August 2013 Blog with Durk and Sandy

APPETIZERS

The problem with doing nothing is not knowing when you’re finished.
— Benjamin Franklin

Time is what keeps everything from happening at once.
— Ray Cummings, The Time Professor (1921)

If any student comes to me and says he wants to be useful to mankind and go into research to alleviate human suffering, I advise him to go into charity instead. Research wants real egotists who seek their own pleasure and satisfaction, but find it in solving the puzzles of nature.”
— Albert Szent-Gyorgyi

And they began to deal with one another as foreigners.
— Montesquieu, The Greatness of the Romans and Their Decline

I’m not here as a serf or a vassal. I’m not begging my lords for mercy. I’m a born-free American woman, wife, mother, and citizen. And I’m telling my government that you’ve forgotten your place.
— Becky Gerritson, founder and president of the Wetumpka Tea Party in testimony before the House Ways and Means Committee 6/4/2013 on IRS abuses against her group

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

FOR THOSE USING METFORMIN, GOOD NEWS

BETTER RESULTS WHEN METFORMIN IS COMBINED WITH THE PREBIOTIC OLIGOFRUCTOSE THAN WHEN EITHER IS USED ALONE IN THE TREATMENT OF OBESITY—A RAT STUDY

A defect in glucagon-like peptide 1 (GLP-1) secretion, a hormone that increases insulin secretion and induces satiety, is believed to be one of the causes of obesity. Overeating is known to blunt the GLP-1 response to food ingestion, whereas prebiotics can improve the response to the hormone. Both oligofructose (a form of the prebiotic inulin) and metformin are known to improve GLP-1 sensitivity. Researchers decided to test whether a combination of these two treatments would result in a greater improvement in obese rats on a high fat high sucrose diet as compared to the result of treatment by metformin or oligofructose alone. They assessed the results by measuring peripheral glucose clearance through the phosphorylation (activation) of AMPK, decreasing gluconeogenesis (glucose release by the liver, which is supposed to be inhibited by insulin but in diabetics is not effectively suppressed) and increasing peripheral glucose uptake in liver and skeletal tissue.

The researchers observed a decrease in energy intake, percent body fat, and blood glucose with both oligofructose and metformin. The combination resulted in improvement as compared to the individual treatments.

“The interaction between OFS [oligofructose] and MET [metformin] affected fat mass, hepatic TG [liver triglycerides], secretion of glucose-dependent insulinotropic polypeptide (GIP) [a satiation hormone] and leptin, and AMPKalpha2mRNA and phosphorylated acetyl CoA carboxylase (pACC*) levels (p<0.05). “The rats in the OFS group had lower fat mass than the control rats, and rats in the MET group and the OFS+MET group had lower fat mass than those in the control and OFS groups. Thus, MET or the combination of OFS + MET resulted in a superior outcome by reducing fat mass as compared to that of OFS alone, while OFS alone reduced fat mass as compared to controls.

Thus, the authors conclude, metformin (already the most utilized treatment for type 2 diabetes) when combined with oligofructose has “the potential to improve metabolic outcomes associated with obesity.”

This is very good news for those taking metformin for diabetes, obesity, or obesity-related metabolic defects (such as insulin resistance), assuming that the metformin-oligofructose combination works similarly in people as it did in the obese rats. (Current data imply that it does.) Simply take supplemental oligofructose (we use long chain inulin) 2 or 3 times a day along with your usual dose of metformin.

* “ACC, the downstream target of AMPK … once phosphorylated, increases oxidation and suppresses fatty acid synthesis … The hepatic [liver] pACC [phosphorylated ACC] level was higher in rats in the OFS + MET group compared to all other groups.”

Reference

1. Pyra et al. Prebiotic fiber increases hepatic acetyl CoA carboxylase phosphorylation and suppresses glucose-dependent insulinotropic polypeptide secretion more effectively when used with metformin in obese rats.J Nutr.142:213-220 (2012).

METFORMIN INCREASES LIFESPAN OF C. ELEGANS VIA ITS EFFECTS ON THE C. ELEGANSRESIDENT BACTERIUM

The implications of this finding (assuming that it is verified) could be enormous when considering the human-microbiota system as a whole. Germ-free rodents weigh less than rodents with a normal gut microbiota, which is believed to be due to decreased extraction of nutrients from food, a form of dietary restriction. Also, rodents with a normal microbiota given a microbiota transplant from fat rodents themselves become obese on a high fat diet. The implication is that, just as the C. elegans gets less nutrients from its E. coli microbiome as a result of metformin’s antibiotic effect on the E. coli, metformin might (by a similar antibiotic effect) reduce the nutrients derived from food (and thus made available to us) by our normal gut microbiota. Indeed, metformin induces weight reduction, among other things, in diabetics that receive it as a treatment.We may be on the verge of a new expanded analysis of life extension that includes the effects of the microbiota living within us starting with a new paper¹ in Cell. There, the researchers found that metformin, said to be the most commonly used treatment for diabetes worldwide, extended lifespan in the nematode Caenorhabditis elegans by acting as an antibiotic that altered the metabolism of the E. coli that are the worm’s resident bacterium. The E. coli, the primary food source of the worm, had a decreased production of nutrients such as folate and methionine as a result of the antibiotic effect of metformin, resulting in nutritional restriction in the worm and THAT was what increased the lifespan of the worm. If this analysis is correct, then the lifespan effects of metformin on C. elegans have to be considered from the point of view of both C. elegans and its microbiome.

Interestingly. “[i]t was recently discovered that C. elegans live longer on an E. colimutant with reduced folate levels (aroD). Moreover, metformin can decrease folate levels in patients.”¹ The authors draw no conclusions from these curious facts, which may or may not be relevant to the effect of metformin in humans. We know of no studies in humans that have provided evidence for a life extending effect of metformin. Humans have such a long lifespan that such studies would be impractical. However, studies of the gene modulating effects of metformin in humans as compared to gene microarrays showing changes of gene expression with age that occur in the absence of metformin supplementation can be used to infer anti-aging gene expression changes with metformin.

It was noted by the authors of the C. elegans-metformin paper in Cell¹ that, while metformin activates AMPK (one of its antidiabetic effects), it does not increase lifespan in Drosophila and suggest that this might reflect the presence of metformin-resistant microbiota in Drosophila. This prediction shouldn’t be difficult to test.

A recent paper² reported that, using a sophisticated analysis of 184,094 sequences of the microbial rRNA genes from 9 individuals, 3 in each of the categories of normal weight, morbidly obese, and post-gastric-bypass surgery, they “detected significantly higher numbers of H2 [hydrogen]-utilizing methanogenic Archaea in obese individuals than in normal weight or post-gastric-bypass individuals.” These researchers therefore propose that “interspecies H2 transfer between bacterial and archaeal species is an important mechanism for increasing energy uptake by the human large intestine in obese persons.”² One implication of this paper’s results would be that reducing the number of methanogens in the gut would be a way to decrease energy uptake for the purpose of reducing weight.

In another paper,³ researchers tested the hypothesis that modification of the gut microbiota with two antibiotics could cause antidiabetic effects, e.g., improvement in whole body glucose tolerance. They thought that this might be the case because of prior work that showed that (for example) an infusion of a low dose of lipopolysaccharide, a component of gram-negative cell wall, leads to excessive weight gain and insulin resistance in mice concommitant with the production of low-grade inflammation. In their study,³ they found that treatment of the ob/ob diabetic mouse and diet-induced obese mice with a combination of two antibiotics, norfloxacin and ampicillin, improved whole body glucose tolerance and reduced liver accumulation of fat.

References

1. Cabreiro et al. Metformin retards aging in C. elegans by altering micorbial folate and methionine metabolism. 153:228-39 (2013).
2. Zhang et al. Human gut microbiota in obesity and after gastric bypass. Proc Natl Acad Sci USA.106(7):2365-70 (2009).
3. Membrez et al. Gut microbiota modulation with norfloxacin and ampicillin enhances glucose tolerance in mice. FASEB J.22:2416-2426 (2008).

 

GLYCINE PROTECTS BRAIN TISSUES UNDERHYPOXIC (OXYGEN DEFICIENT) CONDITIONS

Glycine is being used as a therapy for ischemic stroke² and has been reported to increase the lifespan of cortical neurons under hypoxic conditions.³ A new paper¹ now explains a mechanism underlying this protective effect that has advanced glycine to patient treatment in the clinic. Hypoxia in brain tissues was induced in rats by ligation of the common carotid artery. The resulting hypoxia reduced respiratory control in brain cortex mitochondria from 7.7 ±0.5 to 4.5 ±0.3, indicating impaired respiration. Preliminary oral administration of glycine at 40 mg/kg 4 times with 1 hour intervals almost completely prevented this decrease.The amino acid glycine, which among other things, is part of the regulatory pathways for sleep and has been shown to improve sleep quality, has been reported in a recent paper¹ to protect the brain against energetic disturbances arising under hypoxic (oxygen deficient) conditions. We think that glycine may be a useful supplement for neurological protection in those with sleep apnea.

The authors¹ report that published data “suggest that hypoxia is associated with activation of peroxidation processes in the brain tissue.” The authors, therefore, measured hydrogen peroxide accumulation in mitochondria after short-term exposure to hypoxia and found that the oxidation of succinate was accompanied by a rapid generation of hydrogen peroxide. Hydrogen peroxide formation was significantly lower after incubation of brain cortex slices with glycine. Oxidative phosphorylation (energy generation in mitochondria) was preserved in mitochondria in the presence of 5 mM glycine in the incubation medium. The researchers suggest, therefore, that mitochondria are the target of glycine in the brain cortex under hypoxic conditions. This is particularly interesting because of the fact that substances, such as many antioxidants, that are protective under the oxidative conditions induced by hypoxia frequently are unable to enter mitochondria and are, therefore, unable to provide much, if any, protection there. (Hydrogen is one antioxidant that does reach mitochondria.)

References

1. Selin et al. Mechanism underlying the protective effect of glycine in energetic disturbances in brain tissues under hypoxic conditions. Bull Exp Biol Med. 153(1):44-7 (2012).
2. Gusev et al. Neuroprotective effects of glycine for therapy of acute ischaemic stroke. Cerebrovas Dis.10(1):49-60 (2000).
3. Zhao et al. GABA and glycine are protective to mature but toxic to immature rat cortical neurons under hypoxia. Eur J Neurosci.22(2):289-300 (2005).

CHRONIC INFLAMMATION IMPAIRS ADULT HIPPOCAMPAL NEUROGENESIS PROTECTION AGAINST RADIATION DAMAGE BY HYDROGEN

The researchers also studied the effect of LPS (a bacterial cell wall component that induces a strong immune response) injected into adult female rats to produce an inflammatory cascade. They measured a 240% increase in the density of activated microglia in the dentate gyrus that was accompanied by a 35% decrease in hippocampal neurogenesis. This effect was completely blocked by systemic treatment with indomethacin. (Indomethacin under normal conditions had no effect on neurogenesis.)Using a cranial radiation injury model in adult rats, researchers found that using a dose of 10 Gray cranial irradiation with x-rays, the radiation spared roughly 30% of the neuron progenitor cells proliferative capacity but completely eliminated the production of neurons (neurogenesis).¹ As the scientists reported, “irradiation caused a striking inflammatory response characterized by the persistence of activated microglia relative to the minimal levels in normal control animals.” “If inflammation were the primary cause of the lack of neurogenic signaling within the dentate subgranule zone (SGZ), then inflammatory blockade would be expected to restore neurogenesis. Treating the irradiated animals with indomethacin (a non-steroidal antiinflammatory drug) during and after radiation exposure “partially restored the relative proportion of proliferative cells adopting a neuronal fate relative to untreated, irradiated animals (37% versus 15%, respectively).”¹

The scientists found that activated microglia produced potent inflammatory cytokines including IL-1beta, TNF-alpha (tumor necrosis factor alpha), interferon gamma, and IL-6.¹ Progenitor cells were allowed to differentiate in the presence of each of these cytokines with the result that IL-6 or TNF-alpha decreased in vitro neurogenesis by about 50%, whereas under these test conditions IL-1beta and interferon gamma had no significant effect.

This may be a mechanism by which NSAIDs such as indomethacin protect against Alzheimer’s disease, which does involve inflammation. It has been known for many years that there is a negative correlation between the use of NSAIDs and the incidence of Alzheimer’s.

Another paper² also reports increased inflammation and impaired neurogenesis as a result of exposure to radiation.

Radiation Protection By Hydrogen

Hydrogen is an effective radioprotective antioxidant,^2A as it potently scavenges hydroxyl radicals, which are the source of most tissue damage caused by radiation. Of particular importance, too, is the fact that hydrogen reaches mitochondria, thus providing protection against hydroxyl radicals there as well as other areas of irradiated tissue. As reported in a paper on targeted delivery of radioprotective agents to mitochondria,³mitochondria are the principle sources of the reactive oxygen and nitrogen species, especially hydroxyl radicals and peroxynitrite, that are importantly involved in irradiation-induced apoptosis (programmed cell death); hydrogen is a potent scavenger of both hydroxyl radicals and peroxy­nitrite.

Another natural product providing protection against the oxidative stress resulting from radiation is epicatechin⁴ (found in cocoa, grapes, tea, and apples).

References

1. Monje et al. Inflammatory blockade restores adult hippocampal neurogenesis. Science.302:1760-5 (2003).
   2. Rola et al. High-LET radiation induces inflammation and persistent changes in markers of hippocampal neurogenesis. Radiat Res.164:556-560 (2005).
   2A. Qian et al. Radioprotective effects of hydrogen in cultured cells and mice. Free Rad Res. 44(3):275-82 (2010).
   3. Zabbarova and Kanai. Targeted delivery of radioproective agents to mitochondria. Mol Interv. 8(6):294-302 (2008).
   4. Sinha et al. Epicatechin ameliorates ionising radiation-induced oxidative stress in mouse liver. Free Rad Res. 46(7):842-9 (2012).

ALPHA LIPOIC ACID PROTECTS AGAINST GASTRIC MUCOSA
DAMAGE CAUSED BY NON-STEROIDAL-ANTIINFLAMMATORY
DRUGS: INDOMETHACIN

As we have written before, the amino acid L-arginine taken at the same time as a non-steroidal antiinflammatory drug (NSAID) helps prevent the damage to the gastric mucosa that these drugs cause. A recent paper¹ now reports that alpha lipoic acid (ALA), an important natural antioxidant, is also protective against gastric mucosa damage by interfering with the prooxidant effects of NSAIDs, that includes lipid peroxidation and interference with the antioxidant systems of the mucosa. ALA is known to be an effective antioxidant because it can bind free radicals directly or indirectly and enhances the effectiveness of other antioxidants.¹

In the study, scientists treated rats with the NSAID indomethacin (IND) five minutes after receiving one of seven doses of ALA (50, 75, 100, 150, 200, and 300 mg/kg). Controls got water to a similar amount as that received by the experimental animals. Another group received IND without ALA. “All doses of ALA showed gastro­protective effect against IND-induced gastric damage in rats.”¹ In fact, the 50, 75, 100, 150, 200, and 300 mg/kg doses of ALA reduced the ulcer areas at rates of 88.2%, 89.9%, 91.4%, 93.5%, 95.1%, and 96.1%, respectively compared to the IND only group.

The researchers found that ALA increased the levels of glutathione, glutathione S-transferase, and superoxide dismutase, while decreasing lipid peroxidation, myeloperoxidase activity, and catalase in gastric tissues.¹

Incidentally, if you have ever wondered why protective substances such as ALA and L-arginine are not included in tablets or capsules of NSAIDS, it is all due to the regulations of the FDA. You’re not allowed to do it and you would also not be able to inform product users of the beneficial effects (reduced damaging effects to the stomach lining) even if you could add these protective nutrients. Just another example of how the FDA literally kills people—in fact, at least 16,500 Americans die every year of gastric ulcers brought on by the use of NSAIDS. Does this make the FDA an agency committing crimes against humanity? You bet. The FDA is far more dangerous to Americans than Al Qaeda.

Reference

1. Kaplan et al. Alpha-lipoic acid protects against indomethacin-induced gastric oxidative toxicity by modulating antioxidant system.J Food Sci. 77(11):H224-30 (2012).

THE ROLE OF COMT IN IMPATIENCE:

CHOOSING BETWEEN A SMALL PAYOFF RIGHT AWAY OR
WAITING FOR A LARGER PAYOFF LATER

A molecular genetics study in 2007² identified a particular polymorphism (Val158Met) of the COMT gene as being associated with a steeper DD, that is, linked to a stronger preference for immediate as compared to later rewards. “The Val allele (compared to the Met allele) is associated with higher enzymatic activity and thus lower prefrontal cortex dopamine levels.”¹ The heritability of DD has been reported in a recent twin study to explain up to 50% of the individual differences in DD.¹A new paper¹ reports a reason why people differ in how much they prefer an immediate small payoff rather than waiting for a larger payoff later. This is called the discount rate and, as the researchers note,¹ has a large effect on whether one leads a healthy and successful life. They identify disorders such as substance abuse, pathological gambling, overeating, relationship infidelity, and Attention Deficit Disorder as examples of how impulsively choosing short-term rewards can often lead to costly consequences. Their new research1 focused on the effect of COMT (catechol-O-methyltransferase, a gene regulating the enzyme that degrades dopamine, thus controlling the level of dopamine especially in the prefrontal cortex) on the individual’s DD (delay discounting, the tendency to prefer immediate over future rewards

These researchers used an EEG technique to determine neural baseline (what the authors called a “neural fingerprint”) to establish a stable resting EEG, which they could use for observing COMT influences on the neural baseline activation. The seventy-three healthy Swiss men (mean age = 25.7 years, SD = 5.0 years) had their EEGs recorded in a protocol of 20 seconds eyes open followed by 40 seconds eyes closed, repeated five times. Only data from the eyes closed condition were analyzed. Then they had buccal epithelial cells collected for DNA.

A greater number of Val alleles was associated with a lower level of baseline activation in the left dorsal prefrontal cortex (DPFC), which in turn leads to a steeper DD (greater preference for immediate as compared to delayed rewards), which the authors called “impatient choice.”

An increase in EGCG/green/white tea consumption by a population might well have very substantial long-term effects on the general level of prosperity by increasing savings and investment versus immediate consumption gratification. The populations of both China and Japan save and invest a much higher percentage of their incomes than Americans; perhaps their higher levels of tea drinking has something to do with this.As the paper described in the article before this one explains, EGCG has been found to be a natural inhibitor of COMT, decreasing the degradation of L-Dopa, which increases the availability of L-Dopa to enter the brain to be converted to dopamine. This is consistent with the results of other studies that have reported a reduced risk of Parkinson’s disease in those who drink tea regularly. (Green and white teas contain much higher levels of catechins, including EGCG, as compared to black tea.) It is therefore conceivable that tea drinking may affect delay discounting (DD) of individuals by modulating the activity of COMT to mimic the effects of having a COMT polymorphism that fosters a less impulsive DD.

References

1. Gianotti et al. Why some people discount more than others: baseline activation in the dorsal PFC mediates the link between COMT genotype and impatient choice. Front Neurosci.6:54. doi: 10.3389/fnins.2012.00054. (May 2012).
2. Boettiger et al. Immediate reward bias in humans: frontoparietal networks and a role for the catechol-O-methyltransferase 158(Val/Val) genotype. J Neurosci.27:14383-91 (2007).

BENJAMIN FRANKLIN ON POVERTY

Our new Constitution is now established, and has an appearance that promises permanency, but in this world nothing can be said to be certain except death and taxes …

I am for doing good to the poor, but I differ in opinion of the means. I think the best way of doing good to the poor is not making them easy in poverty, but leading or driving them out of it. In my youth I traveled much, and I observed in different countries, that the more public provisions were made for the poor, the less they provided for themselves, and of course became poorer. And, on the contrary, the less was done for them, the more they did for themselves, and became richer.
— Benjamin Franklin

OUT OF THE GOODNESS OF THEIR HEART

“In July 2003, the FDA began allowing qualified health claims for food in an effort to make it easier for food manufacturers to make health benefit claims for their products. Even if the scientific evidence in support of the claims are conclusive, the FDA has been helping the consumers to obtain accurate, up-to-date science based information about the health effect of these products.”

(Sorry, folks. This quote taken from Functional Foods, Nutraceuticals, and Degenerative Disease Prevention, edited by Paliyath, Bakovic, and Shetty, published by Wiley-Blackwell (2011) is not true. The reason the FDA began allowing qualified health claims is that they lost a Court decision (Pearson v. Shalala) that prohibited the agency from censoring truthful, non-misleading information on labels and in adverts for dietary supplements and foods. If they hadn’t lost this landmark decision, the FDA would still be censoring all truthful health claims in violation of the First Amendment’s guarantee of free speech.)

U.S. SUPREME COURT DECISION IN U.S. V. JONES: SEARCH
WARRANT REQUIRED FOR ATTACHING GPS DEVICE TO
CAR, DECIDED JAN. 23, 2012

In a decision limiting the government’s surveillance powers, a recent U.S. Supreme Court decision (majority opinion written by Scalia) determined that, on the basis of trespass as well as the expectation of privacy, attaching a GPS device to a vehicle was a search within the meaning of the Fourth Amendment at the time it was adopted and, hence, a warrant was required.

The Court agreed 9–0 that this was a search requiring a warrant. Perhaps most interestingly, however, there was a division on the Court as to the reason that this came under the Fourth Amendment’s prohibition on unreasonable searches and seizures. There was the majority opinion in which Scalia was joined by Roberts, Kennedy, and Sotomayer. Sotomayer also filed a separate concurring opinion, while Alito (joined by Ginsburg, Breyer, and Kagan) filed an opinion concurring in the judgment. The Alito concurrence did not agree on a trespass basis for the Fourth Amendment violation, but relied on the “expectation of privacy” argument. The big surprise, however, was the concurring opinion by Sotomayer, which agreed with the majority opinion on trespass and “expectation of privacy” arguments for a Fourth Amendment requirement for a warrant. Moreover, Sotomayer said, “I would also consider the appropriateness of entrusting to the Executive, in the absence of any oversight from a coordinate branch, a tool so amenable to misuse, especially in light of the Fourth Amendment’s goal to curb arbitrary exercises of police power to and prevent ‘a too permeating police surveillance.’”

Sounds as though Sotomayer has (maybe) declared her independence from Obama, at least with respect to the Fourth Amendment.

Though this SCOTUS decision favored Fourth Amendment protections against unreasonable searches and seizures, a more recent 5–4 decision did the opposite by allowing police to take DNA samples without probable cause or a warrant from people who have been arrested but not convicted of anything. Scalia was incensed by the decision and insisted on reading his dissent word for word before the entire court. BRAVO!

Coercively taking a DNA sample from a mere suspect is NOT like taking a photograph or fingerprints! It is forcibly taking a piece of your body containing your internal blueprint, which is a search or seizure going much farther than a mere warrantless search/seizure of your home. Moreover, it is far easier to salt a crime scene with an innocent person’s DNA than with fake fingerprints. Want to imprison someone you hate? Swab their driver’s side car door handle, smear it on a piece of child porn, and send it to the FBI …

Who Needs Data? Just Stick Your Finger in The Air

A study reported in the 1 Feb Science reveals that, when asked whether humans are causing climate change, Democrats were likely to say yes, Republicans likely to say no, but Independents were likely to say yes on unseasonably warm days but to say no on unseasonably cold days. No surprise but it just goes to show that very short term events rather than consideration of the totality of the evidence can be a deciding factor in how people perceive the possibility of human-induced global warming. This is an excellent way for those looking for the “right” response to a survey to plan when to ask people if they think humans are causing climate change.

HAPPINESS RESEARCH

THE EFFECT OF PERIPHERAL CIRCULATING PRO-INFLAMMATORY CYTOKINES AND PERCEIVED HAPPINESS IN MIDDLE-AGED ADULTS IN JAPAN

A recent study¹ reports on a possible connection between the level of circulating proinflammatory cytokines and perceived happiness, where higher amounts of one of these cytokines, interferon gamma, was correlated with lower levels of happiness.

Experiment 1 involved 160 healthy volunteers (77 males and 83 females, ranging in age from 19–40 years). The researchers screened the subjects for their perceived level of happiness by taking the Japanese version of the subjective happiness scale (JSHS), using the results to divide the group into high happiness respondents and low happiness respondents. Statistical analysis of the two groups found that the high happiness group had significantly higher scores on the Japanese translated version of the Short-Form 36 Health Survey in general health, vitality, emotional role, and mental health as compared to the low happiness group. “Interestingly, serum concentrations of IFNgamma [interferon gamma] were significantly lower in the high happiness group … than in the low happiness group.”

Experiment 2 involved 7 romantic couples; 7 males and 7 females aged 21–38 years. They were requested to answer a number of questions concerning their feelings of romantic love for their partners using the Passionate Love Scale (PLS), which contained questions such as “Sometimes I can’t control my thoughts; they are obsessively focused on __________.” “I would rather be with __________ than anyone else.” The participants were considered to have relatively passionate love relationships. The couples then spent 1 hour in a room with closed doors in which they could kiss and hug but not have intercourse. (This study gets more interesting the longer it goes on.) This was called a warm contact session, after which the couples were asked questions such as “Did you kiss and hug your partner very much?” and “Did you sense your partner’s love?” The results indicated that there was a lot of warm contact in the warm contact session.

Before the warm contact session, however, participants were requested to evaluate their present happiness and blood samples were drawn. Then, with 1 partner remaining in the closed room, the other partner was moved to a second room where he or she read a book (not a book about romance) for 1 hour with closed doors. After that, a second blood sample was drawn. There was at least a 2 week interval between the two conditions and the order of the two conditions was counterbalanced across couples. Finally (yes, there is a finally) the participants were asked to evaluate their feelings of happiness on a scale of 1 (not at all) to 7 (Yes, extremely): Do you feel happy at present?

The IFNgamma (interferon gamma) concentration decreased significantly after the warm partner contact but did not change in the control condition (reading a book). Moreover, the IFNgamma concentration was lower and health related QOL was higher in individuals with self-perceived high happiness than in those with self-perceived low happiness.

How Interferon Gamma Relates to Happiness

Interferon gamma is a pro-inflammatory cytokine that has been shown to reduce circulating serotonin levels by increasing the activity of indoleamine 2,3-dioxygenase, an enzyme that degrades tryptophan, hence reducing tryptophan available for the brain to convert to serotonin. Reduced brain serotonin levels can result in depression. “… previous studies indicated that circulating pro-inflammatory cytokine levels in individuals with depressive symptoms were higher than those in individuals with no depressive symptoms.”¹

The researchers also report that their previous study2 found that “the short form of the serotonin transporter gene-linked polymorphic region, which increases serotonin secretion from presynaptic neurons through reduced serotonin reuptake, also enhances amygdala response to desired persons. When IFNgamma levels decrease, the reactivity to positive stimuli increases, and consequently, the evocation of happiness is enhanced.”

The only question remaining, then, is what would have happened to the happiness score and the IFNgamma levels if the couples had been allowed to have intercourse behind those closed doors. We assume that followup experiments will tie up that loose end. In the meantime, we note that since the couples were left in privacy behind closed doors, there is no way to actually know whether they obeyed the instruction to not have intercourse. We leave it to the reader to consider the implications.

References

1. Matsunaga et al. Association between perceived happiness levels and peripheral circulating pro-inflammatory cytokine levels in middle-aged adults in Japan. Neuro Endocrinol Lett. 32(4):458-63 (2011).
2. Matsunaga et al. Genetic variations in the serotonin transporter gene-linked polymorphic region influence attraction for a favorite person and the associated interactions between the central nervous and immune systems. Neurosci Lett. 468:211-5 (2010).

GETTING L-DOPA INTO THE BRAIN

EGCG: SIGNIFICANT ADVANCE IN TREATMENT OF PARKINSON’S DISEASE

The most common treatment for Parkinson’s disease (PD) is a combination of levodopa (L-Dopa) and carbidopa. The L-Dopa serves as the precursor for production of dopamine in the brain where its deficiency (in the striatum) can result in severe movement disorders typical of PD. The carbidopa is a dopa decarboxylase inhibitor and is combined with the L-Dopa because it restricts the peripheral conversion of L-Dopa to dopamine, allowing the L-Dopa to enter the brain and be converted there where it is needed, while reducing the peripheral effects of increased dopamine, such as lowered blood pressure.

A new paper¹ now reports that taking EGCG along with L-Dopa and carbidopa results in a significantly increased beneficial effect of therapy by modestly inhibiting the methylation of L-Dopa by the enzyme catecholamine-O-methyltransferase (COMT), thus preventing the rapid conversion of L-Dopa by the liver to inactive 3-O-methyldopa. “Studies have shown that the use of a COMT inhibitor is particularly helpful in controlling the wearing-off phenomenon in PD [Parkinson’s disease] patients by prolonging the half-life of L-Dopa and improving its brain entry.”¹

The researchers got the idea for testing the effectiveness of EGCG as a COMT inhibitor as part of Parkinson’s disease therapy from the fact that catechol-containing bioflavonoids and tea catechins have been identified as good substrates for COMT. In addition, these compounds have also been found to be strong inhibitors of liver COMT-mediated O-methylation of endogenous catechol estrogens. “Among these dietary compounds, EGCG was found to be the most potent inhibitor, with an IC50 [concentration required to inhibit the enzyme by 50%] of approximately 0.1 μM when 2-hydroxyestradiol was used as substrate.” The authors of the paper¹ also note that “[t]he findings of this study may also shed a mechanistic light on the recent epidemiological observation suggesting that regular tea drinking is associated with a reduced risk of PD.”

Male Sprague-Dawley rats were the experimental animal in the study. The researchers note that an earlier study reported that EGCG given at a daily oral dose of 500 mg/kg for 13 weeks was not toxic in rats. The doses used on the rats in this study¹ were 100 and 400 mg/kg, given two hours before L-Dopa/carbidopa. Results showed that the rats treated with 400 mg/kg had levels of 3-OMD in circulation and in the striatum that were reduced by approximately 30%, revealing the decrease in L-Dopa methylation.

The authors report that earlier human studies showed that “circulating concentrations after oral administration of 800 mg EGCG are higher than its effective IC50 concentrations required for inhibiting L-Dopa methylation in vitro. Therefore, it is possible that oral administration of EGCG may readily reach therapeutically-effective concentrations needed for inhibiting L-Dopa methylation in PD patients.”¹ Moreover, the authors suggest, although daily intake of EGCG through tea drinking may not yield the therapeutically effective concentration, there are other polyphenolic components contained in tea and coffee that also contain the same catecholic structures as does L-Dopa, thereby making them good substrates of and thus inhibitors of COMT.

Interestingly, the authors¹ suggest that the reduction in striatal 3-OMD level may aid in reducing side effects associated with L-Dopa/carbidopa therapy in PD. One study cited by the authors found that the plasma levels of 3-OMD in patients with dyskinesia were significantly higher than those in patients without dyskinesia. Also, they note that it has been suggested that 3-OMD accumulation following long-term L-Dopa treatment might contribute to progression of the neurodegeneration in PD patients.

Reference

1. Ki Sung Kang et al. Dual beneficial effects of (-)-epigallocatechin-3-gallate on levodopa methylation and hippocampal neurodegeneration: in vitro and in vivo studies. PLoS One.5(8):e11951 (Aug. 2010).

PIMA INDIANS: FROM A HEALTHY DIET TO A DIABETES-PROMOTING ONE

When the white men arrived in North America, the Pima Indians were eating a considerable amount of purple corn that they grew themselves. Purple corn is, of course, chock-full of anthocyanins. After the white men put the Indians on reservations and provided “free” food (only free if you disregard the value of the Indian lands seized in the process) that didn’t include purple corn, the Pima Indians became a population plagued by diabetes and hyperobesity. They have been frequently studied as populations with a genetic predisposition to diabetes, but their main problem may be a switch from an evolved diet that inhibited the development of diabetes (with purple corn-derived anthocyanins likely to be a major factor in that protection^1–4) to one (given to them for “free”) that did the opposite.

The moral of this sad story could be to beware of governments bearing free gifts after they have stolen much of your wealth. At a different level, the moral is to beware of making dramatic changes in your diet from the one your forebearers had, over thousands of years, evolved to consume and thrived on.

References

1. Li et al. Purple corn anthocyanins dampened high-glucose-induced mesangial fibrosis and inflammation: possible renoprotective role in diabetic nephropathy. J Nutr Biochem.23(4):320-31 (2011 May 2).
2. Tsuda et al. Dietary cyanidin 3-O-beta-D-glucoside-rich purple corn color prevents obesity and ameliorates hyperglycemia in mice. J Nutr. 133:2125-30 (2003).
3. Regulation of adipocyte function by anthocyanins: possibility of preventing the metabolic syndrome. J Agric Food Chem.56:642-6 (2008).
4. Tsuda et al. Microarray profiling of gene expression in human adipocytes in response to anthocyanin. Biochem Pharmacol.71:1184-97 (2006).

NEUROGENESIS

LITHIUM RESTORES NEUROGENESIS IN MOUSE MODEL
OF DOWN’S SYNDROME, CORRECTING COGNITIVE DEFECTS

A remarkable feat of pharmacological treatment to induce adult neurogenesis in a mouse model of Down’s syndrome¹ suggests the possible correction of cognitive impairments in humans with the disorder.

Cognitive defects are the most prominent features of human Down’s syndrome, resulting from three copies of Chromosome 21 rather than the normal two copies. One would think that to correct the features of the disease it would be necessary to administer genetic therapy. However, researchers publishing a new paper¹ found that treatment with the mood stabilizer lithium markedly increased adult neurogenesis in the subventricular zone (SVZ) of the brain as well as restoring brain volume in several areas where it is smaller than in normal mice.

In individuals with Down’s syndrome, brain hypotrophy is particularly evident in the cerebral hemispheres, frontal lobe, temporal cortex, hippocampus, and cerebellum and shows up early in development.¹

The Down’s syndrome mouse is produced by creating three copies of a distal region of the mouse chromosome 16—“a region that shows perfectly conserved linkage with human chromosome 21.”¹ Treatment with lithium resulted in an 85% increase in the pool of proliferating cells in the Down’s syndrome mice, while the pool was increased in the normal mice by 54%. “In the [Down’s syndrome mouse] the number of Brdu+ [label indicating proliferation] cells became similar to that of the untreated euploid [normal] mice.” DOSAGE: The DS female mice were, starting from the age of 12 months, treated with lithium contained in their food pellets at 2.4 g of Li2CO3/kg of food for one month. This dose scales to approximately that used to treat mania and bipolar disorder in humans. Since renal excretion varies, doses would need to be individualized based on readily available blood tests.

The authors conclude in a carefully worded summation: “If such a treatment will be proven to be effective [in humans], this might open the way to possible therapeutic intervention practicable by human subjects, aimed at correcting defects in brain development in DS individuals.”

LITHIUM AS AN ESSENTIAL NUTRIENT

A 2012 paper² provided detailed information on the presence of lithium in drinking water and vegetation and on its essentiality in a large number of animal and human studies.

The review reported that there is a wide variation in the amount of lithium found in drinking water, spring water, spa water and bottled water. One study of 132 brands of bottled water from 28 countries found lithium concentrations ranging over 5 orders of magnitude (from 0.057 to 5,460 μg/l. “Li concentrations of 8.7 mg/l and of >9 mg/l have been reported for the Friedrich-Quelle, a famous spring in Baden-Baden/Germany, and for the spa water in Pompeya/Argentina, respectively.”²

“The long-term consumption of low-Li drinking water is regarded as a risk factor for higher incidences of suicides, homicides, and crimes as shown in several studies. For example, in 24 counties in Texas/USA with a total population of 6 million (>60% of the state population), during a 2-year study (1967-1969), a significantly inverse relationship between 1) Li concentration of local drinking water, 2) Li concentrations of the urine among the respective residents, and 3) mean annual rainfall amounts in the respective county sites and 1) state mental hospital admission rates, 2) admitting rates for four major mental disorders (psychosis, neurosis, schizophrenia, personality problems), 3) homicide rates, and 4) road distance from resident county to nearest state mental hospital was found (p ≤ 0.05 to ≤ 0.001). The Li levels in drinking water were classified into 4 groups: <11.0; 11.0–29.9, 30.0–69.9; >70.0 μg/l.”²

A second study reported in the review² included 27 counties and lasted for 10 years (1978–1987) and found that that the incidence rates of suicide, homicide, and rape were significantly higher in counties whose drinking water contained low (0–12 μg/l) and medium (13–60 μg/l) lithium concentrations than in counties whose drinking water had high Li concentrations (79–160 μg/l)(p<0.01). They also found associations with the rates of robbery, burglary, and theft significant at p<0.05. These are really remarkable differences that suggest improved mental function with low dose lithium.

On the basis of these and many other studies, the basic requirement of lithium in humans has been assessed at 1 ug/kg. body weight/d in humans derived from intake data in Germany, thus, the lithium requirement for an adult of 70 kg body weight would be 70 μg/d. In another assessment study, Schrauzer suggested a provisional recommended dietary allowance (RDA) of 1 mg lithium/day for an adult of 70 kg body weight.³

References

1. Bianchi et al. Lithium restores neurogenesis in the subventricular zone of the Ts65Dn mouse, a model for Down syndrome. Brain Pathol. 20:106-18 (2010).
   2. Schafer. Evaluation of beneficial and adverse effects on plants and animals following lithium deficiency and supplementation, and on humans following lithium treatment of mood disorders. Trace Elem Electrolytes. 29(2):91-112 (2012).
   3. Schrauzer. Lithium: occurrence, dietary intakes, nutritional essentiality.J Am Coll Nutr. 21:14-21 (2002).

GENOME-WIDE METHYLATION PROFILES OF 656 INDIVIDUALS
REVEALS EPIGENETIC CHANGES IN AGING

CHANGES IN METHYLATION PREDICT AGE
AND ARE ASSOCIATED WITH COMPLEX DISEASES

At a completely different level than the human genome, the human methylome represents a map of the methylation of DNA, which determines how genes are expressed. Consequently, it helps reveal how alterations in the regulation of DNA transcription (whether a gene is turned on or off) takes place throughout life. For example, a new paper¹ discusses the fact that “epigenetic drift” takes place in identical twins, where the methylation marks increasingly differ with age, causing them to “drift” from their starting point with identical DNA at birth. The DNA remains the same (except for mutations) but is expressed differently as a result of methylation-induced changes.

As the authors¹ put it (and we couldn’t have put it better): “the idea of the epigenome as a fixed imprint is giving way to the model of the epigenome as a dynamic landscape that reflects a variety of chronological changes.”

In this fascinating paper, the researchers have determined DNA methylation at more than 450,000 CpG markers (where the methylation takes place) from the whole blood of 656 human individuals, aged 19 to 101. Their model, based upon the data they got from these measurements, can be used to determine the rate at which an individual’s methylome ages.¹ They found an optimal model consisting of a selected set of 71 methylation markers; this model was highly predictive of age, with a correlation between age and predicted age of 96% with an error of 3.9 years.¹ “Nearly all markers in the model lay within or near genes with known functions in aging-related conditions, including Alzheimer’s disease, cancer, tissue degradation, DNA damage, and oxidative stress.”

Another finding was that the methylome of men appeared to age approximately 4% faster than that of women. The scientists also compared the methylome derived from whole blood to that of breast, kidney, lung, and skin samples and found strong predictive power for chronological age for these tissues as well, although noting some linear offset from the expected age prediction. Another finding was that “tumors appear to have aged 40% more than matched normal tissue from the same individual. Accelerated tumor aging was apparent regardless of the primary tissue type.” Moreover, the researchers compared the methylation changes of tumors to normal tissue, examining all 70,387 age-associated markers, where 44% tend to increase and 56% tend to decrease with age. The tumor markers coincided with older values by 74% of the markers regardless of the trending direction (e.g., whether they increased or decreased).

The scientists even determined (using a mathematical model developed by Shannon and Weaver²), the increase in entropy (loss of information content) in the methylome over time. As the researchers explain it, “[a]n increase in entropy of a CpG marker means that its methylation state becomes less predictable across the population of cells (i.e. its methylation fraction tends toward 50%).” The researchers found a highly significant increase in methylome entropy over the sample cohort. “Furthermore, extreme methylome entropy for an individual was highly correlated with accelerated aging rate …”¹

The scientists suggest that this model could be used to assess the aging rate of an individual and to determine whether diet or environmental factors can accelerate or or retard the aging process and diseases of aging.

This is a remarkable new development that is just now beginning to be used in aging research. Better yet would be if such measurements were to become inexpensive enough for individuals such as ourselves to monitor our own aging.

Reference

1. Hannum et al. Genome-wide methylation profiles reveal quantitative views of human aging rates. Mol Cell.49:359-67 (2013).

THE NEW ECONOMICS OF ORPHAN DISEASES

Another article¹ on hot research areas in the pharmaceutical industry notes that the search for orphan drugs has attracted a lot of interest because of smaller clinical trial size, shorter trial time, and commercial benefits such as fast track FDA approval, tax credits, and fee waivers. Not mentioned in the article, though, is what may prove to be the most important incentive to develop orphan drugs: after getting approval for an orphan drug, off-label uses may be the entryway to much larger markets involving common diseases. Importantly, recent court decisions have provided much support of the First Amendment rights of companies to provide truthful, non-misleading scientific information on off-label uses of drugs approved for other purposes. This is a very effective way to increase the availability of therapies for both rare and common diseases and to improve physician (and public) awareness of these therapies.

“Orphan status is granted to drugs for which the costs of developing and marketing a therapeutic are unlikely to be recovered, and in the U.S., to diseases that affect fewer than 200,000 people …” (The reason why the costs would be unlikely to be recovered is, of course, the huge developmental costs imposed by FDA’s rules and regulations for getting approval.) The article further notes that since the Orphan Drug Act of 1983 was passed, the FDA has approved 350 drugs and biologics for approximately 200 orphan diseases. These treatments are said to account for about 22% of current drug sales, with a total global value of about $50 billion, according to the article.¹

We believe that these beneficial court decisions resulted from applying the First Amendment arguments that won our landmark decision in Pearson v. Shalala (U.S. Court of Appeals for the District of Columbia, 1999) (that protects truthful non-misleading speech on the health effects of dietary supplements and foods) to prescription drug marketing.

Reference

1. The new economics of orphan diseases. Genetic Engineering & Biotechnology Newspp. 12-13 (Jan. 1, 2013).

LATEST BLOCKBUSTER TREATMENT FOR LIFE THREATENING BACTERIAL INFECTION: FECES TRANSPLANTATION!

Recurrent Clostridium difficile infection is reportedly difficult to treat. The responsible bug, an enterocolitis bacteria, recurs after antibiotic treatment in about 25% of patients.¹Those who suffer a recurrence are more likely to have a second recurrence after treatment, with the subsequent recurrence rates surpassing 50%.¹

Amazingly, about 50 years ago, doctors tried an infusion of donor feces (fecal microbiota transplantation) for these these life-threatening resistant C. difficile infections and found an “immediate and dramatic” response. Yet it appears the treatment has not won favor with medical practitioners despite what the New England Journal of Medicinecalls an “alarming increase in the incidence and severity of this disorder.”¹ According to the Journal, only the most desperate patients are likely to want feces transplantation. The reasons for the failure of this treatment to catch on are given in the article as: “it is aesthetically unappealing, it is logistically challenging (in terms of harvesting and processing suitable donor material), and there is a lack of efficacy data from randomized, controlled trials.” The problem of lack of data from randomized, controlled trials has been solved by the publication² of a clinical trial of the treatment.

The results of the trial² showed that fecal microbiota transplantation (FMT) was effective in 81% of patients. As the authors of the paper declared, “[t]he results of this study represent a clear precedent in which planned therapeutic manipulation of the human intestinal microbiota can lead to demonstrable, clinically important benefits, thereby bringing FMT to the mainstream of modern, evidence-based medical practice.” The author of the commentary on the clinical trial study¹ suggests similar trials of this sort of therapy for other indications, such as inflammatory bowel disease, irritable bowel syndrome, prevention of colorectal carcinoma, and metabolic disorders, as examples. “As such, it heralds the delayed adolescence of a broad and exciting new branch of human therapeutics.”¹

The authors of the trial² noted that patients receiving the feces transplantation had increased fecal bacterial diversity, similar to that in healthy donors, with an increased quantity of Bacteroidetes species and clostridium clusters IV and XIVa and a decrease in Proteobacteria species.

There is something very amusing about this, as one visualizes the source of the therapeutic medicine. And especially nice to see a disorder that was killing people reined in, even by the likes of resident bacteria in shit. Now we wonder how the FDA will generate rules and regulations to make sure the shit is under their control and, hence, very expensive. To start with, note that the shit is regulated by them as a drug (biological).

SHIT WARS

THE FDA AGAINST MEDICINAL POOP

Now, however, in a more recent report on feces transplantation published this year in Nature,³ we learn that the FDA has declared feces transplantation to be under its authority and has begun issuing rules that will slow down this development and even risk the lives of critically ill people who will be made to wait for the FDA to decide whether to grant their doctor an Investigative New Drug Application before the doctor can proceed with the treatment (the FDA has 30 days to stop an experiment). In typical FDA fashion, the agency simply decreed its regulatory authority over feces transplantation without waiting for Congress to grant them the authority via statute; hence, the FDA has no legitimate authority over medicinal shit.

The June 20, 2013 GenomeWeb Daily News reports that the FDA’s attempt to take over regulation of feces transplants has run into an outcry by doctors pointing out that seriously ill patients don’t have time to wait for the FDA to grant an Investigative New Drug Application. In response, the FDA is reported to be exercising enforcement discretion (e.g., they are still claiming to be in CONTROL of feces transplantation but will (maybe) not prevent (on a case by case basis) a doctor from performing the procedure, depending on whether the agency bureaucrats feel magnanimous that day or not. The rule of law means nothing when all decisions are made at the discretion of bureaucrats.

There is some good news, however. The article¹ points out that, interestingly, “[r]esourceful individuals can [ ] get in on the act at home, by following step-by-step enema instructions from online videos.” The FDA is likely to find it a great deal more difficult to stop the production of how-to-do-it videos, as the First Amendment has the authority (last we heard) over free speech. It might be safer (as well as a lot less messy), however, if people could get the procedure done by a qualified doctor rather than doing it themselves.

One concern is that the fecal material being transplanted is not “standardized” and that there may be considerable variation in their contents. We think that attempting to standardize feces transplants at this point is a mistake because of the limited amount of information on what are the important components (including the probiotics) that produce positive results. More experimentation with different varieties of feces makes sense to us than deciding by decree, in the absence of a lot more experimental data, what would be appropriate in a “standardized” version of feces. One researcher, infection-disease specialist Trevor Van Schooneveld of the University of Nebraska Medical Center in Omaha was reported in the article as having performed about 20 feces transplants since 2011, but in the past few weeks he has had to turn down patients while he submits his Investigative New Drug application. “Van Schooneveld questions whether the agency should preside over an organic, personal substance, rather than a drug. ‘How the FDA plans to regulate human feces is a mystery to me,’ he says.”

We couldn’t agree with Dr. Van Schooneveld more. But the most serious problem of FDA meddling is what happens to people facing a potentially fatal infection and having to wait 30 days while the FDA decides whether it is going to allow their doctors to proceed with a feces transplantation. Is the FDA going to pay for the damages resulting from the delay, including the possible death of the patient? Of course not. Too bad if you die while they are playing games with your brother’s, sister’s, mother’s, or father’s shit. We truly can’t understand how a large majority of the public actually believes that the FDA is protecting the public health!

References

1. Fecal microbiota transplantation – an old therapy comes of age. N Engl J Med. 368(5):474-5 (Jan. 31, 2013).
2. van Nood et al. Duodenal infusion of donor feces for recurrent Clostridium difficile. N Engl J Med.368:407-15 (2013).
3. FDA gets to grips with faeces. Nature.498:147 (13 June 2013).

MINOR SCIENTIFIC MYSTERY SOLVED

IF YOUR UNDERARMS DO NOT SMELL BAD WHERE DO YOU SUPPOSE THE BACTERIA RESPONSIBLE FOR UNDERARM MALODOR HAVE GONE?

A recent paper¹ reports that there is a recessive gene that makes the armpits of a lucky 2% of the European population and most people of Asian descent free of underarm malodor. Those lucky people have two copies of the recessive gene for a transporter that fails to transport the necessary excreta to reach the bacteria living under your armpits that usually feed on this stuff, making a stink while they’re at it. (It is not clear from the article² describing the paper where the excreta actually ends up. Could the underarm microbiota be altered as a result of the rare transport glitch?) As the authors of the article put it people who don’t have smelly armpits may have a malfunctioning transporter gene.

The thing that is weird about all this is that of the people who probably don’t need to use underarm deodorants because of their screwed up stink transporter, 78% still do according to the article. In an attempt to explain the unexplainable, the article authors offer the following: England is still dominated by people with smelly armpits, a constant reminder to people to put on something to suppress what they may not have. In a very informative statistical analysis, the authors point out that since being stink-free is so rare in the U.K., both parents of an “odorless” child are probably heterozygous, e.g., they carry a dominant allele for the stink and a recessive allele for no stink. They themselves do stink. Only ¼ of these parents’ kids will be stink-free. This may explain why people take no chances and put on underarm smell protection. Moreover, they suggest that ubiquitous advertising has overwhelmed people’s thinking abilities to where they naturally assume they must be in need of protection against the socially dangerous stench. (Sandy occasionally uses rubbing alcohol, which kills any bugs lurking around waiting for dinner to chemically convert into a stench. Works like a charm. Durk takes a lot of showers.)

References

1. Rodriguez et al. Dependence of Deodorant Usage on ABCC11 Genotype: Scope for Personalized Genetics in Personal Hygiene. J Invest Dermatol.133(7):1760-7 (2013 Jul).
2. Fear of stink, driven by pheromones. Chemical & Engineering News.Volume 91, Issue 8, p. 48 (Feb. 25, 2013).