September 2005 Blog with Durk and Sandy

It is a commonplace that the history of civilisation is largely the history of weapons … And though I have no doubt exceptions can be brought forward, I think the following rule would be found generally true: that ages in which the dominant weapon is expensive or difficult to make will tend to be ages of despotism, whereas when the dominant weapon is cheap and simple, the common people have a chance. Thus, for example, tanks, battleships, and bombing planes are inherently tyrannical weapons, while rifles, muskets, longbows, and hand grenades are inherently democratic weapons. A complex weapon makes the strong stronger, while a simple weapon—so long as there is no answer to it—gives claws to the weak.— George Orwell, “You and the Atomic Bomb” 
British Labour Party journal Tribune, October 19, 1945

Wherever the real power in a Government lies, there is the danger of oppression. In our Governments the real power lies in the majority of the Community, and the invasion of private rights is chiefly to be apprehended, not from acts of Government contrary to the sense of its constituents, but from the acts in which the Government is the mere instrument of the major number of the constituents.— James Madison, in a letter to Thomas Jefferson 
October 17, 1788

Madison did not see that minorities could exploit majorities when the benefits of government action to those minorities were huge and the costs to each individual in the majority were small.— John Samples, Cato Policy Report 
March/April 2001

A standing military force with an overgrown Executive will not long be safe companions to liberty. The means of defense against foreign danger have been always the instruments of tyranny at home.— James Madison, at the Constitutional Convention 
June 29, 1787

Our peculiar security is in the possession of a written Constitution. Let us not make it a blank paper by construction.— Thomas Jefferson

Restless Legs: The Iron Connection

Before you rush out to buy the latest expensive prescription drug for “restless legs,” you might consider that one cause of this condition is iron deficiency.¹ The prescription drugs used to treat restless legs stimulate the function of dopaminergic neurons. Iron deficiency is known to cause a reduction in dopaminergic activity (as well as a rise in serum prolactin).²

Many people these days have reduced their intake of red meat, the best dietary source of iron. White meat (such as poultry) contains much less. Moreover, those who eat a diet rich in polyphenols—as are found in fruits, in vegetables, and in green, black, and oolong tea, etc.—may be absorbing much less than the quantity of iron they ingest because of the potent iron-chelating properties of many polyphenols (such as quercetin). If you are eating a diet like this and have developed restless legs, it is quite possibly due to iron deficiency.

In a recent study,¹ rats were fed diets that were either iron-deficient (ID) or iron-adequate (CN). Another group of ID rats was given iron supplements (IR). Studies were done on the dopamine, serotonin, and noradrenaline transporter binding in various brain areas. The results showed that ID male rats (but not ID females) had a decrease of 20–40% in dopamine transporter binding in the nucleus accumbens, caudate putamen, and substantia nigra. ID males also had a 20–30% reduction in serotonin transporter binding in the nucleus accumbens, olfactory tubercle, and colliculus, while ID females had 15–25% increased serotonin transporter binding in the olfactory tubercle, zona incerta, anteroventral thalamic nucleus, and vestibular nucleus. [It is possible that this increased serotonin transporter binding is linked to increased sensitivity to depression in females, at least in those who are iron-deficient, since the serotonin reuptake inhibitors, such as fluoxetine (Prozac^®), inhibit the serotonin transporter.] Iron deficiency reduced binding to the noradrenaline transporter in the locus ceruleus and anteroventral thalamic nucleus in ID and IR males but not females. Some, but not all, of the changes induced by iron deficiency were reversed by iron supplementation.

The authors state, “This experiment extends our knowledge to include the olfactory tubercle as a tissue sensitive to iron deficiency. This might implicate iron deficiency in endocrinological difficulties such as hyperprolactinemia.” Prolactin is regulated by dopamine. High levels of prolactin stimulate the growth of breast and prostate tissue; they may thus be a risk factor for developing breast and prostate cancers and would certainly stimulate the growth of such cancers.

We became interested in the connection between iron deficiency and restless legs when Sandy developed the latter condition. It has been completely eradicated with daily RDA-level iron supplementation. Iron supplements should be taken at separate times from other supplements because of the possibility of chemical interactions with vitamin C, resulting in free radical generation, or with irreversible binding to polyphenols, especially quercetin. We suggest using ferrous gluconate; iron-EDTA chelates produce hydroxyl radicals very efficiently in the presence of vitamin C, and ferrous sulfate can be quite irritating.

References

1. Burhans et al. Iron deficiency: differential effects on monoamine transporters. Nutr Neurosci 8(1):31-8 (2005).
2. Barkey et al. Characterization of the hepatic prolactin receptors induced by chronic iron deficiency and neuroleptics. Eur J Pharmacol 122:259-67 (1986).

Tocopherol Radical Regeneration by Antioxidants

A recent paper¹ reports on the ability of various antioxidants to regenerate vitamin E from the vitamin E radical (tocopheroxyl radical). Though vitamin C is a well-known regenerator of the vitamin E radical to its normal nonradical form, there are other antioxidants that can do so, and in some cases even more powerfully than vitamin C. This paper focused on catechins (found in tea): epicatechin (EC), epicatechin gallate (ECG), epigallocatechin (EGC), and epigallocatechin gallate (EGCG). The researchers found that EC, ECG, EGC, and EGCG “have activity similar to or higher than that of vitamin C in vitamin E regeneration at pH 7–12 in micellar solution.”

They also looked at the regeneration capability of other antioxidants. They found that the rate of the regeneration reaction of the tocopheroxyl radical with the natural antioxidants examined increases in the order of: methyl linoleate << rutin < EC < ECG < EGC ~ vitamin C (ascorbate anion) < EGCG < quercetin (pH 8) << CoQ10. The authors suggest that “catechins may function as antioxidants in biological systems.”

It is interesting to note that, in studies of the effect of vitamin E on the course of cardiovascular disease in patients with that condition, most included no regenerators of vitamin E from its radical, leaving excess vitamin E radicals in the circulation. This may have accounted, in full or in part, for the negative impact of vitamin E in those studies. A few studies have used both vitamin E and vitamin C; however, there were no measurements made of the redox state in the circulation, so we don’t know whether the doses of E and C used were adequate to reduce oxidative stress in cardiovascular disease patients.

Moreover, many of the studies of vitamin E and cardiovascular disease with negative results were done on patients with pre-existing cardiovascular disease; most of those patients would have been taking statins. Statins powerfully inhibit the production of both cholesterol and CoQ10, the latter being the most powerful regenerator of the tocopheroxyl radical (see above). All users of statins should take 120–240 mg/day of supplemental CoQ10.

Reference

1. Mukai et al. Structure-activity relationship of the tocopherol-regeneration reaction by catechins. Free Rad Biol Med 38:1243-56 (2005).

Arginine Improves Endothelial Function in Healthy Individuals Older Than 70 Years

As we explained in our last issue, mortality from cancer now exceeds mortality from heart disease except in those over 85.¹ A new study² found oral L-arginine to “partially correct severely depressed endothelial function in healthy individuals older than 70 years. This suggests a novel therapeutic strategy all the more because neither pravastatin nor vitamin E were [sic] effective in correcting endothelial function in asymptomatic men older than 70 years with moderate hypercholesterolaemia.”

The 12 subjects (eight men and four women) in the study were healthy, lifelong nonsmokers with no signs of cardiovascular disease and with a mean age of 73.8 years (70–78). The subjects were studied for the effects of oral arginine (8 grams twice daily) or placebo on endothelium-dependent, NO-mediated vasodilation, as indicated by flow-induced vasodilation in the brachial artery. “Flow-induced, NO-mediated vasodilation of the brachial artery was 2.65 ± 1.15% before L-arginine intake and 0.64 ± 0.89% before placebo intake [not significant] as compared with 11.00 ± 3.4% in healthy young subjects (p<0.01). Supplementation with oral L-arginine significantly enhanced endothelium-dependent vasodilation (to 5.73 ± 1.19%, p<0.05 versus baseline and p<0.0001 versus placebo); whereas placebo had no significant effect …” As the authors pointed out, the decline (from youthful levels) in endothelium-dependent vasodilation measured in this study is compatible with data from an earlier study³ showing a “gradual decline in FMD [flow-mediated vasodilation] with increasing age in 238 asymptomatic subjects aged 15–72 years without known atherosclerotic risk factors.”

The points to note are: (1) The endothelial function was severely depressed in these 12 healthy, nonsmoking subjects over 70 who were examined for and found to have no signs of cardiovascular disease. Hence “healthy” is a relative term, as the endothelial function (as explained in the previous paragraph) in the healthy 70+ year-olds would be considered seriously dysfunctional in the healthy young. (2) Oral L-arginine (8 grams twice a day) was effective in partially and significantly improving endothelial function.

We have been using an arginine + choline + vitamin B5 formulation for almost 30 years. We include choline and vitamin B5 in our formulation, though we haven’t seen these nutrients in other arginine formulations, because the vasodilatory response is mediated through acetylcholine as well as nitric oxide.⁴

In a separate paper,⁵ four weeks of oral supplemental L- arginine (7 grams three times a day) in 27 young hypercholesterolemic subjects aged 29 ± 5 years (19–40) significantly improved (compared to placebo) endothelium-dependent vasodilation (which improved from 1.7 ± 1.3 to 5.6 ± 3.0%).

1. Twombly. News: cancer surpasses heart disease as leading cause of death for all but the very elderly. J Natl Cancer Inst 97(5):330-1 (2005).
2. Bode-Boger et al. Oral L-arginine improves endothelial function in healthy individuals older than 70 years. Vasc Med 8:77-81 (2003).
3. Celermajer et al. Aging is associated with endothelial dysfunction in healthy men years before the age-related decline in women. J Am Coll Cardiol 24:471-6 (1994).
4. Ignarro et al. Endothelium-derived relaxing factor from pulmonary artery and vein possesses pharmacologic and chemical properties identical to those of nitric oxide radical. Circ Res 61:866-79 (1987).
5. Clarkson et al. Oral L-arginine improves endothelium-dependent dilation in hypercholesterolemic young adults. J Clin Invest 97:1989-94 (1996).

Cholinergic Agonists Improve Survival in Experimental Sepsis: Link to Arthritis

We have written previously on protective strategies against out-of-control bacterial infections (sepsis), an increasing risk due to antibiotic-resistant bacteria. We have also written about the cholinergic vagus-nerve anti-inflammatory pathway. Here, a recent study^1,2 reports that cholinergic agonists protected mice against sepsis induced by lipopolysaccharide and by cecal (part of the large intestine) ligation and puncture.

The authors of the study note that they recently identified high-mobility-group box 1 (HMGB1) protein as a late mediator of lethal systemic inflammation in sepsis. In another paper,³ the researchers identify HMGB1 as a “mediator of interest” in human and experimental arthritis; they note that HMGB1 can be either actively secreted by macrophages or passively released by necrotic cells of all kinds and that macrophages and unprogrammed cell death caused by ischemia or activated complement are prominent features of the persistent synovial inflammation of chronic arthritis. The authors³ also note that elevated levels of HMGB1 are present in synovial fluid samples from rheumatoid arthritis patients. Inhibition of HMGB1 (with either neutralizing antibodies or the antagonistic A box domain of HMGB1) was reported to ameliorate collagen-induced arthritis in both mice and rats and to inhibit local overexpression of the inflammatory cytokine IL-1beta in the joints.

The researchers³ note that serum HMGB1 levels are below 5 ng/mL in the serum of healthy animals and normal humans, but that much higher circulating levels (up to 150 ng/mL) were observed in human patients with severe sepsis, with the highest levels in those who died.

The researchers of paper 1 report that they discovered that acetylcholine release through the vagus nerve can modulate circulating tumor necrosis factor-alpha (TNF-alpha) levels induced by endotoxin. In this paper, they find that acetylcholine suppresses HMGB1 release from macrophages through a nicotinic cholinergic receptor. Nicotinic cholinergic receptors are stimulated by acetylcholine (which also stimulates muscarinic cholinergic receptors); selective nicotinic cholinergic receptor stimulators include nicotine, but unfortunately, for many reasons nicotine is not recommended. However, nicotine was used to treat the experimental mice in this study. Their results indicated that nicotine could rescue animals from established severe sepsis.

Our choline supplement includes choline and vitamin B5, as well as other nutrients. Vitamin B5 is required to convert choline to acetylcholine. We take it daily for its cognition-enhancing effects, but would take more if we became infected with an antibiotic-resistant strain of bacteria. It may also help with arthritis, though it is hard to separate the effects from everything else we take.

References

1. Wang et al. Cholinergic agonists inhibit HMGB1 release and improve survival in experimental sepsis. Nature Med 10(11):1216-21 (2004).
2. Matrthay and Ware. Can nicotine treat sepsis? Nature Med 10(11):1161-2 (2004).
3. Andersson and Erlandsson-Harris. HMGB1 is a potent trigger of arthritis. J Int Med 255:344-50 (2004).

Urinary Tract Infections: Nicotinic Acid Prevents Candida Adherence

Most of you have probably read about the effects of certain constituents of cranberry juice that inhibit the adhesion of microbes to the epithelial lining of the bladder and urinary tract, thus helping to prevent and eliminate urinary tract infections. According to a new study,¹ nicotinic acid (niacin) can also help.

The study examined the effect of nicotinic acid on urinary tract infection caused by Candida glabrata. The paper reports that Candida accounts for about 25% of all urinary tract infections relating to indwelling catheters, with C. glabrata accounting for about 15% of the Candida isolates. Adherence to the urinary tract cells is necessary for infection and, in C. glabrata, is mediated by a lectin encoded by the EPA1 gene family. In this organism, EPA6 and EPA7 are normally silenced, but their expression (unsilencing) leads to adhesion in the urinary tract. The authors found that nicotinic acid deficiency in the urinary tract was the cause of the reinitiation of expression of these genes. The way this works is that Sir2p (a silencing gene that is also implicated in longevity) is modulated by cellular levels of nicotinamide adenine dinucleotide (NAD), for which nicotinic acid is a precursor. The authors say that “Here we provide data suggesting that cellular NAD⁺ levels, which in C. glabrata are tied to environmental NA [nicotinic acid] levels, modulate Sir2p-mediated silencing of subtelomeric EPA genes in response to the host environment.”

To sum it up: Relatively low nicotinic acid levels in the urinary tract result in increased adhesion of Candida. Hence supplementation with nicotinic acid ought to help prevent or to eliminate Candida urinary tract infections.

Reference

1. Domergue et al. Nicotinic acid limitation regulates silencing of Candida adhesins during UT1. Science 308:866-70 (2005).

More on Glycogen Synthase Kinase-3, Inhibited by Lithium: 
Alzheimer’s, Neurotoxicity, and Cellular Senescence

Glycogen synthase kinase-3beta is a central figure in many intracellular signaling pathways and is inhibited by lithium.¹ We wrote earlier about this in our discussion of our brain-maintenance formulation that includes low-dose lithium for the purpose of partially inhibiting glycogen synthase kinase-3beta.*

*See “Maintain Your Brain the Durk Pearson & Sandy Shaw Way” in the May 2004 Life Enhancement.

As glycogen synthase kinase-3 is importantly involved in cell survival and proliferation, many new findings are being reported on its effects. Here we report on four of the latest papers we’ve found: inhibition of glycogen synthase kinase-3 as a potential protectant against the development of Alzheimer’s disease,^2,3 how the inactivation of glycogen synthase kinase-3beta protects against kainic acid-induced excitotoxicity in brain cells,⁴and how glycogen synthase kinase-3 accumulates in the nuclei of replicatively senescent human fibroblasts.⁵

Alzheimer’s: A new paper² reports that inhibition of glycogen synthase kinase-3 by lithium correlates with reduced levels of aggregated, insoluble tau. Tau is a normal protein found in the brain, but its abnormal aggregated and insoluble form is found in neurofibrillary tangles, such as are found in aging and in larger quantities in Alzheimer’s disease. This study found that levels of aggregated tau correlated strongly with the degree of axonal degeneration, while lithium-treated mice showed less degeneration when begun during the early stages of tangle development.²

In the next paper,³ researchers found that glycogen synthase kinase-3 protein was increased in white blood cells in both Alzheimer’s patients and those with mild cognitive impairment relative to elderly controls. The authors explain, “These data are in line with previous studies suggesting an altered response to insulin in AD [Alzheimer’s disease]. Glucose regulation is aberrant in AD, and fasting plasma insulin levels are higher; features of insulin resistance indicative of a failure of the normal inhibitory effects of insulin on GSK-3 [glycogen synthase kinase-3]. They are also in line with neuroimaging studies pointing to altered glucose utilization in brain in AD.” [citations omitted] The authors suggest, therefore, that “… inhibition of GSK-3 might be a useful therapeutic strategy.” Moreover, “Our findings raise the possibility that measures of GSK-3 in circulating white cells might be useful in the diagnosis of AD.”

Excitotoxicity: In another paper,⁴ scientists found that lithium was protective against kainic acid-induced excitotoxicity in hippocampal slice cultures.

Cellular Senescence: In the final paper,⁵ an interesting interaction of glycogen synthase kinase-3 with p53 (an important tumor-suppressor protein) in which the activity of p53 was enhanced was reported. When cells are damaged, p53 is induced; p53 suppresses cell division and hence permits damage repair (or apoptosis if the damage is too great to repair) to take place. Senescent cells do not divide; hence, having a large percentage of senescent cells can promote aging by limiting repair by cell division to replace damaged and defective cells. The researchers found that, compared with young and middle-aged human WI-38 fibroblasts, senescent cells contained increased levels of glycogen synthase kinase-3beta in the nucleus (and also tended to contain increased levels of the other isoform, glycogen synthase kinase-3alpha). Upon inhibition of glycogen synthase kinase-3beta with lithium, the senescence-associated accumulation of p53 was reduced. The treated cells exhibited changes (lithium blocked the increases in beta-glucosidase, p53, and p21 normally associated with senescence) suggesting a reversal of senescence into a reversible state of quiescence. These effects were seen for lithium at a dose of 10mM, but not at 1 mM or 3 mM. It is not clear from this study, as it is a cell-culture study, what would be an appropriate and effective, yet nontoxic, dose of lithium in a whole organism, let alone a human, for the purpose of “treating” cell senescence. Nevertheless, we consider safe low-dose lithium supplementation possibly to have a beneficial effect on such senescence, since even small doses may inhibit glycogen synthase kinase-3beta to some extent. It is certainly worth studying further.

References

1. Jope and Bijur. Mood stabilizers, glycogen synthase kinase-3beta, and cell survival. Molec Psychiatry 7:S35-45 (2002).
2. Noble et al. Inhibition of glycogen synthase kinase-3 by lithium correlates with reduced tauopathy and degeneration in vivo. Proc Natl Acad Sci USA102(19):6990-5 (2005).
3. Hye et al. Glycogen synthase kinase-3 is increased in white cells early in Alzheimer’s disease. Neurosci Lett 373:1-4 (2005).
4. Goodenough et al. Inactivation of glycogen synthase kinase-3beta protects against kainic acid-induced neurotoxicity in vivo. Brain Res 1026:116-25 (2004).
5. Zmijewski and Jope. Nuclear accumulation of glycogen synthase kinase-3 during replicative senescence of human fibroblasts. Aging Cell 3:309-17 (2004).

Serotonin Transporter Found in B-Cell Malignancies: 
Inhibition of Cancer Growth by Inhibiting Transporter

The serotonin transporter (SERT) has recently¹ been reported to be present in a large number of B-cell malignancies, including B-cell precursor acute lymphoblastic leukemia, multiple myeloma, Burkitt’s lymphoma, prolymphocytic leukemia, mantle-cell lymphoma, diffuse large B-cell lymphoma, and primary mediastinal B-cell lymphoma. Normal tonsilar B cells, however, contained no detectable SERT. Mitogenic stimulation (causing cells to divide) by phorbol ester, a known cancer promoter, and a calcium ionophore led to the induction of readily detectable SERT in resting B cells that otherwise had no detectable SERT.

The researchers then tested drugs that are known to target SERT, which include selective serotonin uptake inhibitors (the SSRI fluoxetine), the tricyclic antidepressant clomipramine, and the amphetamine derivatives MDMA (“Ecstasy”) and fenfluramine, to see whether they could arrest the growth of the model Burkitt’s lymphoma cell line. Twelve of the 17 derived B-cell lines showed an antiproliferative response to the tested psychotropics. Thus, as the authors note, this study establishes SERT expression as a phenotype common to neoplastic B-cell clones of widely distinct tumor origin.

The concentrations required for MDMA and fenfluramine to elicit an antitumor response were high. However, the effects of fluoxetine and clomipramine occurred at concentrations known to be reached in the serum of patients on standard dosing regimes for anxiety-related disorders; as these two agents pass the blood-brain barrier, the authors suggest that they be studied for the possible treatment of CNS lymphomas.

It is also interesting to note that the potent proinflammatory cytokine tumor necrosis factor-alpha enhances the function of the serotonin transporter,² pointing out a possible mechanism for the depression associated with inflammation and/or cancer.

References

1. Meredith et al. The serotonin transporter (SLC6A4) is present in B-cell clones of diverse malignant origin: probing a potential anti-tumor target for psychotropics. FASEB J 19:1187-9 (2005).
2. Mossner et al. Enhancement of serotonin transporter function by tumor necrosis factor alpha but not by interleukin-6. Neurochem Int 33:251-4 (1998).

Search Studies Show Airline Baggage Inspections a Waste of Time and Resources

A short report in Nature¹ found that, in searches for rare targets, the more infrequently the target is actually there, the greater the risk that human inspectors will miss it. The researchers compared the performance of searchers in an artificial baggage-screening task in which people were to look for “tools” among objects in other categories. The number of objects shown in a display was 3, 6, 12, or 18, and target prevalence was 1%, 10%, or 50%.

In the 1% prevalence condition, 12 paid volunteers searched in 2000 trials (broken into 250 trial blocks) that included 12 target-present trials. Each observer was also tested separately in over 200 trials of the 10% and 50% target-present trials. The 50% prevalence trials resulted in 7% miss errors (failing to notice a target), which (the authors say) is typical for laboratory search tasks of this sort. However, at 10% prevalence, the miss error was 16%, and errors were 30% at 1% prevalence.

These data suggest that the federal government is wasting everybody’s tax money on these searches, while wasting the time of those “inspected.” Where is the safety these inspections are supposed to foster when, supposing the appearance of actual important forbidden objects (such as knives, guns, etc.) is even as high as 1% (though this seems unlikely to us), 30% of these objects are likely to be missed. Add to that the fact that there is little or no accountability for searchers who habitually miss items, and you have to wonder whether these monopoly unionized federal inspectors are even doing so “well” as a 30% error rate.

Next time you or your baggage is searched at an airline, you might think of this. Of course, you mustn’t say anything to the nice inspector about these data, because your First Amendment rights to criticize “your” government do not apply when talking to federal airline inspectors, and you might get thrown off your flight (or fined or imprisoned) for “harassing” the government.

Reference

1. Wolfe et al. Cognitive psychology: rare items often missed in visual searches. Nature 435:439-40 (2005).