Thursday, August 27, 2015

What Does Jimmy Carter Have Against Worms?

One of former President Jimmy Carter’s greatest achievements was made after he left politics. Carter declared war on an insidious infection that was ravaging millions of people, especially children, in underdeveloped nations:  the guinea worm.

A guinea worm is not the type of friendly worm you might imagine.
People become infected when they drink water contaminated with water fleas (copepods) carrying guinea worm larvae. These larvae are impervious to digestion, and the unfortunate victim will soon experience a living nightmare.

Once in your gut, the guinea worm larvae are released from the copepod. Then they turn down the lights, crank up the Marvin Gaye, and get it on in those romantic intestines of yours. A worm is born and, about a year later, it is fully grown and ready to have babies. This adult worm now needs to get out of your body.

Now, if you were an intestinal worm, you'd figure there's a natural opening nearby that provides an easy exit...but the guinea worm does things differently. Why? Because it hates us. Rather than being expelled with waste, the guinea worm travels to your foot or leg and decides to make its getaway much more dramatic by bursting through your skin. Surprise!

The good news is – as horrible as it sounds – a guinea worm infection is not lethal. The bad news is that you can’t just yank the thing out like a slippery spaghetti noodle. It must be painstakingly extracted bit by bit over a long period of time, being wound around a stick.
Removal of a guinea worm is excruciatingly painful and terribly slow. Some of the worms take weeks to extract and the patient often has to miss school and/or work.
As if that weren’t bad enough, the worm also causes a distressing burning sensation at the exit site. This makes the unfortunate victim want to soak the infected part of his/her body in the water. When the worm contacts the water, it releases its larvae, which go on to infect copepods to perpetuate the worm's life cycle. The problem is, in many developing countries, the drinking water often comes from the same source that serves as a bath, laundry, and toilet. This proved to be an extremely successful mode of transmission – over 3 million people a year were getting infected in the mid-1980s.
Guinea worms can grow up to 3 feet in length before emerging from their human host!
Since the guinea worm doesn’t affect developed countries, most researchers don’t bother studying it. And since the people who need treatment can’t afford medicine, no pharmaceutical company could justify investing in research to find drugs or vaccines to defeat this worm. But Carter and his colleagues figured that if they could stop transmission they could stop this worm.

With remarkable efficiency and just a few hundred million dollars (far less than the economic damage the worm causes), Carter’s organization was able to educate would-be victims about the worm and how it is spread. Through simple hygienic measures that many take for granted – filtering the drinking water, treating water with insecticides that kill copepods, reporting infections (and in some cases, giving money to snitches who rat the infected people out) – Carter and his organization achieved one of the greatest global health victories in our time.

Last week we heard the sad news that Jimmy Carter will be undergoing treatment for melanoma in his brain. At a press conference, Carter mentioned that his final wish was to have the last guinea worm die before he did. He may very well get his wish.

Thanks to the campaign that Carter led, the number of guinea worm infections has gone from over 3 million in the 1980s to only 17 cases in 2015 so far.
Well wishes to you, Mr. Carter. You’ve saved millions of lives.


Contributed by:  Bill Sullivan, Ph.D.
Follow Bill on Twitter.

Barry M (2007). The tail end of guinea worm - global eradication without a drug or a vaccine. The New England journal of medicine, 356 (25), 2561-4 PMID: 17582064

Thursday, August 20, 2015

Why Is Bingo His Name-O?

A new school year is upon us, no doubt prompting teachers across the country to teach and sing the old “Bingo Was His Name-O” song…whether they like it or not!

But why Bingo? Have you ever met a dog named Bingo? With so many other “fetching” names to choose from, you probably haven’t encountered too many dog owners calling out “Bingo!” at the dog park. Now consider the name “Antidisestablishmentarianism”. Have you ever met a dog named “Antidisestablishmentarianism”? Well, I used to own one!

My dog, Antidisestablishmentarianism. He was registered with the American Kennel Club under that name, though we usually called him just “Tarry”.
“Antidisestablishmentarianism” contains 28 letters and is one of the longest words in the English language. The first day of a high-school math class a few years ago, I explained to my students where the name came from; the reason has minor mathematical implications. Specifically, I was inspired to call him that by the children’s song, “Bingo”. The first verse goes like this:

There was a farmer had a dog and Bingo was his name-o.
B, I, N G O;
B, I, N G O;
B, I, N G O,
and Bingo was his name-o.

The second verse is the same except that each “B” in the 2nd through 4th lines is replaced by a hand clap. And in each of the four remaining verses, one more letter in those lines is replaced by a hand clap, so that by the last verse those lines consist entirely of claps.

Thus, “Bingo” has one verse per letter of the dog’s name, and the length of each verse is also a function of the number of letters in the name. But I’ve always been amused by thinking about a version in which the dog’s name was Antidisestablishmentarianism! (And when my family gave me the opportunity to name our new puppy that, some years ago, I didn’t say no .)

This suggests the question I asked my students: how much longer would it take to sing if the dog’s name was much longer than “Bingo”—say, the 28-letter word “Antidisestablishmentarianism”? Removing the reference to a farmer to make it easier to squeeze all the syllables in, it might start like this:

There was a dog and Antidisestablishmentarianism was his name.
A N T I D I S E S T A B L I S H M E N T A R I A N I S M;
A N T I D I S E S T A B L I S H M E N T A R I A N I S M;
A N T I D I S E S T A B L I S H M E N T A R I A N I S M;
Antidisestablishmentarianism was his name-o.
There was a dog and Antidisestablishmentarianism was his name.
[Clap] N T I D I S E S T A B L I S H M E N T A R I A N I S M;
[Clap] N T I D I S E S T A B L I S H M E N T A R I A N I S M;
[Clap] N T I D I S E S T A B L I S H M E N T A R I A N I S M;
Antidisestablishmentarianism was his name-o. 
There was a dog and Antidisestablishmentarianism was his name.
[Clap clap] T I D I S E S T A B L I S H M E N T A R I A N I S M;
[Clap clap] T I D I S E S T A B L I S H M E N T A R I A N I S M;
[Clap clap] T I D I S E S T A B L I S H M E N T A R I A N I S M;
Antidisestablishmentarianism was his name-o.
There was a dog and Antidisestablishmentarianism was his name.
[Clap clap clap] I D I S E S T A B L I S H M E N T A R I A N I S M;
[Clap clap clap] I D I S E S T A B L I S H M E N T A R I A N I S M;
[Clap clap clap] I D I S E S T A B L I S H M E N T A R I A N I S M;
Antidisestablishmentarianism was his name-o.

Good luck with the dozens of consecutive hand claps near the end…

Most of my students gave the obvious but incorrect answer, 28/5 times as long. The next most obvious answer, (28/5)2 is much closer but also wrong because it assumes both that the greater number of verses would increase the time by a factor of 28/5 (correct) and that the greater length of each verse would increase the time by a factor of 28/5 (not quite). Do you see why 28/5 per verse isn't quite correct?

The main reason is that --besides the letters in the dog's name-- there are also some words in each verse, and those change length by a different factor. Besides...Okay, I have to admit the problem isn't really well-defined (as mathematicians put it); let's stop here and give you time to do some singing and hand clapping!

Contributed by:  Don Byrd, Ph.D.
Don’s web page.
You can read more from Don at his blog.

Thursday, August 13, 2015

Allergy Medications Are Nothing to Sneeze At

If you were a kid or a parent in the last 4 decades, you may remember the likes of Mr. Tickle, Mr. Greedy, or Little Miss Bossy. These stumpy characters, created by Roger Hargreaves, were intended to teach children lessons by acting according to their namesakes throughout various challenging situations.

So when Mr. Sneeze, with the help of Little Miss Sunshine, discovered that he had allergies, it appeared that educating children about hay fever was the primary goal of this 2003 children’s book. But it didn’t stop there. British pharmaceutical company GlaxoSmithKline, who commissioned the book, took it one step too far and slipped in a couple pages promoting their allergy medications, Piriton and Piriteze.

In the story told by GSK, Mr. Sneeze may be better known as Mr. Sneak.
 Although never available in stores, the book was sold at GSK roadshows and to Tesco (similar to Costco) Clubcard holders and was available through Allergy UK, a charity that collaborated on the book. How it was approved in the first place remains a mystery, as it violated a law prohibiting the direct advertising of any drug to children. Not surprisingly, GSK came under fire as the British government initiated an investigation and GSK eventually withdrew the book. The story made a splash, with many scientific journals and leading news sources, including Nature, the British Medical Journal, BBC news, and the Guardian covering it.

The BMJ article commented that adding to the controversy, the drugs GSK promoted were no longer the first choice of pediatric antihistamines. As if the real travesty was marketing an outdated product to unsuspecting children and their parents. Nevertheless, the comment highlights a key point:  allergy medications have improved drastically over the years, primarily increasing in safety, efficacy, and ease of use.

The active ingredient in GSK’s Piriton is chlorphenamine, a first generation antihistamine (also found in Advil Allergy and Congestion, for example). Another first-generation antihistamine is the ever-popular diphenhydramine, known by most as Benadryl. These antihistamines are inverse agonists, meaning they work by keeping the H1 receptor in its inactivated form, precluding the binding of histamine. Although highly effective, first generation antihistamines are plagued with strong sedative effects. This happens because they cross the blood brain barrier (BBB), where they bind 50-90% of H1 receptors in the central nervous system (CNS) and cause drowsiness. Diphenydramine is such a strong sedative that it is FDA-approved for over-the-counter treatment of insomnia.

Although the drowsiness side effect is undesirable and may impair daily performance, first generation antihistamines are still widely used today, popular because they are fast-acting and relatively safe if used properly. Or, perhaps some people would rather just sleep through allergy season.
The other drug advertised by Mr. Sneeze was Piriteze, which contains cetirizine, a less-drowsy second-generation antihistamine. Second-generation antihistamines, including cetirizine (Zyrtec), fexofenadine (Allegra), and loratidine (Claritin) penetrate the CNS poorly because they are pumped out by P glycoproteins, gatekeepers of the BBB. This greatly reduces the number of CNS H1 receptors that are occupied, with fexofenadine and loratidine binding negligibly and cetirizine binding up to 30% of the receptors. So, cetirizine may still cause drowsiness at recommended doses, whereas fexofenadine and loratidine should not. Second-generation antihistamines are generally preferred over first-generation for their enhanced safety profile.

P-glycoprotein’s command only works on better-behaved second generation antihistamines; the gatekeeper blind to first-generation antihistamines, which pass through the blood brain barrier.
Antihistamines can also be administered intranasally (azelastine and olopatadine); these medications are as effective as or superior to the second-generation oral antihistamines. However, the most effective treatment for seasonal allergies is actually intranasal corticosteroids. Whereas antihistamines block the early phase allergic response, corticosteroids primarily act during the late phase. These work by inhibiting the recruitment of inflammatory cells, such as eosinophils and basophils, and blocking the secretion of pro-inflammatory mediators such as interleukins, causing a decrease in the levels of circulating leukotriene, histamine, and mast cells. The most potent and effective intranasal corticosteroids are mometasone furoate (Nasonex or Nasacort) and fluticasone propionate (Flonase). The furoate and propionate modifications on the drugs are thought to facilitate their absorption in the nasal mucosa and also reduce their systemic absorption, which means less chance of dangerous side effects.

Glucocorticoids are an anti-inflammatory subclass of corticosteroids that include the natural steroid cortisol. Cortisol, and its synthetic analogues, mometasone and fluticasone, work by activating the glucocorticoid receptor, which down-regulates the production of pro-inflammatory molecules. The furoate and propionate side chains are shown in red and blue, respectively.
Yet another treatment, allergen immunotherapy (allergy shots), may be appropriate for allergy patients who have detectable specific IgE antibodies to relevant trigger allergens. Specific immunotherapy (SIT) involves exposure to increasing doses of specific allergen(s). The dose-increase phase usually lasts 14-28 weeks during which desensitization occurs, meaning cells become less reactive or non-reactive to IgE-mediated immune responses. As discussed previously, Type I hypersensitivity reactions are mediated by T-helper 2 cells and allergy-prone infants have diminished T-helper 1 reactions. Perhaps not surprisingly, successful immunotherapy is associated with a shift towards a Th1-type reaction.

So, whereas antihistamines and glucocorticoids treat allergy symptoms, SIT can actually modify the disease and provide lasting protection against allergies. Furthermore, it has been shown to prevent subsequent sensitization to new allergens. In one study, 3 years of immunotherapy provided protection in some patients for up to 12 years and reduced the occurrence of additional allergies in almost half the patients.

Traditionally, SIT is administered subcutaneously (under the skin) by injection. However, last year three sublingual (under the tongue) allergen immunotherapy drugs were approved by the FDA in rapid succession. Oralair, which contains 5 grass pollen extracts (timothy, Kentucky blue, perennial rye, orchard and sweet vernal), became the first FDA-approved sublingual allergen extract. Eight days later, the FDA announced approval of Grastek, which contains only timothy grass extracts. Another 6 days later, Ragwitek was approved for the treatment of short ragweed pollen allergies. Whereas Oralair and Grastek are approved for pediatric use (10+ and 5+ years, respectively), Ragwitek is for adults (18+) only. All drugs showed moderate efficacy in clinical trials, with approximately 20-25% reduction in symptoms and need for symptom-management medication during one allergy season, compared to patients in the placebo group.

If needles aren’t your cup of tea, sublingual immunotherapy may provide a more palatable option.
Interestingly, the allergen extracts given by injection are not tested in clinical trials, but are FDA-approved based on purity, safety, and potency. Nonetheless, subcutaneous immunotherapy (SCIT) has been used safely and successfully worldwide for decades. And although it is new in the US, sublingual immunotherapy (SLIT) has been used successfully in Europe for years. From a cost perspective, immunotherapies compare favorably to pharmacotherapies (drugs like antihistamines and glucocorticoids).

Some people want a spoonful of sugar to help the medicine go down…or perhaps a spoonful of honey in place of medication entirely. Anecdotal evidence suggests that eating local, unfiltered raw honey can have similar effects to SIT by desensitizing the immune system. The idea is logical:  bees incorporate pollen into honey; therefore, eating local, unprocessed honey will expose you to the pollen prevalent in your area. Only a few studies have addressed the efficacy of honey for allergy treatments; one lasted only 10 days (no reduction in allergies observed) or used birch pollen-spiked honey for 5 months (effective at reducing allergies). Unfortunately, neither of these studies properly evaluated honey as an allergy treatment. The first had the right idea, but desensitization requires months (not days) to be effective, and while the second study demonstrates the feasibility of the idea, artificially-spiked honey does not address the real question.

Despite the shortcomings of these studies, the reason honey will never be recommended for allergy treatment is also logical:  the types of pollen bees primarily use are from fragrant flowers, not the wind-carried pollen from grasses like timothy and ragweed or trees like birch, which are responsible for the majority of allergies. Furthermore, the dose of any allergenic pollen in honey is very low and not controlled, making it virtually impossible to achieve desensitization analogous to that observed with SIT.

Searching for an allergy cure in a “hunny” jar will only get you sticky…you’d be better off sticking your head in it to reduce your exposure to wind-carried pollen.
While honey may help clear the bitter aftertaste from intranasal or sublingual medications, it will do little to alleviate your allergies. Better to stick to the tried-and-true methods for real allergy relief - while we may not yet know how best to prevent allergies, certainly many effective options exist to treat them.

Contributed by: Julia van Rensburg, PhD
Follow Julia on Twitter.

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Nasser S, Vestenbaek U, Beriot-Mathiot A, & Poulsen PB (2008). Cost-effectiveness of specific immunotherapy with Grazax in allergic rhinitis co-existing with asthma. Allergy, 63 (12), 1624-9 PMID: 19032235

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Derendorf H, & Meltzer EO (2008). Molecular and clinical pharmacology of intranasal corticosteroids: clinical and therapeutic implications. Allergy, 63 (10), 1292-300 PMID: 18782107

Sur DK, & Scandale S (2010). Treatment of allergic rhinitis. American family physician, 81 (12), 1440-6 PMID: 20540482