Tuesday, July 31, 2012

The Apparent Conflict between Money and Happiness

One of the most elusive, yet highly coveted elements of existence is happiness. The real mystery is not what attributes and traits are necessary to attain happiness, but instead how to acquire those elements. There appear to be four critical psychological elements for a happy existence: autonomy, competence/achievement, connection and self-esteem. The role of all of these elements in facilitating happiness is understandable. First, autonomy underlies one of the greatest gifts and advantages of human existence, conscious freedom, the ability of an individual to make his/her own choices. It is difficult to believe that a person could be genuinely happy if they are unable to make decisions for themselves. The importance of achievement is self-explanatory as even if one has the freedom to make decisions, if nothing meaningful is accomplished from that freedom there is little reason to have it. Such a conclusion is akin to the Samuel Clemens quote of, “The man who does not read good books has no advantage over the man who cannot read them.” In addition it does not take a psychologist to conclude that when an individual succeeds in his/her endeavors it will create a greater sense of pride and esteem versus those times when an individual fails.

Connection is also rather self-explanatory as humans are very social creatures that tend to shun the darkness and isolation, so finding closeness to other human beings is important on two levels. First, this ‘need’ to be social is derived from an evolutionary origin for the world was once a much more savage and dangerous place for man, thus union of manpower and skills dramatically increased the probability of survival. Clearly if survival is enhanced by these teams of individuals, it would be wise to establish these groups even if there was no original underlying genetic predisposition motivating their formation. While the world may not be as dangerous as it was in the past, formation of groups still generates benefits through breadth of skill acquisition and deployment.

Second, human beings frequently need to associate commonality between those they interact with to motivate and feel comfortable with the interaction. These commonalities may diminish some of the uniqueness and diversity of these associated individuals, but also increases the probability of a positive interaction and reassurance that one is not alone or outcast. Finally typically the more confidence an individual has the happier they will be in life. With the characterization of these key elements the next step is to cultivate methodologies and strategies to isolate and enhance these elements.

When reviewing the four critical elements one methodology that immediately jumps to mind to achieve these elements is to become wealthy. Clearly the more money one has the greater the level of autonomy because the number of available opportunities one can choose from increases with the amount of money one has available. Society has determined in a mass-scale approval that the accumulation of wealth is a significant accomplishment that should be aspired to, thus the acquisition of wealth can be viewed as a significant accomplishment potentially validating one’s existence. In addition money should also improve the aspect of connection for the greater number of opportunities an individual can partake in, the greater the level of interaction one can have with different individuals creating more and deeper relationships with other people. Finally self-esteem should be considerably larger in people with significant wealth than those without significant wealth both as a measure of accomplishment, as mentioned above, and as a measure of self-importance as unfortunately in our society the more money an individual has the more importance they are given.

Remarkably, numerous studies reveal that this logical conclusion with regards to the relationship between happiness and money is not correct, at least to a certain extent. Most studies that attempt to correlate wealth and happiness reveal that once a certain ceiling threshold is attained, usually an annual amount of 40,000 - 50,000 dollars, there is little increase in happiness as wealth continues to rise. 1-5 So where is the breakdown between the theory that predicts a corresponding increase in happiness with relation to an increase in wealth and the polling studies that indicate happiness leveling off after a certain point regardless of the amount of wealth acquired?

Four reasonable theories jump to mind to explain this apparent contradiction. First, as individuals gain money they are unwilling or unable to utilize the money to enhance the defined elements that increase their overall happiness. This failure could occur because they do not necessarily know about the elements that drive happiness or they do not know how to correlate those elements to their greater amount of wealth. Therefore, they become the individual that elects not to read good books despite having the ability to read at a college level.

Second, there is an increase in negative behavior and events associated with greater wealth that acts as a counterbalance to the happiness enhancement effects. The increase in negative events is not something to be immediately dismissed because one could attest to an increase in stress with an increase in funds due to a greater sense of responsibility to properly distribute the resources among family members and acquaintances who may request funds. Such a situation can be stressful, but the money belongs to the individual and the final say for the distribution of such funds is that person’s alone and as long as a logical and rational reason exists to support whatever decision made there is no reason to stress over the outcome or how relatives will respond to the decision. An addendum to this negative interaction would be high profile wealth would become a larger target of crime increasing stress through the need for higher levels of security and/or bodyguards.

Third, the polling information could simply be misrepresented in that individuals of a lower wealth standing are mischaracterizing or lying about their total levels of happiness and in reality are more unhappy than what they indicate in this polling information. If this were the case then there would be a larger proportional increase in happiness corresponding to an increase in wealth, thus creating a stronger connection in wealth increasing happiness.

Fourth, while wealth may open the doors of opportunity, the relative system of evaluation primarily used by humans to make judgments on their environment acts as a negative catalyst with regards to money and happiness. The unfortunately reality is that humans judge themselves not on the bases of what they have accomplished, but on what they have accomplished relative to other humans. Such an evaluation system fuels the ego and inherently creates division among humans of unequal standing. Therefore, as one gains wealth one moves further away from the number of meaningful interactions that can be had with other individuals. It is difficult to enjoy an opportunity involving people when one believes he/herself to be superior to others participating in it, thus the human interaction elements of the opportunity flips from positive to negative. Individuals also seem to not savor a reward when given the knowledge that another has also received a similar award.6-9

This monetary ‘betterment’ mindset has been demonstrated both on small empirical scale, with individuals becoming less compassionate after handling money,10 and large empirical scale as the more wealth an individual has the less charitable that individual will be.11 Also the wealth of opportunities available to wealthy individuals may reduce the overall meaning in a given experience, a malaise mindset of ‘that’s all’ could take over. Basically the more extravagant opportunities that become available to wealthy individuals reduces the meaning of the less extravagant opportunities. Unfortunately for wealthy individuals their lives are far more populated by non-extravagant opportunities than extravagant ones. Sadly the wealthy may attempt to change these ratios by gorging themselves on extravagant opportunities, actions that not only cheapen the novelty of the opportunity, but also further push them away from a majority of other individual interactions leaving these wealthy individuals only the opportunity to interaction with very like-minded individuals.

A side question regarding these surveys and studies is the issue of missing linkers in occupational responsibility. Some believe that these happiness studies do not take into consideration the trade-offs involved for jobs with high salaries such as working hours, time spent away from family and loved ones, time spent commuting to and from work, etc. These additional responsibilities increase stress and decrease happiness which may counter-act increases in happiness that stem from the higher salary.

This explanation may have been valid in the past before the era of computers and Internet, but with the way income is distributed in present day it is difficult to view these ‘responsibilities’ as a significant negative component to happiness versus those with lower paying jobs. Modern day specialization has increased efficiency increasing production of the modern higher-salary worker. Unfortunately for most of them that additional efficiency has not been proportionally rewarded through an increase in salary due to the corporate structure.

The simple fact is ask who has more stress in their job individual A who works 2 jobs spanning a 16-hour day just to be able to eat or individual B who works on Wall Street and the answer is rather obvious. One could make the argument that the only jobs that still fit the above description regarding high work with high salary are general practitioners in the medical field and ER doctors because of the large number of patients that need to been seen with a wide variety of diagnostic demands. Incidentally it is not surprising then that there are shortages in these two particular professions.

Other studies seem to support the notion of happiness to human interaction in that when individuals are given the opportunity to redistribute a monetary prize to another person those that do report a higher rate of happiness.12 However, if such an outcome were to suggest correlation between giving money to others and happiness three possible conclusions can be drawn. First, giving away the prize money does indeed accomplish a psychological shift bringing the awarder and the awardee closer together increasing social closeness/connection resulting in greater happiness. Second, there is no real change in social closeness, but instead losing the money reduces the ability of the awarder to partake in some of the more socially isolating opportunities that wealthy individuals have available to them, thus avoiding the lose of sensitivity to the joy elements of less monetary dependent activities. Third, awarding the prize bolsters the ego of the awarder with the mindset of viewing him/herself as being better than the awardee (because he had the ability to give up the money), thus increasing self-worth and happiness.

Sadly based on above discussion the reality of option three being the primary explanation for this increased happiness associated with giving money more than likely increases proportionally to income. This rationality may be part of the reason that wealthy individuals donate so little relative income to charity in that charitable giving is only seen through the scope of ego and most wealthy individuals already view themselves as better than less wealthy individuals, thus there is no reason to ‘confirm’ that belief by giving money to charity.

Overall when looking at the situation objectively the theory that greater wealth begets greater happiness is actually quite sound. Therefore, if people are not happier when acquiring greater wealth they are consciously sabotaging themselves by either generating artificial stresses or not properly utilizing their money to expand and enhance the key attributes of happiness. So apparently the real key to happiness is to be a saboteur instead embracing specific characteristics of uniqueness, strength and conscious freedom in order to capture these happiness elements.


1. Diener, E, and Biswas-Diener, R. “Will money increase subjective well-being?” Social Indicators Research. 2002. 57(2): 119-169.

2. Layard, R, Mayraz, G, and Nickell, S. “The marginal utility of income.” Journal of Public
Economics. 2008. 92(8): 1846-1857.

3. Campbell, A, Converse, P. and Rodgers, W. The Quality of American Life:Perceptions, Evaluations, and Satisfactions. 1976. New York: Russell Sage Foundation.

4. Diener, E, et Al. “Subjective well-being: three decades of progress.” Psychological Bulletin. 1999. 125: 276-302.

5. Headey, B, and Wearing, A. Understanding Happiness: A Theory of Subjective Well-Being. 1992. Melbourne: Longman Cheshire.

6. McBride, M. “Relative-income effects on subjective well-being in the cross-section.” Journal of Economic Behavior and Organization. 2001. 45: 251-278.

7. Stutzer, A. “The role of income aspirations in individual happiness.” Journal of Economic Behavior and Organization. 2004. 54(1): 89-109.

8. Ferrer-i-Carbonell, A. “Income and well-being: an empirical analysis of the comparison income effect.” Journal of Public Economics. 2005. 89: 997-1019.

9. Knight, J, Song, L, and Gunatilaka, R. “Subjective Well-being and its Determinants in Rural China.” China Economic Review. 2009. 20(4): 635-649.

10. Quoidbach, J. “Money Giveth, Money Taketh Away: The Dual Effect of Wealth on Happiness.” Psychological Science. 2010. doi: 10.1177/0956797610371963 .

11. Vohs, K, et Al. “The Psychological Consequences of Money.” Science. 2006. 314: 1154-1156.

12. Dunn, E, et Al. “Spending Money on Others Promotes Happiness.” Science. 2008. 319: 1687.

Thursday, July 12, 2012

Sleep Drugs and Cancer

Sleep drugs (commonly referred to as hypnotic drugs in the pharmaceutical industry) are widely prescribed with an estimated 6-12% of U.S. adults using some form of sleep drug in 2010 and even higher estimates of use in Europe.1,2 Unfortunately one reason the overall level of consumption, both in unique use and repeat use of sleep drugs, is so high is because they do not cure insomnia instead simply reduce its effects. Basically they treat the symptoms of a chronic condition instead of treating the underlying cause. Despite not addressing the cause directly, reducing the influence of insomnia at any level is an important issue because chronic insomnia is thought to significantly increase the probability of developing psychiatric ailments and also reduces wakeful efficiency, productivity and health.2-5

Sleep drugs are commonly divided into pharmacological agents and non-pharmacological agents. While non-pharmacological agents, which range from stimulus control strategies to sleep pattern development with relaxation therapy, are viewed as an initial treatment, most research focuses on pharmacological agents, which are further sub-divided into two categories: benzodiazepines and non-benzodiazepines. The most common sleep drugs are zolpidem, temazepam, eszopiclone and zaleplon with zolpidem as the most prescribed sleep drug between 2002 and 2006 with temazepam in second place.1

Unfortunately meta-analysis has revealed some disturbing information regarding the consumption of sleep inducing drugs and overall mortality. When compared against placebo a number of trials involving commonly used sleep drugs demonstrate a significantly higher rate of cancer including pancreatic, non-melanoma skin, lymphoma, lung, colon or prostate cancer.1,6 The rate of death for those who consume these drugs increases more than three times over those who do not consume these drugs even at the smallest dosage (1-18 pills per year).1 Not surprisingly the probability of death increases as individuals increase the dosage. Also there was no significant difference between the different drugs in relation to how they increase the probability of death,1 thus it appears that these drugs operate over the same or at least a similar mechanism.

One of the more concerning issues with this increased rate of death is that the time variance is scatted; there are probability increases in both short-term and long-term rates of death. The reasoning behind the short-term death increases is currently unknown (peptic ulcers and esophageal damage due to regurgitation are leading theories), but most believe that long-term deaths increases are due to increased rates of cancer.1 In fact in one study the top third of sleep drug consumers (> 132 pills per year) had a 35% greater chance of developing cancer versus non-consumers.1 Another study monitoring 13,177 individuals taking zopiclone determined that 42% of the total deaths were due to cancer.7

The rationality behind the increased probability of cancer development has largely revolved around increasing infections and/or inflammation. The prevailing theory is that sleep drugs somehow suppress immune function.1,6 This suppression of immune function leads to reduced abnormal cell and pathogen destruction resulting in greater rates of cancer and other infections. However, this explanation may not be the only one that accurately describes the increased rates of cancer in individuals that consume sleep drugs.

Most sleep drugs are either benzodiazepines or operate with a similar mechanism of influence on GABAA receptors. Benzodiazepines are agnoists for most GABAA receptors, which increase frequency and duration of their activation. The mechanism of action increases the firing of GABAergic neurons,which reduces the firing rate of excitory neurons increasing the probability of initating sleep and its duration. Application of benzodiazepines result in sedative, anxiolytic, anti-convulsant and hypnotic characterization in the user. There are three types of benzodiazepines largely defined through their residance times: short, intermediate or long.8 Short and intermediate mechanisms are used in controlling insomnia and long mechanisms are used to control anxiety. However, because these sleep compounds are only GABA agnoists their effectiveness is still contingent on the total concentrations of GABA.

Gamma-amino butyric acid (GABA) plays three critical roles in the brain as a signaling molecule, neurotransmitter and metabolite. During development GABA guides neurite outgrowth and directionality.9 Once development of the Central Nervous System (CNS) is complete GABA then alters its function becoming the chief inhibitory neurotransmitter for both the CNS and Peripheral Nervous System (PNS). As the chief inhibitory neurotransmitter GABA plays a role in various neurodegenerative diseases most notably Temporal Lobe Epilepsy (TLE), Parkinson’s Disease (PD) and Huntington’s Disease (HD) stemming from a breakdown in critical components that govern GABA regulation.10-13 However, there is also evidence that GABA plays an important role in the development and progression of certain types of cancer.

GABA has three corresponding biological receptors, which are classified as GABAA, GABAB and GABAC (a.k.a. GABAA-rho). The ion largely associated with GABA receptors is chloride (Cl-), which drives the inhibitory action of GABA. GABAA exists in two activator based constructs, nicotinic and muscimol, and are oligomeric comprised of five different subunits from a pool of seven possible (alpha1-6, beta1-3, gamma1- 3, sigma, epsilon, pi and theta).14-16 GABAA receptors are ionotropic meaning that when an appropriate molecular agent binds the receptor forms a channel/pore in the membrane that allows an appropriate ion to pass through the membrane (direction of passage is largely governed by concentration and charge gradients).17

During development GABAA receptors are more commonly excitatory over inhibitory due to the absence of a chloride pump on the membrane that transfers chloride ions from inside the membrane to the extracellular space. Without this pump there is an excess amount of chloride ions in the cell, thus when the GABAA receptor activates chloride ions escape the neuron along the concentration gradient increasing membrane potential increasing probability of depolarization. Upon the incorporation of the chloride pump the chloride concentration gradient reverses so upon GABAA activation chloride ions flow from the extracellular space into the neuron increasing the probability of hyperpolarization. GABAB receptors are metabotropic activating a G-protein pathway. A majority of GABAB receptors are located on pre-synaptic cells and act as feedback mechanisms.

The third class of GABA receptors, GABAC, is somewhat controversial in whether or not it is uniquely different enough from GABAA to be considered a separate class.18 GABAC receptors are typically insensitive to GABAA receptor allosteric modulators like benzodiazepine and barbiturates because they are exclusively composed of a unique subunit (rho.18,19 This composition does not significantly change the functionality of GABAC receptors compared to GABAA receptors with respect to their interaction with GABA.

Each subunit in a GABAA receptor possesses four hydrophobic membrane-spanning domains.17 Studies have shown that functional GABAA receptors contain at least one alpha and one beta with one gammasubunit typically also involved; sigma, epsilon, pi and thetasubunits are thought to be assembled into GABAA receptors in place of subunits or complementary pairings.20 Overall it is rare to have a GABAA receptor comprised of subunits that lack an alpha or a beta and such a conformation will not be functional.

The importance of receptor composition is largely demonstrated in how individuals subunits are able to confer different sensitivities to GABA and its associated agonists and antagonists.21,22 For example pi subunits appear to highly sensitive to excitation by loreclezole (where non-pi subunit receptors are either unaffected or inhibited), inhibited by lanthanum and unaffected by benzodiazepine diazepam.19,23 Specificially the pi subunit has drawn interest with respects to the role of GABA in the development of cancer.24

Using cDNA libraries the pi subunit was isolated to multiple reproductive tissue (uterus, ovaries, etc.), digestive tissue (gall bladder, small intestine) and specific regions of the brain namely the hippocampus and temporal cortex; two of the major expression cell types in the brain are teratocarcinoma NT2 neuronal precursor and terminally differnetiated NT2-N cells.25,26 However, while NT2 neuronal cells express pi subunit mRNA there is some question to whether those pi subunits are actually incorported into NT2 neuronal GABA receptors.19 Unfortunately despite the apparent importance of the pi subunit, both the developmental expression of the epsilon and pi subunits have yet to be isolated, but both have been cloned.27 From cloning analysis the pi subunit has a 37% relation to the beta subunit, a 35% relation to the sigma subunit and a 33% relation to the rho subunit with very little relation on any of the other subunits.11 Most specifically the pi subunit appears to have similarities to alpha-5, beta-3 and gamma-3.19,27

This similarity of the pi subunits to these other subunits is not surprising in that the pi subunits are commonly incorporated into receptors with alpha-5beta-3 or alpha-5beta-3gamma-3 configurations.19 With respect to insomnia the amplification of benzodiazepine sensitivity is governed by the type of gamma subunit which determines extent of benzodiazepine influence with the requirement of a gamma subunit for a GABA receptor to have signiifcant affinity for benzodiazepines.16,19 Most GABA receptors in the brain have gamma-2 subunits, which demonstrate the highest gamma subunit sensivity to benzodiazepines.16 Receptors with pi subunits are thought to interfere with the ability of the gamma subunit to form the benzodiazepine binding site by either replacing the gamma subunit or blocking the interaction between the gamma subunit and alpha subunit.19,25,28 Receptor interaction with zinc is also influenced by the gamma subunit, but incorporation of the pi subunit into different receptors does not appear to interfear with zinc interaction.19

Receptors that incorporate the pi subunit have demonstrated higher GABA EC50 values, less outward rectification and larger single-channel conductance.19 There is also reason to believe that pi subunits flip activity from hyperpolarization to depolarization in cancer cells.19,24 Therefore, these changes imply longer duration firing over receptors without pi subunits. If this information is accurate then a depolarizing GABAA pi subunit receptor has an advantage over normal hyperpolarizing GABAA receptors demanding greater activity from non-pi subunit GABAA receptors for hyperpolarization and cancer limitation. The extent of pi subunit pentration in cancer cells versus non-pi subunit may also explain the somewhat contradicting results with whether or not GABA aids or hinders cancer development.

The differing action between pi subunit and non-pi subunit containing GABA receptors could offer one reason for why taking benzodiazepine based sleep aids increase cancer rates. Increasing benzodiazepine concentrations act on GABAA receptors, which lead to increased GABAA receptor expression. Increased expression rates would increase the number of mutations simply through volume changes alone (subunit mutation rates may not change, but because more subunits would be created there would be more subunit mutations). Among these subunit mutations could be gamma subunits mutating into pisubunits or pi subunits being incorporated over gamma subunits. Increasing the number of pi subunits would increase the number of GABAA receptors that depolarize instead of hyperpolarize, which would aid cancer development instead of hinder it.

Outside very specific subunit interactions like those involving the pi subunit, the relationship between cancer and GABA appears complex for GABA may influence different cancers in different ways. However, there does appear to be a general pattern of operation between GABA, cancer and the two major GABA receptors. To best understand this relationship temporal issues must be acknowledged between immature/developing cancer and mature cancer. Note that developing cancer refers to cells that have become cancerous and are starting to grow, not cells that are going through the initial mutation stages to become cancerous.

Typically the expression of GABA and its corresponding synthesizing enzyme GAD (both isoforms 65 and 67) significantly increase in concentration in the presence of neoplastic cells ((colorectal carcinoma, breast cancer, prostate cancer, glioma, pancreatic and gastric cancer).29-37 However, what does that increase mean relative to cancer growth? Based on existing evidence it appears that a reduction in GABAA receptor functionality leads to accelerated cancer growth.29,38 Such a result implies that GABA activity when binding to GABAA results in reduced cancer growth, which has been supported through reductions in membrane potentials of cancerous cells.39,40 If GABAA binding is detrimental to cancer growth then why do GABA and GAD concentrations increase in the presence of cancer versus non-cancerous cells? One explanation is that this increased expression may be a general ‘safety’ feedback mechanism designed to curtail excess (i.e. cancer) growth, especially if GABAA receptor expression decreases.38

GABAB interaction appears to play a similar role to GABAA with regards to reducing cancer growth. Activation of GABAB in a cancer cell does not kill the cancer cell, but instead arrests its growth between stages G0 and G1.41 In addition GABAB activation also reduces intra-cellular cAMP concentrations through the inhibition of adenylyl cyclase due to the activation of G-protein alpha-2.42,43 cAMP is important in cellular growth (both normal and cancerous) because it activates phosphokinase A (PKA) which among other things (i.e. ERK1/2 cascade) activates phospholamban.44 Phospholamban activation increases the rate of calcium release from the endoplasmic reticulum (ER). While some of this excess calcium is sequestered by the existing cAMP, in typical situations the calcium release from the ER exceeds the rate of sequestration by cAMP resulting in an increased level of cytosolic calcium.44 This increased cytosolic calcium concentration activates calcium dependent secondary messenger systems increasing the rate of cellular growth. Thus, the ability of GABAB activation to reduce cAMP concentrations reduces the rate of cancer growth through this particular mechanism.

While GABA does appear to influence cancer growth in a negative way regardless of which receptor it binds to it could play an even more important role in cancer migration/metastasis, albeit a slightly confusing one. The confusion in the issue of metastasis appears to come from somewhat conflicting evidence, but the confliction is not insurmountable. First, increased expression of GABA67 is seen in patients with higher Gleason scores30 (note Gleason scores are derived from examination of histological samples in an effort to track cancer progression). Initially such a result could be explained, as mentioned earlier, as a feedback mechanism from the body in effort to control cancer growth and as cancer growth increases (leading to a higher Gleason score) the body compensates further. However, what if there is another explanation, what if GABA actually assists in metastasis? This amplification of cancer metastasis seems to be in play at least for some forms of prostate and lymph node cancers where increasing GABA concentration resulted in an increase in matrix metalloproteinase (MMP) expression due to GABAB activation.30

Metastasis is a complex series of interactions leading from tumor development to detachment from its principle location and movement to a different more distant location in the body. The major events involve detachment of from the primary tumor, invasion of the stromal tissue, entrance to the bloodstream, extravasate, invasion of the new target organ and finally the formation of the metastatic colony.17,30 One of the key steps in this process is the proteolytic degradation of the extracellular matrix and in this step MMPs are critical agents.

Initially MMPs were thought to be degenerative proteases that were limited to cleaving matrix components, but that role has expanded to include the release of growth factors and other bioactive peptides localized at cleaved extracellular matrices.45-47 Most MMP action involves MMP-3 cleaving decorin which releases transforming growth factor-b leading to greater levels of angiogenesis in addition to cleaving TGF-alpha activating MAPK inducing cellular proliferation.48,49 MMPs also cleave matrix receptors that may inhibit metastasis inhibitors like E-cadherin and activate a semi-self-regulating pathway with MMP-3 activating MMP-7 and 9.50

However, there appears to be a problem with concluding that GABA increases metastasis probability through GABAB activation in that another study has demonstrated that GABA decreases metastasis probability through GABAB activation.44 In a study using SW480 colon carcinoma cells cellular locomotion (basically metastasis probability) was reduced due to reduction in cAMP concentration. One possible reason for this difference is the differing cell types, but another line of thought produces another possible solution.

First, the SW480 colon study focused on metastasis induced through norepinephrine, not MMPs. In norepinephrine induced metastasis norepinephrine activates beta-arrestin through the beta-2 adrenoceptor which activates Protein Tyrosine Kinase (PTK) which activates the key agent, protein kinase C gamma (PKC).44 Activation of PKC-gamma results in the dual activation of both inositol-1,4,5-trisphosphate and diacylglycerol.44,51 Inositol-1,4,5-triphosphate opens intracellular calcium channels increasing cAMP activation and diacylglycerol activates PKC-alpha, which has been shown to increase metastasis in cancer cells.52,53

Basically norepinephrine increases cancer proliferation by activating inositol-1,4,5-triphosphate and increases cancer metastasis probability through activating diacylglycerol. This dual activation is important because cAMP cannot activate diacylglycerol on its own, yet it does appear to augment diacylglycerol activity in that if cAMP concentration is reduced diacylglycerol does not aid metastasis. Thus GABAB is able to prevent this form of metastasis by reducing cAMP concentration through secondary messenger inhibition of adenylyl cyclase.

However, while GABAB prevents metastasis through PKC-gamma, why doesn’t the ability to increase MMP expression compensate for the PKC-gamma blocking resulting in greater metastasis versus controls? One explanation may be temporal in nature in that the colon cells were not in a high enough state of maturity to express and/or interact with the MMP that should have been generated from the GABAB activation. If this theory is accurate then GABAB may be a beneficial therapeutic agent in the early stages of cancer, but as cancer progresses its usefulness flips and it becomes more detrimental than beneficial.

Unfortunately the role of GABAA in metastasis may not be as simple. While a number of studies suggest that GABAA binding plays no role in metastasis30,41,44 other studies suggest that GABAA binding increases metastasis probability54 or decrease metastasis.55 Despite this contradiction based on currently understood GABAA behaviors and mechanisms it is hard to believe that GABAA positively influences metastasis if configured properly because of its hyperpolarizing nature. The difference between ‘neutrality’ and reducing metastasis for GABAA may also be temporal, similar to GABAB.

Early in cancer development GABAA has little influence, but has MMP concentrations increase, GABAA works to reduce those concentrations despite GABAB augmenting them.55 Another reason for this disparity may be that in some studies the tumors did not mature to the point where metastasis was at a reasonable probability of occurrence because GABAA activity arrested tumor growth, thus GABAA influenced growth, but not metastasis. Overall it appears that the theory to describe GABA receptor behavior with respect to cancer is that GABAA negatively affects cancer growth and has little influence on cancer metastasis whereas GABAB negative affects cancer growth and has a negative influence on early cancer metastasis and a positive influence on late cancer metastasis.

If the above characterization of GABA receptors with respect to cancer is taken as accurate, then it appears that ability of sleep drugs to increase cancer rates largely relies on receptor subunit configuration. Other than pi subunits47 there is reason to suspect that incorporation of theta or rho subunits also increases cancer proliferation probabilities.56,57 These receptor confirmations may be self-augmenting in that if cancer develops due to their depolarizing characteristics over hyperpolarizing the cancer mutates to produce more receptors with similar configurations explaining why rarer pi and theta subunit configurations, with even rho at times, are so prevalent in cancers.24,27,56,57

Another possibility may be that augmenting GABAA activation through agonists like benzodiazepine may cause greater GABAB activity as a result of feedback. While GABAB activation would be viewed as more cancer-preventative than cancer-aiding, recall that as cancer develops the benefit/detriment ratio for GABAB with respect to cancer prevention decreases. Thus one question to ask is if cancer rates increase with sleep drug administration or does cancer metastasis also increase relative to the increase in cancer rates?

Overall one of the chief concerns is that while rates of death are slightly lower with non-benzodiazepine sleep drugs there is little firm scientific evidence that these non-benzodiazepine treatments result in higher rates of increased sleep time or reduction in wake probability after sleep onset compared against placebo.1,58 Benzodiazepine treatments do decrease sleep latency and increase sleep duration8,58 (although there are some questions regarding the statistical significance of the latter effect despite concerns of overestimation of sleep latency and underestimation of total sleep time),58 thus taking non-benzodiazepine treatments which have less cancer promoting tendencies may not be a suitable alternative to addressing a lack of sleep. While GABA seems to prevent cancer more than aid in its development stimulation of the GABA system through artificial means could also increases the rate of mutation in the subunits which comprise GABA receptors and these mutations significantly increase the probability of generating cancer.

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Tuesday, July 3, 2012

Addressing Debate in Society

One repeating issue in our society is the question of how to address an incorrect, yet stubborn mindset. This issue has once again become relevant with the radicalization (based on recent past attitudes) of the Republican political party in the United States. Basically how should society address groups that continue to advance a viewpoint on a given situation that is not supported by logic or empirical evidence?

In the past when control of information was more manageable news organizations, both in print and broadcast form, would do a reasonable job at presenting truthful information. Of course there were certain less scrupulous organizations, which attempted to bolster their own viewpoint for their own ends regardless of truthfulness. Fortunately there were enough ‘neutral’ organizations with strong anchors that wanted to present the truth to neutralize most of the presented misinformation. Unfortunately that was then and this is now; the nature of news has changed from presenting the truth to presenting what the public is willing to watch in effort to acquire the most advertising dollars to make the most money.

This change in mindset has resulted in news organizations fracturing their information presentation. Instead of focusing on reporting the unbiased truth with a utilitarian slant, which is thought to be best for society as a whole, these organizations have elected to take a viewpoint that plays towards a certain demographic; thus artificially supporting their viewpoints while diminishing contradicting viewpoints regardless of which viewpoint is actually better supported by logic and empirical evidence. In this environment competition has become more prevalent because of the ‘us versus them’ mentality that is catalyzed by supporting a particular viewpoint.

The competition element spills over into what can be viewed in some context as attacks against the other ‘sides’. Some have argued that this mindset spurs more radicalized viewpoints. These viewpoints then demand reaction, which further facilitates a vicious cycle where accuracy and correct solutions to problems disappear in a sea of reaction-reaction conversation. This mindset is largely the domain of progressive thinkers in that they believe other progressives in the media are focusing too much on the personalities that are broadcasting radical options instead of focusing on the statements themselves.

There is also concern that progressives in the media are giving legitimacy to these radical individuals by including their foolish irrational ideas in the discussion and simply provoking them to make more. It is similar to taking someone who states that 2 + 2 = 9 seriously and actually entertaining that statement as a valid opinion. Instead if someone gives an opinion that is similarly foolish and illogical that person should just be ignored. By ignoring these individuals these foolish opinions remain only in an echo chamber of similar believers, which destroys the influence of these opinions. This mindset stems from the belief of ‘any publicity is good publicity’.

While a strategy involving ignoring foolish opinions makes theoretical sense, the problem in reality is that a number of individuals already share these beliefs and will drive the publicity of those opinions themselves. Also this strategy fails because those who give life to these opinions already have a publicity outlet for them (most often Fox News in the United States or its international equivalences), thus not engaging those opinions is not a significant detriment to limiting the publicity of those opinions. Finally due to the corruption of the previously legitimate news media it is thought that attracting controversy will help spur the publicity of these opinions in a pseudo debate in order to increase ratings. Basically where Edward R. Murrow would have said, “A fringe group of fools have started preaching that 2 + 2 = 9, but that belief has long been proven false and those who have it should be ignored.”, Don Lemon now says, “There is a growing sentiment that 2 + 2 may not actually be 4, but 9 join us on CNN later tonight for the controversy.”

Another problem with ignoring certain opinions is the issue of the unopposed certainty. For the myriad of problems in the world there are multiple ideas that people believe could be a valid solution; however, if a ‘solution’ is proposed and no one argues against it, numerous individuals would naturally come to believe that the proposed ‘solution’ is legitimate and appropriate, thus radical ideas must be challenged at some level to neutralize this aspect of human psychology. Overall based on the issues of unopposed certainty and lack of publicity denying influence, ignoring the radical and irrational opinions in the media marketplace is not an appropriate strategy.

So if ignoring and trying to isolate radical ideas is not a consistently viable strategy how does one address radical ideas? Addressing the issue is tricky because research has demonstrated that a simple denial has little effect on destroying the illusionary validity that supporters give to a radical illogical idea. Part of the reason why the simple explanation does not work is the issue of first impressions. Unfortunately human beings place too much focus on first impressions in both people and ideas. If a person agrees with an idea it is difficult to later convince that person that the idea is invalid. This mindset can be split into two parts: first, general laziness in that once people make up their minds they rarely feel the need to revisit those thoughts to see if the information is still valid. Second, most people are simply terrified to be wrong. Unfortunately a long evidence riddled debunking also has its problems largely in maintaining both the attention of the target audience and cohesion of thought.

With these concerns a direct attack against the idea and the individual(s) proposing the idea may not be the best strategy. Instead a better attack strategy would be to drive a natural expansion of the idea beyond a single cause and effect statement. Almost all radical ideas are similar to a house of cards: they are simple, only have depth when viewed from a specific angle and are only stable under ideal conditions. Force radical ideas to expand in their application and they either collapse under their own illogical nature or people realize how inapplicable they are in society.

For example one ‘popular’ radical idea is the libertarian notion of eliminating income taxes. On its face a number of people sympathize with such an idea because of belief in government waste and simple greed disguised as ‘fairness’; however, when expanding the application of the idea to demonstrate all of the services government provides and how those services from infrastructure maintenance to education to law and order will erode without taxes the idea of eliminating taxes falls apart. Basically advancing the idea from theory to practice and addressing the outcomes on individuals and society sheds appropriate light on the idea’s efficacy.

Another issue that should be avoided is focusing on the messenger regardless of how ‘crazy’ one can characterize the messenger. Attacking the messenger will typically lead to backlash and lack of focus. The way to isolate the messenger is to defeat the message, thus denying him/her the ability to propagate a valid message into society. Unfortunately defeating the message is more difficult than simply citing a couple pieces of evidence, which contradicts with certain elements of the message. In addition to the concerns above, human psychology is another troublemaker in this issue because of the backfire effect.

The backfire effect was coined by Brendan Nyhan and Jason Reifler and describes the psychological reaction by individuals to actually strengthen their belief in a particular idea when confronted with valid contradictory evidence. One explanation of the backfire effect is that an individual first develops a belief without the contradictory evidence and when exposed to it rationalizes that because that evidence was previously unknown there must also be unknown evidence that further supports the original belief invalidating the contradictory evidence. This erroneous and laughable reasoning is similar to that perpetrated by supporters of the Iraq War relative to the lack of discovered ‘weapons of mass destruction’ in Iraq, a refrain of ‘just because we didn’t find any weapons of mass destruction doesn’t mean they weren’t there.’ Basically backfire activators are saying, ‘just because this evidence destroys the validity of my opinion on this issue doesn’t mean there isn’t some mysterious unknown evidence that destroys that evidence reaffirming my opinion.’

One strategy to avoid trigger the backfire effect is to attack the radical messages indirectly. Instead of referencing the message directly, attack it indirectly by introducing another contradicting idea with the backing of empirical evidence and logic. Details of the rational and effective idea can be expanded so they are in direct contrast with the radical idea, but do not directly compare the two. This methodology should convince individuals of the superiority of the new idea independently from interaction with the incorrect radical idea, thus when the comparison eventually comes the individual should be more willing to abandon the original erroneous belief.

Of course neither of the above two strategies are guaranteed to work, but they are superior to most of the discourse that occurs in our society with regards to debate and idea exchange. Attacking messengers who express radical expressed opinions rarely works to advance the conversation because rational people, ignorant or not, care about the message, not the messenger and supporters of either side of the argument will typically support that argument in the face of attack regardless of whether or not it is actually accurate. Overall the means to ‘disarm’ radical opinions is optimized through expansion of that idea from a simple talking point to theoretical application in society and how it fails when actually applied or indirect correction.