Thursday, May 24, 2012

Mycotoxicology smackdown: Death Cap Mushrooms vs. Milk Thistle


Images: Archenzo (L), and demott9 (R)

In the fall of 2011 four cases of death cap mushroom poisoning were successfully treated at Georgetown University Hospital (GUH) using a controversial remedy – an intravenously delivered chemical extracted from the milk thistle plant. Manufactured by the German pharmaceutical company Madaus (and sold under the somewhat ironic name Legalon), the drug has been available in Europe since the mid 1980s, but lacks FDA approval in the United States. Why are U.S. citizens being denied this wunder drug? Are we simply at the mercy of mushrooms? Can nothing be done?

As the Georgetown story unfolds, a few particularly striking points jump out. For one thing…

Poison control centers are very, very important.
When the first of the fungus-addled patients turned up at GUH – having eaten what he assumed were edible mushrooms picked from his yard – physicians quickly diagnosed him with amanitin poisoning. Amanitin, the principal toxin in the feared death cap mushroom, can be lethal. The ordeal begins with your standard food poisoning gastrointestinal woes, but can progress to organ failure, specifically in the liver and kidneys. In severe cases, organ transplants are required to save a patient’s life.

Having identified the problem, the medical team’s next move was to phone poison control. That’s right, the same people you would call if you found your child taking swigs from a bottle of laundry detergent. Poison control put the doctors in touch with Santa Cruz physician Dr. Todd Mitchell, who was conducting clinical trials of IV milk thistle (also called silibinin).

So if you’ve ever dismissed concerns about government funding cuts to poison control centers with a glib, “Ppfff, we don’t need those things, we’ve got emergency rooms” then you might want to rethink your stance. Poison control doesn’t just handle calls from panicked civilians, they also advise health care professionals tasked with treating panicked civilians.

But let’s get back to the story. Contacting Dr. Mitchell was far from the last step in the GUH patient’s road to recovery, because as it turns out…

Using non-approved drugs in the U.S. is NOT easy
The FDA allows experimental drugs to be tested if there is an established protocol and review board approval, such as in Dr. Mitchell’s clinical trial. This doesn’t mean that every other hospital out there can also start doling out these drugs. Luckily, the FDA does permit emergency one-time use of an Investigational New Drug (IND), which allowed the Georgetown team to procure and administer silibinin to their patient.

Mitchell himself went through the emergency IND process twice, first in 2007 and then again in 2009, to treat several mycotoxin-sickened patients (the first case was an entire family of six), before finally managing to set up his clinical trial, sponsored by Madaus.

It having been an unusually rainy season in the DC area, the Georgetown doctors got to work immediately writing up their protocol for any potential future poisonings. Still, an emergency meeting of the approval committee had to be called when a second patient materialized before everything was in place, soon to be followed by patients three and four. In the end, all four received the coveted silibinin and recovered without major complications (or liver transplants) and GUH is now an approved referral center for the drug.

So why isn’t every hospital in the country running silibinin trials? What are we waiting for? Well, mushroom poisoning isn’t especially common in U.S. While Europeans have a long tradition of strolling through the woods patrolling for tasty fungi, most Americans are content to buy their mushrooms at the store. According to the journal Nature Medicine, only about 50 cases of amanitin poisoning crop up in the U.S. annually, which isn’t enough to motivate hospitals to plan ahead on the off chance that one these unfortunate victims walks into their ER. But while we’re on the subject of clinical trials…

Does anyone know if this stuff actually works?
With all the hustling for silibinin going on, there must be some pretty strong evidence of its efficacy against amanitin poisoning, right? Well… not entirely. The anecdotal tales are certainly impressive. Patients on the brink of liver failure have reportedly perked up soon after the IV treatment began. But in the world of science, anecdotes aren’t worth much (unless they’re anecdotes about the insane lives of famous scientists, which, of course, are pure gold). The small number of people turning up with these maladies limits the scope of any trial, and denying available treatment to a control group is, well, kinda unethical.

Additionally, even in the absence of IV milk thistle, patients do receive some treatment for death cap poisoning – including intense hydration, penicillin, and activated charcoal (don’t worry, silibinin patients can get these too, it’s not an either/or deal.) and many of them survive. It’s thus difficult to determine what portion of any success story can be attributed solely to milk thistle. Silibinin supposedly works by blocking absorption of the poison by liver cells. It has also been tested against non-mushroom-related liver issues, but the data thus far are underwhelming.

Perhaps Mitchell’s trial will shed some light (it’s scheduled to wrap in late 2012), but in the meantime we can at least acknowledge that milk thistle doesn’t seem to be making anyone sicker (which is more than can be said for penicillin, which gives me hives and triggers anaphylactic shock in certain unluckier individuals.) And finally...

Are mushrooms a recipe for disaster?
Given that wild mushrooms are so potentially lethal, it seems reasonable to suggest that we leave their harvesting to the pros. But what fun would that be? My mother (who grew up in Russia, so it may be inaccurate to call her an amateur) has been picking and cooking mushrooms for decades with no reported fatalities. I’ve had them, and they’re thoroughly delicious. (Though I did spend a wee bit more time contemplating my mortality during that meal than I normally I do.)

Roughly 100 species of poisonous mushrooms reside in the U.S. (out of a total of 5,000 species), so if you’re going to try your hand at the art of mushroom hunting, please do some research first. And also note that taste and smell are not indicators of whether you’ve picked an edible mushroom or a toxic toadstool. In fact, the death cap is said to be rather tasty. As aptly summarized in this Croatian proverb, “All mushrooms are edible; but some only once.”

Friday, May 18, 2012

Sore muscles? Don’t blame lactic acid.


Image Credit: mrflip

With Tim Burton’s film adaptation of Dark Shadows* currently in theaters, it seems fitting to begin this post with a classic trope from vampire comedy, “I just flew in from Transylvania…and boy are my arms tired!” Get it? Arms? Oh, never mind. For me it’s presently more the legs anyway. And it’s not so much fatigue as an excruciating soreness and stiffness of the muscles. An unsolicited preview of old age. Superficially, my suffering was created by an activity called “yard work”, which I discovered only recently and which resulted in several hours crawling around on the ground obsessively uprooting every weed in the vicinity, all in a configuration to which my limbs were apparently unaccustomed.

But what is the actual physiological cause of such aches? If you’d asked me this question a week ago, I would have answered that lactic acid was the culprit, thus making myself look like an imbecile. In case you’re laboring under similar misconceptions, let’s remedy this before any of us has the opportunity to embarrass ourselves in public.

Somewhere along the line many of us learned that lactic acid builds up in the muscles during strenuous exercise and that this causes muscle aches. The basic idea is that lactate (the predecessor of lactic acid) is a byproduct of anaerobic respiration, which is the kind of cellular metabolism that occurs when you’re pushing yourself hard enough to run out of oxygen (on a cellular level, that is, if you’re actually hyperventilating that’s a separate issue). But while lactic acid may be to blame for immediate pain, the proverbial “burn” felt during an extreme workout, it’s long gone from your system by the time the real muscle soreness sets in. This second wave pain typically shows up the next day, reaching the apex of ouch somewhere between 24 and 72 hours after you overdid it at the gym.

The phenomenon is well documented enough to be christened with the badass acronym DOMS (Delayed Onset Muscle Soreness), and it doles out pain as efficiently as its leather-clad namesakes. Science is still working to get a handle on what exactly is transpiring on a molecular level, but the most popular explanation is that DOMS is caused by damage to muscle cells. Sort of like when you sprain your ankle, except instead of one big injury you’re incurring a slew of teeny tiny injuries. As with any other injury, this triggers an inflammatory response, in which your body sends various repair-performing metabolites to the site of the problem, creating a sea of swelling, stiffness and soreness in the process.

DOMS occurs when a person is using their muscles in a way that somehow deviates from the normal routine, either by engaging muscles that typically don’t see much action (as with painting a ceiling or moving a lot of unwieldy boxes) or by ramping up the intensity of one’s existing exercise regimen (i.e., being a competitive jackass in the weight room). But you probably already noticed this trend from personal experience. What you may not be aware of is that some types of muscle movements are more likely to cause DOMS than others. So-called “eccentric” muscle contractions make for the most aches. Eccentric contractions are those in which an elongated muscle braces against an opposing force. This is the converse of concentric contractions, in which shortening of muscles does the work. Imagine that the arm protruding from that building in the photograph suddenly came to life. If it continued curling that weight toward the roof, its biceps muscle would shorten (concentric contraction), but if it lowered the weight toward the sidewalk (in a controlled way, without dropping it on pedestrians), its biceps would elongate (eccentric contraction). Running downhill is a form of exercise notably rife with eccentric contractions.

The amount of lactic acid produced during the activity does not predict the severity of DOMS, so just because you aren’t in pain while in the midst of novel physical exertion, don’t assume that you won’t feel crappy the next day. The best way to avoid the late-blooming agony of DOMS is to make only incremental increases in muscle usage, allowing your body to acclimate to new demands before pushing onward. (Pretty useless advice if your main sources of soreness are all-or-nothing activity binges that you’re unlikely to repeat… weeding a lawn, for instance.)

In any event, lactic acid is the least of your problems. In fact, the human body can even use it as an energy source, at least according to this New York Times article, which explains how certain methods of exercise condition the body to use lactic acid more efficiently. Apparently, if you train like a professional athlete, you can grow massive mitochondria that suck up lactic acid like it's Gatorade, while other folks’ cells are just sitting there gasping for breath. You’ll be the envy of the marathon. Though you might still want to avoid running downhill.

* I haven’t seen it. I probably won’t see it. And I don’t need to know any additional details. Just let me have my fantasy that Tim Burton actually managed to successfully adapt one of my favorite TV shows.

A note on muscle motion: muscles only actively shorten, the lengthening is passive. When the biceps elongates, it’s due to the shortening of a complementary muscle (the triceps). So you always have both shortening and elongation happening simultaneously. But the important factor is which of the muscles is under tension. This may be one case where feeling beats thinking in terms of comprehension. Grab something heavy, then raise and lower it a few times and note which muscles feel most engaged. See what I mean?


Saturday, May 5, 2012

There's more than one way to make a blond


Image Credit: deanwissing.


Typically, if you want a look that combines dark skin with light hair there are two options. Depending on your starting point, you can either brighten your hair with chemicals like Beyonc√©, or darken your skin with UV radiation √† la New Jersey’s “tanning mom”. Yet on the South Pacific nation of the Solomon Islands, 5-10% of the population is just born that way. And now, a group of researchers believe they have traced the genetic cause of this unexpected blondness. And, well, big deal, because we’ve known for ages that hair color was genetically determined. Eye color too. It’s in our biology textbooks even. Nice going, science. But wait, it’s actually more interesting than you might think. It turns out that the Solomon Island blond results from a different, and simpler, genetic variation than the more familiar European brand of blond. This means that fair hair evolved separately at least two times in human history.

Prior to this recent study, which appeared in the latest issue of Science, the golden-haired inhabitants of the Pacific Islands had been the cause of much speculation. Perhaps their blondness resulted from some environment factor, such as diet or sun exposure. Or maybe fair hair was simply imported to the region by European visitors. To solve the mystery, scientists from several universities (including Stanford, located in blond-friendly California) scrutinized DNA samples from 43 blond and 42 dark haired Solomon Islanders. They found that the blonds did indeed have something different in their genes – a single nucleotide missense* mutation on an allele associated with pigmentation. Basically, there was a T (Thymine) where normally there would be C (Cytosine). Further genotyping of 918 Solomon Islanders and 941 individuals from elsewhere around the globe revealed that about 26% of the Solomon Islands population carried such an altered allele, but that it was essentially absent outside of the South Pacific, including European nations.

The findings suggest that South Pacific blondness is produced by a discrete recessive gene. It’s classic Mendelian genetics: individual carrying two mutated recessive alleles (TT) will be blond, whereas those with two standard issue alleles (CC) or a mixed set (CT) will be dark haired. European hair pigmentation, on the other hand, is determined by a bunch of different genes, yielding a variety of shades like platinum blond, golden blond and dirty blond. (Or “iced champagne”, “golden sunset” and the like, if you’re browsing the hair dye aisle.)

Globally, blond hair in adults is rare, and it tends to pair with fair skin. The Solomon Islands study indicates that human evolution has generated this hair pigmentation at least twice now, and seemingly under rather different environmental conditions. Whether the flaxen-haired phenotype confers any benefits on South Pacific individuals is unknown. It seems that light hair might help keep one’s head cool in hot, sunny regions. But then you also have to hear dumb blond jokes all day. Probably it just about evens out.

* DNA single nucleotide mutations (aka point mutations) come in a few flavors. Missense mutations result in a different amino acid being produced (think accidentally typing “tap” when you meant “cap”, it’s still a word), whereas nonsense mutations produce gibberish that shuts down the amino acid making process (more like “ctp” instead of “cap”, spell check does not approve). There’s also something called a silent mutation, which just results in the originally scheduled amino acid, but you don’t need to worry about those for today.