Discretizations

Some months ago we decided to put Discretizations on hiatus while we tried to figure out what to do about the tsunami of scientific papers washing up on PubMed (which was already piled deep in the flotsam and jetsam of publish or perish) now that China, India, Korea, etc. are getting in on the fun. On the one hand we're sorely tempted to take advantage of a situation that presents us daily with awesome posting opportunities like: Hay fever causes testicular cancer! On the other hand we know that most statistically significant findings are in fact false - in no small part because "it is a habit of mankind to entrust to careless hope what they long for, and to use sovereign reason to thrust aside what they do not desire". So, rather than being a part of the problem by propagating noise and not signal we've decided to limit our Discretizations to papers that 1) report an actual observation and not just the spectre of one drawn from data dredging and statistical analysis; 2) reflect an effort to reproduce a previously reported finding (e.g. testing a hypothesis previously drawn from statistical inference but in a different population); or, 3) extend (marginally) some previously established finding. Here goes:

Your word for the day is "immunobiotics": good bacteria that can aid in the production of certain blood cells

Obesity is a risk factor for lumbar radicular pain and sciatica - and it may impair healing mechanisms

Poor folks still have (on average) poor ways (which explains a large portion of the disparity in life expectancy between those in the bottom quartile of socioeconomic status and everyone else) 

Hospital staff and visitors can spread nosocomial pathogens to nearby businesses

How does metformin help patients with diabetes? Maybe by making the gut a happier place for A. muciniphila

No evidence found to support the hypothesis that parental smoking (and the benzene exposure that goes with it) during pregnancy increases a child's risk of developing acute lymphoblastic leukemia (ALL)

Does the debate about segregating cystic fibrosis patients by lung/bronchial microbiome, going so far as to prevent some/most/all-but-one CF sufferers from attending indoor CF Foundation events, presage future debates as more and more diseases are found to have bacterial components? Here are the pros and cons of the CF debate.

Very Little Authority For Now, But Maybe Not For Long

Two yellow pads are full of notes, diagrams, thoughts and arguments and still the answer eludes me. So, rather than continue not to post anything about all the interesting stuff going on in mass torts while I try to figure it out I'll just throw out what I've got so far over a series of posts and move on to something less difficult (and likely more interesting). On then to the question that's been bugging me for a month.

Should alternative liability, in the form of burden of proof shifting, apply in the following case: (1) a neonate contracted a Cronobacter sakazakii infection and was seriously injured; (2)  C. sakazakii is a ubiquitous pathogen and readily forms biofilms on stainless steel, inside household water pipes and upon other surfaces (3) C. sakazakii infections in neonates have also been repeatedly traced to PIFs; (4) plaintiff's experts opined that it's more likely than not that the source of C. sakazakii was the powdered infant formula (PIF) fed to the neonate; (5) PIFs are not sterile since the process of sterilization would destroy the nutritional value of the PIF; (6)  there were two or more suppliers of PIF whose product was prepared for the neonate; (7) none of the remaining PIF fed to the newborn, nor any of the lots from which they were drawn, were found to contain C. sakazakii; and, (7) the wrong complained of was a failure to warn that full term neonates, like the plaintiff, were at risk of C. sakazakii infections.

Alternate liability analysis often begins with Summers v. TiceIn that case both hunters who had fired their weapons in plaintiff's direction had been sued and both could be shown to have breached their duty to safely handle those weapons. Because it was impossible for the plaintiff to show whose buckshot was responsible for his injury, and because it was deemed just that the consequence of that impossibility fall on the culpable defendants rather than the innocent and injured plaintiff, the court held that the defendants, rather than the plaintiff, should bear the burden of proving from which shotgun the pellets had originated. Fair enough.

Here, in Burks v. Abbott Laboratories, both of the manufacturers of PIF consumed by the plaintiff had also been sued. Furthermore, neither's product bore a warning about the hazard which plaintiff claimed they had a duty to disclose. However, not all the possible sources of C. sakazakii (Mother Nature being judgment-proof) were before the court. Nevertheless, the court held, though it "located very little authority on this specific question" that  the determination of whether it was more likely than not  that the source of plaintiff's C. sakazakii infection was the defendants' PIF should be applied to the defendants collectively.

Ponder the consequences. Let's say that 51% of all C. sakazakii infections in neonates are due to PIFs even when C. sakazakii can't be isolated from the product or the lot from which it was drawn, and that 49% of all C. sakazakii infections in neonates are due to C. sakazakii found in the household water used to reconstitute the PIF or on kitchen surfaces. Also, assume the warning could fairly be said to be lacking (which in this case is not at all a given and in fact raises as many questions as stacking defendants to get to the 51% threshold - but that'll be addressed in subsequent posts).

If there's only one supplier of PIF there's no need for alternative liability so assume there are at least two. But what happens when you start dividing up the 51% among the defendants? Unless one of them was responsible for ~99% of the product the result is that you've stacked two defendants who might, but probably didn't, have something to do with plaintiff's infection and handed them all of the liability for it. Is that fair? What if there were 100 suppliers? And what's the justification for stacking defendants? Is it because they're in the same business? If so, how similar must their businesses be to permit such stacking? If in order to get to a 51% likelihood as to the source of the infection you had to stack PIF manufacturers with stainless steel kitchen appliance manufacturers (because C. sakazakii happily lives on stainless steel and creates biofilms that makes it nearly impossible to remove with household cleaning products) could you justify handing them the burden of proof by saying they were all in the food business? 

Or what about reducing defendants' liability by Mother Nature's share? Would that solve the "overdeterrence" problem? What follows from the fact that the potential for these sorts of infections, due to the nature of pathogens, is essentially binary (you get it or you don't) and not of the dose-response variety seen in typical mass tort cases?  These are the sorts of questions that have led to a lot of head scratching but so far few answers.Over the next couple of days I'll type up more of these questions and the paths down which they lead (at least the ones I've thought of and followed).

How a fact pattern like the one in Burks gets resolved is I think a very big deal. That's because an awful lot of diseases laid over the last forty years at the feet of man-made substances and bad habits turn out to have been due to pathogens all along. It also appears we're entering an era in which old scourges reemerge thanks to having evolved antibiotic resistance and new ones arise thanks to globalization.  The resulting morbidity and mortality will makesevery other mass tort pale in comparison and so far juries aren't having much trouble blaming defendants for the depredations of Mother Nature's tiniest critters. We think there's a wave of litigation coming in which plaintiffs will assert liability for facilitating the transmission of pathogenic agents. The answers to questions like those posed by Burks will be critical in determining how it all plays out. 

Squeak Squeak

In the run up to the trial of a case in which we're arguing that the B6C3F1 mouse ain't a man and 1,3 butadiene ain't a human carcinogen just because it causes cancer in the B6C3F1 mouse, out comes "Mice Fall Short as Test Subjects for Humans’ Deadly Ills" by Gina Kolata of the NYTimes. And it's a bombshell. Kolata reports on the paper "Genomic responses in mouse models poorly mimic human inflammatory diseases" and its central finding that immune responses in the mouse, including those related to heart disease and cancer, are no more closely correlated with human responses to the same stimuli than the roll of a pair of dice. It's the long-sought explanation as to why e.g.

"every one of nearly 150 drugs tested at a huge expense in patients with sepsis has failed. The drug tests all were based on studies in mice. And mice, it turns out, can have something that looks like sepsis in humans, but is very different from the condition in humans."

Good stuff, though not all that surprising if you've been following the sad tale of the development of drugs that cure cancer in mice yet have no effect in humans. And it doesn't mean that all scientific studies done on mice are worthless. Far from it. The ability to produce for example so-called knockout mice, rodents lacking a particular gene required to make a particular protein, allows an otherwise forbidden glimpse into the workings of the tiny chemical factories that we call cells. Nevertheless, the study does shatter the assumption that those little factories in mice run just like their counterparts in humans.

However, that's not the end of the story. If you read the whole thing you'll find this:

The study’s investigators tried for more than a year to publish their paper, which showed that there was no relationship between the genetic responses of mice and those of humans. They submitted it to the publications Science and Nature, hoping to reach a wide audience. It was rejected from both.

... reviewers did not point out scientific errors. Instead, [one of the authors] said, “the most common response was, ‘It has to be wrong. I don’t know why it is wrong, but it has to be wrong’ ”

which leads to our final point. Daubert's peer review factor was intended to serve as an independent indicator of reliability. The Court assumed that disinterested scientists on the lookout for bad science served as gatekeepers of the journals through which "scientific knowledge" was disseminated. Perhaps when there were far fewer journals and far fewer academics desperate to be published peer reviewers served such a function. Nowadays they too often serve the status quo - barring from publication the sort of disruptive findings that would discomfit the guild they serve. Thus, if we're not careful, does Daubert risk being effectively transmuted, at least in part, into Frye - i.e. a test of general acceptance rather than a test of sound science.

 

Discretizations

DURC (Dual-Use Research of Concern) Is Your Acronym Of The Day

" ... the influenza virus research community can no longer be the only player in the discussion of whether certain experiments should be done."  That's the conclusion of Dr. Anthony Fauci in an Op-Ed piece posted today at mBio titled "Research on Highly Pathogenic H5N1 Influenza Virus: The Way Forward". And that controversial "gain-of-function" research, the success of which prompted the moratorium made the focus of Fauci's piece, obviously has potential (mis)uses beyond H5N1. Thus, research on at least 15 pathogens will soon be subject to stricter oversight and regulation.

Elsewhere in mBio you can read persepectives on (1) the "social responsibility of science and scientists" and how to counter "the dark specter painted by the critics of genetic engineering" in "The Lessons of Asilomar and the H5N1 'Affair'"; (2) why the self-imposed moratorium makes this a "historic time for science" and why the onus is now on scientists to demonstrate that the benefits of knowing how viruses become easily transmissible outweigh the risks of knowing how to make viruses easily transmissible in "The H5N1 Moratorium Controversy and Debate"; (3) potential approaches to risk communication about, and containment of, potentially catastrophic transmissible pathogen "escapes" in "Rethinking Biosafety in Research on Potential Pandemic Pathogens"; and, (4) a most enlightening discussion of biosafety levels (BSLs) and the rather unsettling (because it's so obvious once you think about it) conclusion that the staggering proliferation of laboratories (from 415 to 1362 in just four years) operating under BSL3 biocontainment protocols necessarily means that the odds of an "escape" are going up just as rapidly - see "Biocontainment in Gain-of-Function Infectious Disease Research".

While laboratory managers nervously await the order to go to BSL4 with all its attendant headaches, some may find solace in knowing that at least they're not going to have to run things like project Wildfire. Not yet anyway.

Discretizations

A New Biomarker To Detect Pleural Mesothelioma Early And To Differentiate Effusions

The New England Journal of Medicine has just published an open access paper, "Fibulin-3 as a Blood and Effusion Biomarker for Pleural Mesothelioma", describing a study of the use of plasma fibulin-3 in detecting mesothelioma early and without generating a lot of false positives among those with significant prior asbestos exposure but who do not have mesothelioma. The results were impressive - sensitivity was 100% and specificity was 94.1%. Fibulin-3 was also found to be particularly useful in discriminating between pleural effusions driven by mesothelioma and those driven by other malignant or benign processes. The latter finding will be particularly useful in asbestos litigation as we still routinely fight over the diagnosis even when immunohistochemical staining at first blush appears definitive. Why?

We're not sure but an answer is suggested in another new paper, this one published in The American Journal of Surgical Pathology. It's "Utility of a CEA, CD15, Calretinin, and CK5/6 Panel for Distinguishing Between Mesotheliomas and Pulmonary Adenocarcinomas in Clinical Practice". If you had four biomarkers repeatedly demonstrated to be useful in deciding the mesothelioma versus adenocarcinoma question you'd think your accuracy would go up as the number of biomarkers confirming your decision went up. But apparently you'd be wrong - at least if the staining was done and interpreted by clinical rather than medical laboratories specialized in immunohistochemical staining. Of the four biomakers commonly used to either rule-in (it's mesothelioma) or rule-out (it's really adenocarcinoma) the disease, errors were so common in clinical medicine laboratories that determinations requiring all four factors to line up as expected were only about half as accurate as those determinations based on which way a majority of the factors pointed.

One answer to our question about why we're still fighting over diagnoses would thus be that a surprisingly high percentage of mesothelioma versus adenocarcinoma decisions based on tissue preparation and staining done in typical clinical laboratories are simply wrong. Another, and in many ways similar answer, is that none of these biomarkers are perfectly predictive so that the more of them you consider the less likely a particular conflicting result is truly dispositive.

h/t LKD

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If The Dose-Response Curve For Carcinogens Isn't Linear At Low Levels What Shape Is It?

J-shaped, according to "Changing the Risk Paradigms Can be Good for Our Health: J-Shaped, Linear and Threshold Dose-Response Models". A J-shape means the dose-resonse curve is either deflected downward at some point or, stranger yet, starts to demonstrate a reduced risk of the harm of which the toxin is accused. How could that be? Doesn't every toxic exposure produce some finite amount of risk? Nope. 

Assume that a stem cell has some finite lifespan. A toxic exposure followed by whatever random (stochastic) processes are required to complete the transition of the stem cell from normal to malignant must obviously transpire before the cell expires or the cancerous transformation won't occur. But what if the toxic exposure shortens the lifespan of some of the cells? Then you'd expect fewer cells to survive to face the cancer roulette wheel of chance every time they divide.

Unless for some reason the body started producing more cells susceptible to the toxin's effect.

At high levels of exposure the body goes into overdrive regenerating the damaged and destroyed cells. The result is that while some are killed early more cells with higher odds of developing the necessary compliment of mutations/transformations needed for cancer (thanks to priming by the toxin) survive to meet the DNA replication wheel of misfortune. Thus the overall odds that one cell will acquire all the changes needed to initiate cancer increases when exposures are high.

The resultant dose-response curve would show escalating risk above the level where the toxic exposure produces regenerative hyperplasia and a sharp downward deflection in risk below that level. (Imagine a J rotated 180 degrees through its vertical axis and leaned over to the right). And if the effect of low level exposures is indeed to marshal those defenses organized to detect and eliminate random errors of a certain variety then "Voila!" Hormesis - the view that low level exposures can in some cases be preventative, suddenly makes sense (Imagine the J leaned again to the right but now the response down by the hook describes a better sort of response - less cancer).

The paper makes a compelling argument that there are better (which is to say more supportive of stated public health goals and more accurate) models of the dose-response curve than the hoary linear no-threshold version hatched decades ago when doses couldn't reliably be measured and the double helix had yet to be imagined. And it's open source in the bargain. Give it a read.

Of Mice and Monkeys and Men

Sorry for yet another absence. We were finishing the second trial this month. Whatever happened to vacation letters?

Anyway, we were looking for something to blog about and came across In Re: Chantix (Varenicline) Products Liability Litigation. Among a number of other justifications for its rulings on motions to exclude plaintiffs' experts you'll find one in which the court relies on the assumption that "[i]n qualitative extrapolation, one can usually rely on the fact that a compound causing an effect in one mammalian species will cause it in another species" as reason enough to allow an expert to opine about Chantix' hypothesized effect on human metabolism based on its effect on the metabolism of one strain of mice. Let's test that assumption in light of some very good news out this week on aging research (well, good news if you don't like being on a near starvation diet for life).

Restricting caloric intake has long been known to dramatically increase life expectancy in mice. Experiments designed to test the effect in single celled organisms like yeast, microscopic multicellular organisms like nematodes (round worms), the always-ready-to-serve-mankind fruit fly and various strains of mice, rats, guinea pigs and even dogs have consistently shown that by reducing calorie intake by a third or more from what the creature would have consumed had it eaten until it was sated, lifespan is extended by 40% or more. Indeed, some studies have shown that the harder they're starved the longer rats live. The effect then would appear to be "highly conserved", which is to say evolution found the algorithm to be highly beneficial long ago and thus widely spread it throughout the chain of life. So it obviously follows that semi-starved people ought to live longer too, right?

Well, assuming we're closer kin to the Rhesus monkey (famed for helping to discover the human Rh blood factor) than to the Sprague Dawley rat it looks as though the metabolisms of mice and men are decidedly different. In an article published this week in Nature a 30% calorie restricted diet over 25 years failed to extend the lifespan of one of our closest relatives.

In retrospect the finding ought not be nearly as shocking as it was made out to be in the media. Click on some of the links above and you'll see that the earlier research findings were always far from unequivocal and universal. Some mice strains are little affected and many aspects of aging (like cognitive decline) have often been shown to be unaltered by caloric restriction even when lifespans were extended. And should we even be surprised by the result, given how much more complex humans are than mice? Experts extrapolating from mice to men ought to give courts pause so long as we can't reliably extrapolate from mice to monkeys.

 

AML Roundup

According to the National Cancer Institute, AML continues to be a significant cause of morbidity and mortality in the United States with the estimates for 2012 being 13,780 and 10,200, respectively.

Cancer isn't one disease, leukemia isn't one disease and AML isn't even one disease. It turns out AML is a heterogeneous disease and as the population ages its incidence is expected to rise significantly. The genetic mutations associated with aging are finally being revealed.

Researchers are zeroing in on the two or three mutations that turn stem cells riddled with age-related mutations but still capable of functioning albeit less effectively, into the clone responsible for AML.  The fact that it's these last few mutations, combined with those genetic insults sustained as a result of the aging process, that are responsible for precipitating AML would seem to support the notion that benzene-induced leukemia was a phenomenon limited for the most part to those first exposed in their forties or later.

Meanwhile biomarkers are being identified to help distinguish between de novo AML and secondary AML.

Why do people with type 1 diabetes have a greater risk of AML?  It could be because they share an intriguing infectious etiology.

Discretizations

PLoS Medicine is Publishing An Attack On "Big Food"

A new series in PLoS Medicine says we're going through another epidemiologic transition; this time it's a "nutrition transition", from a simple traditional diet to a highly processed food diet "resulting in a stark and sick irony: one billion people on the planet are hungry while two billion are obese or overweight". Can you guess who gets the blame? Can you guess what playbook they use? Here are some hints:

"In contrast to the actions of Big Tobacco, soda industry CSR initiatives are explicitly and aggressively profit-seeking."  CSR = corporate social responsibility

Neoliberal policies, including the opening of markets to trade and foreign investment, create environments that are conducive to the widespread distribution of unhealthy commodities by multinational firms.

Big Food attains profit by expanding markets to reach more people, increasing people's sense of hunger so that they buy more food, and increasing profit margins through encouraging consumption of products with higher price/cost surpluses

So are we in the midst of yet another epidemiologic transition? The last one was a bust. It turned out that we never really left the age of infectious diseases. Our bet is that the war on "Big Food" may generate fees but will do little to alleviate either hunger or the obesity epidemic.

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Bending the Dose Response Curve

The linear no-threshold model of dose-response meant that plaintiffs could continue to prevail on toxic tort claims even though their exposures had occurred in the modern era and thus were tiny fractions of those that led to epidemics in years past. Either courts permitted plaintiffs to rely on a one molecule / one particle theory of causation (consistent with the view that some risk is associated with a single molecule or particle) or they allowed plaintiffs to conflate causation with risk.

Eventually some courts began to grasp the absurdity that follows from basing proximate cause on a "one-hit" model in a world of trillions of hits while others began to take notice of the fact that despite probing larger and larger populations with low exposures epidemiology was unable to verify the linear no-threshold model for numerous diseases; thereby suggesting that there is indeed a threshold for diseases including leukemia (a new case making the latter point is Schultz v. Glidden Company.) Meanwhile we have argued that the old cases got it right - that causation in an individual toxic tort case is unfathomable and that the most sensible approach is to estimate the risk imparted (e.g. by a single molecule); to ask why it makes sense to impose liability for creating a 1:1,000,000,000,000,000,000 chance of harm; and, further asking why it wouldn't make sense to impose liability for a 1:100,000 or greater risk.

But all of that assumes risk goes to zero or at least continues to decrease as exposure is reduced below previously measured levels. If that assumption is false, if risk starts heading back up as exposure goes down, especially if unpredictably so, then all bets are off. We will have entered another period of great uncertainty, And it's in such times that toxic tort claims flourish. The horsemen of this new age of uncertainty have published a review paper on the topic and if you want to understand what's coming, why it's pitch perfect for the health and wellness movement and why what happened to BPA will be repeated again and again for other chemicals until some new way is established to either verify or refute their claim that dose doesn't make the poison you need to read it:  "Hormones and Endocrine-Disrupting Chemicals: Low-Dose Effects and Nonmonotonic Dose Responses"

Clostridium Difficile Infections Are At Historic Highs

The CDC has a series of reports out about the growing problem of C. difficile infections contracted via health care-associated activities. The number of deaths attributable to C. difficile has increased more than seven-fold in a little over a decade and now stands at 14,000 annually.

The reports twist together a few threads we've been following for awhile now. First, chronic and often unnecessary antibiotic use in patients disrupts their normal gut microflora and provides an opportunity for C. difficile to gain a foothold and thereafter thrive. Second, these infections aren't just hospital-acquired, or nosocomial, anymore. Infected patients, especially those with diarrhea and on antibiotics transmit the pathogen to surfaces in clinics, nursing homes and doctors' offices and staff thereafter transmit it to other patients; thus they're healthcare-associated infections (HAIs). Finally, the infection is preventable.

The CDC makes the following recommendations to clinicians:

1. Prescribe and use antibiotics carefully. About 50% of all antibiotics given are not needed, unnecessarily raising the risk of C. difficile infections.

2. Test for C. difficile when patients have diarrhea while on antibiotics or within several months of taking them.

3. Isolate patients with C. difficile immediately.

4. Wear gloves and gowns when treating patients with C. difficile, even during short visits. Hand sanitizer does not kill C. difficile, and hand washing may not be sufficient.

5. Clean room surfaces with bleach or another EPA-approved, spore-killing disinfectant after a patient with C. difficile has been treated there.

6. When a patient transfers, notify the new facility if the patient has a C. difficile infection.

If you have a C. difficile case you might want to see how the healthcare provider filled out this form.

For more information try the following links:

CDC's March 2012 "Vitalsigns"

Centers for Medicare & Medicaid Services (CMS) Guidelines for Reducing the Spread of C. difficile.

Finally, there's a brand new research paper from the CDC which discusses the finding that C. difficile is an emergent disease affecting patients recently exposed to antimicrobial drugs.

 

April's "Gut" Has Some Very Interesting Articles.

Have a look at the cover and you'll see why double-dipping chip dippers are frowned upon. Elsewhere you'll find evidence that that if you want to stay lean or if you want to avoid type II diabetes you need to hold down the ratio of Firmicutes to Bacteroidetes that live in your gut. If you're looking for evidence that keeping H. pylori at bay keeps gastric MALT lymphoma away you'll find that too. There's also evidence that pancreatic cancer is associated with just a couple of bacteria found inthe saliva of those at risk of the deadly disease. Here's the link: Gut

Discretizations

You Missed The Zombie Apocalypse

I meant to put this up on Halloween but a trial got in the way; it's only relevant to mass tort litigation if you've been paying attention:

It's no longer contested that certain microbes can hijack the brains of invertebrates and of vertebrates, including mammals.

But is there evidence that microbes can affect human behavior? Lots:

Do gut microbes influence the central nervous system? Yes.

Do microbes talk to your brain? Yes.

Can microbes make you anxious? Yes.

Are microbes likely the cause of schizophrenia and other behavior disorders? Yes.

Do they also cause personality disorders like neuroticism? Yep. (link to follow ;) )

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"The Cost to the Health of Our Microbial Ecosystems"

Gina Kolata has another good read at the NYTimes in "The New Generation of Microbe Hunters". The word, as you can see, is quickly getting out; the old ways of thinking about the determinants of human health are crumbling as the discovery that we are "super-organisms", more bacterial than human - at least from a genetic perspective, sweeps away old notions about what makes us sick, what keeps us healthy and even what (and maybe who) we are.

For other dispatches from the revolution you might want to read about just how big a deal this is, how much we know, how much remains to be understood and the promise of biotherapeutics; or maybe, since there's a little Gilgamesh in each of us, how  changing the bacteria in the gut of mice makes the rodents live significantly longer;  then there's a dysregulated microbiome and rheumatoid arthritis; new insights into how H. pylori causes gastric cancer; and gut microbes can cause cancer of the liver and breast (in mice anyway); and changing the gut microbiota to treat type 2 diabetes and, and, and ... There's a torrent of literature but that'll give you an idea what's out there and what's coming.

None of that is to say "Eureka!" they've found the answer. Likely (as it's wise to hedge bets) the causation onion has many layers still uncovered. No, the point is twofold. First, the 40 year old idea championed by public health advocates pushing what they call social, or environmental, justice - that much if not most human suffering is due to bad industrial chemicals or the bad habits inculcated in consumers by nefarious corporations bent on selling them things they don't want or need - was never sound but now it's just silly. Second, if you've been paying attention, you'll understand that an awful lot of illness and suffering has been caused by stuff nobody, we presume, ever fretted about. But who knows? Maybe somebody somewhere has the disrupted microbiome version of the Sumner Simpson Papers. Wouldn't that be something?

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Curcumin Against Mesothelioma

For decades researchers have been trying potential chemopreventives on members of the Tyler Asbestos Workers cohort; so far without success. Nether beta-carotene, diet nor vitamins have held off the ravages of cancer inflicted by these men's work at the Unibestos facility in Tyler, TX where amosite insulation for nuclear reactors aboard submarines and aircraft carriers was made in the 1960s.

The idea has been to find something with antioxidant properties that might protect workers from the slowly dissolving amphibole fibers in their lungs that are thought to continuously produce free radicals. So far, no luck. But here's a new study from Michigan suggesting that a potent anti-cancer supplement, curcumin, may in fact restart the body's defense mechanisms against malignant pleural mesothelioma (MPM): "Curcumin Suppresses Growth of Mesothelioma Cells In Vitro and In Vivo, in Part, by Stimulating Apoptosis".

Curcumin, like rapamycin, is a very big deal these days. Drop either word into the search window at www.pubmed.gov and you'll see what I mean. After so many false dawns in the war against cancer it's hard not to assume that this isn't another one. Yet somehow, for these two antibiotics, the evidence has piled up to a point where many are starting to think they see some light on the horizon.

Stray Thought: Cancer Fighting Genes As The Targets of Virulence Factors

Some bacteria produce toxins, others hijack cells from the host and drive them around the body to more hospitable climes, yet others make chemical signals that disrupt host immune defenses. But why would bacteria impair tumor suppressor genes? To prevent apoptosis in damaged or infected cells? Maybe, but how about in order to propel the infection behind a vanguard of invasive cancer cells? Don't know but the evidence for p53 modification by h. pylori can be found (free) in "Helicobacter Pylori Cytotoxin-Associated Gene A (CagA) Subverts the Apoptosis-Stimulating Protein of p53 (ASPP2) Tumor Suppressor Pathway of the Host".

What is Cancer?

In toxic tort cases plaintiffs' attorneys and their experts tend to rely on one of two theories about the cause of cancer. The first is the "one-hit" model in which a single mutagenic molecule, particle or fiber causes DNA damage leading to a malignant cell that self-replicates uncontrollably. The second theory imagines that the damage leading to the malignancy is the result, somehow (the hypothesis is never set out in any great detail) of the cumulative effect of exposure to many molecules, particles or fibers. They say "it's like a glass of water that finally overflows when one last drop is added, each drop in the glass was a necessary cause of the overflow."

The one-hit theory is rolled out in low dose cases involving from one to a handful of exposure sources. Here the idea is that carcinogenesis is like playing the skull and crossbones lottery. The more tickets you buy (i.e. exposures you encounter) the more likely you are to wind up with the losing ticket. "All it takes is one bullet and they shot trillions of bullets at my client".

The cumulative dose theory is deployed when there are many sources of exposure and where those responsible for the biggest portion of the exposures are bankrupt or have already settled.  Here the idea is that once the individual's defenses are overtopped a malignant clone is born (initiation) or conditions for propelling the spread of an existing malignant clone are created (promotion). The most odious example of this argument was directed, despite my objection, against a client in an asbestos trial in state court in Galveston  - "It takes several men to have a lynching. One to hold the man, one to get the horse; one to get the rope, etc. They (meaning my client) want you to believe that each and every man in the lynch mob must go free just because the act of each man alone would not have resulted in my client's death. I know that's wrong and you know that's wrong!"

Either way, whether it's a matter of each cell playing the cancer lottery one molecule at a time or of  each cell slowly filling over the years it's carcinogenic reservoir you'd think that the more cells you have in your body the more likely you'd be to hit the losing ticket or see a chemoprotective dam collapse. Even for cancers thought to be caused by mishaps during normal cell division you'd think that if you had a lot more cells you'd have a lot more opportunity for mishaps.

But you'd think wrong. People don't get cancer more often than mice and neither do whales - even though they (obviously) have a lot more cells and also live long enough to have them and their progeny divide many many more times. See  "The Mere Existence of Whales" and "Why Don't All Whales Have Cancer? A Novel Hypothesis Resolving Peto's Paradox". Hat tip Marginal Revolution.

So what's going on? Do bigger organisms have better cancer defenses? Does size confer some advantage as suggested by the hypertumor hypothesis? 

Maybe it's the underlying deterministic model that needs tweaking. Maybe cancer rates scale up with physical size because cancer is a system, or a subystem, rather than a simple switch, Indeed there's a growing body of literature showing a tight association between reproductive optimization, energy availability, aging and cancer. Maybe the 30% cancer rate seen across mammalian species represents an evolutionarily determined risk-of-cancer/benefit-of-plasticity ratio that holds true from mice to whales.

If so, that would mean that we're programmed to run a high risk of cancer.  Not exactly the "cancer is a man-made problem" meme in which labor, environmentalists and their lawyers found a common purpose and a common tool.

A Big Step Forward in Tracing Foodborne Illness Back to Its Source

Where pulsed-field gel electrophoresis failed to distinguish a strain of Salmonella enterica responsible for a major salmonellosis 2009-2010 outbreak from a strain isolated in a prior separate outbreak so-called next-gen DNA sequencing (NGS) has allowed researchers to pinpoint the source of the recent outbreak to a specific spice used on salami.  See Identification of a Salmonellosis Outbreak by Means of Molecular Sequencing.  Note however that traditional epidemiologic traceback techniques had lead investigators to the source of the outbreak.  NGS confirmed the outbreak and further demonstrated that endemic contamination of food facilities by pathogens can lead to the production of new strains thereby making more precise sequencing "essential to the traceback of bacterial pathogens as they emerge in the food supply."

A Disingenuous Take On The Vaccine-Autism Fraud

The British Medical Journal has just published an editorial titled "Assuring Research Integrity in the Wake of Wakefield" that addresses what has finally been revealed to have been an elaborate fraud concocted by a scientist and some personal injury lawyers in an effort to launch a mass tort. Unfortunately, rather than addressing the real problem (which is that the majority of the published peer-reviewed papers purporting to find an association between some drug or exposure or gene and a disease are probably false) the authors of the editorial reference a handful of ethical lapses spaced about twenty years apart and ask "[h]ow could this happen again?"; implying rather obviously that scientific fraud is almost as rare as Piltdown Man but nonetheless something about which the academy ought to be vigilant lest the public lose faith in "science".

They conclude with "We must transcend traditional hierarchies and authority gradients to empower everyone in the research enterprise ... to raise questions and "stop the line". I've no idea what the first part means though it sounds suspiciously like something out of "Transgressing the Boundaries: Towards a Transformative Hermeneutics of Quantum Gravity". The latter part on the other hand, quite inadvertently I assume, manages to expose the real problem with today's "research enterprise". It refers to the ability of factory workers on an automobile assembly line to halt the process when they detect a problem rather than having to wait until a supervisor calls for a stop. Focus then on the idea that many "researchers" aren't involved in the process of discovery or even design. Rather their part is played down on the assembly line of the Science factory - manufacturing the same sort of science; shift after shift, day after day, year after year. Their job is to identify anything that might throw a wrench in the works or cause the product to be defective and thus rejected by the customer, typically the government, industry or an NGO, to repair or engineer around it and to keep the line running.

The authors' concern then is with the process and not the product. But of course, if you've been paying attention, you know by now that the product is the real problem. In studies like Wakefield's, in which statistics are trotted out to test hypotheses, the "science" is probably wrong even if the researcher isn't consciously cooking the books in order to gin up a mass tort. Read and re-read "Odds Are, It's Wrong" from ScienceNews. Let the following quote sink in: "There is increasing concern that in modern research, false findings may be the majority or even the vast majority of published research claims."

Whether or not the product of the Science factory is worth its price or indeed worth anything at all, it keeps on coming in an ever increasing torrent.  Take for example genome-wide association studies (GWAS) - one of the most notorious examples of  too often useless "research" produced assembly line style. (Note there are efforts to improve it. See e.g. "A Knowledge-Based Weighting Framework to Boost the Power of Genome-Wide Association Studies") A quick search of PubMed reveals that 45 new genome wide association studies have rolled off the line in just the last week. That's great news if you're in the business of selling SNP chips to research universities and a sign of a boom (or bubble) in the fortune of researchers. And maybe it's even good for the economy - being after all a form of digging holes and filling them back in. But where does it end?

Ponder the following from "The Future of the Research University" written in 1997: "We need to think seriously, within the community of research universities, about whether we are producing too many Ph.Ds. This is a controversial question, with different answers in different scholarly disciplines, but the general conclusion seems inescapable: The mathematidcs of exponential growth - each professor producing numerous Ph.Ds who become professors who produce numerous Ph.Ds, etc. - has caught up with us."

With that exponential growth in Ph.Ds desperate for something to research and something to publish it's no wonder that so many turn to statistical tools which, when rigorously and repeatedly applied to any mound of data, will inevitably produce a publishable statistically significant, though often false, result. And despite concern that the exponential growth in the number of Ph.Ds "has caught up with us" there's no sign that the factory is cutting back on the number of shifts. Instead, more factories are being built. Indeed what got me thinking about this was a huge billboard on I-45 announcing that what was once the humble but excellent Teachers' College is now itself a Research University! Sure enough, a stroll through their website reveals that they've bought a great pile of extremely expensive analytical equipment and will soon be adding to the mountain of Science being manufactured. Everybody it sometimes seems is getting in on the "research enterprise".

The point then is that research has become an industry; and an enormous one at that. Best then to stay as skeptical of Big Research and Big Research Publication (note the circle the wagons approach of the Lancet's editorial board when they first got whiff of the fraud) as you are of Big Corporation. And best then as well to train your attention on the product of factory Science even if the process by which it was made is sound. Remember, it's generally not enough to say simply that it was made According to Plan.

Are There, At Last, Reliable Biomarkers of Past Benzene Exposure?

A dozen years ago the National Law Journal had a write-up on a benzene / acute myelogenous leukemia case Herschel Hobson and I tried to verdict up in Texarkana, TX in Judge Folsom's court. The case was noteworthy as it was the first time the so-called benzene fingerprint defense had gone to a jury. Over Herschel's objection that it was junk science not generally accepted in the scientific community I got to put on evidence that benzene-induced leukemias are like therapy-related leukemias (t-AMLs), that the plaintiff didn't have the signature loss or deletion of chromosomes 5 and/or 7, and to argue that the plaintiff's leukemia could not therefore have been caused by benzene. Fate was with me however and so Herschel was quoted in the article as saying that the biomarker defense was all a bunch of baloney; or words to that effect.

The effort to identify markers of past benzene exposures continues and is intensifying. Interestingly, it's one of the plaintiffs bar's key experts who's leading the charge. For two brand new papers on the topic see (gated) "Chromosome-Wide Aneuploidy Study (CWAS) in Workers Exposed to an Established Leukemogen, Benzene" and (free) "Global Gene Expression of Profiling of a Population Exposed to a Range of Benzene Levels".

I must admit though that while putting on new science is exciting it's often not the game changer we'd like to believe. What almost certainly carried the day in that case was that the widow on cross examination opened the door to claims she'd made against other defendants over her husbands leukemia. Through another lawyer Herschel didn't know about she'd sued three dozen defendants in New York claiming that asbestos had caused her husband's cancer. (In the past recycling plaintiffs was not uncommon and I've seen a single family recover full damages from each of the asbestos, silica, benzene and butadiene defendants). As she read her New York complaint asserting that asbestos was the sole cause of her husband's cancer and that she was entitled to $40 million from each defendant the jurors one after another crossed their arms and sat back in their chairs. And that, was that.

Welding and Cardiovascular Disease

When it comes to cholesterol the thing to worry about is too little HDL. Your total cholesterol level can be high and your LDL can be high but if your HDL is up there you're swimming in the shallow end of the risk pool. That's what makes "Acute Decrease in HDL Cholesterol Associated With Exposure to Welding Fumes" so interesting.

The finding of a large decrease in HDL without effect upon other lipids following exposure to pm2.5 in welding fumes provides, if replicated, a biological mechanism for some of the maladies laid at the feet of pm2.5. Low levels of HDL lead to inflammation and chronic inflammation leads to a variety of illnesses like hardening of the arteries.

Mesothelioma and Ovarian Cancer: Shared Histogenesis or Shared Etiology?

The growing controversy over a possible link between asbestos exposure and ovarian cancer is driven in large part by the fact that the two malignancies affect the serosal cavities and share a striking number of biomarkers. Does this mean that they both arise from the same sort of undifferentiated cell or that they're both caused by asbestos? See "Association of Malignant Mesothelioma and Asbestos-Related Conditions With Ovarian cancer: Shared Biomarkers and a Possible Etiological Link?"

The Linear No-Threshold Theory: A Crumbling Foundation

The idea that a known cause of cancer, e.g. ionizing radiation, poses a risk of cancer at any dose, no matter how small, is a central thesis informing modern environmental and occupational regulations and modern, which is to say low dose, toxic tort cancer litigation. In the toxic tort context plaintiffs regularly employ the logical fallacy of the appeal to ignorance (argumentum ad ignorantiam) to prove that even the slightest exposure was risky. They say that because defendants cannot establish a safe level of exposure it follows that every exposure is necessarily unsafe. The formal name for the idea that risk doesn't drop to zero until exposure drops to zero is the linear no-threshold dose theory or LNT. The LNT theory, always longer on theory and politics than evidence is increasingly under attack. Now even NIOSH has had to concede that at least in some circumstances there is indeed a safe dose for a carcinogen.

In "Checking the Foundation: Recent Radiobiology and the Linear No-Threshold Theory" the author states "a large and rapidly growing body of radiobiological evidence indicates that cell and tissue level responses to [radiation damage], particularly at low doses and/or dose-rates, are nonlinear and may exhibit thresholds ... this evidence directly contradicts the assumptions upon which the microdosimetric [LNT] argument is based". The idea that a substance that is harmful at high levels can be harmless or better yet beneficial or protective (the idea of hormesis) at low levels is discussed at length in this month's issue of Human & Experimental Toxicology.

The claim that "if it takes an ounce to kill ten men then a drop will thousands" was itself just a theory based on the idea that carcinogenesis was a stochastic process. Getting cancer was sort of like hitting the anti-lottery and the more tickets you bought (exposures you sustained) the more likely you were to lose yet if you were unlucky enough just one ticket could do it. Like black box epidemiology LNT was simply a way to ignore the formerly incomprehensible molecular biological mechanisms responsible for cancer. Now that those mechanisms are being uncovered and understood they can no longer be ignored as they shatter one paradigm after another.

Pesticides and Prostate Cancer: A Two-fer

Epi + Biomarkers = "An Update of Cancer Incidence in the Agricultural Health Study" + "Pesticide Use Modifies the Association Between Genetic Variants on Chromosome 8q24 and Prostate Cancer".

Bisphenol A Roundup

Since it's detected at low levels in 95% of us and since Americans have been exposed to it for more than 50 years you'd think someone would have noticed if exposure to bisphenol A (BPA) were responsible for widespread illness, deformity and death. Apparently not, at least not if the findings from a recent wave of BPA studies are to be believed.

The new findings are, in no particular order, that BPA: (a) damages sperm (b) inhibits the normal development of ovaries (c) alters brain development (d) causes premature birth (e) may be a carcinogen like DES (f) damages blood cells (g) activates breast cancer cells (h) impairs the body's defenses against colon cancer especially in women; and, (i) makes offspring anti-social and neurotic. And those are just a few of the "findings" published in the last two months. Obviously the world that existed before 1950 or so, before  BPA was everywhere used to seal bacteria out of food and dental cavities, had to have been a much healthier and more peaceful one. Alas.

"What Can We Get Away With?"

That's not the kind of question about the current state of medical science that you'd expect to hear from someone charged with understanding and promoting public health. On the other hand, if the point is to demonize food, in this case a drink with sucrose (glucose + fructose),  it makes perfect sense.

The NYTimes has gotten a look at the e-mail exchanges between New York's anti-soda crusading health commissioner and his subordinates and published some of them in "E-Mail Reveals Dispute Over City's Antisoda Ad". The email conversation reveals a determined effort to ignore, dispute and ultimately fudge the science in order to come up with an ad campaign that the commissioner hoped would "go viral". The meme he sought to develop was an equivalence between soft drinks and gooey disgusting fat. The ad is propaganda in its purest and, considering it's governmental origin, most disturbing form.

The demonization of sugar is a head scratcher. Your brain burns glucose and during periods of real starvation your body will start to cannibalize itself so that the brain can have that with which it cannot do without - sugar in the form of glucose. On a typical day of normal brain functioning the brain alone burns as much sugar as is found in three cans of sugary sodas.

Too much of a good thing is never good for you but those people who've joined the anti-sugar crusade and who are pledging to lead "sugar-free lifestyles" are either brain dead or are soon about to be.

Toxoplasma gondii: Sheep and Goats Have a Vaccine Against It. Why Don't We?

It''s becoming apparent that Toxoplasma gondii is responsible for an awful lot of human suffering around the world. The parasitic organism causes birth defects and spontaneous abortions, neurolgical impairment, eye damage and is increasingly suspected in Alzheimer's, schizophrenia and Parkinson's.

T. gondii infects human cells and reproduces within them eventually setting up shop in cysts throughout the central nervous system, heart, muscle, bone marrow and other organs. Persons infected are infected for life. Human infection is most commonly the result of consuming un-/under-cooked cyst-bearing meat though contact with the feces of animals, especially cats, T. gondii's ultimate host, are another avenue of exposure.

While 11% of Americans are infected with the parasite, that figure rises to as high as 70% in some South American countries. The European Food Safety Authority, worried that foodborne infection by T. gondii is on the rise and is responsible for significant yet underreported and undetected diseases within the EU, has recommended Toxoplasma monitoring of lifestock. Recent estimates of the impact of T. gondii-induced disease reveal it to be "one of the most significant causes of foodborne disease worldwide."

The good news is that thanks to demand from sheep and goat producers there's a vaccine that works well in sheep and goats. The problem is that it's a live cell preparation like the Sabin vaccine discussed during oral argument in Bruesewitz, et al v. Wyeth, Inc.,So what's the problem? The problem is that while it works really well, much better than bits of a dead organism, it's more likely to cause adverse effects. Meanwhile, finding all the bits of a dead organism that prime the immune system while weeding out those that might produce harm is a terribly complicated and expensive process. Add to that the threat posed by litigation over the inevitable errors in science's slow but steady progress through trial and error and it ought not be surprising that sheep and goats get protected while human suffering due to T. gondii spreads.

For a new, free and enlightening paper on the topic see "Vaccination Against Toxoplasma gondii: An Increasing Priority for Collaborative Research?"

Schools: Highly Effective Virus Transmission Sites

Two weeks after kids go back to school, doctor visits for flu-like symptoms spiked in 2009. Why? It looks like schools catalyzed "community-wide transmission" of H1H1 pandemic influenza. See "School Opening Dates Predict Pandemic Influenza A(H1N1) Outbreaks in the United States". The authors suggest vaccination begin before kids return to school.

There's good news for people (like me) who hate getting vaccinated. It looks like "Needle-Free Influenza Vaccination" is on the way.

Finally, here's the CDC's picture of the week from the Public Health Information Library. It's what influenza vaccines help your immune system recognize and inhibit.

PHIL Image 10073

Mounting Evidence That Delaying Introduction of Certain Foods to Infants' Diets Causes Allergies

The idea that children, and especially infants, are somehow exquisitely susceptible to environmental harm such that exposures to immune system challenges should be put off until that system is "strong enough" has been around for awhile. The lack of any good science to support the claim hasn't prevented it from becoming established medical guidance; especially when it comes to allergenic foods like peanuts, wheat, cow's milk and eggs. Now there's evidence that the advice to delay by a year or more the introduction of such foods into a child's diet until after she's a year or two old is actually the cause of food allergies.

In "Can Early Introduction of Egg Prevent Egg Allergy in Infants? A Population-Based Study" 2,589 children children were tracked by risk factors (especially a sibling or family member with a food allergy), breast-feeding status, diet, timing of introduction of eggs and finally skin-prick tests to determine sensitization status. Giving babies cooked eggs early significantly reduced their risk of egg allergies irrespective of risk factors or breast-feeding status. On the other hand, delaying the introduction of eggs to the diet significantly increased the risk of egg allergies even in those without risk factors.

If there's ever an accounting of all the harm done by the scaremongers the tally is certain to be staggering. In the meantime, they've created a whole generation of eggshell plaintiffs.

Liability for Changing Someone's Ethics?

What if there was a drug that could change a consequentialist into a deontologist? In other words, what if you gave this hypothetical drug to someone and he went from being a "needs of the many outweigh the needs of the few" sort of guy to a right v. wrong, rules sort of guy? Now what if that drug was prescribed based soley on the perfectly sound decision to relieve him of depression?

To grossly oversimplify, giving serotonin-boosting anti-depressants turned consequentialists (yes, I know there are more flavors of them than of ice cream at Baskin-Robbins but those flavors are just their common deontological side peeping through in different places) into right/wrong thinkers. Better (depending upon your perspective) yet, it made them more rational in "the greatest misfortune that may befall a man is great good fortune for his neighbor" sorts of experiments in which people are tested to see if they'd cut off their own noses to spite their neighbor's face. See: "Serotonin Selectively Influences Moral Judgment and Behavior Through Effects on Harm Aversion". ht: Marginal Revolution

Those are pretty big changes. They affect politics, friendships and so world views. I brought it up though not to discuss liability for making or prescribing such beneficial medicines but rather, I must admit, for a wholly different purpose - to very briefly discuss picking a jury. My number one rule of jury selection, from the defense perspective, is to identify and get rid of depressed veniremen. They tend not to care about rules and to be far too willing to cut off your client's ear and thereafter paint their masterpieces out of piles of her money.

Trichloroethylene + Gene Variant = Renal Cancer?

Workers exposed to trichloroethylene (TCE) who carry at least one copy of the GSTT1 allele are reported to have an 88% increase in risk of renal cancer in the new paper "Occupational Trichloroethylene Exposure and Renal Carcinoma Risk: Evidence of Genetic Susceptibility by Reductive Metabolism Gene Variants." Those workers without the polymorphism had a slight decrease in risk. Given that the allele occurs on a gene coding for cysteine β-lyase, which plays an important role in the metabolism of TCE among other molecules, the finding demonstrates biologic plausibility as well as increased risk.

So back to yesterday's post about risk : which risk, if any, would be relevant in a TCE toxic tort case? The risk given to all workers collectively; the risk at a particular range of exposure; the risk given to those carrying the polymorphism; or, the risk to those with the polymorphism exposed at high levels? And could it be the case that one risk is relevant to the question of whether a defendant's conduct was reasonable while another was relevant to the question of causation? How would that work?

However it works, as the causes of individual susceptibility are identified expect these sorts of challenges to multiply. 

Parkinson's: Not Much Evidence for Manganese; Strong Evidence for Vitamin D Deficiency

In Tamraz v. Lincoln Electric Company, et al the 6th Circuit held that an expert could not stack speculation about mechanisms upon unseen and undetected lesions in the plaintiff to get from manganese exposure to his Parkinson's disease. Furthermore, the court ruled that you can't reasonably arrive at a causation opinion using what's erroneously called a differential diagnosis (it's more properly called simply a process of elimination) when you've no sound basis for ruling anything either in or out.

On the other hand, there's growing evidence that vitamin D deficiency is strongly associated with Parkinson's. Best of all, it makes sense. It looks like the enteric nervous system is first to be degraded in Parkinson's and that system is exquisitely sensitive to the gut mediated immune system which in turn is adversely affected by vitamin D deficiency. See: "Parkinson Disease: Could Sunlight Offer Protection from Parkinson Disease?"

What Do Wrinkles, Rheumatoid Arthritis and Multiple Sclerosis Have in Common?

Apparently, whether you get them or not depends on the microbes that live in your gut.

It may not make sense intuitively (undoubtedly a common problem in times of crumbling paradigms) but the bacteria in your intestines may decide whether your skin responds to UV damage with wrinkles or is instead rejuvenated. See "Probiotics for Photoprotection".

Interested in how the right gut microbes suppress central nervous system inflammation and how the wrong ones cause just the sort of chronic brain and spinal cord inflammation thought to be responsible for MS? Read: "Proinflammatory T-Cell Responses to Gut Microbiota Promote Experimental Autoimmune Encephalomyelitis". Here's one of many interesting takeaways: "... mammals are colonized for life with extraordinary multitudes of indigenous bacteria, and the contributions of this enormous and diverse ecosystem to human health remain poorly understood. Recent studies have launched a revolution in biology aimed at understanding how (and more importantly, why) mammals harbor symbiotic bacteria."

Take a mouse predisposed to rheumatoid arthritis and make it germ free. No rheumatoid arthritis. Then expose it to a single microbe, the segmented filamentous bacteria, "and arthritis rapidly ensued." That was the finding of "Gut-Residing Segmented Filamentous Bacteria Drive Autoimmune Arthritis via T Helper 17 Cells". And for a real eye opener read "Segmented Filamentous Bacteria Shape Intestinal Immunity". How could two genetically identical mice have dramatically different immune systems? By having different microbes in their guts - as in the case of B6 mice from two different vendors.

Memo to self: look into whether different sources of B6 mice might correlate with different results re: butadiene's carcinogenic potential.

BPA: Theory v. Empiricism

Tonight the NYTimes has an article on bisphenol A (BPA) headlined: "In Feast of Data on BPA Plastic, No Final Answer". It's a very good overview of the current status of the research on BPA; which is to say that despite the hyperbolic claims of some there's precious little evidence that BPA causes harm in humans.

Is there a tsunami of literature showing that on a molecular level cells sometimes adapt to BPA? Sure. Is there evidence that these changes lead to any harm? Not so much.

So what's going on? What's going on is a very public battle between theory, hatched from conventional thinking about what constitutes an endocrine and how it should work, and what we witness in the world - i.e. dramatically decreased morbidity and mortality among inhabitants of modern economies exposed to lots of BPA - and no evidence of an excess of morbidity or mortality for those exposed to more, rather than less, BPA.

Much is at stake in this contest. Will the effort to turn scientific research into a sort of blue collar affair in which statistical tools supplant genius be successful? Or will modern research efforts, bounded by old paradigms, be overcome by the simple collection of observations and the unanticipated spark of induction that leads us to a wholly new understanding? It's part of a larger political battle and this time everyone's pulling out all the stops. One side or the other will lose and lose big. Moneywise I'm long on the empiricists.

Koch's Postulates Revised

Whenever epidemiological data is used to support a claim of causation in a toxic tort case a fight over causal inference invariably erupts and for the last twenty years or so that has meant an argument about whether Sir A. B. Hill's so-called causal criteria have been met. Long before Hill tried to prove that smoking causes lung cancer Robert Koch tried to find a defensible argument for the claim that microbes were the cause of anthrax. What he came up with are known as Koch's postulates and they've been around for well over one hundred years. Now, in an attempt to update them for a world in which often only bits of pathogens long gone remain an attempt to update the postulates has been published.

In "Microbe Hunting"  the author summarizes the problem of causal attribution when the responsible bacteria can't be cultured or even found and when their role in disease is the result of an incredibly complex interplay between host, uncounted trillions of microbes and the external environment. He discusses the methods for teasing out pathogens from dense webs of causation and proposes a refined set of causal criteria. It's well worth reading because if you do mass torts you'll be dealing with this issue for years to come.

"[O]ur Old Assumptions About Toxicants and How They Affect Our Bodies Are Being Changed ..."

There's a remarkable but necessary admission in this month's Environmental Health Perspectives.  It is that that a new (some would say old) paradigm has emerged; that pathogens, sometimes in concert with what for 40 years have been known as toxicants, are responsible for a very large portion of human suffering. Unable to deny any longer that diseases of nature inflict a staggering toll on humanity the "NIEHS Office of the Director will be working with division leaders to develop an initiative on infectious disease and environmental health—to incorporate infectious disease into the toxicological paradigm."

The editorial points to "A Niche for Infectious Disease in Environmental Health: Rethinking the Toxicological Paradigm" just published in the same journal. It's a call for the study of infectious diseases in environmental health research. Ultimately it's a recognition that the simple (and simplistic) models of many diseases are collapsing under the weight of modern microbiology. It's an admission that "the complexity of real-world exposures and multifactorial health outcomes" cannot be captured by the simple one-to-one associations that ruled environmental health research for the past four decades.

Years ago real insight, real genius (at least when it came to environmental illness) was replaced by a sort of blue collar approach to science in which grotesquely simplified statistical data dredges could be automated so that a never ending stream of putative causes of human suffering could be manufactured, studies and regulated. Some of the techniques were so malleable that clever researchers could not only manufacture causes, they could also decide in advance what the causes would be. Now, the real causes are uncovered and it often turns out that our ancient enemies, pathogens, were to blame all along.

The long war continues, but now the scales that covered environmental science's eyes for decades are falling.

 

Previously Unknown Species of Deep Water Bacteria Rapidly Degrading Oil in Gulf of Mexico

The oil spilled into the Gulf of Mexico is being degraded more rapidly than expected and without a precipitous decrease in oxygen levels. Those are among the fascinating findings in "Deep-Sea Oil Plume Enriches Indigenous Oil-Degrading Bacteria " just published in Science. An excellent write up can be found at the Berkeley Lab press center under "Study Shows Deepwater Oil Plume in Gulf Degraded by Microbes".

The essence of the findings are summarized in the release as follows:

"Hazen and his colleagues attribute the faster than expected rates of oil biodegradation at the 5 degrees Celsius temperature in part to the nature of Gulf light crude, which contains a large volatile component that is more biodegradable. The use of the COREXIT dispersant may have also accelerated biodegradation because of the small size of the oil particles and the low overall concentrations of oil in the plume. In addition, frequent episodic oil leaks from natural seeps in the Gulf seabed may have led to adaptations over long periods of time by the deep-sea microbial community that speed up hydrocarbon degradation rates.

One of the concerns raised about microbial degradation of the oil in a deepwater plume is that the microbes would also be consuming large portions of oxygen in the plume, creating so-called “dead-zones” in the water column where life cannot be sustained. In their study, the Berkeley Lab researchers found that oxygen saturation outside the plume was 67-percent while within the plume it was 59-percent"

How Does One Defectively Design a Molecule?

In Lance v. Wyeth the plaintiff alleged, among other things, that defendant had somehow negligently designed the molecule dexfenfluramine and that such negligent design was the proximate cause of her daughter's death. The defendant however prevailed on its motion for summary judgment having demonstrated to the trial court that plaintiff did not have any cognizable product liability claims under Pennsylvania product liability law as it applies to prescription drug cases. On appeal the trial court's rulings were affirmed one by one until the appellate court came to the negligent design claim.

The court held "that notwithstanding comment k in section 402A Restatement (Second) of Torts, this claim is actionable under Pennsylvania law." Noting that "a strict liability design defect claim is distinct from a negligence design defect claim" the court examined section 395 (negligent design of products) and found no exemption for unavoidably unsafe products like the one for things like pharmaceuticals found in comment k of 402A. Accordingly, the appellate court determined that "Appellant's negligent design claim is not precluded by comment k, and is a valid cause of action upon which relief may be granted. The trial court thus erred in entering summary judgment in favor of Wyeth on Appellant's negligent design defect claim."

In arriving at its conclusion the court relied on just three cases. For the proposition that plaintiff can lose on a strict liability design defect claim yet prevail on a negligent design defect claim the court cites Phillips v. Cricket Lighters. In that case though the court held that on the strict liability side the question went to whether the lighter was safe for the intended user, in that case an adult, whereas on the negligence side the question was whether the lighter's lack of a safety feature was a design defect given the fact that an unintended but foreseeable user, a child, started the fatal fire. In Lance, of course, the person for whom the drug was intended and its user were one and the same so I don't see the point.

For the proposition that their reasoning applies to pharmaceuticals the court pointed to Toner v. Lederle Labs. In Toner though the question wasn't whether a molecule like dexfenfluramine was defectively designed; the question was whether making a vaccine out of a whole library of bacterial molecules, most, necessarily, of unknown nature and function could have been done more safely by using just a few bits of B. pertussis rather than the whole cell. Ok, but that's mixing apples and sangria.

Finally, for further support for the proposition that you can lose a strict liability design defect claim and yet win on a negligent design defect claim for the same product the court points to Artiglio v. Superior Court. Artiglio was a petition for writ action seeking a reversal of a summary judgment in favor of defendant on plaintiff's strict liability claim in a breast implant case. Plaintiff's petition for writ was denied; the appellate court finding that "the entire category of medical implants available only by resort to the services of a physician are immune from design defect strict liability." The problem with Artiglio and of the case to which it points, Brown v. Superior Court, is that they appear to stand for the proposition that in a prescription drug case there's really no such thing, at least under California law as strict liability defective design case - not that it's somehow different and so equally actionable.

Putting all that aside for the moment, what would it mean to defectively design the small organic molecule that is the essence of any modern medicine?

Surely it doesn't mean that the molecule ought to have been made up of different atoms. If that were the case then it necessarily wouldn't have been the same drug - we're not talking alternate design; we're talking alternate universe. Even in Beaumont twenty years ago the judges tossed out plaintiffs' claim that benzene ought to have been designed with all of its useful properties but with a methyl group in place of one of its hydrogens. 

Maybe the claim could have to do with how the atoms are arranged in the molecule. It's true that some organic molecules can be made in two forms akin to our right and left hands and that each form may have different biological properties. Thus if say, to use a trivial example, D-glucose (right handed) was safe and effective and L-glucose (left handed) was unsafe though effective you might have something to talk about if you'd taken the L- variety. Such a circumstance is mainly hypothetical and the typical finding is that one form is ineffective so that it's never consciously made in the first place leaving at best a manufacturing defect claim, if anything.

Perhaps the claim goes to the design process itself. Drug design has gone from trial-and-error to a find it and bind it approach to mindbogglingly complex efforts involving huge numbers of simulations run on supercomputers. But if something's wrong with the approach then the complaint, again, is not with the product consumed but with the failure to discover a different and better product. Something akin to a loss of chance claim perhaps. Surely the courts won't impose a duty of scientific discovery on companies. If they do they could at least solve the problem of induction first.

All in all it's hard to see how this new negligent design defect claim changes things. Really, what can it possibly mean to say that someone defectively designed something she didn't design, or to say that she defectively designed one thing because she didn't design it like something completely different? Can a car be found defectively designed because it's not an airplane? I hope not.

How Quickly Do Bacteria Evolve? Lots Faster Than You Thought.

It has generally been assumed that bacteria evolve to overcome host defenses at a rate much slower than that of viruses. That assumption appears to be wrong. Helicobacter pylori, a cause of multiple cancers in humans, mutates at a rate similar to many viruses. See: "Microevolution of Helicobacter pylori During Prolonged Infection of Single Hosts and Within Families".

Just how fast can bacteria evolve? Would you be surprised to learn that within the lifetime of mice, bred to be free of gastrointestinal bacteria, bacteria from drinking water cannot only set up shop and colonize their hosts' guts but evolve into whole new species? If you are surprised, read: "Bacteria From Drinking Water Supply and Their Fate in Gastrointestinal Tracts of Germ-Free Mice: A Phylogenetic Comparison Study".

The long war continues, of course; and while we've been basking in our assumed victory over them for the last forty years our ancient enemies, descended from a long line of brilliant sappers, have been hard at work.

SV40 and Mesothelioma: The Perfect Crime?

For years a controversy has raged over whether simian virus 40 (SV40) causes mesothelioma in humans. While the evidence that SV40 causes mesothelioma, brain cancer and lymphoma in some animals is very strong it's a different story when it comes to humans. Evidence of prior SV40 infection in patients with e.g. mesothelioma has been equivocal at best. Just this month, in "SV40 Associated miRNAs Are Not Detectable in Mesotheliomas", researchers again failed to find the genetic fingerprints of SV40 in mesothelioma samples taken from victims of the disease.

Not every viral perpetrator of cancer leaves genetic evidence at the scene of the crime though. That's the finding in today's "Vaccination Against a Hit-And-Run Viral Cancer" (free). For the first time the scientists have been able to demonstrate an experimental animal model for sarcoma in which "virus-triggered oncogenesis" generated cancer cells that lacked viral genomes.

In their dicussion of findings the authors make the following four points: 1) "Most analyses of human cancers have focused on examples of genome retention". 2) The fact that some virus-induced cancers retain viral genomes doesn't prove that all or even most do so. 3) "Relying on viral genome detection to establish aetiology" may dramatically underestimate the role of viruses in cancer. 4) Vaccinations against viruses previously thought to be of little benefit may do far more good than expected.

Does any of this prove that SV40 is a hit-and-run cause of mesothelioma in humans? No, but it does raise the question of whether viruses have played a role in some of the biggest latent cancer toxic torts of all time. To this day the discoverer of one of the most studied cancer clusters wonders whether it was more than a coincidence that almost half of the stricken workers lived in the same boarding house and that three roomed together. More on that another day.

Alzheimer's and the Confounding Arrow of Causation

Back in March we reported on the finding that beta amyloid, which accumulates in the brains of Alzheimer's patients, is a potent antibiotic; thereby generating the hypothesis that its presence wasn't the result of a malfunction but rather was an effect of an immune response to a chronic brain infection. If that's really the case, getting rid of it might not be the way to go.

Today Gina Kolata of the NYTimes is reporting on the dramatic failure of a drug designed to reduce the amount of beta amyloid in the brain. It's not that it didn't reduce beta amyloid; it did. The problem is that it made the subjects' Alzheimer's worse; and the more they took the more their conditions worsened.

None of this proves that the real killer is a chronic fungal infection which is slowed down by beta amyloid but it does prove that when it comes to biomarkers the "which is cause and which effect" trap can ensnare the brightest and the savviest.

What Can We Learn About Oil Spills From Studying Natural Seeps? Also, a Publication About Corexit.

Every day 20 to 25 tons of crude oil seeps up out of the naturally occurring Coal Oil Point off the coast of  Ventura, CA. The amount of petroleum in surrounding sediment remains constant at about 800% to 8000% more than that in sediment at the site of the Exxon Valdez accident and there's a persistent slick and steady plume of hydrocarbons along the continental shelf from the 24/7/365 seepage. Accordingly it presents an opportunity to study the fate of the petroleum, the impact of currents and weather on dispersion, the natural biodegredation by microbes and the differences in habitats inside and outside the zone of weathered petroleum. For a primer see: "Weathering and the Fallout Plume of Heavy Oil From Strong Petroleum Seeps Near Coal Oil Point, CA."

For a discussion of the amazing diversity of life that lives in and on crude oil see (for free): "Microbial Diversity in Natural Asphalts of the Rancho La Brea Tar Pits".

Finally, if you want some reassurance about Corexit, you might want to read "Analysis of Eight Oil Spill Dispersants Using Rapid, In Vitro Tests for Endocrine and Other Biological Activity". A free version looks to be available at the EPA. Long story short: in vitro testing shows no evidence "that any of the dispersants will display biologically significant endocrine activity via the androgen or estrogen signalling pathways."

 

Nano Nannies

The New York Times has an excellent write up of the new article "Human Milk Glycobiome and its Impact on the Infant Gastrointestinal Microbiota" in today's Science section. Two profoundly important points are made both by the write up and the article; they are (1) that we are each individually a "we", an emergent organism dependent upon billions of organisms within us to promote and to maintain good health; and, (2) just because we don't know what something does that doesn't mean it does nothing - it just means we haven't thought about it hard enough.

It turns out that mother's milk nourishes not only her baby it also selectively recruits and thereafter employs (with payment made in special milk sugars that baby can't digest) billions of tiny bacteria which earn their keep by aiding digestion, protecting epithelial cells and assisting the immune system in its never ending war against pathogens. And what of the other forms of milk sugars whose purposes have yet to be elucidated? The search for whatever they're feeding is now on in earnest.

As for the now refuted claim that the indigestible (at least by baby) milk sugars serve no purpose it's important to recognize just how many such claims are falling these days. It was a big deal three years ago when the ENCODE researchers announced "You know those non-coding DNA segments? You know, the flotsam and jetsam of millions of years of evolution that doesn't really do anything? Well, guess what?" These days stories about aspects of our selves once thought to be vestigial shadows of distant ancestors turning out instead to be critical determinants of health are common. As a result, we live in a time of great promise but also of great uncertainty.

So what does this have to do with mass torts? First, there's the issue of causality. The task of unraveling causation becomes fantastically complex once we understand the role that genetics, epigenetics, diet and social interactions, including swapping bacteria, play in disease. Second, there's the matter of what bacteria we host unconsciously due to the food that we eat and the impact on our health of the bacteria we will consciously choose to populate our bodies when we consume probiotics. So far the news on probiotics is quite promising but it must always be borne in mind that we are at the beginning of a great revolution whereby we come to understand ourselves as superorganisms and the complex interactions of genetics, epigenetics, diet, social networks and environment (and all that entails, known, unknown and unknown unknowns) that make us what we are. As with most revolutions, because of the uncertainty they bring, it's best to expect the unexpected.

PM2.5: Diabetes, Heart Attack, Lung Cancer, Premature Death, etc

Etc indeed. The list of maladies laid at the feet of inhaled particulate matter smaller than 2.5 micrometers (thus PM2.5) is long and growing. You can add diabetes to the list thanks to "Association Between Fine Particulate Matter and Diabetes Prevalence in the United States" and lung function deficits in early childhood too ("Effect of Prenatal Exposure to Fine Particulate Matter on Ventilatory Lung Function of Preschool Children of Non-Smoking Mothers").

Is it a certain type of ultrafine particle that's responsible? Some studies say yes and others say no. In vitro toxicity testing tends to suggest that altered function is due simply to particle size while epidemiology studies tend to cast blame on one sort of particle rather than another though the findings vary from study to study and often conflict (a common problem when looking for weak effect associations). Do the observed effects meet the so-called specificity criterion for causal inference? At first the reported ill effects of exposure were said to be cardiovascular but now everything's in play especially since several studies have linked PM2.5 and Premature Death - All Causes.

So, is PM2.5 a universal toxicant and among the leading causes of death? Or could it be that people who live in urban areas with higher PM2.5 levels tend to have higher rates of unhealthy living? Is there anything good to be said about PM2.5? For example, why do farmers, who are often exposed to high levels of PM2.5, especially from endotoxins (think bits of bacteria), often have lifelong protection from many allergies that afflict those exposed to lower doses?

There's also the question of what's to be done about PM2.5. Farmers produce lots of it what with their gravel roads, grain bins, diesel tractors and plowed fields. EPA intends to regulate PM2.5 down on the farm and much more strictly than in the past but at what cost? And for those who don't like cost-benefit analyses what if the changes needed to reduce farm PM2.5 simply causes generation of ultrafine dust to be shifted elsewhere; and to increased markedly? See "The Environmental Cost of Reducing Agricultural Fine Particulate Matter Emissions".

Finally, of course, there's the issue of whom shall be sued. The finding that a speck of cotton dust from your shirt is as toxic (or as non-toxic, depending on how things shake out) as soot from combusted diesel fuel is an obvious impediment to to the diesel litigation plus there's a new study of truck drivers demonstrating that their presumed PM2.5 mortality may not be due to their work but rather can be, at least in part, explained by ultrafine dust exposures in and around the home: "Long-Term Ambient Multi-Pollutant Exposures and Mortality". Efforts to target other deep pockets will have to wait until science produces more definitive answers about what's to blame and how it can be determined that the PM2.5 in question was the cause in fact of the plaintiff's demise - likely an impossible task since causation in such circumstances is almost certainly the result of a constellation of factors; a constellation to be explored by something called eco-epidemiology. More on that another day.

Twenty Suspected Carcinogens

The American Cancer Society is calling for new research to settle the issue of whether or not twenty different agents do indeed cause the types of cancer in which they've been implicated. The twenty are:

(1) Lead and lead compounds; (2) indium phosphide (used in many flat screen TVs); (3) cobalt with tungsten carbide; titanium dioxide; (4) welding fumes; (5) refractory ceramic fibers; (6) diesel exhaust; (7) carbon black; (8) styrene oxide and styrene; (9) propylene oxide; (10) formaldehyde (does it cause leukemia?); (11) acetaldehyde; (12) formaldehyde; (13) methylene chloride; (14) trichloroethylene; (15) tetrachloroethylene; (16) chloroform; (17) PCBs; (18) DEHP (a phthalate); (19) atrazine (a herbicide and the subject of a coordinated attack by various activists groups resulting in a new EPA review); and, (20) shift work (the presumed exposure being "light at night" leading to a disruption of circadian rhythms and the most commonly associated malignancy being breast cancer).

You can find the press release here: Report Outlines Knowledge Gaps for 20 Suspected Carcinogens; and you can find the IARC report summarizing past rationale for assigning these suspected carcinogens to groups 2A - 3, the new evidence forming the basis for the recommendation that the status be updated and the sorts of epidemiological and mechanistic studies necessary to answer the question of whether they ought to be added to the list of 107 Group 1 agents known to be carcinogenic to humans, here: Identification of Research Needs to Resolve the Carcinogenicity of High-Priority IARC Carcinogens.

Mighty Microbe

Sometimes The New York Times just publishes the press releases of zillionaire trial lawyers and fellow traveler advocacy groups in its Science and Health sections. Most of the time though, when power and money aren't apparently in play anyway, The Gray Lady does the best job in the business of reporting on scientific advances.

One advance that we've been covering for the last year is the staggering realization that most of the cells in "our" body aren't ours; that much of the heavy lifting that keeps us healthy is done by the aliens inside of us; and, that genetic determinism is a fairy tale.

Read "How Microbes Defend and Define Us" for an excellent introduction to the topic of the Mighty Microbe that saves the day.

Let's Hope Not

"'What we have heard back from drug companies is that, if it has the word 'PPAR' in it, it's dead,” says Bruce Spiegelman, a cell biologist at the Dana-Farber Cancer Institute." That's from "Diabetes Drug Woes Spell Trouble for the Entire Drug Family." The most famous PPAR-gamma drug out there is, of course, Avandia.

Why hope PPAR-gamma drugs aren't dead? Well, read "in Vitro and In Vivo Therapeutic Efficacy of the PPAR-gamma Agonist Troglitazone in Combination With Cisplatin Against Malignant Pleural Mesothelioma Cell Growth". The PPAR-gamma agonist not only inhibited malignant pleural mesothelioma cell growth it also lengthened survival.

Trichloroethylene Stars in That 70s Show

Remember the Ames test ? Test a substance and if it causes mutations then it ought to be a carcinogen, right? After all, isn't cancer the result of a mutation that causes a cell and its descendants to grow out of control? That was the thinking anyway. Unfortunately (or fortunately) lots of things that cause mutations don't cause cancer and as a result the Ames test sparked more than a few bogus health scares and plenty of baseless tort cases.

Now, in a flashback to the days of starting with an unproven premise about the origin of cancer and stacking inference upon inference upon inference until mass litigation over an industrial chemical emerges and metastasizes, molecular epidemiology gives us an association between trichloroethylene (TCE) and non-Hodgkin lymphoma (NHL). See: "Occupational Exposure to Trichloroethylene is Associated with a Decline in Lymphocyte Subsets and Soluble CD27 and CD30 Markers". 

So what of this association between TCE and NHL? Have workers with long occupational TCE exposures gotten NHL at a high rate? No. Has there been however a small but consistent increase in NHL among TCE workers? No. So the causal claim fails the two big prongs, strength and consistency of the association, of every causal inference test. End of story, right? Not anymore.

Cancer epidemiology had a great run. Uncovering the epidemics of cancer in chimney sweeps, smokers and many others were profoundly important discoveries. Yet a decade ago many were wondering if it was time to call it a day for epidemiology. The strong and consistent causes had already been rooted out while subtler causal associations like that of H. pylori and peptic ulcer disease were being missed and non-existent associations between electricity, peanut butter, etc and cancer were repeatedly being discovered one week only to be refuted the next.

But if the tools work why not apply them to the new and fertile ground of molecular biology? In other words, why not look for strong and consistent associations between molecules as a way to uncover the links in the causal chain from genotype to phenotype? It was a great idea but nature failed to cooperate.

First, the reductionist approach to genetics ran into trouble when it became clear that a gene doesn't do the equivalent of say executing schematics for an alternator but rather is part of a larger algorithm dedicated to finding a way to convert available mechanical energy into electrical energy. Second, it became apparent that within largely known biochemical pathways there were often so many other factors influencing outcomes that meaningful p-values might often end up having something like "x 10-6" appended to them - in other words you might want to consider rejecting the null hypothesis only if the odds of the results observed being due to chance alone fall below one in a million.

Sadly none of that will stop some from arguing that TCE causes NHL and citing the new paper referenced above. Read it through and here's what you'll learn: Eighty workers were exposed to TCE. None got sick. However, they had lowered levels of lymphocytes, some of which lymphocytes have something to do with some of the cells involved in the immune response. Meanwhile some other people with some unstated change in their immune response are sometimes at a somewhat increased risk for NHL. Therefore it's somewhat more biologically plausible that TCE is possibly a cause of NHL.

I kid you not. Nevertheless you can bet that this paper will be cited in courtrooms and the Federal Register for the proposition that TCE causes cancer just as the Ames test was cited for the proposition that coffee causes cancer.

Which Came First, the Mutation or the Cancer?

The current paradigm, some 40 or 50 years old now, would say it was the mutation. As the first plaintiff's expert witness I ever cross examined at the courthouse said of the chemical in question "it messes with your DNA and if your DNA is messed up anything, especially cancer, can happen". By the way, for the younger set, before Daubert and Robinson/Havner that's what all too often passed for "science" in the courtroom.

Yet in the new Million Women Study of breast cancer, mutations associated with higher risk and environmental insults associated with higher risk seem to have no relation with one another such that hormone replacement therapy doesn't increase the risk of breast cancer even in women with genes predisposing them to estrogen-receptor positive disease. How can that be?

Well, here's some food for thought. Where do we come from? Bacteria, way back when. How do bacteria talk to each other? Quorum sensing (by the way, don't you wish all your teachers had been like Bonnie Bassler?) So if our stem cells want to monitor how many undifferentiated cells they need to be making and if those cells want to monitor their path to differentiation might they not do it via the same signaling pathways that their ancestors employed? If that's the case then could it be that a disruption in signaling causes runaway production of immature cells (cancer) and that the mutations only occur later? There's more than a scintilla of evidence for it.

What recruits bone marrow cells to the gut where their signaling is disrupted? Is it significant that many of the benzene workers thought to have developed leukemia as a result of exposure lived not only in the same building but were roommates? Is the parallel between the fall in cancer mortality and the rise of antibiotic use suggestive? It's something to think about anyway.

Vitamin D Deficiency and Multiple Sclerosis (MS): Who Pays?

In "The Lancet: Neurology" you'll find "Vitamin D and Multiple Sclerosis"  as well as "Vitamin D: Hope on the Horizon for MS Prevention?" Could it be that  the old mocked wisdom of "a healthy dose of sunshine" wasn't so silly after all? Could it be that the health panic precipitated by activists who demanded everyone stay out of the sun actually caused horrific and needless suffering? Could be.

I just got back from a vacation in Destin, Florida. While there I learned that there are people who cover every exposed surface of their kids with zinc oxide before letting them out in the sun. These parents think they're doing the right thing. Their kids seemed about as happy as I'd have been sent out into the world in a powder blue leisure suit. But while powder blue leisure suits don't cause rickets and MS, vitamin D deficiency does. When disease strikes will there be a viable cause of action against the scaremongers who caused it? It's an interesting question.

Chronic Chlamydia Pneumoniae Infection and Lung Cancer

Smoking, asbestos, silica, hexavalent chromium, nickel and radon have all been blamed for cases of lung cancer. Now there's a new paper from the National Cancer Institute implicating C. pneumoniae: "Chlamydia pneumoniae Infection and Risk for Lung Cancer". Be sure to note the significance of the finding that it's the marker of chronic infection with which a significantly increased risk of lung cancer is associated.

Clostridium Difficile in the News

Can C. difficile be spread through the air? What does C. difficile have to do with COPD? How should physicians treat the new and especially virulent strain of C. difficile? At what temperature should you cook ground meat to kill C. difficile and its spores? Do alcohol-based gels kill it? Why do antacids administered in hospital increase the risk of infection? Are there new antibiotics that work against C. difficile?

Click on the links for a sense of current thinking on these issues.

How, and Why, Do Some Bacteria Facilitate Cancer Metastasis?

When you ask a physician or researcher how bacteria cause and/or promote cancer usually the only answer you get is "inflammation" and some hand waiving. It sort of makes sense. Lots of new and different stuff is going on, lots of new and different cells are running all around and lots of old cells are busily dividing and multiplying - surely a recipe for an accident.

But what if the bacteria are actively promoting the metastasis? That's the finding in "Bacteria Peptidoglycan Promoted Breast Cancer Cell Invasiveness and Adhesiveness by Targeting Toll-Like Receptor 2 in the Cancer Cells". Why, in the "what's in it for them" sense, would bacteria promote something that kills their host? Something to ponder over the weekend.

E. Coli O157:H7: Not the Only Bad Apple in the Family?

E. coli O157:H7 produces Shiga toxin, a cause of dysentery, and in some cases hemolytic uremic syndrome followed by kidney failure, particularly in the young. The government and industry have become increasingly vigilant in screening food for the bacterium. But what about all the kissing cousins of this promiscuous bug?

According to a new article in the NYTimes the recent outbreak of illness caused by lettuce wasn't due to E. coli O157 but rather by E. coli O145. In the article the owner of an organic food farm is quoted as saying that E. coli O145 and a handful of other non-E. coli O157 relations are being found more and more often in even organic food. Read all about it: "In E. Coli Fight, Some Strains Are Largely Ignored".

Life evolves to exploit underexploited energy dense environments. To microbes, we're still walking, talking energy dense environments. The long war continues.

How Do Statins Work?

Could the answer, at least in part, be inferred from the following?

Statins appear to reduce the risk of sepsis and nosocomial pneumonia ; Antimicrobial and Immunomodulatory Attributes of Statins ; Unexpected Antimicrobial Effect of Statins ; Fungal rDNA Signatures in Coronary Atherosclerotic Plaques

It's quite an eye-opener, to glance through all the articles being published demonstrating links between good health or disease and the vast previously unappreciated hordes of microbes that live in and on us. And it makes you wonder what the President's Panel on Cancer was thinking when it prepared its report since, to anyone caring to look, the evidence that our ancient nemeses are responsible not just for acute infections but for a large part of cardiac disease and cancer is overwhelming.

 

Nanoparticles to the Rescue

While some fret that man-made nanoparticles may bear unanticipated hazards that won't manifest for decades cancer researchers press forward with the development of revolutionary nano-scale drugs. What are they? How will they work? Will they be regulated as drugs, devices or biologics? An excellent (and free) discussion can be found at Nature Reviews: Clinical Oncology in "Conscripts of the Infinite Armada: Systemic Cancer Therapy Using Nanomaterials".

An Epidemic of Head and Neck Cancer

Cancer of the oropharynx in men is on the rise. Such cancers have traditionally been blamed on smoking and/or drinking so what accounts for its increase in a time of reduced rates of smoking and alcohol abuse? A virus; human papillomavirus (HPV). See "HPV-Associated Head and Neck Cancer: A Virus-Related Cancer Epidemic".

Remember, (1) the focus of this year's World Cancer Day was a call for greater awareness of the contribution of infectious disease to cancer; and, (2) the "age of receding panemics" never really passed - we just stopped looking for them.

 

But Sometimes Causation is Really, Really, Really Easy

As we wrote yesterday, causal attribution in most toxic tort cases is hard and the discovery that life and many of its diseases are emergent rather than predetermined phenomena has made the exercise even more complex. That said, sometimes causal attribution is easy - as in the cases of falling, being shot or developing mesothelioma after exposure to erionite.

50.5% of all deaths were due to mesothelioma in one village in Turkey and of women who moved from areas without erionite to this same village 69% of all deaths were due to mesothelioma. Read about it in: "Endemic Malignant Mesothelioma: Exposure to Erionite is More Important Than Genetic Factors".

Is there any carcinogen as potent as erionite? What do these numbers suggest about the mode of action of erionite? It sure looks as though the biological insult from erionite is more akin to that of some physical trauma than from some molecular biological disruption as in the case of a genetic mutation.

Humans: Modularly Programmed

Causation seems to just get harder and harder. A recent case in point being the finding that Chinese with myelodysplastic syndrome don't seem to suffer -5 and/or -7 chromosomal abnormalities even after extraordinarily high exposures to benzene. So much for that paradigm. What gives?

As we've written before the reductionist ideal seems clearly to have failed of its promise. But that's not to say that cancer causation is impossibly complex. Instead, more and more it's looking like our relentlessly efficient ancestors were keen on finding what works and refining it. And when they found something that worked, whether from yeast or plants or whatever, they shamelessly violated all patents and made it their own.

If you don't read anything else today read this in the NYTimes. It's big. It's a part of the beginning of a new paradigm; a new metaphor; it's part of the beginning of the idea that our physical systems are not all that different from those of modern computer code - bits of borrowed script, some improvised, some archaic and artifactual, but most of it off-the-shelf modules tried and true and ready to be plugged in and used as, for example, a do while loop.

Foodborne Illness is Trending Down

Shiga toxin-producing E. coli infections are trending down and so are hospitalization and mortality rates. The same is true for Campylobacter, Listeria and Salmonella since 1996.

That said, the rates for Vibrio are increasing and plateaus for Campylobacter, Listeria and Salmonella show worrying trends towards leveling and rebuilding. Of course, if you've ever spent time looking at bacteria under a microscope you'll know that these bugs are like Rocky - sometimes they're down, but they're never out.

The long war continues. Read the latest dispatch from the CDC.

Bad News About Chemotherapy

You know all those immunohistochemical stains for different types of cancer; the ones that say what a patient has and what chemo works for her? Well, because we live in a time of discovery, and thus of great uncertainty, standards and scoring vary greatly from laboratory to laboratory. We know this from the leukemia, lung cancer and mesothelioma litigation. Now Gina Kolata has written about it in the breast cancer context in the NYTimes in: "Cancer Fight: Unclear Tests for New Drug"

Years from now, we hope, when it's all clear and obvious, historians will look back on this era and marvel at our tolerance for untested treatments, primitive diagnostics and a swing-for-the-fences approach to our health. For now though it's the best we can do.

Good News About Chemotherapy

Chemo's dirty secret is that many patients, oftentimes most, will be made wretchedly sick yet receive no benefit in the bargain - they won't even be playing the remission lottery. That's because cancer isn't one disease called "cancer". It's a highly individualized disease. Yet because until now no one could identify who would respond to what everybody with a given type of cancer got whatever worked best for the most people.

Now, efforts at M.D. Anderson Cancer Center to identify biomakers that refine the diagnosis of the disease well beyond say small cell lung cancer are starting to pay off and drugs that might never have been prescribed because they only helped a tiny subset of victims can now be targeted at only those people who have the sort of lung cancer susceptible to the drug. Read about it at Bloomberg.

And how individualized will cancer turn out to be? Very, if things continue to go as they've gone with Vectibix, a colon cancer drug.

So much for economies of scale.

"The Only True Wisdom Is In Knowing You Know Nothing" - Socrates

It has been just over a decade since the human genome was sequenced. Now that we know the "code of life" cures for all sorts of maladies like cancer, birth defects and even aging are just around the corner, right? A missing or mutated gene causes a problem so provide the protein it would have produced or suppress the errant one it does or even use a virus to replace the faulty or missing gene with a new one, right? Well, it might have worked out like that if what everybody knew about DNA and gene regulation was true. Instead the discoveries of the last ten years have exploded one dogma after another and left many scientists despairing that life may be impossibly, incomprehensibly complex.

One of the biggest "Huh?!" moments came with the announcement by the folks running the ENCODE project that all that non-coding DNA, the allegedly meaningless flotsam and jetsam of 3 billion years of evolution, was, in fact, coding little bits of RNA which turned out to play mysterious yet essential regulatory roles.

And one of the most depressing "Uh Oh" moments seemed to come collectively when one day everyone began to look at all the pretty graphical images of signaling pathways, which look like a snapshot of the grand finale of a Fourth of July fireworks display, and to realize that just as a Martian could study such pictures forever and still never understand why we were shooting off fireworks, likewise researchers could never comprehend what was going on in a living organism just by studying simple causal nexuses.

There is an excellent write-up of these issues at Nature in a special and free report called "The Human Genome at Ten". Read it.

Yet just because things have turned out to be vastly more complex than hoped for and expected that doesn't mean truth can't at least be more closely approximated. More and more it's beginning to look to me like modular computer programming is a better metaphor for these biological processes than the older purely reductionist one. If so then most of what's going on research-wise today is replacing "FOR N = 1 TO 100" with "FOR N = 1 TO 85" and then trying to figure out just where, and what, in the game just got a little bit more or less likely. Once the principle, the function, of a cluster of effects is understood perhaps maladies like cancer will at last begin to yield to the enormous amount of effort expended. If so then perhaps the following is the better quote about wisdom:

"Patience is the companion of wisdom" - Saint Augustine

Gut Instincts

Does diet soda cause Type II diabetes? There are a couple of studies that suggest as much and now a hypothesis, yet to be tested, about how un-sugar could trigger a response to chronically too much sugar has emerged.

In "Stomach's Sweet Tooth" published online at ScienceNews the author considers the evidence for the proposition that artificial sweeteners essentially cause confusion in the body's metabolic processes by sending one signal via the tongue and another via previously unknown taste receptors in the stomach and intestines. How the release of various hormones and enzymes in response to the stomach and intestines "tasting" sugar when none is present might lead to diabetes or metabolic syndrome is unknown but apparently a large amount of research into the question is underway.

The long under-appreciated gut is now thought to be the largest hormone-releasing organ and the body's "second brain" with more neurons than than the spinal cord. And there's a new word for the study of this system: Neurogastroenterology. Neurogastroenterology?! We certainly live in interesting times.

Occupational Exposure to Endotoxins: A Good Thing?

In the newest edition of the journal Cancer Causes and Control you'll find a paper titled "Endotoxin Exposure and Lung Cancer Risk: A Systematic Review and Meta-Analysis of the Published Literature on Agriculture and Cotton Textile Workers". The authors examined 28 studies of workers occupationally exposed to high levels of endotoxins and their risk of developing lung cancer. Previous studies had suggested acute and chronic lung conditions could be caused by endotoxins.

Interestingly, endotoxin exposure was consistently associated with a large and statistically significant decrease in lung cancer. Furthermore, the protective effect was strengthened as dose was increased.

Also this month, in Cancer Epidemiology, Biomarkers & Prevention, you'll find "Lower Risk of Lung Cancer After Multiple Pneumonia Diagnoses". It turns out that getting pneumonia three or more times is even better than high exposure to endotoxins if you want to avoid lung cancer.

What is it about these biological challenges to the lung that leads to significant anti-lung cancer protective effect? It's anyone's guess but perhaps keeping your immune system tuned up is part of the answer.

Why Do So Many Non-Smokers Get Lung Cancer?

Read: "A Susceptibility Locus on Chromosome 6q Greatly Increases Lung Cancer Risk Among Light and Never Smokers". If you've got the gene your risk of lung cancer goes up nearly 500% even if you never smoke (in fact smoking only weakly increases your risk if you've got the gene). Interestingly, if you don't have the gene and you smoke your risk goes through the roof.

Distinguishing Reactive Mesothelial Cells From Malignant Mesothelioma

Even though cells drawn from a pleural effusion stain positive for calretinin and negative for CEA that doesn't mean the person has mesothelioma. Those mesothelial cells may be non-malignant yet still react to immunohistochemical stains used to identify malignant mesothelioma.

Is there a way to distinguish between malignant and merely reactive cells? According to a new paper in Cancer Cytopathology, "The Use of Immunohistochemistry to Distinguish Reactive Mesothelial Cells From Malignant Mesothelioma in Cytologic Effusions", a positive epithelial membrane antigen (EMA) stain coupled with a negative desmin stain strongly points to mesothelioma while the opposite pattern strongly suggests reactive mesothelial cells and not mesothelioma.

Coronary Heart Disease: Neither Degenerative Nor Man-Made?

In "On to a Fifth Age? How About We Finish the Second?" we discussed a JAMA editorial wherein Dr. Michael Gaziano asserted we may be entering a fifth age of the so-called epidemiologic transition. These transitions are claimed to be changes in the primary causes of morbidity and mortality and Dr. Gaziano opined that we are moving into an era in which obesity and inactivity will drive preventable illness. We discussed the origin of the idea of epidemiologic transitions and questioned  whether we'd ever finished the second age which would have required the conquest of infectious diseases.

The so-called third age was supposed to be the "age of degenerative and man-made diseases" but it keeps turning out that many illnesses thought to be due to wear and tear, lifestyle or pollutants actually have an infectious disease process at their core. Now there's growing evidence that coronary heart diseases (CHD) may in many cases have more to do with a number of infections, including influenza, than with lifestyle or the environment.

Here's a link to a letter published in the Reflections section of The Lancet: Infectious Diseases that nicely summarizes the pre-1970 thinking that pointed to infections as the cause of CHD, the subsequent predominating narrative of chronic diseases not being caused by infections, and the new evidence that chronic diseases are in fact often caused by previously undetected infectious processes: "Inflammation as the Cause of Coronary Heart Disease". And here's a link to a written debate about "this nascent field associating chronic diseases with infections" from 2002 with the author of the recent Lancet paper cited above: "Debate on the Paper by Maria Ines Reinert Azambuja & Bruce B. Duncan".

Given the enormous renewed interest in infections as a possible cause of chronic illness and the ease with which scientists can now find traces of bacterial, fungal and viral DNA (or RNA) at the scene of the suspected microbial crime it's fair to assume that we'll be seeing many more such stories in the future.

Something to Think About When You're Thinking About Biomarkers

Mitochondrial DNA, or mtDNA, is increasingly assayed for early evidence of a disease which will eventually become manifest. Take a sample, amplify the DNA, examine it and look for change - makes sense, right? Your genes are the ones you're born with, right? And if they've changed that can't be good, right?

Well, it turns out that you, or your mitochondria at least, evolve or mutate within the course of your lifetime - and it's perfectly normal. We may have started out with Mom's mitochondria but it looks like by the time we're adults mitochondria in different parts of the body don't just express different genes, they have different genes. That's the conclusion of "Heteroplasmic Mitochondrial DNA Mutations in Normal and Tumour Cells" just published in Nature.

There's a great write-up of the findings at TheScientist.com and it makes two very important points for those of us dealing with litigation involving mtDNA biomarkers.

1) "we have to keep in mind [that] some of the changes we see may not really be [disease-related] mutations." - quote from author Nickolas Papadopoulos

2) "there's a big question mark about how early this increase in mtDNA variation appears in the blood. If it's only apparent once the cancer is well established then it isn't much use as a biomarker." - email from molecular biologist Ian Holt to The Scientist

These Genes Determine Your Health: And They're Not Yours

The genes belong to bacteria living in your gut. They, along with their fellow microbes in and on "your" body outnumber human cells 10 to 1. But their genes collectively outnumber yours 150 to 1. These findings are just part of what you'll find in "A Human Gut Microbial Gene Catalogue Established by Metagenomic Sequencing"  published in Nature and free online.

The authors conclude that  this catalogue of bacterial genes found in the human gut "will lead to a much more complete understanding of human biology than the one we presently have." I think it's fair to say that the realization that the microbes we host have so much control over our lives will lead to a revolution in how we think of ourselves and how we prevent, diagnose and treat conditions like obesity, diabetes and cancer.

A Promising Vaccine for Mesothelioma

You can read about a new vaccine based therapy for mesothelioma that is both safe and, in some at least, effective in "Consolidative Dendritic Cell-Based Immunotherapy Elicits Cytotoxicity Against Malignant Mesothelioma"

Toe Bone Connected to the Foot Bone ...

In May of 2006 PLOS One published an excellent paper summarizing the evidence that the reductionist approach embraced by medicine over the last century or so had done about as much as it could and was actually hindering further advances. You can find a free copy of that paper, "The Limits of Reductionism in Medicine: Could Systems Biology Offer An Alternative?" at PLOS One.

Modern medicine, the authors wrote, tends to assume (a) that each disease has a single cause; (b) that any deviation from homeostasis requires beating down levels of whatever is up and pumping up levels of whatever is down; (c) that a risk factor for disease in one person is a risk factor for disease in another person; and, (d) that in the case of multiple disease states they can each be treated separately rather than cumulatively. While this approach has been quite successful, particularly for certain diseases, the view of the body and its functions as a bunch of disconnected parts to be dealt with by hyperspecialized parts doctors is beginning to give way to a view that a deeper understanding of disease will occur only when when the complex systems governing the whole organism are understood.

Now there's another paper advancing this idea that afflictions of the body are more than just the sum of their signs and symptoms. In "Systems Biology as a Paradigm Shift in Clinical Research" available free at Oxford Journal of Nephrology Dialysis Transplantation. In particular the authors note the failed promise of biomarker identification to uncover either the causes of illness or effective treatments.

"Simply stated, molecules in a living cell are involved in networks of interactions that regulate the cell's basic functions ... [d]isruption of a partner in these interactions does not result in linear and definable effects but rather in global and often unpredicted perturbations of the whole network." The authors conclude with an overview of the systems biology approach and its promise particularly with regard to understanding and treating chronic diseases.

Maybe It's the Worm, Not the Apple, That Keeps the Doctor Away

At least that may be the case for parasitic worms, also known as helminths. In the review article "Parasitic Helminths: New Weapons against Immunological Disorders" its authors discuss the recent literature supporting the hygiene hypothesis - the idea that the modern hygienic lifestyles of children deprive them of the immune system priming necessary to provide protection later on against diseases like diabetes, allergies, arthritis, Crohn's disease and cancers like Hodgkin's. Later in the article they turn to the evidence showing that one especially unhygienic aspect of an infestation, the helminths laying eggs in your body, is especially good for you.

So what does this have to do with mass torts? Well, a number of ailments attributed to chemicals, diet or drugs may in fact have their roots in our having rather suddenly and dramatically distanced ourselves from the microbiological environment that shaped us over the eons. Thanks to the elucidation of the molecular pathways responsible it may now be possible to identify those plaintiffs whose unmatured immune systems are the real culprits.

Podoplanin With Calretinin Better Than CK5/6 and WT-1

In an article just published in Diagnostic Cytopathology, "Podoplanin is a Useful Marker for Identifying Mesothelioma in Malignant Effusions", the authors conclude that calretinin plus podoplanin (part of an immunohistochemical staining panel) would significantly improve the specificity of pleural effusion diagnostics in suspected cases of malignant pleural mesothelioma (MPM). In other words, the suggested technique would do a better job of differentiating MPM from adenocarcinomas of the ovary, lung and breast.

As more and more putative mesothelioma cases have been filed, particularly by women plaintiffs with de minimis or even nonexistant amphibole exposures, battles over diagnosis have become more common. On the other hand, plaintiffs' counsel are now seeking to tie adenocarcinoma of the ovary to asbestos exposure. Perhaps both then are just new new levels in the never ending Whac-A-Mole game that is asbestos litigation.

Rx: Sunbathe q.p.m for 15 Minutes

Reuters Health is reporting on a new study in the Journal of Investigative Dermatology in which British researchers publish the results of their study on Vitamin D deficiency and sunshine. The short version is: you were made to be exposed to sunlight, you can get sick without it but moderation, as in all things, is the key.

There's a lot more of interest in this study available free online at Nature.

World Cancer Day - Focus on the Link Between Infections and Cancer

Tomorrow, February 4, is World Cancer Day and the International Union Against Cancer (UICC) is calling for greater awareness of the contribution of infectious disease to cancer cases around the world. "Cancer can be prevented too" is the theme of the effort. According to the press release the campaign is backed by a new scientific report: Protection Against Cancer Causing Infections which focuses on the nine known infections that can lead to cancer.

There's already a highly effective vaccine against human papillomavirus that prevents cervical cancer, a dreadful disease that took the life of one of my law school classmates within a year of her graduation, though it's still not widely given for a variety of reasons associated with culture and values. There's also a vaccine to protect against hepatitis B virus which causes a staggering number of cases of liver cancer worldwide yet it too is grossly underutilized. For more on World Cancer Day 2010 try these links: UICC World Cancer Campaign, World Health Organization,  European Hospital and this book: Infections Causing Human Cancer 

Life Breaks Free

"If there is one thing the history of evolution has taught us it's that life will not be contained. Life breaks free, expands to new territory, and crashes through barriers, painfully, maybe even dangerously." -Dr. Ian Malcom, Jurassic Park

That's the quote that came to mind when I read the story about infectious cancer in Tasmanian devils from The New York Times. It's about a cell that became "malignant" and then set out on its own to be parasitic on others of the species. So far, only one similar case has been found - that of canine transmissible venereal tumor in dogs. But then, how long have researchers been looking for cells that left the multicellular super organism of which they were once a part to set up shop and find a new way of growing and propagating?

The dogmatic view that chronic diseases like cancer must be due to chemicals or behavior is now yielding to an older view that many of our woes are instead due to a nature red in tooth and claw.

 

 

Interesting News on Antidepressants

The LATimes is reporting on a new study finding that neuroticism and extraversion in patients suffering from major depressive disorder are respectively alleviated and enhanced in patients taking Paxil. As compared to those taking placebos, Paxil patients not only experienced longer lasting relief from depression they also saw significant positive personality changes becoming less neurotic and more outgoing. "That is a dramatic change," said Robert McCrae, a leading researcher on personality, now retired. "If you were these patients or someone in their family, you'd notice a difference."
 

Six Viruses Responsible for 10 - 15% of All Cancers Worldwide

Despite decades of emphasis on putative man-made carcinogens, and a corresponding tendency to dismiss nature's brutish side as a possible cause of cancer, the case for viruses in causing human cancers has only gotten stronger. In "Human tumor-associated viruses and new insights into the molecular mechanisms of cancer" the roll of Epstein-Barr virus (EBV), human papillomavirus (HPV), hepatitis B and C (HBV and HCV respectively), human T-cell lymphotropic virus (HTLV-1) and Kaposi's associated sarcoma virus (KSHV) in a significant percentage of human cancers is discussed along with insights into molecular biological mechanisms and some very interesting thoughts about how these insights might reveal other heretofore unsuspected viral-induced cancers, novel treatments and public health strategies to reduce cancer by preventing viral infections.

A Biomarker of Past Benzene Exposure?

In their paper "Benzene-induced mutational pattern in the tumour suppressor gene TP53 analysed by use of a functional assay, the functional analysis of separated alleles in yeast, in human lung cells" Billet et al hypothesize that benzene-induced leukemia is the result of one or more mutations in the tumor suppressor gene known as TP53. They then report on their efforts to identify mutations in TP53 caused by benzene or its metabolites. It turns out that of the mutations linked to benzene exposure it is those in which guanine is substituted for adenine (A>G) that produce a pattern similar to that seen in benzene-induced acute myelogenous leukemia.

The authors conclude by suggesting that such an A>G transition could be "a fingerprint of benzene" that might help identify cases of AML produced by very low levels of past benzene exposure.

Is Non-Small Cell Lung Cancer Caused by the Measles Virus?

Why is the rate of lung cancer among nonsmokers increasing? In this paper published in Experimental Lung Research the authors not only found measles virus antigens in 83% of non-small cell lung cancer cases, they found that infection with the virus resulted in an excess of a protein typically seen in excess among lung cancer patients.

A Biomarker for Past Crocidolite Exposure

It was only a matter of time before molecular biological methods allowing screening for past potentially toxic exposures were developed.  In "DNA Double Strand Breaks by Asbestos, Silica and Titanium dioxide: Possible Biomarker of Carcinogenic Potential?' the authors from NIOSH, Health Effects Laboratory Branch, report that crocidolite was much more likely to produce  DNA double strand breaks leading to a molecule that can be detected by fluorescent antibody.  What this will mean for mass torts is anyone's guess but its implications for cases involving medical monitoring claims or mesothelioma claims where the plaintiff has failed to identify any amphobile exposures are obvious.

Interestingly, while similar effects were seen for crystalline silica and titanium dioxide, they were significantly less pronounced than that induced by crocidolite.

Do Carbon Nanotubes Cause Fibrosis and/or Mesothelioma?

In this paper the authors, including Arnold Brody, report that carbon nanotubes are responsible for inflammation on the pleural surface of mice following a brief exposure.  A subsequent immune response lead to areas of pleural fibrosis.  Non-fiber shaped carbon nanoparticles failed to produce a similar outcome suggesting that the fibrous tube structure may be an important aspect of this phenomenon.  The authors suggest minimizing inhalation of nanotubes until longer term assessments are completed.

Deposing a Hematologist and Need to Understand "CD4"? There's an App for That!

This is cool: BioGene.

Hat tip: OpenHelix.

Long-Term Disappearance of Mesothelioma

A Japanese man who was diagnosed with advanced malignant pleural mesothelioma is disease-free more than two years after being treated with a mushroom extract containing agaricus blazei Murill Kyowa and a modified form of acupuncture. The authors, who note that the patient had undergone debulking and chemotherapy but thereafter, as is typically the case, fared poorly, conjecture that his remarkable recovery may be due to “some immunological reactions of the host to the tumor” induced by either or both of the alternative treatments. The free paper was published in the Journal of Medical Case Reports.

What Role Does Immunosuppresion Play in the Pathogenesis of Mesothelioma?

Although the precise mechansim for mesothioma is currently unknown, one study has postulated that immunosupression plays a role in the pathogenesis of this cancer. Mesothelioma in an HIV/AIDS patient without history of asbestos exposure: possible role for immunosuppression in mesothelioma: a case report, involved the study was of 41-year-old man who had asthma, HIV with progression to AIDS in the past 3 years, and a 20-pack year smoking history, was diagnosed with malignant mesothelioma.  This individual had no occupational history of asbestos exposure but did have a brief history of assisting in the demolition of a house over an 8-hour period a year before his diagnosis but it was unknown if he was exposed to asbestos during that work.

The authors of the study noted that the polyoma virus SV-40 has been implicated as a participant in some cases of mesothelioma. Studies have postulated that since the virus inactivates anti-tumor genes such as retinoblastoma, it promotes immunosuppression that may lead to enhanced susceptibility to mesothelioma. Similar to SV-40 virus, HIV is also an oncovirus and therefore capable of inducing cancer. Because HIV suppresses the immune system the authors think that HIV increases the susceptible to mesothelioma.

The authors also noted that transplant patients are immunosuppressed due to administration of drugs to prevent transplant organ rejection and elderly patients undergo physiologic immunosenescence which is characterized by reduced immune responses. Mesothelioma has been reported in transplant patients, without notable asbestos exposure, and mesotheliomas are classically reported in elderly patients.

The study notes that mesothelioma may be more prevalent in SV-40 virus-infected patients, HIV/AIDS patients, organ transplant patients, and elderly patients, than in the general population. The study concludes the development of mesothelioma in patients with HIV/AIDS, SV-40 infection, organ transplant, or advanced age suggests that chronic immunosuppression enhances susceptibility to mesothelioma.

Trichloroethylene: A Risk Factor for Cancer?

US EPA has been working on a risk assessment of trichloroethylene (TCE) for some time now. Here’s a link to the EPA Issue Papers through 2005. Now a comprehensive review of the issues has been published in Critical Reviews in Toxicology. The article is entitled “Trichloroethylene risk assessment: A review and commentary” and it provides an excellent overview of the developing molecular biological and molecular epidemiological approach to causal attribution and risk; one we’re sure to see increasingly in asbestos, benzene and other mass tort litigation.

Collateral Damage

There are some interesting articles in the scientific literature about a war of which you've likely never heard. It's the one going on inside your body. A war pitting microbe against microbe. A conflict in which chemical warfare, the secretion of toxins, may well result in collateral damage - with the collateral damagee being you and the damage being cancer. More about that in the coming days but for now, here's an article about colon cancer risk and some of the bacteria working night and day to keep you from developing it. Here's the link.

SV40 Infection in Glioblastoma Multiforme

Immortalized cells in a patient suffering from glioblastoma multiforme showed signs of infection by the SV40 virus. link. Further evidence of an alternate cause, particularly among who received the polio vaccine when it was contaminated with SV40, in brain cancer cases.

For the latest on the SV40 / mesothelioma debate see this article noting that both asbestos and SV40 cause calretinin (you remember - calretinin- from all those mesothelioma immunohistochemistry path reports you're always reading) to rush to the defense of mesothelial cells eventually, perhaps, exhausting some ill defined mechanism and leading to mesothelioma.

Aneuploidy: Inducer of Tumors? Or Suppressor?

Lots of things cause aneuploidy but does that mean they cause cancer? Could it be that it's actually protective?

Nat Rev Mol Cell Biol. 2009 Jul;10(7):478-87. Boveri revisited: chromosomal instability, aneuploidy and tumorigenesis

Golden Delicious Apples and Cancer

Here's an another article for the health conscious suggesting that Golden Delicious apples contain a chemical that inhibits the growth of a bacterium called helicobacter pylori (h. pylori).  H. pylori is known to cause MALT lymphoma and stomach cancer and is increasingly suspected as a causative agent in a host of other cancers often the subject of mass tort litigation.

Though IARC declared h. pylori a Class I human carcinogen for gastric cancer in 1994, unflinching efforts to demonstrate links between h. pylori and neoplasms as diverse as colon cancer and lymphoma commenced only recently.  

In another post on this topic I’ll discuss the big drum that always gets beat in mass tort cases, epidemiology, and how it fared in elucidating the real cause of gastric cancer.  Teaser: When it came to finding the real cause, h. pylori, epidemiology produced an epic failure.

See "Carotenoids with Anti-Helicobacter Pylori Activity from Golden Delicious Apple"

"The Unrecognized Epidemic"

Chronic beryllium disease may result from very low levels of exposure to beryllium which occurred decades before any manifestation of the illness. The mechanism is thought to be a delayed immune response triggered by unknown environmental and genetic factors but at its heart due to sensitization to beryllium.

In this paper the authors present a history of the disease and current knowledge of its molecular biochemical mechanisms. They conclude that the current very low OSHA exposure limits still do not protect workers and suggest screening methodologies to identify those at risk.

Aggressive Prostate Cancer Caused by Gene Altering Virus

Bloomberg is reporting in "Prostate Cancer’s Worst Form Linked to Gene-Influencing Virus" that a virus linked to the most aggressive form of prostate cancer, the XMRV virus, may insert itself in a cell's genome setting up shop next to genes coding for cell growth and thereby leading to uncontrolled growth.


Daily the 20th century scientist's belief that nature is benign yields to the wisdom:

Tho' Nature, red in tooth and claw
With ravine, shriek'd against his creed
 

  - In Memoriam A.H.H. - Alfred, Lord Tennyson

HRT Litigation: An Alternate Cause or Perhaps an Explanation

In the hormone replacement therapy litigation there's obviously a fight over whether estrogen caused the plaintiff's breast cancer. Is the demarcation simply a line between those breast cancers fueled by estrogen and those that aren't? If so, are there alternate causes of estrogen-fueled breast cancers?

What about human papillomavirus? It's been identified as the cause of cervical as well as head and neck cancers. Now HPV has been suggested as a cause of breast cancer.  http://www.nature.com/bjc/journal/vaop/ncurrent/full/6605282a.html

But is HPV a cause independent of estrogen or does estrogen facilitate whatever HPV does that leads to breast cancer? And if it's the latter, how do you sort out causation?

Invasion of the Body Snatchers

The idea that fungi, bacteria, viruses, etc. invade much more complex organisms and force them to do their bidding is not new but the extent of the control they can exert is just now beginning to be revealed.

For a good discussion of one method by which an organism invades another to create something new see this article - though perhaps the title of it needs to be altered slightly to read "how endosymbosis is changing life on earth".

But for a really interesting read about one life form hijacking another see this story about zombie ants.  Hat tip www.MycoRant.com.

And what does this have to do with mass torts?  1) Again, there's increasing evidence of a paradigm shift in the thinking about causes of cancer and a number of infectious disease processes are being associated with cancers seen in toxic tort cases; and, 2) infectious disease, maybe including those that decades later result in cancer, may soon be among the most massive of mass torts.

Next week in Munich, Germany - The 2009 Benzene Symposium

Here's a link to the program and abstract book: http://www.tum-benzenesymposium.de/AbstractBook_FINAL_082509.pdf

Given the current state of benzene litigation among the most interesting presentations will be those pertaining to (1) latency (whether attributable cases drop dramatically after 10 years or so); (2) disease endpoints (just AML, just certain subtypes of AML, or NHL, MM and even ALL); (3) molecular biology/epidemiology (biomarkers and pathways) for assessing past exposures; and, (4) risk assessment.

Details to follow.

A Biomarker for 1,3 Butadiene in Brain Cancer?

Or would a better title be something like "Back to the Future"? When I got out of law school I worked on more PAHs, nitrosamine and butadiene cases than dust cases. Some early and fairly primitive epi studies had suggested causal associations with brain cancers in southeast Texas but the litigation never really went anywhere - or at least it didn't turn into the next asbestos. There were a few bladder cancer cases that got interesting but the literature on glioblastoma pretty uniformly concluded that it had no known etiology and the brain cancer cases died out.

See: Human exposure to selected animal neurocarcinogens: a biomarker-based assessment and implications for brain tumor epidemiology. You'll have to register (and pay) to get more than the abstract.

The Dose Doesn't Make the Poison?

From bisphenol-A to benzene some researchers are claiming that some toxic substances not only don't have a no observable effect level (NOEL) but also that the shape of the dose response curve for these substances at low levels is supralinear.  What that all means is that the bane of any toxic tort litigator, the linear dose response assumption implying that even one molecule poses some risk, understates the actual risk associated with very low levels of exposure.

In "Evidence That Humans Metabolize Benzene via Two Pathways" by Rappaport, et al. hypothesize that at low levels of benzene exposure (less than one ppm) humans metabolize  the aromatic molecule much more efficiently than at higher levels due to some as-yet unidentified metabolic pathway.  Consequently "true leukemia risks" from exposure to benzene at what are considered acceptable ambient levels may instead pose significantly greater risks than are currently contemplated by regulators, according to the authors.

Diagnosing Mesothelioma

Distinguishing a mesothelioma from a lung adenocarcinoma is critical in asbestos malignancies. Over time, diagnoses made on the basis of morphology and the presence of asbestos bodies gave way to immunohistochemistry. Immunohistochemical staining panels keep changing and debates often rage over whether say a positive calretinen, etc. and negative CEA, etc. is enough or whether they merely show for example an adenoma of mesothelial origin. Now there's a new paper out discussing the use of epigenetic (your genes aren't so deterministic after all) profiles. Its title is "Differentiation of lung adenocarcinoma, pleural mesothelioma, and nonmalignant pulmonary tissues using DNA methylation profiles" and you can buy a copy of it there.

Of course all these new methodologies raise the obvious question of "What happens when you try to draw causal inferences about a case diagnosed today from epidemiological research conducted at a time long before these diagnostic techniques existed?" Will these then be, at least with regard to the litigation, distinctions without a difference?

Cancer Causation: An Emerging Narrative

One contemporary narrative goes like this: most cancers are preventable because most cancers are the result of man’s disregard for “nature”; whether due to pollution or ad campaign-induced bad habits like eating too much. But what if it turns out that a group of microbes that set up shop in our bodies are the real cause of many if not most cancers? 

Lung cancer has been the injury at issue in a number of mass tort cases.  A host of recently published papers indicates that human papillomavirus may trail only cigarette smoking as the leading cause of lung cancer.  See "Incidence of Human Papilloma Virus in Lung Cancer" and "The Role of Human Papilloma Virus in Lung Cancer: A Review of the Evidence"

Human papillomavirus has been associated with lung cancer in numerous studies though there is considerable debate as to whether the correlation is coincidental or causative. The first article reviews the literature and argues for a causative role for HPV in lung cancer. The second article suggests a biologically plausible mechanism for the production of lung cancer by human papillomavirus.