November 2015 Blog with Durk and Sandy

APPETIZERS

AI theorist Eliezer Yudkowsky coined Moore’s Law of Mad Science: Every eighteen months, the minimum IQ necessary to destroy the world drops by one point.

The task is … not so much to see what no one has yet seen; but to think what nobody has yet thought, about that which everybody sees.

—Erwin Schrodinger

The important thing in science is not so much to obtain new facts as to discover new ways of thinking about them.

—Sir William Lawrence Bragg

When everything is connected to everything else, then anything can be explained in terms of any single piece that is a part of that everything.

—Sandy Shaw

(Sandy’s comment: Do you ever wonder why some scientists, having discovered an important biological fact that connects other things in biology that had hitherto not been connected to it, begin to try to explain everything in terms of that newly discovered connection. It is because everything in biology is connected to everything else in biology at a certain level, so you really CAN explain everything in terms of any one factor in that whole. Of course, the same is true for physics or chemistry as well.)

The mind is its own place, and in itself 
Can make a heaven of hell.

—John Milton, Paradise Lost

“Nasrudin went into a bank with a cheque to cash. “Can you identify yourself?” asked the clerk. Nasrudin took out a mirror and peered into it. “Yes, that’s me all right,” he said.”

—Idries Shah, The Subtlties

OF THE INIMITABLE MULLA NASRUDIN... the “me“ who is responsible and whom society recognizes as responsible resides in the ability to control the diverse systems within [the mind]. Something has to command the wheeling in and out of one or the other small minds. In [one] view, the separate minds clamor and fight for control and the strongest wins, with no directing force.

—Multimind by Robert Ornstein, pg. 179, said to be “A New Way of Looking at Human Behavior” (Major Books, 2003). See below for recent scientific publication that supports this prescient view of how “pieces” of the mind “clamor and fight for control and the strongest wins.” The science of the mind of man meets science fiction. ‘Tis amazing.

Finally, we have this fascinating quote from Adam Smith in his The Theory of Moral Sentiments (1759):

When I endeavor to examine my own conduct… I divide myself as it were into two persons, and that I, the examiner and judge, represent a different character from the other I, the person whose conduct is examined into and judged of. The first is the spectator… The second is the agent, the person whom I properly call myself, and of whose conduct, under the character of a spectator, I was endeavoring to form some opinion.

 

AUTOPHAGY AGAINST TYPE II DIABETES

Pancreatic Beta Cells Protected By Autophagy Against Amyloidogenic Degradation That Induces the Onset of Type II Diabetes

Aggregates of Amyloid Involved in Type II Diabetes Very Similar to the Aggregates of Neurotoxic Amyloid in Alzheimer’s Disease

TREHALOSE, An Inducer of Autophagy, May Be a Possible Protectant Against Amyloid Aggregation

VITAMIN D3 Induces Autophagy, Protects Against Inflammation and Infection

Following a trail of damaging mechanisms that cause type II diabetes, we find that an important source of protection is the process of autophagy.¹ A new paper¹ reports on how the loss of autophagy along with beta cell expression of IAPP (amyloid islet polypeptide, also called amylin), a 37 amino acid protein coexpressed and released by pancreatic beta cells along with insulin, results in the death (apoptosis) of beta cells. IAPP forms amyloid deposits in beta cells remarkably similar to the amyloid deposits that form in the brain during Alzheimer’s disease; these deposits are composed of aggregated, misfolded proteins that are normally cleared by the process of autophagy. In the absence of adequate autophagy, the toxic effects of IAPP deposits induces endoplasmic reticulum stress that kills beta cells and can, in that way, lead to type II diabetes.

In the paper (Rivera, 2014) the researchers report on their experiments with rodent beta cell islets, showing that when autophagy was stimulated by the autophagy-inducing drug rapamycin that (at the dose used) beta cell IAPP content was reduced by 54% ±5.5% versus untreated (no rapamycin) cells. More interestingly, since the rodent form of IAPP does not form amyloidogenic aggregated, misfolded cytotoxic deposits, the researchers duplicated their experiments using HUMAN islets and found that rapamycin decreased IAPP content by 31% ±12.4% as compared to untreated human islets.

The researchers cite a paper (one which we already had) (Zang, 2007) that listed a number of FDA-approved drugs that, like rapamycin, had also been found to have autophagy-enhancing effects. What is particularly interesting among these identified autophagy-enhancing drugs is the safe and relatively inexpensive over-the-counter drug loperamide, which is used to treat diarrhea. (Not unsurprisingly, one possible side effect of using too much is constipation. Side effects of the drug are generally mild. Though loperamide is a mu opioid agonist, it does not pass the blood-brain barrier except in those rare individuals with “leaky” blood-brain barriers.)

The researchers conclude that their paper presents “the first line of evidence” that establishes a protective effect of autophagy against human IAPP-induced toxicity in human beta cells and protects the cells from being killed, part of the process resulting in type II diabetes. They propose “the players of the autophagy pathway as key therapeutic targets for treatment and prevention of T2D [type 2 diabetes].” (Rivera, 2014).

Enhancing Autophagy With TREHALOSE or Loperamide

If you have type II diabetes and would like to try loperamide to induce autophagy to possibly improve your diabetes, we suggest you follow the label instructions. The limited amount of loperamide as given on the label is particularly aimed at avoiding constipation, but if you are under the supervision of a physician, you might ask him or her about taking up to twice that amount and simply reducing your dose if you encounter constipation.

Note that TREHALOSE, the natural osmolyte that acts as a chaperone to help proteins fold properly (found in our protein folding formulation), is also an inducer of autophagy. In a different paper on autophagy, IAPP, and the development of type II diabetes, TREHALOSE was used to induce autophagy to promote clearance of the amyloidogenic IAPP in mice fed a high fat diet (Kim, 2014).

VITAMIN D3 Is Another Natural Inducer of Autophagy

Recent research (Wu, 2011) reports that VITAMIN D3 induces autophagy in and provides protection during inflammation and infection. “Vitamin D deficiency is a critical factor in the pathology of at least 17 varieties of cancer, as well as autoimmune diseases, diabetes, osteoarthritis, periodontal disease, and more.” (Wu, 2011) “Autophagy … plays important roles in the degradation of damaged cytosolic components and misfolded proteins and in organelle turnover.” (Yuk, 2009).

References

• Cheng et al. Coffee components inhibit amyloid formation of human islet amyloid polypeptide in vitro: possible links between coffee consumption and diabetes mellitus. J Agric Food Chem.59:13147-55 (2011).
• Huxley et al. Coffee, decaffeinated coffee, and tea consumption in relation to incident type 2 diabetes mellitus. Arch Intern Med.169(22):2053-63 (2009).
• Kim, Cheon, Jeong, Quan, et al. Amyloidogenic peptide oligomer accumulation in autophagy-deficient beta cells induces diabetes. J Clin Invest.124(8):3311-24 (2014).
• Rivera et al. Autophagy defends pancreatic beta cells from human islet amyloid polypeptide-induced toxicity.J Clin Invest. 124(8):3489-3500 (2014).
• Wu and Sun. Vitamin D, vitamin D receptor, and macroautophagy in inflammation and infection. Discov Med.11(59):325-35 (2011).
• Yuk, Shin, Lee, et al. Vitamin D3 induces autophagy in human monocytes/macrophages via cathelicidin. Cell Host Microbe.6:231-43 (2009).
• Zhang et al. Small molecule regulators of autophagy identified by an image-based high-throughput screen. Proc Natl Acad Sci U S A.I 104(48):19023-8 (2007).

 

COFFEE COMPONENTS INHIBIT AMYLOID FORMATION OF HUMAN IAPP IN VITRO: MAY EXPLAIN THE INVERSE RELATION BETWEEN COFFEE CONSUMPTION AND TYPE II DIABETES

Significant Inverse Association Between Tea and Type II Diabetes Incidence

Another aspect of the IAPP-type II diabetes link is found in a recent paper (Cheng, 2011) reporting that three major components of coffee, caffeine, caffeic acid, and chlorogenic acid, all inhibited the toxic aggregation of human IAPP in vitro. The protection was greatest for caffeic acid and least for chlorogenic acid. The paper also reports that in other studies EGCG (especially enriched in green tea) can inhibit the fibril formation of human IAPP (EGCG also inhibits the toxic amyloid formation in Alzheimer’s disease) as well as having protective effects on pancreatic beta cells.

A paper (Huxley, 2009) in a recent issue of Archives of Internal Medicine provided a meta-analysis of 18 studies involving00,000 people on the associations between the consumption of coffee and tea on the incidence of type II diabetes, finding an overall reduction in the risk of the disease. (Protection against the cytotoxic effects of IAPP could be one of the mechanisms responsible, but others are likely to be involved.) The beneficial effects of coffee, decaf coffee, or tea was found for those who ingested four cups a day, with the paper (Huxley, 2009) reporting that “every additional cup of coffee consumed in a day was associated with a 7% reduction in the excess risk of diabetes, 0.93 [95% confidence interval, 0.91-0.95] after adjustment for potential confounders.”

References

• Cheng et al. Coffee components inhibit amyloid formation of human islet amyloid polypeptide in vitro: possible links between coffee consumption and diabetes mellitus. J Agric Food Chem.59:13147-55 (2011).
• Huxley et al. Coffee, decaffeinated coffee, and tea consumption in relation to incident type 2 diabetes mellitus. Arch Intern Med.169(22):2053-63 (2009).
• Kim, Cheon, Jeong, Quan, et al. Amyloidogenic peptide oligomer accumulation in autophagy-deficient beta cells induces diabetes. J Clin Invest.124(8):3311-24 (2014).
• Rivera et al. Autophagy defends pancreatic beta cells from human islet amyloid polypeptide-induced toxicity.J Clin Invest. 124(8):3489-3500 (2014).
• Wu and Sun. Vitamin D, vitamin D receptor, and macroautophagy in inflammation and infection. Discov Med.11(59):325-35 (2011).
• Yuk, Shin, Lee, et al. Vitamin D3 induces autophagy in human monocytes/macrophages via cathelicidin. Cell Host Microbe.6:231-43 (2009).
• Zhang et al. Small molecule regulators of autophagy identified by an image-based high-throughput screen. Proc Natl Acad Sci U S A.I 104(48):19023-8 (2007).

 

MOST HEART ATTACKS ARE NON-FATAL, SO THE REPORTED HIGHLY PROTECTIVE EFFECT OF NIACIN

AGAINST THE INCIDENCE OF NON-FATAL HEART ATTACKS IS OF MAJOR IMPORTANCE

In a paper (Keene, 2014) reports a meta-analysis of 117,411 patients, very interesting differences between the effects of niacin taken by patients NOT RECEIVING STATINS (this was before the statin era) and those who, later, were taking niacin and statins showed very statistically significant results that in those patients NOT taking statins, niacin was associated with a significant reduction in non-fatal heart attacks (myocardial infarction) (odds ratio was 0.69, 0.56 to 0.85, p=0.0004). However, in studies where statins were already being taken, niacin showed no significant effect on the incidence of non-fatal heart attacks, the researchers say. In the current era of widespread use of statins in dyslipidemia, substantial trials of these three agents [niacin, fibrates, or CETP inhibitors, all of which increase HDL levels] do not support this concept [that increasing HDL would generally reduce cardiovascular events].” Statins interfere with an important protective effect of niacin.

NON-FATAL MYOCARDIAL INFARCTIONS ARE THE MOST COMMON TYPE OF HEART ATTACK, SO REDUCTION OF THESE HEART ATTACKS IS NOT AT ALL UNIMPORTANT, THOUGH THE USE OF THE DESCRIPTOR “NON-FATAL” MAY CAUSE PEOPLE TO UNDERESTIMATE THE SIGNIFICANCE OF THESE RESULTS.

Studies with statins and cholesterol-reducing agents (niacin or fibrates) have repeatedly shown that reductions in LDL cholesterol with these in combination with statins are able “to reduce cardiac events and all cause mortality in the setting of both secondary and primary prevention.” However, the increased protection against cardiovascular events expected by increased HDL has not been seen. See paragraph above. Hence, something in the interaction of statins with niacin and fibrates, where niacin and fibrates increase HDL cholesterol and which (when taken WITHOUT CONCURRENT INGESTION OF STATINS) reduces the risk of non-fatal myocardial infarctions, results in a loss of that protective effect of niacin or fibrates.

The studies with niacin were confounded by the fact that some of the patients were given aspirin or laropriprant to inhibit flushing. Laropriprant is thought to interfere with prostaglandin pathways which, as is explained in Sandy’s paper on prostaglandins and the niacin flush (Sandy Shaw, 2015), could be important and the authors of this paper(Keene, 2014) suggest that interference with prostaglandin pathways “could confound the effect of niacin.”

References

• Keene et al. Effect on cardiovascular risk of high density lipoprotein targeted drug treatments niacin, fibrates, and CETP inhibitors: meta-analysis of randomised controlled trials including 117,411 patients. 349:g4379 (2014) doi: 10.1136/bmj.g4379 (published 18 July 2014).
• Sandy Shaw. Why the Niacin Flush May Be Surprisingly Beneficial to Your Health” in the July, August, and September 2015 issues of the web edition of the Life Enhancementmagazine (www.life-enhancement.com).

 

WHY RELIGIONS TEND TO HAVE PUNISHING GODS: PUBLIC GOODS GAMES MAY REVEAL PART OF THE REASON

BY SANDY SHAW AND DURK PEARSON

A “new” hypothesis to explain the success of the major religions posits that belief in judgmental gods that punish those who violate social norms have been a key to the cooperation needed to build and sustain large complex human societies (Wade, 2015).

The major successful religions tend to have punishing gods. Why might this be? The results of some public goods games on what humans are willing to contribute to the punishment of bad guys may help elucidate the source of this preference for punishing gods.

Some experiments have shown that a phenomenon called altruistic punishment is a form of human behavior, in which people have been shown to be willing to pay to punish bad guys (those who do not comply with social norms) by donating resources to their punishment even when it costs the donors more than they get back in benefits to themselves (e.g., their contribution acts as a public good by providing benefits to anyone whether they donate to the funding of the punishment or not). This could help to explain at least in part why people are willing to pay tithes to religions with punishing gods, even when they themselves do not benefit any more than those who do not pay such tithes. (Part of the reason for donating tithes may be a hope of getting into heaven. This reward would, if realized, be a privatized benefit rather than a public good.)

It appears that punishing bad guys is a strong motivation that supports altruistic punishment by inducing humans to pay to punish even when it costs them more than they can get back for their own individual benefit. Hence, punishing gods may be a mechanism by which humans seek to enforce cooperation with respect to social norms. The fact that religions with punishing gods have done so well indicates that they have been successful (so far) in this. However, some major religions evoke cooperation among their believers for the enforcement of social norms that differ from the social norms of other religions, leading to a sort of war of punishing gods as we see now in extreme Islam versus Christianity or Judaism.

During the fall of the ancient Grecian civilization, there was a veritable war of the gods, with polytheism where people chose sides by supporting various gods. Once again, we see a similar result from the loss of faith in central government as the instrument of punishment. Perhaps a war of punishing gods in religions is something like the war for power between different governments or even parts of governments such as we see now in the declining stages of Western governments. And notice how these different parts of government are moving more and more in the direction of punishing regimes of regulatory rules and regulations, with EPA, FDA, and NSA as particularly dangerous examples in the United States. The rapidly increasing sizes of “fines” for supposedly bad behavior is an example of where these agencies are heading.

When, in the Middle Ages, people lost the ability to believe in organized religion due to factors such as widespread corruption (with religions selling absolutions, you didn’t have to be good to get a ticket to heaven, etc.), it caused a major breakdown in civil order. You couldn’t trust God to be doing His job of punishing bad people. The disastrous result we suspect would be more violence as people looked to secular processes to do the punishing. This was finally resolved by the Reformation and Martin Luther to (some extent) restore God back to do the punishment.

The design of the American Republic with its innovative Constitution represented a form of restoration of government from an increasingly incoherent/punishing European model. Now we have an increasingly incoherent/punishing model for both European and American governments, so where this is going to end up and what will glue things back together into something coherent is impossible to predict from our current situation. John Galt isn’t going to do it; we think his imagination was too limited and nobody on the scene looks like John Galt, anyway. Donald Trump could, I suppose, be John Galt with severely limited long-term principles, but with the frank talk and honest depiction of the bad guys (other than himself) that we expect from Mr. Galt. In this new rendering, Mr. Galt’s inventive genius is applied to the benefit of Mr. Galt, while appearing to be (by Mr. Trump’s telling) on the side of everybody else, too. The occasional seizure of an old lady’s house by Mr. Trump to build a Trump superstructure has to be (suspend your disbelief) to the benefit of the overall society by adding a fabulous superstructure (a limousine parking lot for the Trump casino in Atlantic City, for example) to improve economic conditions, offer jobs, etc. It wouldn’t quite make the cut for John Galt, though. In fact, such behavior (seizing people’s houses for your own benefit) fits the pattern of a sociopath.

The very fact that people are turning to somebody like Trump indicates, as we see it, that at least some people are looking for that individual who will represent their desire for a punishing State, a really bad sign for the possible appearance of somebody like Hitler or Lenin. But the rise of Trump also suggests, we think, that people are looking for somebody who can restore a coherent punishing function of the government, when their faith in the extant government as the effective punishing agent is collapsing. A good model is the collapse of the Weimar Republic and the emergence of Naziism in Germany.

A good friend of ours suggested that this need for a punishing state is a defect in human intelligence, perhaps a fatal flaw. We have to agree. If people living in a large political entity cannot learn how to live together without having a Big Brother government forcing people to follow His rapidly increasing numbers of rules and regulations or be severely punished, what sort of future can Homo sapiens have?

One solution is to decentralize—reduce the sizes of political entities. Fifty states offer a lot more opportunity to find congenial rules and regulations than one giant superstate. That’s why the Founders designed the Constitution as they did. The passage of the 17th Amendment was a severe blow to that design as it eliminated the Senate as a body that represented the interests of the fifty states; after its passage, the entire Congress served the federal government. Federalism was given a mortal injury and we see the results today with ever increasing federal hegemony over the states. States aren’t perfect, but a choice of 50 as compared to one federal government ain’t chicken feed, either.

References

• Fehr & Gachter. Altruistic punishment in humans. 415:137-40 (2002).
• Fowler, Johnson, Smirnov. Egalitarian motive and altruistic punishment. 433:E1-E2 (2004).
• Birth of the moralizing gods. Science.349:919-22 (2015).

 

RESTLESS LEGS

PERSONAL OBSERVATIONS

BY SANDY SHAW

My experience with restless legs finds that, at least in my case, it can be brought on or made worse by:

1. Drinking carbonated beverages—Carbon dioxide inhalation can induce arousal by activating serotonin receptors (Richerson, 2004). Certain serotonin receptors surprisingly, induce arousal. “It is now clear that 5-HT [serotonin] actually causes arousal.” (Richerson, 2004, pg. 451) “Serotonergic neurons in the midbrain are also chemosensitive, and might mediate non-respiratory responses to increased carbon dioxide, such as arousal.” (Richerson, 2004) This arousal may be what drinkers of carbonated beverages are looking for. I find that drinking carbonated beverages increases my symptoms of restless legs. How serotonergic activation would do that I do not know. It is known that serotonin receptors can be involved in motor control (Richerson, 2004). The absorption of carbon dioxide from drinking carbonated drinks may be modulated by taking GAS-X or similar remedy to cause the carbon dioxide gas to be “burped” out, reducing the amount that is absorbed in the gastrointestinal tract. (There has to be a reason why humans go to the trouble and expense of getting carbon dioxide into so many drinks. Yes, it is pleasurable, but why? It may have a stimulating effect to increase awareness and arousal via serotonergic receptors. There may be, however, other chemoreceptors involved in the arousal response to carbon dioxide. See (Buchanan, 2010).
2. Eating foods on an empty stomach when the food contains more than about 20 grams of sugar (sucrose). This may be due to the release of insulin and subsequent release of noradrenaline (Watson, 2006). “Thus, changes in insulin levels may modulate synaptic NE [norepinephrine/noradrenaline] levels and behaviors normally associated with noradrenergic activity.” (Watson, 2006). Although noradrenaline levels decrease with aging, there is the possibility of compensatory hypersensitivity (increased reactiveness to NE). (Ah, yes, it is a delicate balancing act to get the dose of noradrenaline just right.)

Eating sugar with a meal should reduce the likelihood of stimulating restless legs because of the dilution of the sugar and the consequent slower absorption of it. Good sweeteners that avoid insulin release include erythritol (unlike other sugar alcohols, doesn’t cause diarrhea), xylitol, other sugar alcohols, palatinose (a natural sugar, found in honey and sugar cane). These slowly releases sugar for a very low glycemic index effect and little increase in insulin). Synthetic sweeteners such as saccharin, aspartame, sucralose, and others have been shown to have a detrimental effect on the gut microbiota. Stevia may also have similar detrimental effects. See below for article on the potential adverse effects of various non-sucrose sweeteners, both natural and synthetic.

3. I speculate (this is purely a speculation) that restless legs may be a symptom of temporal lobe epilepsy (Ottoson, 2015), which I have, and the symptoms of which increase in my own case concurrently in response to the same inducing factors, such as #1 and #2 above. Moreover, the drugs and nutrients I use to control temporal lobe epilepsy, such as gabapentin (with GABA receptor inducing effects), glycine, and taurine, also are effective in controlling restless legs in my case. The latter are personal observations only. I make no claim of cause and effect or generalizability.
4. Drinking very cold drinks can bring it on in my case, perhaps due to adrenergic stimulation. (Rossato, 2014) “In vivo cold sensation is detected by specific sensors for cold temperature expressed on peripheral cutaneous nerve endings leading to adrenergic stimulation.” (Rossato, 2014) (There has to be a reason why humans prefer very cold drinks and throughout history have gone to great lengths and expense to get what is necessary (refrigeration, ice, deep storage in the earth, etc.) to get their drinks cold. One has to presume that there is a preferred psychopharmacological state. I think it may be, in this case, adrenergic activation (Rossato, 2014) —and/or possibly cholinergic activation—by very cold-detecting sensors in the mouth or gastrointestinal tract. People like the effects of being stimulated.)

“The effect of adrenoceptors agonists on the production of other important mediators involved in inflammation have also been investigated. Prostaglandins are produced via the metabolism of AA [arachidonic acid] by a cyclooxygenase (COX) and subsequently by prostaglandin synthases.” “Our laboratory has also demonstrated that NE [norepinephrine, noradrenaline] is able to increase COX-2 expression in LPS-stimulated microglia.” (Schlachetzki, 2010). LPS is lipopolysaccharide, a bacterial cell wall component that activates the immune system and its inflammatory effects. However, noradrenaline levels decline with aging, a detrimental effect on cognition (Schlachetzki, 2010). Clinical trials treating patients with dementia or cognitive impairments with beta adrenergic receptor blockers has resulted in both beneficial results and detrimental results. In other studies, increasing noradrenaline by treatment with insulin resulted in improvement cognition in demented patients but in another study increased the level of inflammatory markers in the CSF (cerebral spinal fluid). The data are conflicting at this point (or as of 2010).

References

• Buchanan, Richerson. Central serotonin neurons are required for arousal to CO2. Proc Natl Acad Sci U S A. 107(37):16354-9 (2010).
• Ottosson, Wu, Nolting, et al. Resin-acid derivatives as potent electrostatic openers of voltage gated K channels and suppressors of neuronal excitability. Sci Rep.5:13278 (2015). “Many diseases that affect a large number of people, such as epilepsy, cardiac arrhythmia, and chronic pain, depend on increased electrical excitability.” Restless legs is a disorder that clearly involves increased electrical excitability.
• Serotonergic neurons as carbon dioxide sensors that maintain pH homeostasis. Nat Rev Neurosci.Jun;5(6):449-61 (2004).
• Rossato, Granzotto, Macchi, et al. Human white adipocytes express the cold receptor TRPM8 which activation induces UCP1 expression, mitochondrial activation and heat production. Mol Cell Endocrinol. 183:137-46 (2014).
• Schlachetzki et al. Function of norepinephrine in neuroinflammation and chronic neurodegenerative diseases. In Biochemistry and Histocytochemistry …  1. Edited by Fuchs and Auer. Hauppauge NY: Nova Science Publishers, Inc. 2010.
• Watson, Bernhardt, Reger, et al. Insulin effects on CSF norepinephrine and cognition in Alzheimer’s disease. Neurobiol Aging.27:38-41 (2006).

SAFETY ISSUES IN THE USE OF SWEETENERS AS ALTERNATIVES TO SUCROSE

ERYTHRITOL —A recent paper (Chung, 2013) reported that, using the Ames test and a test for the formation of micronuclei in the bone marrow cells of male ICR mice, erythritol was not mutagenic to bacterial cells and did not cause chromosomal damage in mammalian cells either in vitro or in vivo.

STEVIA, SACCHARIN —The OAT (organic anion transporter) is involved in the elimination by the kidneys of certain drugs (Schiffman, 2012). Competition with this transporter can have serious effects if drug elimination is reduced. An example given in Schiffman, 2012 is the interaction at OATs between non-steroidal-anti-inflammatory drugs and methotrexate that can result in severe methotrexate toxicity. When SACCHARIN coexists in the plasma with drugs that are substrates of OATs, it is said to potentially compete for transport and modulate the drug’s pharmacokinetics (Schiffman, 2012). STEVIOL, the metabolite of steviol glycosides (stevioside and rebaudioside) are also excreted with the involvement of OATs. It is not known what the clinical significance is of the interaction of saccharin or steviol with OATs (Schiffman, 2012). Interestingly, the Schiffman paper notes that steviol is sold commercially (Sigma Aldrich, 2012) as an OAT inhibitor. Stevioside was also associated with DNA aberrations in the liver, spleen, and brain as detected by comet assays, though the effects were possibly due to steviol, a metabolite of stevioside.

The Schiffman paper also notes that studies in rodents have found that sucralose (Splenda^®), acesulfame-K, and saccharin were shown to increase the expression of the Na+-glucose cotransporter SGLT1 and the glucose transporter GLUT2 via interaction with sweet taste receptors in the gastrointestinal tract. Schiffman reports that interaction of these same sweeteners with sweet taste receptors in pancreatic beta cells has been shown to induce insulin secretion. These and other effects discussed in the Schiffman paper indicate, the author says, that more research needs to be done on these sweeteners. For example, he notes, it was not known at that time (2012) whether these sweeteners passed the blood-brain barrier.

Another thing reported in the Schiffman paper was that neuroimaging studies had shown in a 2011 paper that routine use of artificial sweeteners altered responses to sucrose in the amygdala and insula as measured by fMRI scanning.

Another paper (Schiffman and Rother, 2013) provided a very lengthy (52 pages) discussion of the various effects of sucralose, including its alteration in the composition of the gut microbiota.

The safest sweeteners appear to be sugar in small amounts and sugar alcohols (such as erythritol, xylitol). In the case of sugar alcohols, it is useful to know that erythritol is by far the least likely of the sugar alcohols to cause diarrhea in excessive amounts and has almost no calories, being excreted largely unchanged in the urine. Another possibility for a safe sweetener is Palatinose™ (isomaltulose, a disaccharide composed of glucose and fructose linked by an alpha-1,6-glycosidic bond), a natural sugar found in honey and sugar cane extract that is digested only very slowly, has a low glycemic index, and increases insulin levels very little. Palatinose is also easy on teeth, as it is not usable by oral bacteria. (See “Isomaltulose” in Wikipedia.)

References

• Abou-Donia, El-Masry, Abdel-Rahman, McLendon, Schiffman. Splenda alters gut microflora and increases intestinal p-glycoprotein and cytochrome p-450 in male rats. J Toxicol Environ Health A. 71(21):1415-29 (2008).
• Chung and Lee. Genotoxicity assessment of erythritol by using short-term assay. Toxicol Res. 29(4):249-55 (2013).
• Rationale for further medical and health research on high-potency sweeteners. Chem Senses. 37:671-9 (2012).
• Schiffman and Rother. Sucralose, a synthetic organochlorine sweetener: overview of biological issues.J Toxicol Environ Health B Crit Rev. 16:399-451 (2013).

A SCIENTIST COMPLAINS OF THE DIFFICULTY OF GETTING FUNDING FOR UNUSUAL PHENOMENA FOR WHICH THERE IS NO HYPOTHESIS

BY SANDY SHAW & DURK PEARSON

An article by Steven McKnight, the President of the American Society for Biochemistry and Molecular Biology (which publishes The Journal Of Biological Chemistry and The Journal of Lipid Chemistry) in the June/July 2015 issue of ASBMB TODAY (Vol. 14 No. 6, pp. 2-3) deplores the difficulty in getting funding to study very interesting scientific puzzles for which there is no hypothesis. (Such research may be an important way of developing data to suggest hypotheses.)

He pointed to a particular puzzle as an example. He noted that “[d]uring hibernation, the core body temperature of ground squirrels goes from 37 degrees C down to 4-5 degrees C. Perplexingly, with robust periodicity, hibernating ground squirrels warm back up to 37degrees C around once every 10 days [reference provided]. These brief periods of warming are called interbout arousals. What is the utility to the hibernating ground squirrel to periodically warm up for about a day?”

Sandy has a suggestion for a possible reason for the warming. She suggests that it is to activate neurons (possibly of the serotonergic, cholinergic, and adrenergic nervous systems) that are known to die if not activated for a certain period of time. Durk suggests that one way to test this is to see if hibernating bears also have interbout arousals about every 10 days, similarly to the squirrels. Another question is whether the neurons die in ten days or less if they remain inactivated.

Durk suggests that the warming (the arousal from hibernation) may be needed for effective immune system function. He notes that snakes seek greater heat when ill, and will become infected with pathogens if this increased warmth is unavailable.

Incidentally, we agree with Dr. McKnight that it is a shame that more far reaching research that looks for hypotheses rather than investigates hypotheses you already have is hard to get funding for. But this is perhaps a more risky way of spending government money than when you have already advanced to having a hypothesis based on available data. Bureaucracies do not tend to engage in risk when it is so much safer to put money into research that is more fully developed. Look to entrepreneurs in the private sector for investment in risky new science and technology.

In the News: Women’s Dementia Worsens Faster Than Men’s

So says a headline in the July 22, 2015 The Wall Street Journal. According to the study (398 subjects who participated in the Alzheimer’s Disease Neuroimaging Initiative), women’s cognitive decline took place about twice as fast as men’s. The good news is that it is very likely, based on scientific studies showing that women need more choline than men do (Fischer, 2007), and that, as choline has been identified as a nutrient important to cognition (Poly, 2011), a deficiency of choline is one cause of this vulnerability to dementia in women. Not only does estrogen play an important role in the cholinergic nervous system (Fischer, 2007, Craig, 2010)—estrogen declines rapidly following menopause—it is known that in older people, choline is taken up less effectively into the brain (Cohen, 1995). In addition, women are much more susceptible to autoimmune diseases than men are and the cholinergic nervous system is a major antiinflammatory system (Tracey, 2007).

Add it all up and the evidence points to a need for additional choline in older women. The amount of choline recommended by the Institute of Medicine (IOM) for non-pregnant women, 425 mg a day, is (in our judgment) too low to supply adequate amounts of choline to older women when you consider the reduced ability to transport choline into the brain, the loss of estrogen, and also the variation dietary composition (van Wijk, 2012).

Choline consumption, genetic and epigenetic differences in the ability to absorb choline from the diet, get it into the brain, and then convert it to phosphatidylcholine (via biochemical pathways) varies between individuals suggesting that the amount that may be adequate for much of the population per the IOM recommendation may not be adequate for YOU. Note that human nutrition experiments are usually performed on young healthy college students, not on elderly people.

In short, choline is a major nutrient for keeping your cognitive function in good condition, as you get older. Durk takes 2 grams a day of choline in the form of choline dihydrogen citrate. Sandy is now taking CDP-choline, a form of choline that is a step closer in the synthesis of phosphatidylcholine (Carter, 2008) (a defect in this synthesis is now believed to be a major cause of Alzheimer’s disease) and has recently been identified as being epigenetically tagged by the cytidine diphosphate and, hence, may have some benefits over choline alone in the complex use of choline in the function of the cholinergic nervous system. She also takes 1 gram of choline a day as choline dihydrogen citrate in our sugar-free choline formulation.

References

• Carter, Demizieux, Campenot, et al. Phosphatidylcholine biosynthesis via CTP:phosphocholine cytidylyltransferase beta2 facilitates neurite outgrowth and branching.J Biol Chem. 283(1):202-12 (2008).
• Cohen, Renshaw, Stoll, et al. Decreased brain choline uptake in older adults. An in vivo proton magnetic resonance spectroscopy study. 274(11):902-7 (1995).
• Craig, Brammer, et al. The interactive effect of acute ovarian suppression and the cholinergic system on visuospatial working memory in young women. 35:987-1000 (2010).
• Fischer et al. Sex and menopausal status influence human dietary requirements for the nutrient choline. Am J Clin Nutr. 85(5):1275-85 (2007).
• Poly, Massaro, et al. The relation of dietary choline to cognitive performance and white-matter hyperintensity in the Framingham Offspring Cohort. Am J Clin Nutr. 94:1584-91 (2011).
• Physiology and immunology of the cholinergic antiinflammatory pathway.J Clin Invest. 117(2):289-96 (2007).
• van Wijk, Watkins, et al. Plasma choline concentration varies with different dietary levels of vitamins B6, B12 and folic acid in rats maintained on choline-adequate diets. Br J Nutr. 107:1408-12 (2012).

 

CHOLINE REQUIREMENT ASSOCIATED WITH GENETIC POLYMORPHISMS

New Study Reports Genetic Differences Between Ethnic and Racial Groups in Amount of Choline Required

The Institute of Medicine of the National Institute of Health defines the “adequate intake” (AI) for choline as 550 mg/day for men and 425 mg/day for women. Many Americans are said not to ingest the AI for choline, which can result in fatty liver, liver damage, and muscle damage. In this new paper (da Costa, 2104), scientists report that genetic differences (identified as single nucleotide polymorphisms, SNPs) between ethnic and racial groups indicate that the amount of choline required will differ between these groups. Seventy-nine humans were fed a low choline diet and 200 SNPs in 10 genes related to choline metabolism examined to determine associations with organ dysfunction. Some people on low choline diets presented with muscle damage, others with liver damage.

As the researchers note, the setting of dietary recommendations has not (or has rarely) considered genetic diversity in the need for daily intake of nutrients. They suggest that the simplest and safest way to deal with this is to set dietary recommendations at a level high enough to meet the needs of those with the greatest requirements. That may indeed be the simplest and safest way, but what these researchers probably have not considered is that dietary programs (school lunches, food stamps, etc.) are based upon these dietary recommendations and setting the level high enough to meet the needs of those with the greatest requirements could be quite a bit more expensive for these government programs than setting it at a level that would meet the requirements of the average American. Moreover, when you think of the case of choline, the foods that can supply it (eggs, dairy, and fish, for example) tend to be on the expensive side.

Add to the genetic variation the decreasing ability of older persons to transport choline into the brain (Cohen, 1995) and it appears likely that a significant fraction of the populace may require a higher intake of choline than that recommended by the Institute of Medicine of the National Institute of Health.

It as also been reported that choline acetyltransferase, the enzyme needed to convert choline to acetylcholine, is inhibited by exposure to excitatory amino acids (Louzada, 2004). Taurine and the antiinflamatory compounds naturally formed from it, taurine bromamine and taurine chloramine, are able to provide protection against these inflammatory excitatory amino acids and, hence, are likely to help prevent the suppression of choline acetyltransferase formation resulting from exposure to excitatory amino acids.

How Something That Looks More Complicated Can Actually Be a Simplification

As you connect more and more of the dots in a regulatory pathway, you actually “simplify” the overall understanding of how the pathway works. The increased connections between the dots improve the explanatory power of the overall picture because you reduce the number of independent elements in the analysis. It is like what happens when you increase the number of data points in a statistical analysis to where the statistical “power” of the analysis allows it to explain more than it otherwise could.

References

• Cohen, Renshaw, Stoll, et al. Decreased brain choline uptake in older adults. An in vivo proton magnetic resonance spectroscopy study.”JAMA. 274(11):902-7 (1995).
• da Costa, Corbin, Niculescu, et al. Identification of new genetic polymorphisms that alter the dietary requirement for choline and vary in their distribution across ethnic and racial groups. FASEB J. 28:2970-8 (2014).
• Louzada et al. Taurine prevents the neurotoxicity of beta-amyloid and glutamate receptor agonists; activation of GABA receptors and possible implications for Alzheimer’s disease and other neurological disorders. FASEB J. 18:511-8 (2004).

UR-INE CONTROL 
WHEN IT DOESN’T PAY TO PEE ON SOMEBODY ELSE’S WALL

A clever new way to deter people from urinating on your walls, doors, etc. was reported in the Sept. 28, 2015 Chemical & Engineering News, Newscripts, pg. 56.

We hope this will find a positive reception from those under attack by people who find it convenient to pee on your doorstep. Even if they don’t have anyplace to use a toilet, they could still pee into a bush or against a telephone pole rather than on somebody’s wall. It seems to us pretty likely that there is a certain malicious intent involved in doing it on somebody’s door or wall of their house. Reminds us of how cats will do that sometimes to show humans that they can do what they like whether you like it or not.

The city of San Francisco is said to be testing a superhydrophobic coating sprayed onto walls that is so water repellant that it causes any urine hitting them to bounce back onto the culprit who emitted the pee, hitting them on their shoes or even on their pants. The city’s director of public works is calling it “pee-back” for bad behavior. The coating is manufactured by UltraTech International in Jacksonville, Florida and named Ultra-Ever Dry.^® “It is sprayed onto a surface in two coats. The base coat contains xylene and tert-butyl acetate, while the primary substance in the top coat is acetone.” It is said to create a nanoscale surface texture with geometric shapes that have peaks that repel water-based liquids.

It is interesting that San Francisco, home of politicians and bureaucrats wildly averse to “chemicals” and with a tendency to see deadly effects from any “chemicals,” that they have considered the use of this stuff. They must be desperate. Or perhaps they are becoming reasonable about the risk/benefits of the use of chemical substances —but, Nah, that seems unlikely.

Originally Published in Our Newsletter of June 2015 (Vol. 18 No. 2):

REVOLUTIONARY NEW VIEW OF CONSCIOUSNESS:
SCIENCE FICTION MERGES WITH REALITY
THE BRAIN AS A COMMUNITY OF INTERACTING PIECES

We were amazed to see that, in the May 2015 Nature Neuroscience, a paper was published (X. Wan et al. Neural encoding of opposing strategy values in anterior and posterior cingulate cortex,” pp. 752-759; commentary on pp. 616-617) that goes a very long way in supporting the notion that the brain is made up of discrete areas that, in decision-making, come to a decision by a consensus process, with competition between the differing areas as to what the areas would prefer as a decision. In other words, the idea that our personalities are not homogeneous, there really may be different characters inside our heads, and there is a continuous process of negotiation going on between these characters to produce a single decision that includes “everybody” in the decision-making process. What was nuts yesterday could be scientifically respectable today!

The way the authors of the commentary put it: “This result speaks to the idea that decisions may be realized via a distributed consensus, a viewpoint that argues that no single brain area is critical in decision-making, but that decisions instead emerge via competitions occurring in many brain regions.”

The process called “automatic writing,” which, since William James’ (Koutstaal, 1992) early writings on the subject (1885-1899), was used to describe how an author of fiction could write a story and just let the words flow—it seems as if the text writes itself—without consciously interceding in the process would be entirely consistent with this viewpoint of distributed consciousness. The flow is where you allow the different brain areas to interact, watching them while they do this rather than directing them via central control. You might have to be a fiction writer to have had the experience of writing this way, with characters seeming to emerge spontaneously from the subconscious.

Reference

• Skirting the abyss: a history of experimental explorations of automatic writing in psychology. J Hist Behav Sci. 28:5-27 (1992).

This dissociation of the consciousness into mutually exclusive parts is evidently a phenomenon destined, whenunderstood, to cast a light into the abysses of Psychology.

—William James (Koutstaal, 1992)

Getting to the actual experiments described in Nature Neuroscience (Kolling, 2015): The researchers used a Japanese game called shogi in which the players make decisions concerning moves that have either an offensive or a defensive purpose. The game is well suited to this, it is said, because the moves are so clear as to whether they are defensive or offensive. So while the players are making these decisions/moves, they are followed by fMRI to identify which parts of the brain are interacting. The result was that they found very specific areas worked together when you made a defensive decision and very specific other areas worked together when you made an offensive decision. Posterior cingulate cortex reflected the subjective value of offensive strategies, while rostral anterior cingulate cortex activated as a function of the subjective value of the defensive strategy. These two regions interacted with the dorsolateral prefrontal cortex, which is said to be implicated in cognitive control. The commentary’s authors (Wan, 2015) put it this way: “… the functional connectivity results of Wan et al suggest that, in addition to distributed competition, changes in connectivity could be crucial for understanding how flexible choices could be implemented.”

This is a revolutionary view of human consciousness that appears now to have emerged from science fiction to reach a highly reputable scientific journal.

References

• Kolling and Hunt. Divide and conquer: strategic decision areas. Nat Neurosci.18(5):616-7 (2015).
• Wan, Cheng, Tanaka. Neural encoding of opposing strategy values in anterior and posterior cingulate cortex. Nat Neurosci.18(5):752-9 (2015).

 

FAMOUS PHYSICIST, DR. FREEMAN DYSON, SAYS CLIMATE MODELS USED TO PREDICT WARMING ARE GETTING WORSE, NOT BETTER

Freeman Dyson, 91 years old, has made a public statement* deploring the fact that President Obama, who Dr. Dyson says he likes and also says “I’m 100 percent Democrat myself,” has chosen the “wrong side” on the climate change issue. Dyson speculates that the issue is only partly explained by following the money (billions of government grant money on “climate change”), but also reflects (he thinks) a kind of collective yearning for apocalyptic doom.

Dr. Dyson was quoted as saying that the current scientific obsession with climate change is “not a scientific mystery but a human mystery. How does it happen that a whole generation of scientific experts is blind to the obvious facts?” It may have something to do with the recently noted (in Science and Nature) phenomenon of scientists having biases in favor of particular interpretations of data that support their political orientations. This is causing some concern among scientists who see this as something that could undermine public trust in science. (See, for example, the lead editorial in the 8 Oct. 2015 Science. Let’s think about cognitive bias.” A couple of quotes from the editorial: “One enemy of robust science is our humanity—our appetite for being right, and our tendency to find patterns in noise, to see supporting evidence for what we already believe is true, and to ignore the facts that do not fit.” “Another common fallacy in research is the Texas sharp-shooter effect—firing off a few rounds and then drawing a bull’s eye around the bullet holes.”)

* In an interview with Andrew Orlowski of THE REGISTER (a British rag). Reported in https://www.breitbart.com/big.government/2015/10/13/top-physicist…