May 2012 Blog with Durk and Sandy

You will find that the state is the kind of organization which, though it does big things badly, does small things badly, too.

— John Kenneth Galbraith

The most incomprehensible thing about the world is that it is comprehensible.

— Albert Einstein

If Rome and Sparta could perish, what state could hope to live forever?

— Jean-Jacques Rousseau

Illusions commend themselves to us because they save us pain and allow us to enjoy pleasure instead. We must therefore accept it without complaint when they sometimes collide with a bit of reality against which they are dashed to pieces.

— Sigmund Freud

The house of representatives ... can make no law which will not have its full operation on themselves and their friends, as well as the great mass of society. This has always been deemed one of the strongest bonds by which human policy can connect the rulers and the people together. It creates between them that communion of interest, and sympathy of sentiments, of which few governments have furnished examples; but without which every government degenerates into tyranny.

— James Madison, Federalist No. 57, 1788 
(quote received from The Patriot Post 2 Feb. 2012 http://patriotpost.us/document/)

(D&S Comment: James Madison had it right when he said that when the government’s laws applied to everybody, including those in the government and their friends, that that creates a sympathy of interests between the government and the people but he had it wrong when he opined that (based on his understanding of the Constitution and he ought to have had a pretty clear under­standing being the primary architect of the said Constitution) “the house of representatives ... can make no law which will not have its full operation on themselves and their friends.” Unfortunately, we cannot but agree that when those of the government put themselves above the law then we see a government that has degenerated into tyranny. (A good example of such special privilege — e.g., when the law that applies to everybody else does not apply to them — is the exemption of those in government, including the President, Congressmen, and Senators, by their own self-interested actions from participating in Social Security and Medicare. They get their own, much better, plans while generating taxes that don’t apply to them on the American taxpayers shackled to the much inferior plans. Is it any wonder that the taxes to support these plans for the ordinary Americans keep on going up while the “benefits” provided by them continually deteriorate? It’s no skin off the noses of the exempt government folks.)

A Couple of Tips From “SHTF [when the shit hits the fan] Planning: 20 Lessons from the Streets of Cairo”

Posted by Mac Slavo on Feb. 1, 2012 @9:41 am in EMERGENCY PREPAREDNESS. Article printed from SHTF Plan — When It Hits the Fan, Don’t Say We Didn’t Warn You: http://www.shtfplan.com

Lesson #8 ... Just because the shit is hitting the fan where you are does NOT mean it is hitting the fan even 10 miles away. This is not bugging out ... just moving. (D&S Note: These folks were living in Cairo during the recent riots and violence that led to the collapse of the political structure of Egypt and imposition of military rule. They found that they were much better off a mere ten minute drive away from where they were driving to the airport. As they say, “We didn’t realize for 10 days that all we really had to do was find a new apartment or take a nice hotel room 20 miles away from our current location.”)

Lesson #9...When the players in a conflict become ill-defined, it’s time to step aside. If you know who the bad guys are, you can play this game but when it becomes a war of all against all, it becomes imperative to stay out of the game where EVERYONE loses. The Feb. 2 riots that took place the night we left were a perfect example of this. It was no longer looters we were worried about, it was EVERYONE.” “If SHTF starts to look too much like civil war, it’s ‘game over’ and time to make a change.”

It would be thought a hard government, that should tax its people one-tenth part of their time, to be employed in its service.

— Benjamin Franklin, in “The Way to Wealth” (1758)

(D&S: One-tenth?? We should have it so good ...)

One to-day is worth two tomorrows.

— Benjamin Franklin (Poor Richard)

(D&S Comment: Well, one would certainly think that one today is worth more than one tomorrow unless you were Ben Bernanke who thinks that interest for loans over a few years should be virtually zero (that is, you do not place a value on having money now rather than later, where interest is the price you pay for having money today but paying it back tomorrow). The result, of course, is that the price you pay for having money now is artificially set by the FED as the same as having it later, destroying the signal that interest is supposed to provide to tell people how much markets value present versus future payoffs. The result? Lots of malinvestments. Thanks, Mr. Bernanke!)

Old men do not grow wise. They grow careful.

— Ernest Hemingway

Vitamin D3 Rejuvenation of Aging Eyes in Elderly Mice by Reducing Inflammation and Clearing Amyloid-Beta

The important antiinflammatory effects of vitamin D3 are becoming a hot research topic, with increasing numbers of papers being published on its use in the prevention and treatment of autoimmune and age-associated inflammatory diseases.² One recent paper¹ now reports that, in aged mice, vitamin D3 treatment for only 6 weeks significantly impacted the aging process, decreasing visual decline with the reduction of amyloid-beta in the Bruch’s membrane of the eyes. Note, importantly, that amyloid-beta is also accumulated in Alzheimer’s disease where it plays a key role in the degenerative effects of the disease. Hence, we speculate that the ability of vitamin D3 to reduce the accumulation of amyloid-beta in the eyes might also apply to a reduction of amyloid-beta in areas of the brain where it accumulates in Alzheimer’s disease.

In the study of vitamin D3 and the “rejuvenation” of aging eyes, treatment was administered by subcutaneous injection every 3 days with either 0.9 µg vitamin D3 in 0.1 ml. of safflower oil or the equivalent amount of safflower oil alone as a placebo. The authors explain that with aging, there is an increase in retinal inflammation and the gradual deposition of extracellular material along Bruch’s membrane, which reduces the permeability of the outer blood retinal barrier as well as increasing inflammation. They found that “[l]evels of Abeta [amyloid beta] along Bruch’s membrane were significantly reduced in Vitamin D3 treated retinae compared with controls in immunostained sections.” These data were confirmed with Western blots. “This showed not only a reduction in Abeta, but that proportionally a greater amount of the relatively more neurotoxic heavier oligomers in the region of 50–64 kDa [kilodaltons] appears to be removed as a consequence of vitamin D3 treatment.”

Increased Phagocytosis by Retinal Macrophages in Response to Vitamin D3

Moreover, the researchers found that retinal macrophages, which are responsible for phagocytosis (removal of cellular garbage) and become activated in association with chronic inflammation, were radically altered in Vitamin D3 treated mice to become a more ameboid type that is both more mobile and more phagocytic.

The results showed elevated retinal function in the treated mice.

In their summation, the authors said, “... hand in hand with this [evolution of man in Africa, where there was greater exposure to sunlight and, hence, likely higher vitamin D3 levels] is the issue of aging. Life expectancy in the early Neolithic was approximately 20–25 years, while now in the Western [more accurately, the economically advanced] world it is close to 80 years, driving it into periods where there is significant age-related extracellular deposition and inflammation. Hence, the Western human population is living 4 times longer, but on a daily basis now probably has significantly less vitamin D3than it did for more than the previous 99.99% of its evolutionary history. This may be a cogent argument for vitamin D3 supplementation in our aging population.”

References

1. Lee et al. Vitamin D rejuvenates aging eyes by reducing inflammation, clearing amyloid beta and improving visual function. Neurobiol Aging(Jan. 2 2012). Epub ahead of print.
2. Guillot et al. Vitamin D and inflammation. Joint Bone Spine77:552-557 (2010).

 

IS THE FDA TRYING TO KILL THE GRANDFATHERS? ARE THEY AIMING AT YOUR FAVORITE GRANDFATHER RIGHT NOW? 

FDA Expands Into New Territory Where NOBODY Has Standing To Challenge Them Before a Court

If an agency announces in the Federal Register that it is considering adopting some regulation, which then allows for public comment, this is called “notice and comment” and is how regulations are supposed to be introduced under the Administrative Procedures Act. Anybody can comment for the record and anyone who comments automatically has “standing” to sue the agency before a federal court in an objection to issues brought up by themselves or anybody else in public comments that they deem not to have been adequately dealt with by the agency.

Now the FDA has cleverly broadened the scope of some earlier regulations by simply adding lots of stuff that was never in the regulation originally filed in the Federal Register as a proposed new regulation and allowing for a “notice and comment” period. Nobody can comment on these new regulations that are simply tacked onto existing regulations without an announcement in the Federal Register and, hence, without public “notice and comment;” therefore, nobody has the automatic standing and, folks, it is very hard to get standing where courts are overloaded or don’t really want to hear your complaint.

We are thinking here, specifically, of new rules — cleverly called a “policy guidance” — tightening restrictions on what constitutes an “old dietary ingredient” (that is, one that was on the market — grandfathered — as of the passage in 1994 of the Dietary Supplement Health and Education Act (DSHEA). We call it the FDA’s War on Grandfathers. An example of a rule change is found in this description from a trade publication:¹ “A key issue is determining whether an ingredient is in fact an NDI [new drug ingredient, a non-grandfathered dietary supplement that is not FDA approved] or whether it is an old dietary ingredient (ODI) that has been ‘chemically altered.’ Chemical alteration of a botanical does not include physical alterations such as drying or pulverizing but does include, according to FDA’s new draft guidance, the use of any extraction solvent other than water and/or ethanol.” This is a usurpation, without any legal basis, of the statutory limitations set by Congress in the DSHEA that is the law without any new Congressional legislation or, if in the form of a regulation, any public notice and comment. What about extractions with supercritical carbon dioxide among many other long-used and safe methods? Presumably they are no longer allowed for dietary supplements. Another gift to the pharmaceutical industry.

One Grandfather That Has Already Been Declared Not to Be a Dietary Supplement — You’ll Need a Prescription to Get It

An example of a dietary supplement that has already been removed by the FDA from the grandfathered list was one listed by the Natural Nutritional Foods Association (downloaded in 1995) as being in use before October 15, 1994 (the date when DSHEA took effect); this was pyridoxamine, a lipid soluble form of vitamin B6, that has been found to have potent protective effects against the formation of AGEs (advanced glycation end products), which have been identified as causative factors in aging, diabetes, cardiovascular, and other diseases. A couple of years ago, the FDA suddenly banned pyridoxamine from being sold as a dietary supplement (without any basis in terms of health and safety); a pharmaceutical company has subsequently filed for approval of pyridoxamine to be sold as a prescription drug at an immensely higher price. If pyridoxamine had still been available for use in dietary supplements, we would have included it in our anti-AGEs formulation AGEless,™ but we did include vitamin B6which has some anti-glycation effects, though not as potent as those of pyridoxamine.

But there’s more — and worse. The FDA “Guidance” says that any new combination of old grandfathered ingredients constitutes a “new dietary ingredient.” There is no basis in either law or existing regulations for that innovation-killing usurpation, either.

Reference

1. Mark Blumenthal, Dear reader. HerbalGram91 (2011).

 

EATING TIP

Replace Calorigenic Oil in Natural Peanut Butter with MCT Oil

We enjoy eating natural peanut butter (contains only peanuts and perhaps a little salt), sometimes just a spoonful right out of the jar. But, if you have bought natural peanut butter you know that when you buy it, the peanut oil has separated into a layer on top of the solids and you have to mix them together. (It’s easier with the simple natural peanut butter mixer you can get from Lehman’s catalog (1–877–438–5346) for $9.95.) What Sandy likes to do is to pour off the peanut oil into a measuring cup (to determine exactly how much oil is in there), dump that oil and replace it with the same amount of medium chain triglycerides (MCTs), an oil that is less likely to be converted into stored body fat; MCTs also contain slightly fewer calories than other edible oils. Mix, then refrigerate. Our Functional Gourmet™ MCT Oil has no taste, either, so it will have no effect on the flavor of your peanut butter.

Moreover, MCTs are far more oxidation resistant than peanut oil. We have 18 year old plastic bottles of this MCT oil that neither smells nor tastes rancid, hence, exhibiting potent resistance to free radical attack.

Pearson v. Shalala Makes It to the U.S. Supreme Court — Sort Of

Well, it was another commercial speech case that arrived at the Supreme Court not too long ago, but the basic issues were very similar to those in Pearson v. Shalala and the First Amendment won by a vote of 6–3 (very surprisingly, Sotomayer voted with the majority to uphold the free speech rights of pharmaceutical companies while, unsurprisingly, Breyer, Ginsburg, and Kagan dissented). The case was Sorrell, Attorney General of Vermont et al v. IMS Health, Inc. et al (No. 10-779, decided June 23, 2011.

In that case, the State of Vermont wanted to prohibit the use of prescriber-identifying information by pharmaceutical companies to help determine the interests of individual physicians in order to better market their drugs. The prescriber-identifying information is freely available to anybody in Vermont and the State had not imposed any restrictions on its use except in the case of pharmaceutical companies. Therefore, it was a clear case of the government discriminating against particular speakers, which is not permitted under the First Amendment and its jurisprudence. The Supreme Court held the Vermont law to the standards of strict scrutiny under the First Amendment. We are quite confident that Pearson v. Shalala would be upheld (e.g., it is unconstitutional, under the First Amendment, for the FDA to prohibit the communication of truthful nonmisleading information about dietary supplements) if it were to be argued before the Supreme Court. With this new decision in hand, we hope that we will see some more aggressive First Amendment litigation against the FDA which is still limiting communication of most truthful and nonmisleading information to the public by manufacturers and vendors when it pertains to dietary supplements and foods.

A few quotes from the majority decision are given below. Note: we didn’t include most of the case citations. You can get all that from the published Court decision.

“Heightened judicial scrutiny is warranted.” (pg. 2 of the syllabus)

“But ‘the fear that people would make bad decisions if given truthful information’ cannot justify content-based burdens on speech.” (pg. 4 of syllabus)

“Speech in aid of pharmaceutical marketing, however, is a form of expression protected by the Free Speech Clause of the First Amendment. As a consequence, Vermont’s statute must be subjected to heightened judicial scrutiny. The law cannot satisfy that standard.”

“The First Amendment requires heightened scrutiny whenever the government creates ‘a regulation of speech because of disagreement with the message it conveys.’”

“An individual’s right to speak is implicated when information he or she possesses is subjected to ‘restraints on the way in which the information might be used’ or disseminated.”

“This Court has held that the creation and dissemination of information are speech within the meaning of the First Amendment. See, e.g., Bartnicki, supra, at 527 (‘[I]f the acts of “disclosing” and “publishing” information do not constitute speech, it is hard to imagine what does fall within that category’; Rubin v. Coors Brewing Co., 514 U.S. 476, 481 (1995)(‘information on beer labels’ is speech) ...”

“... Vermont made prescriber-identifying information available to an almost limitless audience. The explicit structure of the statute allows the information to be studied and used by all but a narrow class of disfavored speakers.”

“If pharmaceutical marketing affects treatment decisions, it does so because doctors find it persuasive. Absent circumstances far from those presented here, the fear that speech might persuade provides no lawful basis for quieting it.”

“The First Amendment directs us to be especially skeptical of regulations that seek to keep people in the dark for what the government perceives to be their own good.” 44Liquormart, supra, at 503 (opinion of Stevens, J.)

“The State has burdened a form of protected expression that it found too persuasive. At the same time, the State has left unburdened those speakers whose messages are in accord with its own views. This the State cannot do.” 

www.supremecourt.gov/opinions/10pdf/10-779.pdf 
http://www.law.cornell.edu/supct/cert/10-779

 

The Challenges of Translating Basic Research into Therapies: 
Resveratrol as an Example

A paper published early this year¹ provided a very illuminating explanation of the difficulties of turning research results from the study of natural products into treatments. As the authors note in their introduction: “Solving problems in rodents is deceptively easy. Diabetes has been cured numerous times, exercise can be delivered in pill form, and just a few months ago, scientists were able to reverse age-related degeneration.”

The authors used the case of resveratrol, a natural molecule that has been the subject of a large amount of research for its potentially very valuable health benefits. Yet, as they explain it, the translation of this research into usable therapies for human disease is far from a simple matter.

The authors and many other scientists attended what they say is the first international conference on resveratrol and health, Resveratrol2010, which was held in September of 2010 in Helsingor, Denmark. “A clear theme of the conference, which was attended by all of the authors [of paper #1] was that multiple mechanisms are likely to contribute to the beneficial effects of resveratrol, making it difficult to agree on a specific dose, biomarker, or outcome that can define the molecule.”

The article went on to describe some of what is known about the fate of resveratrol after consumption (as part of red wine, for example). “An enterohepatic [intestine-liver] cycle of the metabolism of resveratrol has been proposed in both rats and humans. Resveratrol is quickly taken up by entero­cytes [intestinal cells] and metabolized to glucuronide and sulfate conjugates, which are secreted back to the intestine where they may be deconjugated and reabsorbed or excreted in the feces. The enterohepatic cycle reduces the concentration of the free compound reaching the body lumen. Thus, the enterohepatic cycle, along with a rapid metabolism in the liver, likely explains the low concentration of resveratrol in the bloodstream.” “It is clear that only a small fraction of the ingested resveratrol reaches the body as the parent compound. Furthermore, the amount of resveratrol ingested from dietary sources, such as red wine, juices, and so on, would very rarely exceed 5 mg, resulting in plasma levels that are either not detectable or orders of magnitude below the micromolar concentrations employed in vitro.”

The authors report that in rodent models, the doses of resveratrol can range over four orders of magnitude, from 0.1 to 1,000 mg/kg with even higher or lower doses occasionally being used. They explain that you can get different effects depending on whether a dose is high or low. “... resveratrol frequently exhibits biphasic effects. For example, resveratrol at low doses (~5 mg/kg/d) has been shown to cause weight gain in mice fed a high-fat diet, whereas at high doses (~400 mg/kg/d), there is marked weight loss. Moreover, cardioprotective effects of resveratrol that are observed at 2.5 or 5 mg/kg/d are reversed when the dose is increased to 25 or 50 mg/kg/d.” The researchers suggest that, in the face of these complications, determining a human dose from a rodent dose is a severe problem: “... there is simply no way to be confident without performing the human studies.”

The upper safe dose for resveratrol was discussed at Resveratrol2010. “Two different commercial suppliers of resveratrol, DSM Nutritional Products and Fluxome, have each reached the conclusion that 450 mg/day can be considered safe for a 60-kg individual, based on their own studies in rats and literature review (² and www.fluxome.dk, respectively). Although the panel [at the Resveratrol2010 conference] as whole was not prepared to adopt this position without further human data, it is certainly consistent with the small number of clinical trials that have been published, several of which have included doses at or above 1 g/day without serious side effects (although the studies were short term, so long-term side effects are not known.”

Moreover, the interactions between molecules such as resveratrol and other nutrients and drugs complicate the situation further for recommending a dose for nutraceutical formulations. “Synergism of various polyphenols with resveratrol has been observed experimentally and is the specific intention of many nutraceutical formulations. In addition, resveratrol can directly interact with many drug-metabolizing enzymes and induces expression of others transcriptionally.”

Unexpected negative effects can happen as well. The authors describe how “[a] clinical trial in which multiple myeloma patients were given a proprietary formulation of resveratrol at 5 g/day was recently terminated after 5 of 24 participants developed cast nephropathy [kidney damage].” As they explain further, this sort of kidney damage is a “normal” complication of multiple myeloma, but the Wall Street Journal (December 1, 2010) reported that dehydration due to vomiting and diarrhea in the resveratrol-treated patients may have exacerbated the underlying disease. Unfortunately, as the authors note, the primary data from the trial are not available and “are not likely to be.”

Exact Mechanisms May Not Be Known

“One common concern with many drugs and supplements is that the exact mechanism of action is often unknown. From a clinical standpoint, a thorough understanding of mechanism of action is not necessarily required for widespread use. This is best exemplified in the use of general anesthetics, which are not fully understood yet are an essential component of modern medicine.” The authors note that resveratrol may affect a great many regulatory pathways. For example, “SIRT1 [thought to be activated by resveratrol] controls a number of other key regulatory factors associated with metabolism and inflammation, including p53, FoxO1, NF-kappaB, and PGC-1alpha. This complexity makes it difficult to pinpoint the events mediating beneficial effects of resveratrol or to prospectively identify potential adverse effects.”

Because exercise increases mitochondrial biogenesis through a SIRT1-dependent mechanism, it was expected that this would be observed in studies where animals were supplemented with resveratrol and, indeed, this has been observed in mice. However, “there is currently insufficient evidence to support or refute an effect in humans due to lack of research in this area. Likewise, quercetin has been demonstrated to increase markers of muscle and brain mitochondrial biogenesis, as well as endurance performance, in mice but such has not been observed in humans. Interestingly, despite the lack of effect on mitochondrial biogenesis, increased exercise performance has been reported in some but not all studies of humans taking quercetin.”

Very Few Adverse Events, But Remain Vigilant

Concerning adverse events, the researchers say, “[a]lthough there have been very few adverse events reported following resveratrol supplementation in healthy humans, there is a clear need to remain vigilant as larger populations become exposed to this, or any other nutraceutical.”

The authors suggest that a good starting point for addressing the problem of comparable efficacy between various treatments, including nutraceuticals and drugs would be to fill a “major void” by directly comparing nutraceuticals to prescription drugs. We would like to suggest that such studies are very unlikely to be done, first because pharmaceutical companies would be appalled if certain nutraceuticals were to be shown to be comparable to their far more expensive drugs in the treatment of some medical conditions. Second, nutraceutical companies are unlikely to have the many tens of millions, possibly hundreds of millions, even billions of dollars, required for such a study. Finally, no such studies would ever provide “definitive” results because it would always be possible that the choice of different doses or a longer trial or changes to a great many other variables could produce different results.

Safely Using Dietary Supplements

The one clear rule of thumb for safely taking a single dietary component or combination of dietary components that usually occur together in a food is to stick as closely as possible to the amounts ingested by people in a diet rich in those substances and that has been consumed over an extended period of time. Other than that, you should consider yourself a self-selected guinea pig, as we do when trying dietary supplements that do not fall into the class that can be correlated to dietary intake or exceed what is generally consumed in a diet rich in that substance or substances.

References

1. Smoliga et al. Challenges of translating basic research into therapeutics: resveratrol as an example.J Gerontol A Biol Sci Med Sci 67(2):158-67 (Feb. 2012).
2. Williams et al. Safety studies conducted on high-purity trans-resveratrol in experimental animals. Food Chem Toxicol47:2170-82 (2009).

Summers in Washington, DC are usually awful. Before the invention of air conditioning, everyone who could, including Congress, headed for the exits in early June and didn’t return until the end of August. Unfortunately, technological progress has unforseen consequences, and thanks to our ability to cool our buildings, DC now legislates all summer long.

— Patrick J. Michaels, CATO Institute, 
Regulation magazine Fall 2011

Measure what is measurable, make measurable what is not.

— Galileo Galilei

Watermelon Juice is a Rich Natural Source of Citrulline, Precursor of Arginine — Protects against Hyperglycemia, Hyperlipidemia

A new paper¹ reports on the benefits of watermelon juice, noting that watermelon is one of the few foods naturally rich in the amino acid citrulline, with amounts varying from 0.7 to 3.6 mg/g of fresh weight.

In this study, diabetic rats were treated with drinking water containing 0.2% arginine and two different concentrations of watermelon juice (63% or 94.5%) and the results compared to that of an untreated diabetic control group and a diabetic group that was treated only with 0.2% arginine in their drinking water. The researchers found that, as compared to the control untreated diabetic rats, rats receiving drinking water supplemented with watermelon juice had enhanced arginine bioavailability and increased arginine serum concentration and also had significant hypoglycemia, hypolipidemic, anti-oxidative stress effects, with the best effect resulting from 94.5% watermelon juice. For example, HDL-C was 72.47 ± 0.45 in normal controls, 57.37 ± 4.87 in diabetic controls, 91.56 ± 2.10 in the 0.2% arginine treated group, 82.47 ± 4.10 in the 0.2% arginine and 63% watermelon juice treated group, 95.10 ± 4.92 in the 0.2% arginine and 94.5% watermelon juice group.

The authors note that 1 to 3 grams of oral citrulline increase plasma arginine concentrations by 50% in patients with sickle cell anemia. As we have reported before (for example, see the interview with us, “Putting More Power Into Your Life” in the April 2006 issue of Life Enhancement Magazine), citrulline is derived from arginine when nitric oxide synthase uses arginine to create nitric oxide, an important signaling molecule and vasodilator, but then citrulline is recycled back to arginine.² We include citrulline in our higher level arginine, citrulline, choline, plus cofactors formulation specifically to increase arginine recycling. In another paper referred to by the authors, oral administration of watermelon pomace* juice increased the mass of brown adipose tissue (the type of fat that expends energy creating heat), reducing excess white fat mass and serum concentrations of risk factors for cardiovascular disease, as well as increasing nitric oxide enodthelial function in Zucker diabetic obese rats.³

* Watermelon pomace juice preparation was described in the paper given by reference #1: “Pomace was prepared from the water­melon using a rack and cloth hydraulic press. Immediately before use, the pomace was squeezed using a juice maker. The resulting juice was filtered through a fine screen to obtain fluid, which was then added to drinking water for rats [at 63 or 94.5%].”

References

1. El-Razek and Sadeek. Dietary supplementation with watermelon (Citrullus ianatus)juice enhances arginine availability and modifies hyperglycemia, hyperlipidemia, and oxidative stress in diabetic rats. Aust J Basic Appl Sci 5(6):1284-95 (2011).
2. Hecker et al. The metabolism of L-arginine and its significance for the biosynthesis of endothelium-derived relaxing factor: cultured endothelial cells recycle L-citrulline to L-arginine. Proc Natl Acad Sci USA 87:8612-6 (1990).
3. Wu et al. Dietary supplementation with watermelon pomace juice enhances arginine availability and ameliorates the metabolic syndrome in Zucker diabetic fatty rats. J Nutr 137:2680-5 (2007).

When Good Cholesterol Goes Bad: 
Activated Platelets Contribute to Dysfunctional HDL

As we have discussed before, under certain conditions, HDL loses its ability to protect against atherosclerosis and actually becomes pro-atherogenic. A new paper¹ now identifies the important contribution of activated platelets (platelets that are more prone to clump together, forming blood clots) to the HDL modifications that attenuate its protective effects by, for example, inhibiting its ability to cause the efflux of cholesterol from cells and to block the oxidation of LDL.

The researchers studied C57B1/6 mice that had been genetically modified to have high-level baseline expression of the human version of sPLA2 (secretory phospho­lipase A2, released by platelets primarily in response to stimulation with proinflammatory cytokines). “... products of the sPLA2 reaction, namely lysophosphatidylcholine (LPC) and nonesterified fatty acids (NEFAs), themselves have proinflammatory effects. They are known to promote acute injury in the lung and prothrombotic and proatherogenic changes in vascular cells.”² “Increased circulating levels of sPLA2 have been linked to obesity, insulin resistance, type 2 diabetes, and metabolic syndrome, and they were found to predict coronary events in patients with cardiovascular disease (CVD).”

1. (References cited in these quotes have been deleted here)

Moreover, a high level of spontaneous and stimulated platelet activity has been identified in numerous investigations to be associated with risk factors for CVD, including tobacco smoking, hyperlipidemia, hypertension, and diabetes.¹ The authors¹report that “[t]he results of this study demonstrate that activated platelets contribute to proatherogenic modifications of circulating LDLs and HDLs and that sPLA2 released from platelets is a key player in the process.” The study provides direct evidence that activated platelets “can modify circulating lipoproteins in vivo and that the property of platelets from distinct mouse strains is tightly related to the respective expression levels of active sPLA2.” “Earlier studies indicated that platelet-conditioned medium can modify LDLs, thus contributing to increased uptake by macrophages [part of the process of atherosclerotic plaque-forming foam cells]. In the present studies using various agonists, these oxidation-related changes were found to occur only after platelet stimulation.”¹

References

1. Blache et al. Activated platelets contribute to oxidized low-density lipoproteins and dysfunctional high-density lipoproteins through a phospho­lipase A2-dependent mechanism. FASEB J 26:927-37 (2012).

When Good Cholesterol Goes Bad: 
Activated Platelets Contribute to Dysfunctional HDL

As we have discussed before, under certain conditions, HDL loses its ability to protect against atherosclerosis and actually becomes pro-atherogenic. A new paper¹ now identifies the important contribution of activated platelets (platelets that are more prone to clump together, forming blood clots) to the HDL modifications that attenuate its protective effects by, for example, inhibiting its ability to cause the efflux of cholesterol from cells and to block the oxidation of LDL.

The researchers studied C57B1/6 mice that had been genetically modified to have high-level baseline expression of the human version of sPLA2 (secretory phospho­lipase A2, released by platelets primarily in response to stimulation with proinflammatory cytokines). “... products of the sPLA2 reaction, namely lysophosphatidylcholine (LPC) and nonesterified fatty acids (NEFAs), themselves have proinflammatory effects. They are known to promote acute injury in the lung and prothrombotic and proatherogenic changes in vascular cells.”² “Increased circulating levels of sPLA2 have been linked to obesity, insulin resistance, type 2 diabetes, and metabolic syndrome, and they were found to predict coronary events in patients with cardiovascular disease (CVD).”

1. (References cited in these quotes have been deleted here)

Moreover, a high level of spontaneous and stimulated platelet activity has been identified in numerous investigations to be associated with risk factors for CVD, including tobacco smoking, hyperlipidemia, hypertension, and diabetes.¹ The authors¹report that “[t]he results of this study demonstrate that activated platelets contribute to proatherogenic modifications of circulating LDLs and HDLs and that sPLA2 released from platelets is a key player in the process.” The study provides direct evidence that activated platelets “can modify circulating lipoproteins in vivo and that the property of platelets from distinct mouse strains is tightly related to the respective expression levels of active sPLA2.” “Earlier studies indicated that platelet-conditioned medium can modify LDLs, thus contributing to increased uptake by macrophages [part of the process of atherosclerotic plaque-forming foam cells]. In the present studies using various agonists, these oxidation-related changes were found to occur only after platelet stimulation.”¹

References

1. Blache et al. Activated platelets contribute to oxidized low-density lipoproteins and dysfunctional high-density lipoproteins through a phospho­lipase A2-dependent mechanism. FASEB J 26:927-37 (2012).

Increasing Platelet Production without 
Increasing the Risk for Blood Clot Formation

Thrombocytopenia, a condition of low platelet counts and sometimes abnormal bleeding is difficult to treat because of the potential risk of increasing blood clots, particularly in patients with inflammatory disorders. A new paper¹ reports a possible remedy for this.

As the researchers explain, although platelets are “vital to hemostasis and have a critical role in immunological and inflammatory processes in the human circulation ... continuous activation of platelets is a major contributor to chronic inflammatory vascular diseases such as atherosclerosis and type-2 diabetes.” The paper reports that parthenolide, a component of the herb feverfew, which is already being used as an herbal medicine to treat inflammatory conditions such as arthritis and migraine headaches, was able to stimulate functional platelet production from human megakaryocyte cell lines and from primary mouse and human megakaryocytes in vitro, it also importantly decreased platelet activation by inhibiting NFkappaB, an important mediator of inflammation. The results suggest, therefore, that parthenolide could increase the production of functional platelets but modulate the platelets to reduce their activation when stimulated.

References

1. Sahler et al. The Feverfew plant-derived compound, parthenolide enhances platelet production and attenuates platelet activation through NF-kappaB inhibition. Thromb Res127:426-34 (2011).

Reversal of Several Features of the Metabolic Syndrome in Mice with Dietary Inorganic Nitrate

We discussed some of the health benefits of dietary nitrate (as found in green leafy vegetables, such as spinach) in the Jan.-Feb. 2012 issue of this newsletter. As we reported there, a recent paper¹ in which researchers studied the effects of spinach consumption by healthy human volunteers found a substantial acute augmentation of nitric oxide status and a small, but significant increase in flow-mediated dilation (expansion of the brachial artery in response to nitric oxide). As the paper’s authors had explained, “[t]his is consistent with previous studies which demonstrated that high-dose nitrate increased plasma nitrite levels, improved endothelial function, and lowered blood pressure when given in a dietary (beetroot juice) or pure (KNO3 capsules) form.” The dietary (not high dose) amount of nitrate provided by the 200 g serving of spinach in the spinach study was 182 mg.

Studies of the effects of dietary nitrate has become something of a hot research area, as the nitric oxide supplied by nitrate (after conversion to nitrite by the salivary glands and swallowed) has been identified as an important alternative source of nitric oxide besides the nitric oxide produced by nitric oxide synthase from the amino acid arginine. In a recent study,² researchers looked at the effects of supplementing eNOS deficient mice (e.g., mice that cannot make nitric oxide in endothelial cells in blood vessels because they do not have the necessary form of nitric oxide synthase) with supplemental inorganic nitrate. The dose used was comparable to the amount a human would get from a diet with a rich intake of vegetables as the nitrate source.

The results² support the results of earlier work which established a nitrate-nitrite-nitric oxide pathway and showed that the operation of this pathway (via the ingestion of dietary nitrate) can partly compensate for disturbances in endogenous nitric oxide production in animals deficient in eNOS. The eNOS-deficient mice that received 10 weeks of nitrate supplementation had an almost normalized blood glucose concentration curve as compared to the untreated eNOS-deficient mice, which had a disturbed blood glucose concentration curve. The glycosylated hemoglobin levels, a measure of long-term blood glucose control, were lower in the nitrate fed eNOS-deficient mice. Moreover, the nitrate treated eNOS-deficient mice had reduced amounts of visceral fat and lower levels of circulating triglycerides as compared with untreated animals.

NOTE OF CAUTION: Nitrate consumption can increase the risk of stomach cancer because nitrates can become converted to carcinogenic nitrosamines. This risk can be minimized by being sure to take plenty of vitamins C and E along with your meal (or supplement) containing nitrate.

References

1. Bondonno et al. Flavonoid-rich apples and nitrate-rich spinach augment nitric oxide status and improve endothelial function in healthy men and women. a randomized controlled trial. Free Radic Biol Med52:95-102 (2012).
2. Carlstrom et al. Dietary inorganic nitrate reverses features of metabolic syndrome in endothelial nitric oxide synthase- deficient mice. Proc Natl Acad Sci USA107(41):17716-20 (2010).

Research and Development Costs for 
Getting FDA Drug Approval Soar

Forbes Magazine’s Matthew Herper and Scott DeCarlo came up with new estimates of drug development costs by dividing pharmaceutical company’s research and development budgets by the number of approved drugs over 15 years. From their calculations, which are said to build off of figures from Bernard Munos at the InnoThink Center for Research in Biomedical Innovation, the pharma company AstraZeneca spent $12 billion on R&D for every new approved drug, while Amgen spent $3.7 billion. Is it any wonder that new medications cost a great deal, that pharmaceutical companies try to get in bed with (e.g., bribe) the regulatory authorities and lawmakers, and that so few new treatments ever get to market?

Selenium Shown to Specifically Stimulate 
Repair of Oxidative DNA Damage in 
LNCaP Prostate Cancer Cells

Some epidemiological studies have found an inverse relationship between selenium intake and incidence/mortality of certain cancers, including prostate cancer. In an effort to identify possible mechanisms for these protective effects, researchers investigated the effect of low doses of selenium on the stimulation of DNA repair systems in LNCaP human prostate adenocarcinoma cells in response to four different sources of DNA damage.¹ They examined DNA damage caused by UVA (ultraviolet light A), hydrogen peroxide, methylmethane sulfonate (MMS), or UVC (ultraviolet light C). Overall, their results showed that selenium was a very potent protector against cell toxicity and genotoxicity induced by oxidative stress (UVA or hydrogen peroxide) but not from the agents that induce other types of deleterious DNA lesions (MMS or UVC). In addition, they found that selenium treatment resulted in increased DNA repair capacity in oxidative DNA damaged cells.

The researchers noted that “the most robust results of the Nutritional Prevention of Cancer Trial (NPC Trial) came from the analyses of the complete data for prostate cancer incidence, which showed that dietary supplementation with 200 µg/day of yeast-enriched selenium resulted in a 63% reduction in prostate cancer risk.” Another study of the effects of selenium on the incidence of prostate cancer was performed by a different group, which used aged beagle dogs because dogs and humans are said to be the only two species in which prostate cancer occurs spontaneously with appreciable frequency;² they reported efficient protection against DNA damage.

The researchers used two types of selenium in their study: sodium selenite or selenomethionine. Cells were cultured in medium either with or without selenium supplementation (30 nM sodium selenite or 10 µM selenomethionine) for 72 hours. The LNCaP human prostate cell line they used are wild type for both p53 and Rb genes (not mutated), although both genes are mutated in the vast majority of human prostate cancers.1 It may be, therefore, that the beneficial effects of selenium reported in this paper¹ — reduced carcinogenesis and increased DNA repair — might apply to prostate cells without mutations in these genes but not apply once prostate cells had become cancerous in conjunction with mutations in these genes. As reported in another paper.³however, sodium selenite redox cycling can kill cancer cells.

References

1. de Rosa et al. Low doses of selenium specifically stimulate the repair of oxidative DNA damage in LNCaP prostate cancer cells. Free Radic Res 46(2):105-15 (2012).
2. Waters et al. Effects of dietary selenium supplementation on DNA damage and apoptosis in canine prostate. J Natl Cancer Inst95(3):237-41 (2003).
3. Olm et al. Extracellular thiol-assisted selenium uptake dependent on the x(c)- cystine transporter explains the cancer-specific cytotoxicity of selenite. Proc Natl Acad Sci USA106(27):11400-5 (2009).

Negative and Competitive Social Interactions Are Predictive of Increased Proinflammatory Activity

Increased stresses in a society of diminishing economic potential (and, hence, uncertainty about future financial status) and a rapidly shrinking domain of personal freedom has effects on health and behavior. A new paper¹ reports on the increased release of proinflammatory cytokines IL-6 and TNF-alpha (tumor necrosis factor-alpha) in participants in relation to their exposure to social threat. The participants were recruited at a large university via ads offering $120 for taking part in the study. The final sample consisted of 122 students and employees (63 men and 69 women, with 38.5% being European American and 61.5% being Asian American.

The participants first kept daily diaries for 8 days that recorded positive, negative, and competitive social interactions. This was followed by laboratory stress challenges (the Trier Social Stress Test) and the measurements at baseline and at 25 and 80 minute poststressor from oral mucosal fluids of IL-6 and soluble receptor for tumor necrosis factor-alpha (sTNFalphaRII).

As the researchers explain in their introduction, “increases in proinflammatory cytokines IL-6 and TNF-alpha have been linked to hypertension, atherosclerosis, coronary heart disease, depression, diabetes, and some cancers.”¹ Moreover, they report that “[p]eople who are socially integrated or have larger social networks have been found to have lower IL-6 and C-reactive protein (CRP), a byproduct of IL-6 activity.” “Chronic relationship stress characterized by conflict, mistrust, and instability, although not consistently related to basal levels of pro­inflammatory cytokines, have been tied to greater lipopolysaccharide-stimulated IL-6 production 6 mo. later.” Lipopolysaccharide is a bacterial product that activates the immune system. The researchers wanted to investigate the implications for inflammation of everyday social encounters, including competitive interactions, in natural (not laboratory) settings. They focused on three types of competition: competitive leisure time activities such as sports, academic or work-related competition, and competition for another person’s attention, such as romantic partners or friends.

The three categories of competition were evaluated for their prediction of relation to baseline proinflammatory cytokine levels and reactivity during acute stress (the lab tests). Leisure time competition did not predict any of the cytokine measures. Academic/work-related competitive encounters predicted baseline IL-6 (marginally significant) and sTNFalphaRII, while competing for another person’s attention significantly predicted baseline levels of IL-6. (The analysis was based on 522 competitive interactions; the researchers suggested that further research on subtypes of competitive events on inflammatory activity is needed. Presumably, this is a hint that they would be delighted if they were provided with grants to perform the necessary research!)

Negative social interactions were also found to significantly predict higher baselines of sTNFalphaRII, sTNFalphaRII and IL-6 responses following a social stressor, and total output of sTNFalphaRII.

The authors suggest that “[p]hysiologically, stress hormones may mediate the link between daily social interactions and inflammation. Social stressors, including negative social interactions, lead to increased cortisol, and cortisol tends to have a suppressive effect on inflammatory processes ... However, repeated exposure to social stress and cortisol may lead to resistance to the anti-inflammatory effects of glucocorticoids.”

Curiously, in this study the results did not support the hypothesis that positive daily social interactions would be tied to lower proinflammatory cytokine levels and reactivity to stress, as the researchers had supposed. A possible explanation, they suggest, is that some positive social interactions occurred as efforts at social support when participants were experiencing stress.

As the researchers note, these results are correlational and, hence, cannot provide definitive conclusions on causality. However, there is a substantial body of evidence supporting negative effects of chronic inflammatory activity on health and cognition.

Reference

1. Chiang et al. Negative and competitive social interactions are related to heightened proinflammatory cytokine activity. Proc Natl Acad Sci USA109(6):1878-82 (2012).

Anti-inflammatory Drugs Protect Brain from Age-Related Decreases in Volume in Normal Older Adults

Because of the reports in previous studies suggesting a reduced risk (up to a 50% decrease) of developing Alzheimer’s disease in people using antiinflammatory drugs, such as NSAIDS (non-steroidal antiinflammatory drugs), authors of a new paper¹studied the cross-sectional effects on volume changes in gray and white brain matter in 36 women taking antiinflammatory drugs for arthritis or pain and compared these changes to those of 36 age and education matched women as controls. Participants were 52–92 years of age. The antiinflammatory drugs used by participants included non-selective NSAIDS, COX-2 inhibitor type NSAIDS, aspirin, and other drugs.

The changes in mean gray and white matter volume were reported to be small, but “AI [antiinflammatory] drug use interacted with age, such that the non-AI group showed significantly greater age-related volume changes in regions of both gray and white matter compared to the AI drug users.”

As the authors explain, the study was cross-sectional (e.g., differences in brain volume were compared between women of different ages but brain volume changes in individuals with time were not measured) and, hence, “cannot assess true age-related decline in brain volumes, the results are consistent with the notion that age-related decreases in brain volume that occur in cognitively normal older adults may be attenuated in individuals who have taken AI drugs for at least 2 years in the past.” They conclude that “[t]he current results are consistent with the notion that neuro-inflammation plays an important role in volume declines observed as part of the normal aging process and that suppressing the inflammatory response with anti-inflammatory medications has a moderating effect on normal age-related decreases in both gray and white matter regions.”

Reference

1. Walther et al. Anti-inflammatory drugs reduce age-related decreases in brain volume in cognitively normal older adults. Neurobiol Aging32:497-505 (2011).

Some Natural Products Have Potent 
Antiinflammatory Properties

Natural products have been investigated extensively for their antiinflammatory effects. Protection against inflammation has been reported for curcumin,¹ orange juice,² fish oils,³ grape skin extract⁴ and the cognition enhancer vinpocetine,⁵ to name just a few. See the first article in this issue for information on vitamin D3, an important regulator of immune sys­tem-induced inflammation.

References

1. Targeting inflammation-induced obesity and metabolic diseases by curcumin and other nutraceuticals. Annu Rev Nutr 30:173-99 (2010).
2. Ghanim et al. Orange juice neutralizes the proinflammatory effect of a high-fat high-carbohydrate meal and prevents endotoxin increase and Toll-like receptor expression. Am J Clin Nutr91:940-9 (2010).
3. Bouwens et al. Fish-oil supplementation induces antiinflammatory gene expression profiles in human blood mononuclear cells. Am J Clin Nutr90:415-24 (2009).
4. Hogan et al. Dietary supplementation of grape skin extract improves glycemia and inflammation in diet-induced obese mice fed a Western high fat diet. J Agric Food Chem59:3033-41 (2011).
5. Vinpocetine as a potent antiinflammatory agent. Proc Natl Acad Sci USA 107(22):9921-2 (2010).

Is this funny or is it just pathetic?

You Don’t Have to Buy This Lemon—Assuming You Could Afford It—But You Do Have to Pay Taxes to Subsidize It

An article by the staff of Consumer Reports, “Bad Karma: Our Fisker Karma plug-in hybrid breaks down,” reveals the ongoing farce of taxpayer funded politically correct industries. Consumer Reports purchased a Fisker Karma taxpayer subsidized automobile for $107,850 and took it to their Consumer Reports Auto Test Center. With less than 200 miles on its odometer, the vehicle became undriveable with an error message indicating a major fault. The article noted that Consumer Reports buys about 80 cars a year and “this is the first time in memory that we have had a car that is undriveable before it has finished our check-in process.”

Fisker Automotive, the electric car maker that developed and is trying to market the hybrid, received a half-billion dollar loan from the federal government (e.g., taxpayers), but recently announced it is laying off 26 workers at a former General Motors plan in Wilmington, Delaware, and jettisoning another 40 contractors and employees who were working on design and development of Fisker’s Karma luxury car in Anaheim, California.

Now get this — the layoffs came as Fisker is seeking to renegotiate its loan agreement with the Department of Energy. Fisker has already received $193 million of the $529 million DOE loan. If you want to read more: http://www.foxnews.com/leisure/2012/02/07/fisker-announces-layoffs-as-company-misses-targets-has-doe-loans-frozen/

There is a big donor to the Democratic Party involved in this but we do not have his identity immediately at hand.

Help someone when they are in trouble, and they will remember you when they’re in trouble again.

— John Wayne (attributed)

When you see that trading is done, not by consent but by compulsion, When you see that in order to produce, you need to obtain permission from men who produce nothing, When you see that money is flowing to those who deal, not in goods, but in favors, When you see that men get richer by graft and by pull than by work, and your laws don’t protect you against them, but protect them against you, When you see corruption being rewarded and honesty becoming a self-sacrifice — you may know that your society is doomed.

— Ayn Rand, Atlas Shrugged (1957)