Charles marched an army of about 28,000 professional soldiers equipped with the most advanced artillery of his time toward Western Switzerland. The region around Lake Geneva was under the rule of the Count of Savoy who was allied with the Duke. On February 8, the troupes crossed the Jura mountains into Switzerland and soon attacked the town of Yverdon on the banks of Lake Neuchâtel. The town had been occupied by the Swiss Confederation in the preceding year. Now the occupiers abandoned their position, burning down everything behind them. They withdrew to the fortress at nearby Grandson with the Duke's men in hot pursuit. The Duke ordered a siege. On February 21, the Confederates surrendered on promise of free conduct. As the men filed across the drawbridge disarmed, they were taken to a mighty tree nearby and hanged one next to the other from its branches. The fortress has survived intact and houses the municipal administration today. The tree also survived. It is huge with numerous massive, horizontal branches. There is easily space for a score of bodies on each. Contemporary depictions of the despicable act show rows of corpses strung up like chicken on a line. Reportedly, a total of 412 men were strung up in the tree within 4 hours.

In retaliation, the Confederates surprised the Duke's army in the vicinity of Grandson on February 27 and captured a good part of the artillery. Most importantly, they happened upon the Duke's treasure of legendary riches. Its bounty was so exorbitant that the looters fought over their shares for a number of years. A peace treaty was needed to put the quarrels aside for once and all.

The gruesome end of the Confederates at Grandson sent a clear message to the towns in the region. Commonly, the burghers avoided armed conflict. Negotiating an agreement with the aggressors, even if it was costly, was often less disastrous than battle. Moreover, the burghers in West Switzerland did not care whether they paid taxes to some feudal lord or the city of Berne which dominated the region. Moreover, the francophonic locals felt more comfortable with the French culture of the Duke than with the Teutonic culture of the Swiss Confederates. Many small towns would have immediately switched sides in the face of the ducal forces, had the conditions of surrender seemed decent and fair. But, the horrible events at Grandson proved to the burghers that they could not expect benevolence from the Duke.

The second Burgundian thrust into Confederate territory started in June with a regrouped army of 21,000 men from fields above the city of Lausanne. On the march to the city of Berne, the army reached the town of Morat on the banks of the lake with the same name. The Burgundians began to lay siege on June 9.

The Bernese government had preempted a negotiated surrender of the town by sending the experienced commander Adrian of Bubenberg to oversee the local garrison. He ascertained that the burghers resolve did not falter in the bombardment of the Burgundian artillery. They had to hold out until the very end which was close on June 22. The Duke's heavy artillery had been persistently pounding the town's defenses. The wall and a tower had already crumpled in on the northern side three days earlier, but the defenders had repulsed the enemy's advance through the breach after eight hours of fighting. Now, it was only a question of time, until other breaches were wide enough for a final assault.

Bubenberg had written desperate pleas for help to Berne. The members of the Swiss Confederation were gathering an army to confront the Burgundians, with the Bernese constantly reminding the others of the oaths of mutual support they had sworn. This was no easy feat. The Swiss Confederation was not directed by a ruler, but was led by consensus. Plenty rivalry existed between regions and towns. Heated debates were raging whether it was wise or profitable enough to come to the rescue of the Bernese. Some compatriots felt it best to stay out of a conflict that did not affect them directly. In Zurich, the final decision to join the cause fell only days before the battle. Once it was made, 4,000 soldiers force-marched the 70 miles from Zurich to Morat in three days. Six-hundred did not arrive. During the night of June 22, the Zurichois united with the 25,000 Confederates and allies from Alsace and Lorraine that were already assembled behind a forest about 3 miles from the Duke's positions. Now, the Swiss outnumbered the Burgundians.

The Confederates had found in the Southern German Herter of Hertenegg an expert military leader for their endeavor. With the help of the Swiss captains, he managed to expediently whip the diverse lot into an attack formation that was classic in his time. The men were divided into a 5,000-strong avantguard, a 10,000-strong bulk and, arguably, a rear guard made of the rest of the troupes. The three battle groups were to enter the battle field in close succession. The avant guard was supported by 1,100 cavalry deployed on their left. Avantguard and bulk were to advance tightly packed in arrow formation with lancers wearing body armor on the flanks protecting the less armored helbard bearers in the middle from enemy projectiles.

Jockeying for the best positions and the most valiant jobs lasted into the morning. Promotions were handed out. The arguing went on. But the Swiss could not wait any longer. The militia men did not have any provisions. Hertenegg and 500 men rode to the forest's edge to view the enemy positions. Meanwhile, deployment for battle continued in the forest, though heavy rain fell.

The Duke's soldiers had been expecting the Swiss for days. They knew the location where they would emerge from the forest. The Duke's planners had set up a palisade fence and other fortifications to corral the Swiss militia men into a trap in the shape of an L with the short stroke, that is the line of artillery, pointing upwards and the long stroke, that is the line of archers, pointing sideways. On arrival the Swiss would be annihilated in a hail of arrows from the front and cannon fire from the right side. The enemy's left side opposite the artillery was left open for the charge of 2,100 cavalry, waiting behind the lines ready to mop up.

The Burgundians had been lying in their battle positions for several hours on this day and for hours on end on the days before. As on the other days, the enemy did not seem to attack. The weather was abysmal and lunchtime approached. The officers decided to stand most troupes down. At this very moment, the rain stopped and sun broke through the clouds. The Swiss avantguard advanced. The bulk of the force followed on their heals. The men poured against the Burgundian fortifications and were welcomed by arrows and artillery. Though only skeleton crews were at hand, the Burgundian army unleashed dense clouds of projectiles. Despite, the fiercely determined Swiss avant guard managed to breach and circumvent the fortifications within an hour. The cannon fell silent. The bulk of the Swiss force spilled like an avalanche through the breaches toward the Burgundian camps ringing the town. The Burgundians did not have a chance to ready themselves. Disarray and mayhem ensued. The Duke's officers tried to organize a counter offensive. The line faltered. The men took flight. A complete route unfolded. The Swiss succeeded in surrounding the fleeing troupes on three sides. The fourth side was taken by the lake. Countless Burgundian soldiers drowned or were drowned in a desperate attempt to flee across the water. It is said that a third of the Duke's army perished. The Duke and his immediate household escaped narrowly.

Louis Braun, Schlacht bei Murten, 1893
Lore has it that at the day's end, the Confederate contingent from the city of Fribourg sent a messenger home with a branch from a linden tree to announce the victory. The distance is about 11 miles. There are two steep grades on the way and a final 0.7-mile ascend through Fribourg toward downtown. The branch of the tree was supposedly planted in front of City Hall in memory of the great battle. A massive linden actually stood there until about 30 years ago. Sadly, it succombed to pollution. But, for 75 years the messenger's feat has been commemorated by a run held on the first Sunday in October.

Tens of thousands of people from all over the world attend. Olympic medalists cover the distance in a bit more than 40 minutes. Morat looks very much the same today as it did at the time of the battle. Ramparts and towers survived.

Charles the Bold was a military man to the hilt whose confidence in battle was strengthened by several successes at young age. He was an involved leader and said to be popular with the soldiers. At the height of his Swiss campaign, he slept in battle dress until his limbs swell and he could not walk. He involved himself deeply and directly even in small affairs to the point that his commanding officers loathed his interference. On the downside, his inability to accept advice and his mistrust of those who were not members of his immediate household may have impeded effective leadership.

Yet, the strategy Charles used at Morat was consistent with the military thinking of his time. History had proved that victory belonged to those who picked the location of the fight and could prepare the battle field to their advantage. This commonly outweighed the disadvantage of having to wait for the enemy. The Duke commanded the best weapons of his time. He had introduced innovative battle formations combining different types of soldiers into fighting units in which they could complement each other. His standing army consisted of experienced professionals and practiced regularly. After the battle, the foreign military observers present and the Duke himself blamed the debacle on ill timing. Had everybody been on their battle stations, the Swiss would have perished for certain.

However, it can be argued that the Burgundian soldiers, most of whom were contracted, were no match against the independently-minded militia. The Swiss were bound only by their determination to win. Otherwise they were free to take any decisions they saw fit in the field.

The Duke's greatest flaw may have been his own inflexibility in judging the Swiss. This renaissance man fatefully stood on the threshold between the old and the new. He embodied the contradictions of a modern minded leader who loved technical innovation, but could not grasp the novelty in his enemy's mindset. The Swiss militia may have used crude, antiquated strategies on the battle field. Yet, they were motivated by a consensus solidly forged by communal deliberation. Common people making own decisions of this magnitude had no place in the feudal system. Charles II was a proponent of the God-given order in which he and his kind were entitled to all worldly decisions. Granting commoners too much freedom would bring only chaos. The Duke's subjects were rewarded as long as they gladly played the roles he assigned them in fulfillment of God's will. He saw it as his duty to severely punish those who rebelled against this order. Change was not acceptable.

At the time, the victory of the Swiss Confederates sent a profound signal across Europe. Like any other victory of commoners against feudal lords, this one proved that anyone could prevail, if they were free to use their abilities to the fullest. Success against the odds was possible, when the like-minded exercised solidarity and broadly shouldered the burden of action. The example of the Swiss Confederates demonstrated that anyone with resolve, unrestrained by feudal bondage and station, could take destiny in their own hand, take advantage of their abilities and use them to improve their circumstance of life. The events at Morat were at the beginning of a movement that would eventually lead to the Declaration of Independence and the Storming of the Bastille 300 years later. The persistent determination of the common people to free themselves from the feudal yoke precipitated the standard of living and the freedoms we enjoy today.

Addendum
  • In his post on boingboing.net today entitled "Draft of Declaration of Independence named subjects, not citizens", Rob Beschizza describes in detail how Library of Congress researchers using hyperspectral imaging recently discovered an important change in Thomas Jefferson's draft of the Declaration of Independence. He first wrote "subjects", smudged out the wet ink, and replaced the word with "citizens". This small, willful change constitutes such an extraordinary example for the sea change in zeitgeist in Jefferson's time, reflecting the end of feudalism and the beginnings of modern society. It is yet another prove that free will exists (07/03/10).

Friday, June 13, 2008

Metro Nashville Public Schools: A System under Construction

About a month ago we were invited to the graduation ceremony of our neighbor's daughter at Hillsboro High School in Nashville, Tennessee. It was the first time I attended a U.S. high school graduation. I received my secondary school education abroad.

The ceremony was festive with hundreds of graduates and a huge crowd of family members filling a college basketball stadium. I was struck by the diversity of the students and their achievements. Scores were honored for their successful participation in advanced placement courses. Others had fulfilled the requirements for the international baccalaureate, permitting them to study overseas.

A number of students were recognized for their accomplishments in the sciences and the languages. Among the high achievers was a young man with Asperger's syndrome who addressed the audience in a passionate speech. The student who received the loudest cheers had Down syndrome. It was an evening of elation. Everyone was very proud. The students seemed equipped and ready for great careers to come.

These impressions are in stark contrast to the district-wide performance of Metropolitan Nashville Schools. The school system is in a deep crisis. A number of schools have missed government-set benchmarks for student performance (TCAP) for four years in a row. The passed director of schools was the second choice at the time of his appointment. He worked hard on improving instruction for the children of recent immigrants with poor knowledge of English. His rule was draconian. His personnel decisions were not well received. The teachers chafed under his reforms. The introduction of school uniforms complicated lives and did not make a difference. His days were eventually counted, when his unpopular measures did not deliver the successes that the school district direly needed.

Stipulated by the disastrous test results, the Tennessee Department of Education sent emissaries to institute reforms. A private company is being hired short-term to pay special attention to the students at schools with poor showing. Nashville is looking for a new superintendent. The search will not be easy. Apt candidates with career ambitions may hardly be interested in a position that may reduce them to expediters of state policy with little prospect of earning own acclaim. The public debate about Metro Schools' future is heated. Nashvillians want to improve their school system, but are wary of increased taxes. The local newspaper The Tennessean provides comprehensive coverage.

To date, most change precipitated from the top down. Yet, the student performance problems are specific to neighborhoods. The socioeconomic and geographical nature of the problems suggests that solutions must be sought at the individual schools in discussion between the educators teaching the affected children and the communities where the children live. Traditionally, these communities have had little confidence in the system. Great expectations have been raised in the past and proved too hard to fulfill in actuality. They have been disappointed many times. Any proposal for change may be perceived as yet another short change.

In this situation, newly created facts on the ground must disprove any false perceptions. Short-term fixes are not going to win the confidence of the affected communities. Solid investments have got to be made that produce lasting, palpable and visible results locally. The children and parents will embrace reforms only, when they are convinced that the offered help is more than just a promise.

Addenda

  • Jesse Register, the newly appointed Director of Metro Nashville Public Schools, took office Jan. 15, 2009. Today The Tennessean's Jaime Sarrio in her article entitled "New schools chief calls for unity" on his first public statements about his vision of leadership for the school district delivered to the Metro council's education committee (02/03/09).
  • Updated facilities constitute the smallest part of the effort. The greater part will consist of keeping the students to attend school. During the last summer, the implementation of truancy programs was widely discussed in the community as a measure too improve the abysmal attendance in the schools that did not meet the criteria of the No Child Left Behind Act, known as Title I schools. Here, attractive and affordable after-school care may motivate students to come to school on a regular basis.

    My children have been enrolled in a superbly-led after-school care program while at Eakin Elementary School in Nashville. The program has had a deep, positive influence on the development of their social skills and homework ethics. The prospect of meeting friends after school has been a cheerful motivator on dreary mornings. Exactly such programs are needed in the under-attended schools. The children would benefit highly from the exposure to a socially structured environment in the afternoons where conflicts can be resolved under adult supervision, where they can study, do homework, can explore computers, learn crafts and handiwork to develop their fine motor skills as well as have pure fun playing games and enjoy each others company. The children would wish to be at school.

    In my experience, such programs do work for all children. One summer, my son attended a Boy Scout Summer Camp in Nashville's Shelby Park. Most children were from so-called distressed neighborhoods. My son was hesitant about meeting them at first, but got quickly acquainted with his new pals. The kids got along fine. The group experienced one troublesome incidence during the week. Nobody was hurt. The councilors immediately sat the boys down to discuss how to resolve the conflict. They told us parents about the event in the evening. I walked away convinced that social engineering can work. In addition to good teachers, effective after school care may be essential to progress at under-performing schools (02/24/09).
  • I have written more about the value and the needs of education in this state in my posts dated Jan. 24 and Jun. 27, 2008 (03/12/09).
  • Today The Tennessean's Jaime Sarrio reports in her article entitled "Nashville schools to tackle key needs all at once" on the reform plans of the new director of schools announced yesterday. The plan focuses on improvements for children with special needs and children who speak English as a second language. In addition, attention will be paid to improvements of school safety and climate (04/01/09),
  • Nashville Mayor Karl Dean bought into the idea of boosting after-school care, according to Heidi Hall's post in the Tennessean entitled "Dean plans to expand after-school programs" yesterday (05/08/09).
  • With incredulity, I found out today that our new Director of Schools decided to move one of the most competent principals I ever met, Roxie Ross, from our daughter's school, Eakin Elementary. Roxie oversaw the relocation of the school into newly built and restored facilities a few years ago and led the school with greatest professionalism and enthusiasm as a place of learning for all children. Eakin has performed above expectations under her guidance, fulfilling the requirements of the No Child Left Behind Act year after year. No reasons were given for the decision. No parents were consulted. It seems highly demoralizing for the teachers, the children and the parents to remove a principal from a post in which she excelled. Parents trust in the continuity of the system, when they commit their children to its schools. Functional schools are precious and should not be tampered with. Without them, a city loses its attraction as a place for families to raise their children (07/07/09).
  • Last year the school board decided to rezone the district. The idea was that the rezoning would improve the underperforming schools by steering students to schools in their neighborhoods with the hope that this might facilitate parent school involvement. Most parents of the affected students were highly skeptical that rezoning was a step in the right direction. Many perceived the plan as an erosion of school integration. A federal law suit was filed. Regardless, the school board went ahead with a shaky implementation of its controversial plan this school year. Today The Tennessean's Chris Echegaray reports in his article entitled "North Nashville students get books day after judge's order" that as a result students of one rezoned middle school received their text books only now, that is three weeks after the school year began (09/03/09).


Friday, June 6, 2008

Professor Max Wertheimer's Synergy

Seventy-five years ago, the New School for Social Research began its graduate program in psychology. One pillar of this program was Prof. Max Wertheimer, co-founder of Gestalt Psychology. The Wertheimers had just moved from Frankfurt am Main to New York at the time. Wertheimer was one of the many Jewish scholars who lost their academic appointments to the race regulation the Nazi's introduced in German public service in 1933. It took Germany up to the present to recover from the gigantic brain drain that ensued.

Professor Wertheimer spent many productive years as a faculty member of the Johann Wolfgang Goethe University, Frankfurt am Main. The city had been a free city ever since Charlemagne's rule and has always been a free-spirited place that had comparably friendly relations with its Jewish community before the Nazis came to power. A bit more than one hundred years earlier the most prominent Jewish banking family of Frankfurt, the Rothschilds, had used their influence in France to save the City from plunder by the Napoleonic armies that were self-providing. Self-provision commonly meant that, at the least, there was no food left after the citizen soldiers were through. However, the French government had borrowed heavily from the Rothschilds for the war effort and the head of the household requested in a letter to the French commanding generals that the troupes please kindly pass Frankfurt by. The French granted the request and the City was spared one more time.

The Mertons were another Jewish family of importance, particularly to Professor Wertheimer. This family made a fortune with a now metal trading business that recently fell victim to fraudulent derivatives trading (die Metallgesellschaft) and raised funds for a Business School around the beginning of the last century. A few years later, state government took over and The Johann Wolfgang Goethe University where Wertheimer would teach grew from this seed.

I am certain that many Frankfurters were saddened by the forced departure of so many good citizens, colleagues, friends and neighbors. The City had been governed by Social Democrates during the Republic of Weimar. Support for the Nazis was not running very deep. Three years after the Wertheimers had left, der Fuehrer paid the City an official visit. A rally was to be held in the largest in-door venue (die Festhalle) on the City's fairgrounds. The multi-purpose sports complex could hold more than 30,000 people. Der Fuehrer arrived by train at the Main Train Station downtown and proceeded in an open convertible along the avenue that led from the station to the hall. It is a short distance. You can walk it in 15 minutes. But it was more impressive for der Fuehrer to ride in a procession. Masses of supporters and spectators lined the street. As usual, the affair was highly choreographed. Heavy security ensured that any opposition did not stand a chance of disrupting the event. Plenty prearranged public jubilation was put on display. On arrival at the hall, der Fuehrer walked up the podium set up high and began to speak. At a certain point, disturbance erupted in the crowd. Hecklers started shouting. Cat calls rang out. Der Fuehrer broke off his speech. The calls rang louder. He folded his script, turned round and left the podium without a word or looking back. He never returned to the City of Frankfurt. The incidence was hushed up. The hall, which is architectonically impressive, survived the war.

After the war, the Jewish community began to return to the City. It would take many years of reconstruction and healing before any Jewish academic would consider living and working there. Yet, ever so slowly times changed. Thirty-six years after the incidence with Hitler's speech, The Rolling Stones gave a series of great concerts in the very same hall. Mick Jagger sang "Sympathy for the Devil" and the Frankfurter audience chimed enthusiastically. Professor Wertheimer might have had a ball, had he been able to witness this.

Professor Wertheimer was born and raised in Prague He began studies at Charles University, but moved on to continue at German universities. He completed his doctorate at Julius Maximilians University in Würzburg. History has it that his most famous idea struck him while he was traveling by train across Germany in 1910. From the rolling train, he watched the sequential blinking of twin red lights at railroad crossings and discovered that when the speed was right, the separate red dots fused into one dot racing back and forth. He deduced that the perceived whole, that is the dot in motion, was more than the sum of the pieces and conceived a series of psycho-physical experiments on the perception of motion to test his fresh hypothesis.

He mused about simple motion pictures like the crude flip book shown in the clip below.



Viewing a single picture frame does not reveal the action. The frames have to be viewed in a particular sequence. The presentation speed needs to be constant and in the appropriate range to project meaningful action.

By the time the train reached Frankfurt, he was supposedly so excited that he abandoned his trip, hastened to the University's Department of Psychology, where he parlayed his ideas into a job. Gestalt Psychology was born.

Although it is unlikely that the events unfolded precisely like that, they make a great story of discovery. Years ago, I had the opportunity to retrace Wertheimer's steps described in E. G. Boring's History of Experimental Psychology.
The path is still there. But the ambiance changed.

Figure 1: My Vaterstadt!
The photographs in Fig. 1 show from top left counterclockwise, a view of the modern City from the opposite bank of the Main River, the interior of the Main Train Station, the composer quarters, and Wertheimer's destination. The Professor would have been astounded to see the skyline of the modern city. Much of what he must have been familiar with perished on a weekend in late 1943. The Rothschilds' old family seat and 19th century mansion went with it. The Professor would have recognized the shed of the train station, though. It is still the same as in his day. However, the trains have changed. He would have been enthralled by the white high-speed ICE trains of today. At 200 miles/h, the red dot he saw would have raced at hyper speed.

Embarking from the Main Train Station's North side, it is an easy walk of about 25 minutes to Wertheimer's destination, half ways following the route der Fuehrer took 30 years later. But before we reach the multi-purpose hall, we veer right into the composer's quarter of Frankfurt's posh Westend. On the third picture, we find ourselves in Schumannstrasse, the street he most likely walked westward toward the University until he reached Kettenhofweg across from the old university campus. At the intersection of Schumannstrasse and Kettenhofweg we find the address where Wertheimer must have knocked on the door. The last picture shows the villa. The building has survived and still houses a part of the Department of Psychology. I saw no plaque of commemoration. But, this must have been the cradle of Gestalt Psychology.

Professor Wertheimer's idea on the train applies far beyond Gestalt Psychology. In organic chemistry, molecules are known to possess the same sum formula, that is they are composed of the same atoms. Yet, they exhibit distinctly different chemical and physical properties depending on the differences in structural formula, that is the arrangement of the atoms. For example, propionaldehyde and acetone are composed of three carbons, six hydrogens and one oxygen atom.

Figure 2: Proprionaldehyde
Figure 2 shows a molecular model of propionaldehyde. The carbons are gray, the hydrogens white, and the oxygen is red. The oxygen is bound to a carbon at the end of the molecule.

Figure 3: Acetone
Figure 3 shows a molecular model of acetone. The oxygen is bound to the carbon in the middle of the molecule. The molecular models were rendered with BallView (Moll and others, 2006).

The difference in arrangement of the pieces, that is the atoms, leads to distinct differences in properties of the whole, that is the molecule. To highlight one difference, propionaldehyde melts at -81° C, whereas acetone melts at -94.9° C. In other words, the qualities of the whole result from the relationships among its pieces.

In analogy, the dynamic reorganization of connections among nerve cells in the brain produces changes in behavior, although the nerve cells remain the same.

Addenda
  • Amos Elon wrote a concise and compelling early history of the Rothschilds in Frankfurt entitled "Founder: A Man and His Time" (03/03/10).
  • Cinematography captures motion. As Max Wertheimer recognized, the temporal sequence of still pictures bestows a new quality on the ensemble, weaving a tapestry of visual language depicting action. No one is better positioned to describe the fundamental impact of movies on our mind's eye, their harnessing of time and their power of witnessing history to unfold than the distinguished film director Martin Scorsese in his National Endowment for the Humanities Jefferson Lecture in the Humanities at the JFK Center of Performing Arts in Washington, DC, with the title "Persistence of Vision: Reading the Language of Cinema" delivered Apr. 1, 2013. Watch the snippet of a British movie describing the discovery of motion pictures at the beginning of Scorsese's presentation. While the clip is concerned with the method of recording motion on film, Wertheimer on his train ride was pre-occupied with our mind's perception of motion. Presentation and perception constitute crucial components of cinematography. Martin Scorsese devotes his lecture to the importance of preserving old films. He emphasizes that motion pictures so powerfully resonate our zeitgeist that they must be preserved as part of our cultural heritage for generations to come (09/02/2013).
References


Tuesday, June 3, 2008

Glioblastoma multiforme: The Octopus in the Brain

Cancer is a life-changing experience. Senator Edward Kennedy has been diagnosed with brain cancer. The ensuing media attention to this horrible disease has touched on a number of fundamental issues. However, the reporting has remained often vague. The vagueness is the inevitable result of the uncertainties involved.

To begin with, uncertainty is an integral part of any cancer. Prognoses of outcome for cancer therapies are probabilistic, diametrically opposed to our craving for definitive answers. We are challenged to beat odds. Yet, we only feel safe, when we know for sure what is going to happen to us. With cancer therapy there can be no assurance of success, only indications from prior experience that the therapy may prolong our lives and hope.

Senator Kennedy's tumor was located in the parietal lobe of the cerebral cortex. This area is large. Nerve cells on its borders process sensory information of mainly one modality. Nerve cells in its interior process multi-modal input, integrating information across multiple senses. The cortical regions that truly fit the idea of the center for a particular function are few. Primary sensory areas may fulfill this requirement best. They receive the most direct input from a particular sense organ and process predominantly information of this sense's modality. For example, a stroke in the primary somatic sensory area at the forward border of the parietal lobe predictably impairs the sense of touch. Therefore, this area may be designated a cortical center for touch. By contrast, injuries in the large swath of parietal cortex stretching backward from the primary somatic sensory area may only lead to subtle loss of sensory function. Attention, speech comprehension and short-term memory may be affected, dependent on the location of the damage. Hence, the uncertainty in the prognosis of the tumor's impact on brain function is rooted in our incomplete understanding of parietal lobe function. More research is needed in this area.

Even less is known about the nature of Senator Kennedy's tumor. Nerve cells and glia represent the most prevalent cell types in brain tissue. Nerve cells multiply at high rate only in the developing brain. In the mature brain, nerve cell proliferation is much reduced and restricted to a small number of regions. In contrast, glia retain the ability to multiply throughout life. The glia in the brain's gray matter essentially consist of astrocytes and microglia.

Astrocytes play vital roles in support of nerve cell function. For example, astrocytes remove the excitatory neurotransmitter glutamate from the space between cells. Neurotransmitters are substances that mediate the transfer of information between nerve cells. Too much glutamate in the extracellular space triggers a program in nerve cells leading to their death (apoptosis). Microglia support the brain's immune response.

After an insult to the brain, astrocytes and microglia increase in number at the site of the injury, owing to cell division and migration. Astrocytes form a glial scar encapsulating the damaged tissue. Microglia are known to incorporate debris of severed nerve cell connections (axons). The glial reaction extends from the site of the injury, following the tracts of severed connections. If the glial reaction progresses normal, the debris is digested and the tissue heals. The glia cease dividing and decrease in number.

At times, however, glia begin to proliferate abnormally without any known reason and the cells do not stop dividing. Aggressive, fast growth of a tumor ensues. Astrocytes develop the most malignant tumors known as glioblastoma multiforme, or GBM for short. Once the tumor reaches a certain size, the blood-brain-barrier is breached. Fluid invades the brain tissue, forming an edema. Nerve cell function is severely impaired, leading to seizures and often hemiparesis. Glia hitherto uninvolved in neoplastic growth react to the injury. The glial reaction possibly recruits abnormal glia and fans out along the disrupted nerve cell connections, infiltrating healthy brain tissue.

At this juncture, the steps to be taken for Senator Kennedy seem straight to the point. The tumor's bulk has been excised. The edema has been addressed. Now, the remaining abnormal astrocytes have to be stopped from dividing. Ionizing radiation will be used to damage the DNA of the cells dividing in the margins of the tumor, arresting the cycle of cell division. Cytostatic chemotherapeutics will be administered to stop astrocytic division in regions outside the focus of radiation. In addition, the growth of blood vessels into cancerous tissue may be slowed with drugs that inhibit angiogenesis (but see addendum, dated Apr. 10, 2009).

I lost my father and two good friends to glioblastoma multiforme and sincerely wish that this regimen will benefit Senator Kennedy in the best possible ways. However, as scientist I know that this vicious disease will only be defeated, once we identify the molecules that signal glial proliferation and devise a method that permits us to specifically inhibit the proliferation of astrocytes.

Addenda

  • Most likely, the molecule signaling glial proliferation is epidermal growth factor (EGF) and the EGF tyrosine kinase receptor needs to be inhibited (8/30/08).
  • Perhaps, the phosphorylated protein is Annexin/Lipocortin 1 (Melzer and others, 1998) (10/02/08).
  • Glioblastoma multiforme is a rapidly growing tumor, showing regional differences from normal brain tissue in its metabolism of sugar as a source of energy. F.M. Santandreu and others (2008) provide a comprehensive description of such metabolic aspects in Cellular Physiology and Biochemistry 22:757-768. Since the tumor cells can store little sugar, the resource has to be delivered constantly with the bloodstream. The fast tumor growth induces growth of blood vessels. Therefore, anti-angiogenic drugs that inhibit vessel growth may help to shrink the tumor (02/18/09).
  • Hai Yan and others (2009) report somatic mutations of the mitochondrial enzyme isocitric acid dehydrogenase crucial for sugar metabolism in 70% of astrocytomas and oligodendrogliomas as well as glioblastomas that developed from these tumors (New England Journal of Medicine 360:765-773). The mutations are discussed as potential predispositions for tumorigenesis (02/19/09).
  • Microglia reactive to nerve cell injury are shown in my post dated Oct. 17, 2008 (03/04/09).
  • To date, there is no compelling evidence that the use of contemporary cell phones causes glioblastoma multiforme. See my post dated Aug. 21, 2008 (03/05/09).
  • You may be interested in reckoning with the odds in my post dated Mar. 5, 2009 (03/06/09).
  • Erika Check Hayden summarizes the latest insights into the effectiveness and pitfalls of angiogenesis inhibitors in this weeks issue of the journal Nature, vol. 458: 686-687 (04/10/09).
  • Using RNA interference (RNAi), Australian scientists developed a method with which the expression of tyrosine kinase receptors can be blocked, making tumor cells more vulnerable to chemotherapeutics and diminishing the tumor cells' ability of developing resistance against the drugs (MacDiarmid and others, 2009). Michael Perry reported on this progress in his post with the title "Scientists kill cancer cells with 'trojan horse'" published online on Reuters yesterday (06/30/09).
  • Senator Kennedy passed away yesterday (08/26/09).
  • Last Tuesday, Sep. 7, 2009, National Public Radio's Talk of the Nation aired an interview by Neil Conan with the British neurosurgeon Henry Marsh on his charity work in the Ukraine and general aspects of his profession. National Public Television's POV showed a movie on his work that evening. The movie, "The English Surgeon", will available on DVD Nov. 3. Particularly towards the interview's end, Dr. Marsh highlights in striking clarity the importance of finding an experienced neurosurgeon for the successful removal of a glioblastoma (09/10/09).
  • A recent clinical study by Sampson and others (2010) reported promising results in the treatment of glioblastoma multiforme (GBM), using vaccines that target epidermal growth factor receptor variant III, or EGFRvIII for short. The receptor is extraordinarily prevalent on the surface of the most-aggressively growing GBM cells, owing to a genetic mutation. Thirty-five patients with GBM were enrolled in the phase II clinical trial; all underwent surgery, radiation therapy and chemotherapy with temozolomide. In addition, 18 were inoculated with vaccines.  Adding vaccines almost doubled median survival time from 15 to 26 months, extending the progression-free period from 6.3 months to 14.2 months. The vaccination eliminated all cancer cells carrying EGFRvIII, except in one patient. Half of the patients showed an immune response. Six developed antibodies specific for the receptor and three showed a T-cell response, supporting the contention that the increased survival may be associated with the immune response. Nine of eleven patients, whose recurring tumors were examined, tested negative for EGFRvIII, indicating that the cells with this mutation had been persistently eradicated. Taken together, the findings suggest that vaccines may prove a promising new avenue of treatment, though not a cure, for glioblastoma muliforme. Celldex Therapeutics and Pfizer developed the currently tested vaccine known as rindopepimut or CDX-110 and PF-04948568, respectively (10/05/10).
  • Listen to this interview with Gordon Murray by Robert Siegel broadcast on National Public Radio's All Things Considered today and find words of strength and encouragement from a man with GBM who is making the best of his situation (12/17/10).
  • Siddhartha Mukherjee, a hematologist/oncologist at Columbia University, wrote an informative book entitled "The Emperor of All Maladies: A Biography of Cancer" on recent advances in cancer medicine. The author was awarded a Pulitzer Prize for his exploration earlier this month. Note that he specializes in blood cell cancer and the particular experience influences his assessment of the role of stem cells in tumorigenesis and metastasis. Terry Gross interviewed him Nov. 11, 2010, on National Public Radio's Fresh Air in her show with the title "An Oncologist Writes 'A Biography Of Cancer'" (04/22/11).
  • Color-coded image of a transaxial FDG PET scan from a GBM patient with a recurrent tumor in the left cortical hemisphere.  High local cerebral metabolic rates for glucose starkly delineate the tumor (low rate - blue; high rate- white; courtesy L. Sokoloff). 
    The functional image above was acquired from a patient with a glioblastoma multiforme in the left cerebral hemisphere. The initial primary tumor and had been surgically removed. The removal was incomplete. When symptoms suggested a recurrence of the tumor, the surgery had altered the anatomy of the cortical hemisphere to such extent that an evaluation of structural brain scans was impossible. However, a new tumor could be localized with positron emission tomography and the [18F]fluorodeoxyglucose (FDG) method (Di Chiro and others, 1982). This method allows us to image and measure the local glucose consumption of brain tissue. The rate of glucose utilization was highly increased in the core of the new tumor. Under normal physiological conditions, brain cells metabolize glucose to produce adenosine-triphosphate (ATP) in an oxygen-consuming metabolic pathway called aerobic glycolysis. ATP represents a ubiquitous high-energy molecule that cells need to maintain vital functions. Because glia possess only a small capacity of storing glucose and oxygen cannot be stored at all in the brain, the blood supply must continuously deliver both to the brain tissue. An increase in demand stimulates angiogenesis, that is blood vessel growth. However, in fast growing tumors angiogenesis cannot keep pace with demand. Moreover, the activity of certain types of key enzymes for glucose metabolism, known as mitochondria-associated hexokinases I and II, can be increased as much as 200-fold in tumor cells, leading to extremely high rates of aerobic glycolysis (Warburg effect) which compound the local oxygen shortage. Moreover, using tumor genome sequencing Yan and others (2009) identified a mutation that changes arginine 132 in the product of gene IDH1 isocitrate dehydrogenase. Isocitrate dehydrogenase is a key enzyme in the Krebs cycle providing substrates for aerobic glycolysis. This change in amino acid modifies the function of the enzyme such that the enzyme's substrate isocitric acid is turned into a novel product which cannot be used in the Krebs cycle, hampering the efficiency of aerobic glycolysis. More than 70 percent of 445 tested central nervous system tumors were astrocytomas, oligodendrogliomas and glioblastomas that had developed from lower-grade tumors. These rapidly-growing, malignant cancers possessed the mutation. As a consequence, glucose may be metabolized in the malignant tumor's core without the use of oxygen, though this anaerobic glycolysis is much less efficient in generating ATP than aerobic glycolysis. The observations may be taken to suggest the possibility of starving neoplastic astrocytes to death with a diet extremely low in carbohydrates. Alas, cells in other tissues of our body, e.g. muscles, routinely use vast amounts of glucose in anaerobic glycolysis to meet rapidly increasing energy demands while oxygen is in short supply. A no-carb diet is not going to be selective for the tumor and may rather weaken the body's overall resilience. By contrast, avoiding high-fructose corn syrup and sucrose used to sweeten countless foods and beverages may be beneficial, because the fructose in these sugars may stimulate insulin-like growth factors that promote neoplastic growth (see Gary Taubes' article with the title "Is Sugar Toxic?" published online in The New York Times on Apr. 13, 2011) (01/13/2012).
  • Dang and others (2009) report that when IDH1 mutations turn arginine 132 into histidine, the gene's changed product isocitric acid dehydrogenase may catalyze the formation of R(-)-2-hydroxyglutarate known to be conducive to tumor growth (02/06/2012).
  • The leader of the four-decade effort to develop the deoxyglucose method for the use in tumor imaging (see image above) Dr. Louis Sokoloff presented a historical lecture for the public with the title "Development of the [18F]Fluorodeoxyglucose Method: A Serendipitous Journey From Bench to Bedside" on the endeavor at Brookhaven National Laboratory Oct. 19, 2012, to celebrate the designation of its Chemistry Department by the American Chemical Society as a historical site for its role in this accomplishment (10/29/2012).
  • Personal accounts of GBM patients describing their experience with treatment are rare. Two days ago (Sep. 23, 2013), the Washington Post published Fritz Anderson's post with the title "Surgery, radiation and chemo didn’t stop the tumor, but an experimental treatment did" published online. Dr. Anderson, a retired cardiologist, writes about his situation eloquently with great sensitivity and encouragement. After surgery, radiation therapy and chemotherapy his tumor regrew and he decided to participate in an experimental phase I trial of a therapeutic that consists of an altered polio virus (PVS-RIPO) that glioblastoma cells preferentially bind, infecting and destroying the cells. The trial is led by Prof. Matthias Gromeier at Duke University's Preston Robert Tisch Brain Tumor Center. The procedure is invasive, requiring a craniotomy, because the drug must be administered directly to the tumor tissue in one six-hour session. The therapy shrunk the tumor decisively, and Dr. Anderson continues to enjoy life. Four of five treated patients were blessed with success to date (Sep. 25, 2013).
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