September 2012 Blog with Durk and Sandy

APPETIZERS

When faced with a problem you do not understand, do any part of it you do understand, then look at it again.— Robert A. Heinlein, The Moon is a Harsh Mistress, 1966

Nothing uses up alcohol faster than political argument.— Robert A. Heinlein, The Moon is a Harsh Mistress, 1966

He’s dead, Jim.— Dr. McCoy, first time said, in Star Trek episode “The Enemy Within,” 1966Never trust a species that grins all the time. It’s up to something.— Terry Pratchett [on dolphins], Pyramids, 1989

The researches of many commentators have already thrown much darkness on this subject, and it is probable that, if they continue, we shall soon know nothing at all about it.— Mark Twain, quoted in
The Sciences, Sept.-Oct. 1989

HYDROGEN THERAPY UPDATE

We continue here our series on the emerging new area of the use of hydrogen as a therapy for diseases associated with oxidative stress and inflammation. We refer you to our original article “Hydrogen Therapy” (see June issue of Life Enhancement) in which we describe mechanisms that may explain how hydrogen works, as has been reported in scientific and clinical studies, to provide beneficial effects in ischemia/reperfusion injury (as occurs in heart attacks and strokes), insulin resistance, protection against radiation-induced tissue injury, neuroprotection (as studied in animal models of Parkinson disease and cognitive impairment), atherosclerosis, and others.

Hydrogen is a selective antioxidant that protects against the highly toxic hydroxyl radicals and against the potent oxidant peroxynitrite (a natural product of the reaction between superoxide radicals and nitric oxide). Conveniently, hydrogen gas is produced naturally in the gut by certain resident bacteria and diffuses throughout the body, reaching even into mitochondria and crossing the blood-brain barrier, leaving the body largely by exhalation from the lungs (though some of the hydrogen is taken up and used as energy by hydrogen-metabolizing bacteria). Importantly, hydrogen production by those resident gut bacteria that produce hydrogen (as a byproduct of fermentation) can be enhanced by eating appropriate prebiotics (foods for your intestinal microbiota). We feed our microscopic friends two or three times a day.

Hydrogen (In the Form of Hydrogen-Rich Saline) Reported to Attenuate Vascular Dysfunction in Spontaneously Hypertensive Rats

The authors of a new paper¹ studied the possible protective effects of hydrogen (administered via hydrogen-rich saline (HRS) that was injected intraperitoneally each morning for 3 months in the experimental animals) on the usual development of hypertension in spontaneously hypertensive rats (SHR).

The rats were 8 week old male SHR and age-matched normotensive Wistar-Kyoto (WKY) rats. The animals were divided into four groups (with 12 animals in each group) and treated for 3 months as follows: WKY treated with saline only (containing no dissolved hydrogen); WKY treated with HRS; SHR treated with saline; and SHR treated with HRS.

Results showed that HRS significantly improved endothelium-mediated vascular relaxation in the hydrogen-rich saline treated SHR as compared to the SHR that received only saline. SHR had increased oxidative stress in aorta (total ROS, superoxide, and peroxynitrite were all significantly higher than in WKY animals), but treatment with HRS resulted in a significant reduction in all of these markers of oxidative stress. Anti-inflammatory effects of HRS were revealed in treated SHR, which had a significant reduction in levels of pro-inflammatory cytokines IL-6 and IL-1 beta in serum and aorta as compared to untreated SHR. HRS also significantly reduced activation of NF-kappaB, a major regulator of inflammation, in aorta of SHR as compared to SHR that did not receive HRS.

Interestingly, mitochondrial dysfunction in SHR (reduced activities of Complex I and III and reduced ATP production) was ameliorated via significantly decreasing ROS production, increasing ATP production, and reducing mitochondrial swelling. These results confirm that hydrogen is able to enter mitochondria to provide protective effects.

The results of this study showed that hydrogen treatment had potent antioxidative and antiinflammatory effects in spontaneously hypertensive rats.

Reference

1. Zheng and Yu. Chronic hydrogen-rich saline treatment attenuates vascular dysfunction in spontaneous hypertensive rats.Biochem Pharmacol83:1269-77 (2012).

HYDROGEN AMELIORATES INFLAMMATORY ARTHRITIS IN MICE

Another recent study² reports on the use of hydrogen in cell culture and mouse studies to detect the effects of inflammation induced by LPS (lipopolysaccharide, a bacterial cell wall component that potently induces release of inflammatory components of the immune system such as proinflammatory cytokines) in cells (mouse macrophages) and as a result of intravenous injection of an arthritis-inducing cocktail in five week old female BALB/c Cr Slc mice.

Hydrogen treatment in the cells significantly reduced the nitric oxide release induced by exposure to LPS and the interferon-gamma released as a result of that exposure. Stimulation with LPS/IFN-gamma upregulates expression of pro-inflammatory genes such as the gene expressing iNOS (inducible nitric oxide synthase) and COX2. The authors report “a robust increase in protein expression of iNOS and COX2 at 6 hours after treatment [with LPS], which was markedly suppressed by treatment with hydrogen.”²

The animals receiving treatment with the arthritis-inducing cocktail (a model for human rheumatoid arthritis) were given LPS by injection after introduction of the cocktail to increase the incidence and severity of the response. The animals developed redness and swelling of the hind and front paws, which was alleviated in mice fed with hydrogen-rich water compared to mice receiving ordinary (control) water. The left and right hind paw volume decrease in hydrogen-treated mice was statistically significant only for the left hind paw.

“Taken together, our studies indicate that hydrogen inhibits LPS/IFN-gamma-induced NO [nitric oxide] production through modulation of signal transduction in macrophages and ameliorates inflammatory arthritis in mice, providing the molecular basis for hydrogen effects on inflammation and a functional interaction between two gaseous signaling molecules, NO and molecular hydrogen.”

Reference

2. Itoh et al. Molecular hydrogen inhibits lipopolysaccharide/interferon gamma-induced nitric oxide production through modulation of signal transduction in macrophages.Biochem Biophys Res Commun411:143-149 (2011).

HYPOTHESIS: HYDROGEN THERAPY MAY BE AN EFFECTIVE TREATMENT FOR DEADLY APLASTIC ANEMIA

A new paper³ has been published by Chinese scientists who propose hydrogen therapy as a way to treat aplastic anemia, a rare bone marrow failure disorder with a high mortality rate. The paper is a hypothesis paper as they have not yet begun trials for treating the disease: “We propose that our study on treating aplastic megaloblasts with hydrogen gas will start as soon as possible.” What they may mean here is “as soon as we get the money.” The paper which was itself funded by a grant from the National Natural Science Foundation of China (No. 30,770,503) appears to be a solicitation for additional funding aimed at the Chinese military.

A comment (not part of the paper) from Beijing Navy General Hospital of Qian Liren said (in our —Thanks, Will — translation from the Chinese): “Hydrogen can also treat the disease? If considered from the perspective of infection, inflammation, toxicity, pathogenesis, may be hydrogen have some therapeutic effect on the disease. But may not be sure, there is no any studies have shown treatment of the disease. The point of view need to study confirms.”

The hypothesis paper was published.³ In it, the authors referred to (with included citations) hydrogen’s antioxidant and antiinflammatory effects as suggesting that it might be effective in treating aplastic anemia. They noted that “[t]he key cellular events in the development of aplastic anemia (AA), are the activation and expansion of T cells, which leads to an autoimmuune response and hypersecretion of inflamatory cytokines such as IFN-g [interferon-gamma] and TNF-alpha [tumor necrosis factor-alpha]. The autoimmune response results in destruction of hematopoietic stem and progenitor cells in the BM [bone marrow] by cytotoxic lymphocyytes … Many studies have suggested … that abnormalities of TNF-alpha and IL-6 [interleukin-6] may play important roles in the pathogenesis of AA. The production of TNF-alpha and IL-6 has been found to be significantly elevated in the AA patients. Elevated TNF-alpha levels may also contribute to bone marrow failure by upregulating the Fas receptors on the progenitor of the cells, which leads to apoptosis [a type of programmed cell death] of the target of hematopoietic precursors and by enhancing production of reactive oxygen free radicals, which are detrimental to progenitors.” (References in the paper have not been shown here.)

The researchers describe currently used treatments for aplastic anemia that include immunosuppression and hematopoietic stem-cell transplantation therapy, noting that they may alleviate the disease but are associated with many adverse effects, such as anaphylaxis, fever, chills, and hives in the case of one drug (ATG) and severe allergic reactions, chest pain, diarrhea, fast or irregular heartbeat, flushing of the face, etc. in the case of cyclosporine, an immunosuppressive drug. “In addition, it is difficult to avoid complications, particularly second malignancies, even with conditioning regimens. Our hypothesis is that hydrogen gas may have a therapeutic effect on aplastic anemia.” “Our hypothesis is based on the theory that hydrogen can selectively reduce hydroxyl and peroxynitrite radicals [sic. peroxynitrite molecules are potent oxidants, but are not radicals] and down-regulate cytokines such as IL-6 and tumour necrosis factor-alpha (TNF-alpha). Free radicals have been suggested to play an important role in aplastic megaloblasts [references provided but deleted here]. The production of TNF-alpha and IL-6 have been found significantly higher in AA patients.”

An earlier paper by a different group of scientists^3b found that hydrogen-rich saline treatment in a rat model of amyloid-beta-induced Alzheimer’s disease resulted in a reduction in TNF-alpha, which has been detected at elevated levels (compared to healthy controls) in bone marrow plasma and peripheral blood plasma from patients with aplastic anemia.^3c However, this reduction (shown in Fig. 4 graphics in the paper,^3bwhile it may be statistically significant, is very small and, hence, may not be physiologically meaningful. It certainly doesn’t qualify for the authors’ description that “hydrogen-rich saline PREVENTED the elevation of IL-6 and TNF- alpha.” (Emphasis added.) Unfortunately, this is the only paper we’ve seen in which the effect of hydrogen therapy on TNF-alpha was measured. Hence, we conclude that the experimental evidence supporting a potentially therapeutic effect of hydrogen on aplastic anemia is weak. (You have to watch out for scientists competing for limited grant money and for glory, especially in a newly developing area of science, and the tendency arising from these conditions to hype their experimental results.)

In fact, if you do enough very precise measurements, you are likely to find statistically significant changes that may not be physiologically meaningful.

In conclusion, the authors hypothesize that hydrogen gas may provide therapeutic treatment of aplastic anemia with few adverse effects.

Our comments: We do not see any problem in trying hydrogen as a therapy for aplastic anemia but think that the scientific basis as described by the researchers³for expecting positive results in a trial are weak (though not nonexistent) due to very limited data. We note that the Chinese military is (quite reasonably) concerned about the 30,000 plus atomic bombs still in the hands of the Russian military and no certainty that a state of “peace” between China and Russia will continue indefinitely. Hence, the Chinese military are worried about having to deal with widespread radiation injury and radiation-associated medical conditions such as aplastic anemia, difficult to treat and with a high mortality. Hydrogen therapy is, therefore, of considerable interest as a potential low cost low toxicity treatment that has already been shown to have protective effects against radiation damage in animal studies (probably largely because of its efficacy in detoxifying hydroxyl radicals, the major cause of tissue damage by radiation).

References

3. Qian et al. Hydrogen therapy may be an effective and specific novel treatment for aplastic megaloblasts.Med Sci Monit18(6):HY19-22 (2012) [in Chinese] [Epub ahead of print] PubMed PMID: 22,648,259.
   3b. Li et al. Hydrogen-rich saline improves memory function in a rat model of amyloid-beta-induced Alzheimer’s disease by reduction of oxidative stress. Brain Res 1328:152-161 (2010).
   3c. Schultz and Shahidi. Detection of tumor necrosis factor-alpha in bone marrow plasma and peripheral blood plasma from patients with aplastic anemia,” Am J Hematology 45:32-38 (1994).

U.S. Government Supports Drug Development Against Radiation Sickness

Interestingly, the U.S. government “has launched programs to support the development of medical countermeasures (MCMs) against radiological, nuclear, and other threats.”⁴That includes prevention and treatment of radiation poisoning. The National Institute of Allergy & Infectious Diseases (NIAID, a part of the National Institutes of Health) guides the radiation MCM research, while the Biomedical Advanced Research & Development Authority (pronounced “authoriteh,” as per South Park’s Cartman), part of the Dept. of Health & Human Services supports later-stage product development at small firms and university centers. According to an article on the MCM programs that appeared in the 25 June 2012 Chemical & Engineering News (a publication of the American Chemical Society), “[s]uccess is far from ensured. The Food & Drug Administration, which launched its MCM initiative in 2010, has yet to approve a single drug for treating radiation syndrome (ARS).”⁴

Apparently, the use of hydrogen as a cheap, safe therapy for radiation sickness (a potent scavenger of hydroxyl radicals, the source of most tissue damage from radiation) that is already available^4b is not even being considered. Being considered are such treatments as granulocyte-colony-stimulating factor Neupogen and a PEGylated version called Neulasta, both developed and marketed by Amgen (the two drugs have combined annual sales for about $5 billion for use (with antibiotics to attenuate the side effects, which include potent immunosuppression) in the treatment of cancer patients. But to get these drugs approved for radiation sickness will require an immense investment of more money. (The purpose of the government MCM programs is presumably to provide at least some of this money, or else why would anybody bother to become part of the program.) New drugs, such as the encouragingly named AEOL-1050 and GI-ARS, are being studied as candidates for radiation treatment. (For example, Aeolus signed a five-year, up to $118 million contract with BARDA for lung-ARS.) “The BARDA contract [with Aeolus] is designed to produce the data needed for FDA approval under the agency’s ‘animal rule’.”⁴ That rule allows the drug to be approved for use in people on the basis of studies in two validated animal models, when a drug cannot be tested in people. Aeolus says that its BARDA contract “anticipates a regulatory filing at the start of 2016.” “‘Most of the work done in the first 12 months of the contract was in the chemistry, manufacturing, and controls area,” says the company’s representative, also noting that the company has also met with the FDA to discuss the appropriate animal models.

There is a lot more along the same lines as the examples given above. Over the past five years, the article reports, NIH’s radiation countermeasures program has interacted with more than 130 companies and, in the coming five years, the agency plans to expand its search to more small and large drug companies. Right. Of course, nothing is approved yet, while hydrogen is available, safe, has proven effective in cell culture and animal studies of the prevention of radiation damage and its treatment, and is cheap. Unfortunately for hydrogen, however, its use as a radiation therapy would not support the jobs of (probably) thousands of government bureaucrats in MCMs wielding large sums of money to distribute to their favorite companies.

This use of hydrogen gas is also an unpatentable discovery under U.S. patent law; hence, there is no incentive for any private party to pay for the astronomical FDA approval costs.

Your tax money at work, folks. By the time the government approves treatments for radiation, we’ll all be dead … but probably not from radiation, since hydrogen therapy is already available. See our article on “Hydrogen Therapy” in the June issue of Life Enhancement.

References

4. Thayer. The drugs that may never be used.Chem Eng News90(26):23–26 (June 25, 2012).
   4b. See, for example, Qian et al. Radioprotective effect of hydrogen in cultured cells and mice. Free Radical Res 44(3):275-82 (2010); also, see Chuai et al. Hydrogen-rich saline protects spermatogenesis and hematopoiesis in irradiated BALB/c mice. Med Sci Monit 18(3):BR89–94 (2012).

HOUSEKEEPING FOR A LONGER LIFE: CLEARING UNWANTED OR TOXIC CELLULAR DEBRIS BY INDUCING AUTOPHAGY WITH THE SUGAR TREHALOSE

Autophagy is a natural process in which bulk degradation of cellular cytoplasmic contents takes place, allowing for the removal of unneeded and/or toxic material such as aggregation- prone proteins, including mutant huntingtin (a gene variant associated with Huntington’s disease) and alpha-synuclein (associated with Parkinson disease).¹Other aggregation-prone proteins include amyloid-beta (Alzheimer’s disease) and prions (various prion diseases, such as mad cow disease and possibly Alzheimer’s disease). “Autophagy is an essential process for both the maintenance and the survival of cells, with homeostatic low levels of autophagy being critical for intracellular organelles and proteins.”² In fact, in a recent paper,³ the researchers concluded that “autophagy is universally required for the lifespan-prolonging effects of caloric restriction and pharmacological Sirtuin-1 activators.”

“Autophagy deficiency during aging has been proposed to be the main cause of this biological ‘waste’ accumulation. In support of this theory it has been found that loss-of-function in autophagy genes resulting in intracellular accumulation of damaged proteins and organelles in mice, accelerates aging and life span shortening in Caenorhabditis elegans and Drosophila melanogster. In contrast, elevating autophagy activity increases life span in Drosophila and rescues aged cells from accumulating dysfunctional mitochondria.”^3a

Another paper^3b found that an autophagy-related protein (beclin 1) was expressed at a reduced level in early Alzheimer disease and that the protein regulates amyloid beta accumulation in mice. Beclin 1 was strongly reduced in the brains of Alzheimer’s disease patients and was also expressed at a lower level in the brains of individuals with mild cognitive impairment as compared to the brains of control patients. Moreover, in an accompanying commentary paper,^3c the authors note that in other papers (references given) elimination of basal neuronal autophagy was sufficient to cause neurodegeneration in the absence of other insults. However, other work suggests that autophagosomes in AD patients may be dysfunctional and in a paper using a cell culture model, increased induction of the autophagy pathway through pharmacological manipulation led to elevated amyloid beta accumulation.(^3d, paper cited in ^3c).

“… recent evidence suggests that autophagy is mostly a cytoprotective mechanism that allow cells to mobilize their energy reserves and to recycle damaged organelles in conditions of lacking nutrients, hypoxia, endoplasmic reticulum stress, accumulation of misfolded proteins, or DNA damage.”³ Misfolded alpha1-antitrypsin, which is a proteinase (the properly folded version functions to break down proteins) is an example of a misfolded protein and evidence indicates that it may be a causative factor in some forms of chronic obstructive pulmonary emphysema and has been found to be eliminated via autophagy.⁴

A recent paper² found that in adipose (fat) tissue of insulin resistant mice and hypertrophic (enlarged, insulin resistant) 3T3-L1 adipocytes (fat cells), autophagy was suppressed. Autophagy-related gene expression was also reduced. The suppression of autophagy increased the inflammatory responses in adipocytes (fat cells) via ER (endoplasmic reticulum) stress. The ER is a cellular structure where protein folding takes place and, under conditions of overnutrition (as occurs in obesity and diabetes), results in an accumulation of misfolded proteins; that accumulation and the need to get rid of it (either by destroying the misfolded proteins or refolding them properly) is what causes ER stress. Thus, the researchers conclude that autophagy is “an important regulator of adipocyte inflammation in systemic insulin resistance.”² Another group reported^2a that defective liver autophagy in obesity promotes ER stress and “is a critical component of defective insulin action seen in obesity.”

In an earlier issue of this newsletter (see “The Origami of Aging” in the September 2008 issue of Life Enhancement), we reported on the protective effects of small natural molecules called osmolytes that act as chaperones to help properly fold proteins, a complex process that takes place in the ER. One of these osmolytes, the natural sugar trehalose, has been reported¹ to be a novel enhancer of autophagy, which was the mechanism identified in this paper for its ability to accelerate the clearance of aggregation- prone proteins mutant huntingtin and alpha-synuclein. In an earlier paper⁵by a different group of scientists, trehalose was also reported to alleviate the pathology induced by insoluble polyglutamine-induced protein aggregates in a mouse model of Huntington disease, though autophagy was not investigated as a potential mechanism; the researchers found trehalose to stabilize the partially unfolded polyglutamine-containing protein. The trehalose was administered to the mice in the Huntington mouse model study in their drinking water, with the protective effect being most prominent in the animals drinking 2% trehalose.⁵

Trehalose is found naturally in many organisms, including bacteria, yeast, fungi, insects, invertebrates, and plants and is protective against a variety of environmental stimuli, including heat, cold, desiccation, dehydration, and oxidation, by preventing protein denaturation.¹ We both take a trehalose containing supplement every day.

References

1. Sarkar et al. Trehalose, a novel mTOR-independent autophagy enhancer, accelerates the clearance of mutant huntingtin and alpha-synuclein. J Biol Chem282(8):5641-52 (2007).
2. Yoshizaki et al. Autophagy regulates inflammation in adipocytes. Biochem Biophys Res Commun 417:352-7 (2012).
2a. Yang et al. Defective hepatic autophagy in obesity promotes ER stress and causes insulin resistance. Cell Metab 11:467- 478 (2010).
3. Morselli et al. Caloric restriction and resveratrol promote longevity through Sirtuin-1-dependent induction of autophagy. Cell Death Dis (2010) 1, e10; doi:10.1038/cddis.2009.8
3a. Yen and Klionsky. How to live long and prosper: autophagy, mitochondria, and aging. Physiology 23:248-62 (2008)
3b. Pickford et al. The autophagy-related protein beclin 1 shows reduced expression in early Alzheimer disease and regulates amyloid beta accumulation in mice. J Clin Invest118(6):2190-9 (2008).
3c. Lee and Gao. Regulation of Abeta pathology by beclin 1: a protective role for autophagy? J Clin Invest 118(6):2015-8 (2008).
3d. Yu et al. Macroautophagy —a novel beta amyloid peptide- generating pathway activated in Alzheimer’s disease. J Cell Biol 171:87-98 (2005).
4. Sifers. Clearing conformational disease. Science 329:154-5 (2010).
5. Tanaka et al. Trehalose alleviates polyglutamine-mediated pathology in a mouse model of Huntington disease. Nat Med 10(2):148-54 (2004).

 

NEW DATA HELPS EXPLAIN WHY LARGE VITAMIN E HUMAN CLINICAL TRIALS HAVE NOT CONSISTENTLY PROVIDED CARDIOPROTECTION

A new paper¹ offers additional clues on why large randomized human clinical trials of vitamin E have not substantiated the benefits of vitamin E found in in vitro and animal as well as short-term human mechanistic studies.

The researchers explain, in their paper’s introduction, that despite promising results in cell culture and animal studies, the results of cohort and supplementation studies with alpha tocopherol have been inconsistent. They note that the Nurses’ Health Study of over 80,000 nurses found a 30% reduction in the risk of developing coronary artery disease in subjects who took vitamin E supplements as compared to those who didn’t (after adjusting for age, smoking status, and intakes of beta carotene and vitamin C). A cohort study of 5133 Finnish residents taking vitamin E supplements and followed for 14 years, however, revealed no reduction in the incidence of coronary artery disease. Moreover, the Physicians’ Health Study of over 80,000 male physicians reported no association between vitamin E supplementation and mortality due to cardiovascular disease. There are many more studies, some showing protective effects of vitamin E and others reporting no such protection or protection only for certain classes of subjects (e.g., those with deficiencies of vitamin E) and even increased risk of disease.

Attempts at explanations (and there have been many) have run up against the difficulty of determining causality in large trials in which there are so many variables (some unknown at the time the study was designed and conducted). The new study examined the effects of vitamin E supplementation on the production of inflammatory cytokines in 160 apparently healthy middle aged men who took either 75 IU (low dose) or 600 IU (high dose) alpha-tocopherol for a period of 6 weeks. The production by their peripheral blood mononuclear cells (PBMCs) of pro-inflammatory TNF-alpha and IL-1beta, IL-6, and the anti-inflammatory IL-10 was measured at baseline and then again after 6 weeks. In addition (and this is something that only became possible very recently) the genetic polymorphisms (variants) in genes involved in inflammation or in responses to oxidative stress were also determined in the subjects.

The results showed that the ability of alpha-tocopherol to affect the levels of various proinflammatory cytokines (TNF-alpha, IL-1beta, or IL-6) was influenced by the polymorphisms of genes that regulate the production of those cytokines by PBMCs.

Thus, “[i]n healthy control subjects, the effect of alpha-tocopherol supplementation on the production of inflammatory cytokines appears to be dependent on an individual’s genotype. These genotype-specific differences may help explain some of the discordant results in studies that used vitamin E.”¹ Thus, the authors propose, their “data suggest that individuals with a lower antioxidant capacity might be those who would benefit most from intake of alpha-tocopherol.”

Reference

1. England et al. Variants in the genes encoding TNF-alpha, IL- 10, and GSTP1 influence the effect of alpha-tocopherol on inflammatory cell responses in healthy men. Am J Clin Nutr 95:1461-7 (2012).

 

INCREASED INFLAMMATORY ACTIVITY ASSOCIATED WITH COGNITIVE DECLINE

Another new paper¹ reports that, in a human study, increased (detectable) levels of a peripheral marker of inflammation, C-reactive protein (CRP), was associated with decreased performance in episodic memory and delayed recall and recognition memory as compared to those with lower (undetectable) levels in a sample of people recruited to participate in a study of healthy aging and cognition. Moreover, those with detectable levels of CRP were found by MRI to have smaller volumes of their brains’ left medial temporal lobe, an area the authors explain is known to mediate verbal memory consolidation.

The subjects were 141 apparently neurologically healthy older adults aged between 65 and 90 years, with 76 of those having detectable levels of CRP and 65 having undetectable levels of CRP. Some earlier studies had found that non-demented older adults with higher levels of systemic inflammatory markers performed less well on verbal memory tests at baseline and were at risk for future decline. However, the authors note that, “the relationship between inflammation and memory is not consistent, as additional cross-sectional and longitudinal studies have failed to find an appreciable connection between inflammation and memory function.”¹ They explain that “the relative lack of neuroimaging data renders it difficult to interpret prior evaluations of the relationship (or lack thereof) between verbal memory and laboratory indices of inflammation, as discrepancies in results may be due to changes in cognitive function that are not dependent on the medial temporal lobes.”¹ The neuroimaging showed that the volume of the left medial temporal lobes in participants with detectable CRP was 7.71 cc, SD = 0.7, while the volume of the same brain area in those with undetectable CRP was 8.02 cc., SD – 0.8, the difference was significant. However, no group differences were detected in other brain areas imaged, including left temporal neocortex, left middle frontal, left lateral frontal, or left parietal neocortex.

The authors caution that in the interpretation of the results, it should be kept in mind that the study is cross-sectional (thus allowing for associations but not for causal inferences) and used only one inflammatory marker (CRP) to stand in for inflammatory activity.

In sum, these results, suggest the authors, “underscore a potential role for inflammation in cognitive aging.”

Reference

1. Bettcher et al. C-reactive protein is related to memory and medial temporal brain volume in older adults. Brain Behav Immun 26:103-8 (2012).

OVEREXPRESSION OF GENE ENCODING VITAMIN D3 BREAKDOWN IS AN INDEPENDENT MARKER OF POORER SURVIVAL IN LUNG CANCER PATIENTS

A recent paper¹ studied the relationship of the expression of CYP24A1, the gene that encodes the main metabolizing enzyme of 1,25-D3 (calcitriol, the active form of vitamin D3) and the likelihood of survival in human lung cancer patients.

The researchers found that CYP24A1 mRNA was elevated 8- to 50-fold in lung adenocarcinoma (the most common form of lung cancer).¹ Adenocarcinoma accounts for over 50% of all non- small cell lung cancers. Sadly, at least 60% of patients with lung adenocarcinoma are discovered to have the disease at an advanced stage III/IV metastatic disease.¹

The results of this study showed that, “[a]t 5 years of follow-up, the probability of survival was 42% (high CYP24A1, n=29) versus 81% (low CYP24A1, n=57)(P=0.007). The validation set of 101 tumors showed that CYP24A1 was independently prognostic of survival (multivariate Cox model adjusted for age, gender, and stage, P=0.001).”¹ The authors concluded that, “CYP24A1 overexpression is associated with poorer survival in lung AC [adenocarcinoma]. This may relate to abrogation of antiproliferative effects of 1,25-D3 in high CYP24A1 expressing lung AC.” Indeed, “the cell lines with high expression of CYP24A1 (example A549) exhibited the lowest expression of VDR [vitamin D receptor] mRNA; the converse was observed with SKLU-1 [a different cell line].”¹

The researchers mention that overexpression of CYP24A1 has also been observed in colon, cervical, ovarian, cutaneous squamous cell, and esophageal carcinomas.¹ They also note that findings concerning CYP24A1 have led to research to find new vitamin D analogues (because very high doses of vitamin D can cause hypercalcemia, excessive calcium levels) and specific CYP24A1 inhibitors.

We suggest that Vitamin D3 supplementation at levels unlikely to cause hypercalcemia (we recommend 2000–4000 IU/day, though the two of us take 6000–8000 IU/day). may be a way to help prevent the development of lung cancer adenocarcinoma. It will be helpful, of course, when it is possible for individuals to have their CYP24A1 expression measured to help predict the outcome and need for aggressive therapies (if they already have lung cancer) or to assess the likelihood of getting it in the first place. In order to make genetic testing available on a widespread basis to those who desire to and are able to purchase it, the FDA’s blockades to such access will have to be eliminated.

Reference

1. Chen et al. CYP24A1 is an independent prognostic marker of survival in patients with lung adenocarcinoma. Clin Cancer Res 17(4):817-26 (2010).

TRANSPORTATION SECURITY ADMINISTRATION LIES
ABOUT RISKS TO PASSENGERS FROM X-RAY MACHINES

Just a little health tip, here. If possible, avoid exposure to passenger scanning X-ray machines at airports. The cancer risks are understated by a factor of about 1,000 to 10,000 times. Here’s why:

There are three different very serious underestimations in the Federalie risk calculations for the airport X-ray back scatter passenger scanners: 1) All the ionizing radiation is absorbed by your skin so about 1% of your bodies tissue receives 100% of the dose. 2) The risk of development of cancer from a given dose of radiation depends, for a given species, on the rate of cell division, with more rapid cell division resulting in a higher cancer risk. Your skin cells are among the most rapidly dividing cells in your body. 3) Dose rate makes a huge difference! Your cells have mechanisms for detecting DNA breaks and repairing most of them, but this takes time. It also usually takes roughly 5 critical mutations in a single human cell to cause cancer. If the dose is slowly accumulated over a year, the 5,000 millirem that nuclear power plant workers are allowed to receive each year does not cause an increase in cancer, even over a 40 year career—a total of 200,000 millirem. On the other hand, a CAT scan to a child’s head delivers about 3,500 millirem over about 30 seconds—and increases their risk for brain cancer by about 30% from a single exposure. 30 seconds is not long enough to detect DNA damage and repair it. This dose rate effect can also be seen in the Hiroshima and Nagasaki atomic bomb survivors; cancer rate is substantially increased in those who were within 1 Km of ground zero because they received the radiation as a short intense pulse. Those who were a mile away, even if subsequently exposed to months of fallout, had relatively little increase in cancer. The airport X-ray back scatter scanners that Chertoff has been promoting deliver a dose of less than 1 millirem but do so in less than 1 millisecond, which is about 10 times the radiation delivery rate of a CAT scan. Those who rarely fly are unlikely to develop cancer from the few exposures that they receive, but frequent business fliers are may not be so lucky as they may be exposed to a hundred or more doses per year. Considering the large number of frequent fliers, those X-ray machines may end up killing more airline passengers than the terrorists did on 9/11. One of us (Durk) read an announcement yesterday that terrahertz (millimeter wavelength microwaves which cause no mutations) made by L3 company in Massachusetts will be slowly replacing the back scatter X-ray scanners—even though L3 doesn’t have Chertoff pimping them. Perhaps someone else came to the same dire conclusions. Because of this and other reasons (being groped and muzzled—don’t you dare exercise your First Amendment rights by complaining about treatment by TSA agents—are a couple of others), we avoid commercial air flights these days. We drive or, if speed is of the essence, fly by private plane with a hired private pilot. This isn’t always possible (the expense, for one thing) but we thought you might like to know that you are being lied to about the supposedly very low cancer risk of TSA’s X-ray machines. This risk could be particularly important for people who already have skin damage due to high levels of sun exposure and have developed cancer-prone nevi, which already have some unrepaired mutations.

It would be better to avoid the excessive X-ray exposure in the first place but, if you have to go through an X-ray machine at an airport, it might be a good idea to take supplemental radioprotectants beforehand. Radioprotective agents include antioxidants such as vitamins C and E.¹ Hydrogen is a particularly interesting radioprotectant as hydrogen selectively scavenges hydroxyl radicals, considered to be the major cause of radiation injury. One way to increase your body’s hydrogen supply is to take prebiotics such as long chain fructooligosaccharides (a form of inulin) that are fermented by certain bacteria in the gut, resulting in the release of hydrogen. Most of the hydrogen diffuses into all tissues, even entering mitochondria and passing through the blood-brain barrier, eventually being excreted through the lungs. (see “Hydrogen Therapy” in the June issue).

Incidentally, another type of scanner, shown at right, uses millimeter radio waves (shorter wavelength than those that cook food in your microwave oven) and could do the job the X-ray machines are now being used for. With this type of scanner, the photons are not energetic enough to cause mutations and, hence, there really is no risk of cancer. So why aren’t these being used instead of X-ray machines? It all boils down to this: (1) political connections and lobbying by the folks selling the X-ray machines and (2) [think of somebody rubbing their fingers together] certain corrupt “officials” at the Transportation Security Administration who choose scanners on the basis of personal gain while either ignoring injury to travellers or (just as bad) don’t know anything about how radiation causes cancer.

1. Zabbarova and Kanai. Targeted delivery of radioprotective agents to mitochondria. Mol Interv 8(6):294-302

INCREDIBLY COMPLEX NEW CODE FOR MEDICAL BILLING:
SOUNDS LIKE A JOKE, BUT PRISON ISN’T FUNNY

As reported in The Wall Street Journal, WSJ.com, 13 Sept. 2011

In their ever expanding search for ways to justify their jobs, federal bureaucrats have now developed a new federally mandated version that, starting in about a year, will increase the number of codes to specify medical services from about 18,000 to around 140,000. Just what your local physician needed!

Remarkably funny items are included in the new codes, such as whether a patient’s injury occurred in a chicken coop, opera house, art gallery, squash court, and nine locations in and around a mobile home, from the bathroom to the bedroom. A code specifies that a doctor visit took place because of walking into a lamppost on an initial encounter or took place because of walking into a lamppost on a subsequent encounter. Another code identifies injuries related to macaws(!) Yet another specifies injuries involving a “burn due to water-skis on fire” (!!) Then there are the insults, such as a code for having a very low level of personal hygiene or having a bizarre appearance. There are codes to identify injuries received while sewing, ironing, playing a brass instrument, crocheting, doing handcrafts, or knitting, but not while shopping.

This sounds to us like somebody’s idea of having a lot of fun at the expense of you and me and healthcare providers. Yes, it’s funny except for the fact that real people trying to provide medical services (such as doctors) will have to figure out what code to use when billing for the service with the ever-present danger of ending up in prison or fined a bunch of money for a mistake. And, of course, the extra expense imposed upon healthcare providers struggling to identify the correct codes will end up being paid for largely by private patients, making the healthcare system even more expensive for individuals caught up in the web of central planning.

We can thank the Centers for Disease Control and Prevention and the Centers for Medicare and Medicaid Services for developing the system (called ICD-10 for International Classification of Diseases, 10th revision) and the World Health Organization for developing an earlier, less complex version on which it is based.

 

PROPRANOLOL, BETA BLOCKER USED MOST FREQUENTLY IN THE TREATMENT OF HIGH BLOOD PRESSURE, FOUND TO REDUCE IMPLICIT NEGATIVE RACIAL BIAS

Just to prove that governments are not always the ones to fund “socially meaningful” scientific studies, we get this gem that was funded by the Wellcome Trust.

The study¹ was conducted to help identify underlying neurobiological mechanisms in implicit negative attitudes toward other races. By implicit, the authors mean attitudes that individuals have that they may not be aware of. “It has been suggested, however, that implicit measures best predict subtle and spontaneous biased behavior whereas explicit prejudice measures predict deliberate behavior.”¹

The researchers used the IAT, implicit association test, to detect implicit attitudes toward social outgroups that can include race, sexual orientation, gender, or political preference. The authors claim that “IATs were developed precisely to reduce the effect of social desirability responses which might affect explicit prejudice responses.” They say that several studies have suggested that “compared to explicit prejudice, implicit prejudice involves a stronger emotional component.” For example, one study found that there was increased amygdala (a brain area involved in emotional processing) activity when white participants viewed faces of unknown black people, which was said to be confirmed by other studies (citations provided). The magnitude of amygdala activation was correlated with participants’ IAT scores. However, they note that previous studies they cited were largely correlational in nature and, therefore, couldn’t establish causality.

The authors hypothesized that beta-adrenoceptor blockade, which reduces emotionality, both in terms of observable behavior as well as physiological measures such as heart rate and blood pressure, would reduce implicit racial attitudes as measured by the IAT without a corresponding reduction in measures of explicit prejudice.

And, indeed, this is what they found. In their discussion, the authors point out that, since “the amygdala plays a key role in the early non-conscious appraisal of threat … [that it] may therefore also be involved in the mediation of implicit racial prejudice.”¹ In support of this, they cite neuroimaging studies in which increased amygdala activation was associated with implicit but not explicit racial attitudes.

The authors note the recent discovery that in-group favoritism is increased by the hormone oxytocin² and that there are interactions between oxytocin and noradrenaline pathways; they also note that in animals propranolol can lower oxytocin levels.

Studies of this kind can provide some useful information on social behavior, such as prejudices, but they cannot account for the experiential background to an individual’s evaluation of the likely results of interacting with members of “other” groups. A noteworthy example was famously provided when the Rev. Jesse Jackson told an anecdote of how once he was walking through a rough area of a city and, hearing footsteps behind him, turned around and then seeing that it was a group of white people was relieved that they weren’t black. He was not happy about this realization, but admitted that he had in fact experienced a sense of relief. Indeed, most crimes against black people are committed by other black people, which could result in amygdala sensitization to a sense of threat when interacting with blacks especially in “bad” sections of town.

It is also true that one downside of propranolol treatment of high blood pressure is that it tends to cause a general flattening of emotional affect, so it would not be at all surprising if it flattened emotional affect as it relates to implicit racial bias. Finally, one ought, perhaps, to be more concerned with those who are willing to take action against outsider groups, the effectuating of explicit racial bias and here we come to the matter of how one can use the discipline of the criminal law to reduce the incentive to initiate physical aggression against others.

References

1. Terbeck et al. Propranolol reduces implicit negative racial bias. Psycho­pharmacology DOI 10.1007/s00213–012–2657–5.
2. see, for example, De Dreu et al. The neuropeptide oxytocin regulates parochial altruism in intergroup conflict among humans. Science 328:1408–1411 (2010); De Dreu et al. Oxytocin promotes human ethnocentrism. Proc Natl Acad Sci USA. J108(4):1262-6 (2011).

To refuse a hearing to an opinion because they are sure that it is false, is to assume that their certainty is the same thing as absolute certainty. All silencing of discussion is an assumption of infallibility.— John Stuart Mill

(D&S: And we all know who “they” are …)

Though the silenced opinion be an error, it may, and very commonly does, contain a portion of truth; and since the general or prevailing opinion on any subject is rarely or never the whole truth, it is only by the collision of adverse opinions that the remainder of the truth has any chance of being supplied.— John Stuart Mill

ARE LIES PROTECTED BY THE FIRST AMENDMENT?

The quote just above offers a very good point and one that provides excellent counterpoint to the view that the First Amendment does not protect “lies.” The very words of the First Amendment “Congress shall make no law … abridging the freedom of speech …” make it clear that the establishment of federal “truth police” is specifically prohibited under Congress’ lawmaking powers. What part of “NO” don’t the feds understand? (If one is actually injured by false speech, civil suits are available for the recovery of damages.)

The FDA was denied its assertion of absolute authority to prohibit a health claim for a dietary supplement on the basis that the evidence in support of it was not conclusive (thus allowing the agency to silence the entire health claim including all the evidence that truthfully supported the claim) in Pearson v. Shalala (Court of Appeals of the D.C. Circuit, 1999). The Court ruled that health claims containing truthful information cannot be prohibited but that the FDA can require a disclaimer if they believe claims are potentially misleading.

There is an important case now before the U.S. Supreme Court, United States v. Alvarez, in which the question—are lies protected under the First Amendment?—is asked. The case involved a man running for the Municipal Water District board in a small California town who claimed he was a retired Marine and had been awarded the Congressional Medal of Honor. The man never received the Medal and, in fact, never even served in the military. He was charged under the federal Stolen Valor act for lying about awards received for military service. U.S. v. Alvarez, 617 F.3d 1198 (9th Cir. 2010), reh’g denied, 638 F.3d 666 (9th Cir. 2011), cert granted 80 U.S.L.W. 3237 (U.S. Oct. 17, 2011) (No. 11-210) Stolen Valor Act of 2011, H.R. 1775 and S.1728, 112th Congr. (2011) See story on this case in Lozare, “Stolen Valor” The News Media & The Law, Winter 2012 (published by the Reporters Committee for Freedom of the Press)

UPDATE: We were pleased to learn that the U.S. Supreme Court on June 28, 2012, in United States v. Alvarez, overturned the Stolen Valor Act 6–3 as a violation of the First Amendment (Alito filed a dissenting opinion that was joined by Scalia and Thomas).

Going even beyond the above two cases, however, the feds have criminalized lying to the federal government when, in the course of the investigation of a possible crime, somebody lies to the feds even when the lie has nothing to do with the potentially criminal act under investigation and, indeed, has no connection to any criminal act at all. Lying to the feds itself about anything whatever is now deemed a criminal offense for which one can be imprisoned. (One could lie, for example, as to where they were on a certain date at a certain time when that date and time have nothing to do with any crime.) A recent notorious example of this took place in the case of I. Lewis “Scooter” Libby, who ended up in a federal trial related to the leaking of information concerning the identity of CIA officer Valerie Plame Wilson. He was indicted for two counts of lying to federal investigators, two counts of perjury, and one count of obstruction of justice (because of lying). He was acquitted on the second count of making false statements.

Note that Libby WAS NOT indicted for actually leaking anything, but for lying to officals about how and when he learned that Plame was a CIA agent. IN FACT, THE GRAND JURY WAS UNABLE TO DETERMINE WHETHER THE LEAK EVEN VIOLATED FEDERAL LAW. Libby was sentenced to 30 months in prison and fined $250,000 as well as being disbarred. (The 30 months in prison was commuted by President George W. Bush, but Libby still had to serve the probationary period plus pay the large fine and suffer disbarment.) Our point here is not whether the punishment was appropriate or whether it was “fair” that Libby got a commutation from Pres. Bush whereas most other people would not have, but whether lying to the feds should be treated as a crime without a conviction for committing a crime in which the lying played a part. Politicians can lie all they want and not have to worry about going to jail or paying large fines for doing so. Why should a private citizen be treated any differently?)

A complete description of the Scooter Libby case can be found at Wikipedia (http://en.wikipedia.org/wiki/Scooter_Libby). Also, a useful discussion of the federal statute on making false statements to federal officials can be found at http://www.law.cornell.edu/uscode/18/1001.html. According to Wikipedia, “[t]he purpose of the statute is to ‘punish those who render positive false statements designed to pervert or undermine functions of governmental departments and agencies.’” This sounds suspiciously like the Alien and Sedition Acts of 1798, in which one could be fined or imprisoned for criticizing the government, which might be interpreted as “undermining” function of government. The Wikipedia account also states that “[e]ven constitutionally explicit Fifth Amendment rights do not exonerate affirmative false statements.” So much for the Fifth Amendment’s protection against compelled self-incrimination (“… nor shall [any person] be compelled in any criminal case to be a witness against himself …”).

WHY MONETARY INCENTIVES MAY NOT PRODUCE THE EXPECTED RESULT OF IMPROVED PERFORMANCE

The publication of studies of increasingly sophisticated game playing, often with neuroimaging to follow activation (or not) of various areas of the brain, are resulting in a rapidly enlarging scientific literature to help understand how people make decisions in economic and social situations. Some of the pioneering work in the area of experimental economics was recognized when Vernon Smith shared the Nobel Prize for Economics in 2002.

On a practical, everyday level, this work may be useful in terms of how to market your goods and services. Some of the results of these studies offer surprises when people don’t behave as you expect.

A new paper¹ reports such a result: an increasing financial incentive for greater employee performance that resulted in the exact opposite of what was expected when there was a decrement in performance in response to the increased incentive.

What the researchers found was that learning of the availability of the bonus money activated the ventral striatum of individual participants’ brains. This is an area of the brain known to be involved in mediating the effects of rewards on increases in motor performance. “The ventral striatum has been implicated in interactions between a Pavlovian system in which reflexive conditioned responses come to be elicited by a stimulus that predicts the subsequent delivery of a reward, and an instrumental system in which actions are selected flexibly in order to increase the probability of obtaining reward.”¹ “All of the above studies [citations given in text] have focused on the role of ventral striatum in mediating enhancements in responding, as opposed to decrements. In this study, we aimed to investigate the role of the ventral striatum in mediating response decrements as a function of large incentives.”¹

The initial finding was that “the only brain region commonly active between the time of incentive presentation … and the execution of the motor task … was bilaterally encompassing ventral striatum.” What the researchers then observed, however, was that at the time when execution of the task required to get the offered incentive commenced, the ventral striatum went from being activated to being deactivated. “Such deactivation was strongly correlated with a behavioral measure of loss aversion.”¹

As a result of further experiments conducted as part of this study, the researchers concluded that “an individual’s incentive resulting in peak performance and her performance decrements for large incentives are due specifically to loss aversion” rather than to risk aversion, which was defined as “a more general aversion to increased variance in potential gains or losses.” (Loss aversion was defined by the authors as “a tendency to value losses greater than equal magnitude gains.”) The authors called performance decrements in the face of large incentives “choking.”

Hence, the potential reward available for improved performance only “worked” while the people receiving the offer were considering the possible gain, but tended to become a fear of loss when the “opportunity” came to actually achieve the payoff.

The authors report early attempts by economists on how to design incentive contracts so as to increase incentive but to avoid inducing risk aversion that limits performance. They cite Adam Smith, 1776.² They have found in their earlier work that “people with less striatal sensitivity to incentive (i.e., the most stable neural response over the range of incentives) perform high stakes tasks with more proficiency.”¹ They suggest that getting individuals to focus away from the prospect of failure might help to mitigate performance decrements.

Suppose you want somebody to work extra hard in exchange for a possible large money payoff. There is a risk for that person in that he or she may invest a lot of time/energy in the project and not get the monetary payoff. If it is a large payoff, one could easily imagine this being perceived as an even larger risk of not getting the payoff because of an expectation of even greater productive work to get it. In the book Secrets of the Moneylab, ³ the authors point out that a logical strategy to deal with this problem is to reduce the risk.

We suggest that one possible way to reduce the risk of not getting a large monetary reward would be to break up the large payoff into a series of smaller payoffs. The small payoff would provide an incentive to be more productive but it would not be so large as to turn greed into fear of loss. At the same time, the possibility of more payoffs later could still function to increase the anticipation of gain reflected by activation of the ventral striatum.

In fact, that is very similar to the way payoffs from slot machines work. You can play the slot machine and you may win a payoff of a few coins. The odds are against you, but not greatly so. If you sit there and keep on playing long enough, you have a chance to win a giant jackpot; the odds of winning the jackpot are against you, but far more so than they are for winning a small payoff, with a lure of possibly going for a giant jackpot. It would be interesting to see what the ventral striatum is doing while people are playing slot machines where there are small payoffs but also a potential jackpot. We hypothesize that the ventral striatum would be activated while playing for a small payoff where your loss would be small, but remain activated by the possibility of playing for the jackpot.

Catching Arrows—The Zen Buddhist Approach to Avoid Choking

As mentioned above, the researchers¹ had explained that earlier work of theirs indicated that individuals who had less striatal response to incentives over a range of incentives were more likely to perform well—not to choke—no matter the level of the incentive. That reminded us of an approach that allows people to train themselves* to avoid choking: the ancient art of Zen Buddhist arrow catching.

 

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* We know of no data identifying brain areas affected by this training. That would make an excellent subject for research.

 

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Arrow catching is exactly what it implies, catching an arrow that is shot at you out of the air. The cost of failure would appear to be potentially high, yet an expert arrow catcher claimed that 80% of people could learn to catch arrows. (This particular expert had never heard of anyone dying as a result of attempting to learn the art, however.) It basically involves learning how to not care about the outcome so that the actual act of arrow catching is unimpeded by a choking response, a way of simply going with the flow. Buddhism itself is based upon a similar concept, that in the search for a life without bad karma, one should learn not to care about outcomes. (This may have developed as a result of historical circumstances—during the early period of Buddhist emergence as a major religion, life was very hard and not caring could be an effective way to deal with this. Indeed, the Christian religion’s focus upon an eternal life (that existence following the end of your regular life) rather than on the events of your life on Earth could be looked upon as another way to reduce concern about life’s outcomes (other than that you had better end up “living” your eternal life-after-death in heaven or you’ll be sorry).

References

1. Chib et al. Neural mechanisms underlying paradoxical performance for monetary incentives are driven by loss aversion. Neuron 74:582–94 (2012).
2. Adam Smith, The Wealth of Nations Fifth Edition (London: Methuen & Co., Ltd.); originally published in 1776.
3. Kay-Yut Chen (Lead Economist, HP Labs) and Marina Krakovsky, Penguin Books, 2010.