In response to the shortage of critical drugs, President Barack Obama signed an executive order last month that more than doubles FDA staff devoted to drug shortages ...
(D&S Comment: Whew, what a relief! The answer to the problem, of course, is more meddling (er, involvement) by the FDA.)... and puts pressure on drugmakers to notify the agency of anticipated supply problems.
(D&S Comment: Wonder what they mean by “pressure.” We hope they don’t forget to include criminal penalties for negligence in failing to produce the needed drugs.)
The [executive] order does not include mandatory reporting.
(D&S comment: What?? They could have created a lot of jobs for unemployed lawyers by including mandatory reporting.)
— the quotes above came from a report in the Nov. 21, 2011 Chemical & Engineering News (C&EN),published by the American Chemical Society
Another article in the same issue of C&EN complains that the House-led investigation of huge subsidies being handed out to “clean” energy firms like Solyndra will lead to uncertainty in the market for “clean” energy (as in, uncertainty that the public money spigot will remain open and flowing) and, hence, reduce “investment.” The article reports that there has been a sharp drop from 80% of the public who endorsed greater federal spending on clean energy a few years ago to 68% today. Terrible!
I consider the foundation of the Constitution as laid on this ground: That “the powers not delegated to the United States by the Constitution, nor prohibited by it to the States, are reserved to the States … or to the people.” [Tenth Amendment.] To take a single step beyond the boundaries thus specially drawn around the powers of Congress, is to take possession of a boundless field of power, no longer susceptible of any definition.
— Thomas Jefferson, Opinion on the Constitutionality of a National Bank, 1791
(D&S Comment: Sadly, many steps have been taken beyond the boundaries “thus specially drawn around the powers of Congress” and we are indeed lost in the boundless field of power by the federal government foreseen by Jefferson. It will be interesting to see whether there is anything whatsoever left of INTRAstate commerce after the Supreme Court rules on whether the Commerce Clause limits federal regulation under Obamacare.)
If you think that science is certain — well that’s just an error on your part.
— Richard Feynman
Standing for office is like a public colonoscopy.
— from Scroogled by Cory Doctorow
A new review paper1 reports that cholecalciferol (vitamin D3) reduces mortality in adults more than placebo or no treatment but that other forms of vitamin D do not. The other forms that didn’t reduce all-cause mortality included vitamin D2(ergocalciferol, alfacalcidol, or calcitriol). The meta-analysis reports that vitamin D3(cholecalciferol) reduced all-cause mortality by 6% (a very impressive reduction!), but not cardiovascular or cancer mortality. (The reason for the finding of reduction in all-cause mortality, but not in cardiovascular (CV) or cancer mortality, which might seem surprising, is that the total number of individuals in the analysis for all-cause mortality were much higher than those for the analysis of CV or cancer; hence, the statistical analysis didn’t have the power to detect a possible effect on the CV or cancer components of the total all-cause mortality.)
The meta-analysis was assembled from reviews of several databases, including MEDLINE, EMBASE, Cochrane Library, and others, to Jan. 2011, plus ongoing trial databases and reference lists to find randomized controlled trials where human subjects were taking supplemental vitamin D or no intervention in adults =18 years of age who were healthy or had stable disease (not including secondary-induced osteoporosis or cancer or women who were pregnant or lactating) or vitamin D deficiency. That included 50 trials of 94,148 subjects with mean age 74 years and of which 79% were women.
The commentary2 on the review concluded that “... the results of the meta-analysis by Bjelakovic and colleagues should encourage providers to consider cholecalciferol (vitamin D3) as their preferred choice for vitamin D supplementation.”
Prolactin, although better known as the hormone that induces human lactation, also acts as a local growth factor in the prostate gland. Recent research now identifies increased local overexpression of prolactin (that which is produced locally in the prostate, though prolactin is also produced and released into the circulation from the anterior pituitary gland of the brain) as an amplifier of the pool of basal/stem cells which have been identified as originators of prostate cancer.1 Moreover, the locally produced prolactin may mediate the progression of castrate-resistant (androgen independent) cancer.1
Although elevated circulating levels of prolactin “are not clearly linked to increased prostate risk,”1 there is now growing evidence of such a link to excess local (within the prostate gland) production of prolactin. The circulating prolactin and locally produced prolactin share the same sequence and are believed to exhibit the same efficacy towards the prolactin receptor; however, “it is possible that local prolactin secreted directly into the extracellular space achieves elevated concentrations and saturates the PRLRs [prolactin receptors].”1
The researchers1 report that “analysis of human prostate cancer specimens showed prolactin immunostaining in 54% of a series of 80 prostate cancer specimens, and was positively correlated with high Gleason scores and activation of Stat5a/b, its major signaling protein. Furthermore, prolactin was also expressed in 50% of recurrent prostate cancer samples in a series of 183 specimens, including hormone-refractory cancer (54% of positive cases), and those from patients with lymph node metastases (67%).”
The usual treatment of excess prolactin derived from the pituitary is with dopamine agonists such as bromocriptine (Parlodel®) that trigger the D2 dopamine receptor (D2R) on lactotroph cells. “However the efficacy of this class of drugs in regulating the prolactin gene in the human prostate (as in other extrapituitary sources) has yet to be demonstrated, and based on the fact that D2R expression has only been occasionally reported in human prostate samples,” according to papers cited by the authors,1 “they are anticipated to be ineffective for targeting extrapituitary prolactin expression.” We will not know for sure until further research is done.
According to the authors,1 “[p]rolactin has recently entered the limited panel of nonandrogenic signaling pathways that are emerging as potential candidates for targeted therapy in a subset of prostate cancer patients. Indeed, evidence has accumulated within the past few years to suggest that activation of Stat5, the downstream effector of the canonical PRLR [prolactin receptor] signaling pathway, has a key role in prostate cancer progression.”
In the meantime, we would consider it prudent for those with elevated circulating prolactin levels (levels above the normal range) to reduce those levels to low to mid normal range with a therapy such as bromocriptine.
New research continues to be published on the beneficial health effects of cruciferous vegetables (the Brassicaceae family which includes broccoli, cabbage, brussels sprouts, cauliflower, and mustard). Much of this new work concerns a link between normal intestinal immune function and the aryl hydrocarbon receptor (AhR), for which the cruciferous vegetables contain moledules that are ligands (activating the
One paper1 reports that intraepithelial lymphocytes (IELs) from intestine and skin promote epithelial repair following injury, as well as limiting epithelial cell invasion by the hordes of indigenous bacteria that reside in the gut.1 In answer to the question of what normal physiological signals activate the AhRs, researchers found that certain tryptophan derivatives found in plants (such as indole-3-carbinol, as is found in cruciferous vegetables) are converted into high-affinity AhR ligands as a result of encountering the acidic environment of the stomach.1 The commentary article2 on the paper by Li et al1 proposes that the link between diet, AhRs, and intestinal immunity “suggest a mechanistic basis for the epidemiological link [between diets low in fruits and vegetables and inflammatory bowel disease] and offer the prospect of using AhR ligands as ‘nutraceuticals’ to boost intestinal immunity.”
In the paper by Li et al,1 the authors note that “[a]s a consequence of low AhR activity [in intestinal epithelial cells], the intestine is in a heightened state of immune activation, dominated by a type 1 [proinflammatory] response and more susceptible to immunopathology.” In one experiment performed by the authors and reported in Li et al,1 the researchers induced colitis in mice using dextran sodium sulfate (DSS). In control mice, DSS treatment resulted in rapid weight loss but full recovery following withdrawal of DSS after 6 days. However in mice lacking AhR, DSS caused accelerated weight loss, extreme shortening of the colon, and severe hemorrhaging, with 11 of the 16 AhR-deficient mice losing over 20% of body weight. But the AhR-deficient mice fed the purified diet supplemented with indole-3-carbinol showed only mild signs of colitis, reduced weight loss and reduced shortening of the colon with rapid recovery after withdrawal from DSS.
In the paper by Kiss et al,4 the researchers sum up the paper’s research: “Our results establish a molecular link between nutrients [AhR ligands] and the formation of immune system components [intestinal lymphoid follicles] required to maintain intestinal homeostasis and resistance to infections.” The researchers note that, interestingly, “the diverse glucosinolates play an important role in plant resistance to mildew fungi and insect herbivores, suggesting an evolutionarily conserved role in immune defense pathways.” This helps explain why the cruciferous vegetables go to the trouble of making these molecules in the first place.
Even the New England Journal of Medicine5 has reported on the two new studies (Li et al1 and Kiss et al4) linking AhR ligands from cruciferous vegetables and intestinal immunity. In its commentary, the New England Journal of Medicine author notes that the two studies suggest that AhR ligands may not only help prevent diseases such as inflammatory bowel disease (IBD) but may be effective treatments for IBD, metabolic syndrome, and other diseases. Moreover, the author says, “[b]eneficial effects of AhR ligands are known to be associated with an increase in levels of interleukin-22, a cytokine that supports intestinal integrity, and the production of mucus and defensins (a class of anti-microbial peptides).”
How to Eat Cruciferous Vegetables for Greatest Benefit
As reported in a recent paper,6 cruciferous vegetables contain “high levels of glucosinolates, a class of phytochemicals not found in any other vegetable.” In order to get the healthful metabolites (isothiocyanates, ITCs) that include sulforaphane and indole-3-carbinol requires the activity of an enzyme, myrosinase, found in the cruciferous vegetables themselves and also in gut microbial flora. “A small number of studies in animals and humans have found that inactivation of myrosinase decreases the availability of ITCs.” As this paper6 also reports, the glucosinolate precursors to sulforaphane are highest (measured as concentration per plant weight) in the seeds followed by the sprouts. The authors compared the urinary isothiocyanate metabolites in healthy subjects who ate either broccoli sprouts or a broccoli supplement (no myrosinase) containing equivalent amounts of glucosinolate. They found significantly lower amounts of ITC metabolites excreted in the urine of those consuming the supplement as compared to the sprouts, which they attribute to the lack of myrosinase in the supplement.
Plasma measurements of sulforaphane were made in people who had consumed broccoli soup (100 g. florets microwaved for 90 seconds); levels reached 2-3uM which the authors report is almost entirely excreted in the urine within 24 hours.7 Thus, the authors of this paper7 assumed “that higher SFN [sulforaphane] plasma levels may be reached by consuming broccoli sprouts, which contains 100 times higher levels of glucoraphanin or by the intake of synthetic glucoraphanin or purified SFN.”
In another study reported in the Oct 2011 Food Technology (shamefully, no reference was provided, other than that the work was done by researchers at the University of Illinois, Urbana), pairing fresh broccoli with certain spicy foods which contain myrosinase (mustard, horseradish, and wasabi) provide the maximum health benefits of the broccoli by ensuring that sulforaphane is formed and absorbed in the upper digestive tract.
Sulforaphane in the Treatment of Pancreatic Cancer
Incidentally, the broccoli isothiocyanate sulforaphane “was recently identified as being capable of eliminating highly therapy-resistant pancreatic carcinoma (PC) cells without inducing toxic side effects.”7 As the authors7 explain, “[h]igh levels of glucoraphanin, the glucosinolate precursor of SFN, are present in broccoli and cauliflower.” “SFN has attracted much attention since the discovery of its anti-tumor effects in PC [pancreatic carcinoma] and several other tumor cell lines.” Three references are cited in Ref. 7 as documentation for the anti-tumor effects of SFN in pancreatic cancer. As pancreatic cancer is highly deadly (with a mean 5-year survival rate of less than 1%), we hope there is significant followup on the potential use of SFN in its treatment (one of Sandy’s aunts died of the disease, so she is personally interested in its treatment in case there is a genetic relation to risk). However, as sulforaphane is a natural compound, it cannot be patented; hence, it is unlikely to be of interest to pharmaceutical companies except as a lead to the development of synthetic analogs.
*See our take on some recent legal arguments on whether the federales have the Constitutional authority to force you to buy broccoli (as an analogy to the Obamacare mandate that forces you to buy government health “insurance”) in the June-July 2011 issue of Durk Pearson & Sandy Shaw’s® Life Extension Newsletter.™
A new paper explored the hypothesis that chronic low grade inflammation as is found in aged individuals might play a role in the neuropsychiatric symptoms (such as lassitude, reduced motivation, anorexia, and pessimism) commonly occurring in the aged.1 The researchers first note that inflammation affects the activity of two enzymatic pathways involved in the regulation of tryptophan (indoleamine-2,3-dioxygenase, IDO) and phenylalanine and tyrosine (guanosine-triphosphate-cyclohydrolase-1, GTP-CH1), suggesting a possible mechanism for the link between inflammation and neuropsychiatric symptoms. Interestingly, tryptophan metabolites generated by the kynurenine pathway (which includes IDO) are thought to play an important role in neurodegenerative disorders, such as Alzheimer’s and Huntington’s diseases1a and possibly in the development of senile cataracts.1a2
“Indoleamine-2,3-dioxygenase can be induced by inflammatory cytokines, including most notably interferons (IFN) in a variety of immune cells such as monocyte-derived macrophages and microglia. When activated, IDO catalyzes the rate-limiting step of tryptophan conversion into kynurenine ... In vivo, the ratio of kynurenine/tryptophan (Kyn/Trp) reflects tryptophan breakdown and is considered to represent one estimate of IDO activity.”1
In their study,1 284 subjects were included, with the mean age of 79.9 years (SD=4.5 years). “The older participants were, the lower were tryptophan levels and the higher were IL-6, kynurenine, and neopterin [produced by activated GTP-CH1] concentrations and the ratio of Kyn/Trp. In addition, there was a trend [not quite significant] for a relationship between age and tyrosine concentrations, with increased age corresponding to decreased tyrosine levels.”
“Neuropsychiatric scores were evaluated by the MADRS, MFI, and NRS scales. Higher MADRS scores of lassitude were associated with lower tryptophan and phenylalanine concentrations. Moreover, there was a trend for a relationship between reduced tryptophan concentrations and increased MADRS scores of pessimistic thoughts.”1“Reduced phenylalanine turnover has been documented in various medical conditions characterized by chronic inflammation.”1 “Altogether, these findings indicate that age-related chronic inflammation is associated with potent alterations in enzymatic pathways that are strongly involved in the biosynthesis of neurotransmitters, incliding serotonin, dopamine, epinephrine, and norepinephrine.”
The researchers note that nutritional interventions such as tryptophan supplements might not work if the added tryptophan is overcome by breakdown of tryptophan by IDO induced by chronic inflammation or if adequate vitamin B6 (a cofactor for tryptophan production) were not present. (Note: Our serenity line of tryptophan and
A paper2 reporting on the effects of aspirin on tryptophan degradation found that
A paper on inhibition of IDO by niacinamide1f indicated that, in human subjects with HIV infection, IDO induced by interferon gamma was suppressed (resulting in an increase of tryptophan levels by 40%) by 3 grams of niacinamide a day. Niacin was reported in the same paper (though no study was cited) to also inhibit tryptophan degradation by IDO. Unfortunately, the flushing side effect makes niacin intolerable to many people, but if you don’t mind it, you can take up to 800 mg of niacin a day without having liver tests. That may help prevent degradation of tryptophan. Niacinamide is more toxic than niacin and, consequently, we do not recommend using it, certainly not at the 3 gram dose a day unless under close medical supervision. Interestingly, increased degradation of tryptophan has been reported in blood of patients with rheumatoid athritis.3 As the authors explain in their introduction: “The kynurenine-tryptophan ratio (kyn/trp) allows an estimate for IDO activity and was found to be increased in states of persistent immune activation, i.e., infectious and malignant diseases.” “The data [in this study] point to a role of immune activation and Th1 [proinflammatory]-type cytokine INF-gamma to induce elevated tryptophan degradation in patients with RA [rheumatoid arthritis].”3
1. Capuron et al. Chronic low-grade inflammation in elderly persons is associated with altered tryptophan and tyrosine metabolism: role in neuropsychiatric symptoms. Biol Psychiatry 70:175-82 (2011).
1a. Zwilling et al. Kynurenine 3-monooxygenase inhibition in blood ameliorates neurodegeneration. Cell 145:863-74 (2011).
1a2. Pereira et al. Indoleamine 2,3-dioxygenase inhibitors from the northeastern pacific marine hydroid Garveia annulata. J Nat Prod 69:1496-9 (2006).
1b. Wirleitner et al. Resveratrol suppresses interferon-gamma-induced biochemical pathways in human peripheral blood mononuclear cells in vitro. Immunol Lett 100:159-63 (2005).
1c. Young-II Jeong et al. Curcumin suppresses the induction of indoleamine-2,3-dioxygenase by blocking the Janus-activated Kinase-protein kinase Cdelta-STAT1 signaling pathway in interferon-gamma-stimulated murine dendritic cells. J Biol Chem284(6):3700-8 (2009). “Recent in vivo studies suggest that IDO-expressing DCs [dendritic cells] isolated from tumor-draining lymph nodes contribute to the progression of tumors by creating local immunosuppression.”
1d. Cheng et al. Indoleamine 2,3-dioxygenase, an immunomodulatory protein, is suppressed by (-)-epigallocatechin- 3-gallate via blocking of gamma-interferon-induced JAK-PKC-delta- STAT1 signaling in human oral cancer cells. J Agric Food Chem58:887-94 (2010).
1e. Winkler et al. Vitamins C and E suppress mitogen-stimulated peripheral blood mononuclear cells in vitro. Int Arch Allergy Immunol 142:127-32 (2007).
1f. Murray. Tryptophan depletion and HIV infection: a metabolic link to pathogenesis. Lancet Infect Dis 3:644-52 (2003).
2. Schroecksnadel et al. Aspirin down-regulates tryptophan degradation in stimulated human peripheral blood mononuclear cells in vitro. Clin Exp Immunol 140:41-5 (2005).
3. Schroecksnadel et al. Increased degradation of tryptophan in blood of patients with rheumatoid arthritis. J Rheumatol 30(9):1935-9 (2003).
An amusing paper1 reports on a multiple choice test where fruit flies got to choose the desirability to them of sugar mixed with various amounts of bitter substances. The more bitter the mixture, the less the flies consumed of it. Thus, the flies exhibited marked dose-dependent aversions to the consumption of bitter substances, much as humans generally do, which included berberine, lobeline, nicotine, papaverine, strychnine, and theophylline. Apparently there is an evolutionarily conserved aversion to eating foods that are more likely to be poisonous based on their having a bitter taste. To wit, we are sorta like flies or maybe they are sorta like us. Cute, but one has to wonder whether taxpayers were ripped off to fund this.
You probably saw some of the old-time Popeye cartoons where Popeye, caught in the middle of a dire situation (usually involving being attacked by Bluto), produces a can of spinach, quickly opens it, and glugs it down, all while the heroic Popeye theme song is urging him on and we see his muscles suddenly bulging so he can take care of the bully, with Olive Oyl looking on adoringly.
Of course you always knew that it didn’t happen like that.
But the good news is that spinach can really deliver a punch when it comes to improved health. Green leafy vegetables, such as spinach, are among the richest sources of nitrate in the diet.1 A new paper1 reports that spinach consumed by thirty healthy volunteers recruited by newspaper ads resulted in a substantial acute augmentation of NO (nitric oxide) status and a small but significantly higher flow-mediated dilation (expansion of the brachial artery in response to nitric oxide) and a lower systolic blood pressure. “This 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. However the level of nitrate intake tested in these studies has ranged from approximately 500 to 1500 mg/day with chronic supplementation and from 400 to 2400 mg acutely. These intakes exceed the mean dietary intake of nitrate, which is estimated to be between 0.4 and 2.6 mg/kg or 31 and 185 mg. In the current study the intake of nitrate provided by the 200g of spinach included with the lunch meal was 182 mg.”1 The spinach used in the study was taken from a single batch of frozen spinach from a commercial supplier and thawed before use.
One of the problems with green, leafy vegetables, though, is that nowadays much of what is available in the U.S. is imported from countries that do not have a similar level of hygienic standards for growing commercial vegetables as in the U.S. Unfortunately, California, which used to supply about 60% of all the veggies available in the U.S. has pretty well destroyed its once flourishing agricultural production due to the Federal government cutting off water to the western half of the Joaquin Valley in order to protect an “endangered” fish. According to an FDA Report entitled “Pathway to Global Safety and Quality,” between 10 and 15 percent of all food consumed in the U.S. is imported, while the U.S. Government Accountability Office (GAO) estimates that imports account for nearly two-thirds of the fruits and vegetables and 80% of seafood eaten domestically.2 A lot of these veggies and fruits come from places like Mexico, China, Asia, India, and Africa, where hygienic standards are far inferior to those in the U.S. and it is not uncommon for workers to urinate and defecate in the fields while picking the crop. Pathogens in green leafy vegetables cause a considerable amount of disease and even deaths in the U.S. every year.
Though Sandy is a big fan of salads that include a lot of green leafy vegetables, consideration of the risk of pathogens in raw veggies (and the possibility that this is what caused her recent bowel obstruction that required surgical correction) has resulted in her choosing to eat only cooked green leafy vegetables. While cooked lettuce (yech) is a limp, mushy turnoff, cooked spinach is (at least to Sandy) tasty and she likes it for a snack, especially with a dollop of butter-olive oil added to it.
The Food Safety Modernization Act of 2011 (FSMA) is another factor promising unforeseeable but undoubtedly very considerable increases in regulatory expenses for the food industry that will, typically for government regulations, be likely to impose far higher costs than the improved food safety benefits, if any, that they deliver. What this will mean, among other things, is a significant decrease in the number of small and medium sized food companies (hence, reduced competitive market forces and reduced innovation that frequently comes from smaller, more entrepreneurial companies) and another increase for consumers in the cost of food products to add to the already increasing food prices, with little improvement in food safety.
Not surprisingly, the Act passed both houses of Congress because it was supported by major food companies and lobbying organizations including the U.S. Chamber of Commerce and the Grocery Manufacturers Association (though produce organizations opposed it).1 This follows the usual pattern in which, sensing huge new expenses to come from oncoming regulatory programs, large companies and other large stakeholders rush to be in on the ground floor hoping to have a hand in controlling the resulting regulations to hopefully benefit themselves or at least shift the harm to somebody else. This is the same pattern as we saw in the passage of the FDA’s Good Manufacturing Practices for dietary supplements which, supported by the larger companies and lobbying groups in the industry, helped the FDA get sweeping new authority that has resulted in very complex (even, in places, incomprehensible) and expensive new regulations that are unlikely to improve dietary supplement quality and safety but are sure to very significantly increase the costs of producing them and, hence, increasing what consumers have to pay for them. (We have written a critique of the FDA’s GMPs for dietary supplements in an earlier newsletter.)
As reported in a food industry publication,1 a food industry analyst, David Acheson, thinks “[w]e’ve got a tsunami building for the early part of 2012.” This is, the article reports, because FDA officials are “intent on having regulations in place before 2013, IN CASE AN ANTI-REGULATION ADMINISTRATION OCCUPIES THE WHITE HOUSE AFTER THE NEXT PRESIDENTIAL ELECTION.”1 (emphasis added) “Before that [the unveiling of the regulations] happens, food companies may rue their early support of FSMA [these guys never learn!], but at least the present uncertainty will be replaced by known expectations for food safety systems.”1 (Yeah, right, then you will know the real disaster you are facing rather than just imagining what the disaster might be. Thanks a lot, government asslickers!)
A new paper1 proposes a mathematical model for the interaction of cooperation, social adhesion, and individual self-interest (greed). “Our results, therefore, suggest that, as long as social dilemma situations are not too severe, a main determinant of social stability and wellbeing is the greediness of individuals. Moderate greediness promotes cooperation and the stability of dense social relationships, whereas high levels of greediness destabilize the social fabric, undermining cooperation and social agglomeration.”
The authors propose that their mathematical model supports the concept that, “a model society of individuals with low levels of greediness is unable to realize social benefits. It lacks the drive to develop effective cooperation and agglomeration because non-greedy individuals become easily satisfied with whatever payoffs they obtain and thus, maintain their strategy and position.” “On the contrary, moderate greediness causes individuals’ dissatisfaction, making them explore other strategies and/or positions and experience the benefits of being cooperative in a cooperative neighborhood.” “At high levels of greediness, finally, individuals are so difficult to satisfy that they keep exploring other locations and strategies, thereby destroying cooperative clusters.”
The authors warn, however, that the beneficial influence of moderate greediness could lead to maladaptations if the projection of current growing payoffs into the future lead to an increase of greediness to levels at which social cohesion ultimately breaks down. The two of us propose that a moral for this story of adverse outcome might be: Beware of politicians offering free gifts. Those who get them (as well as those who don’t get them but hope they will) are likely to become ever more greedy, leading to the predicted disruption in social cohesion.