Sunburns, Sunscreens, and Skin Cancer

Summertime and the living's easy. Easy enough, for instance, to fall asleep in the sun and wake up medium rare. As our parents taught us, before hitting the water we should slap on the sunscreen, lest we become extra crispy, or worse, we get skin cancer.

We put on sunscreen to block out one particularly vicious element of sunlight: ultraviolet (UV) rays. These are waves of light that are a higher frequency than visible violet rays, and are known for their ability to damage the DNA of our cells, for instance creating a bond between two Thymidines in our DNA known as a Thymidine dimer or introducing free radicals that can then damage the cell. When too much damage is dealt to a cell's DNA, it triggers a type of abort sequence and that cell undergoes programmed cell death, or apoptosis. When UV light hits your skin, it can injure the cells that populate the epidermis, or outermost layer, of the skin: commonly, keratinocytes and melanocytes. By then undergoing cell death, the epidermis becomes inflammed and reddened in the phenomenon known as sunburn, or solar erythema. If too many cells die the epidermis may seperate from the dermis underneath it, resulting in the blistering so common to second degree burns.

Actually, in some ways the sunburn is a good sign: it means that the cells that have been damaged by the sun are dying. On the other hand, if damage is not "caught" and the skin cells don't die by apoptosis, certain DNA injuries may cause malignant changes. The most common skin cancers (95%) are basal cell and squamous cell carcinomas, which stem from keratinocytes. Melanocyte (pigment cell) cancers, or melanomas, only make up 5% of skin cancers but are responsible for 75% of the mortality associated with skin cancer. This can be a brutal illness, often metastasizing to the liver, lungs, bone, and brain. The interesting thing is that there appears to be an association between the type of UV light and the type of cancer. UVB light, which has long been associated with sunburns, creates Thymidine dimers, which are more easily seen by the cell and usually cause cell death, but may also cause cancer. This was the light normally blocked by most sunscreens. There is also UVA light, which is a longer wavelength and does not nomally cause burns. However, it may cause sub-lethal mutations in your skin cells, particularly melanocytes, which can mean cancerous change. So while your sunscreen blocks UVB, it may let UVA through with deleterious results.

The bottom line: have fun in the sun but be safe. Make sure you use a sunblock that works against both UVA and UVB light. And, as an article on sunscreen from The New York Times last week discusses, make sure that you use it correctly. A shotglass of sunscreen for the body and a teaspoon for the face, reapplying every few hours. Don't let a sunburn (or worse) get in the way of your summer fun.

Poison Ivy and Hypersensitivity Reactions

It is a common summer scene: you are on a camping trip, or looking for a lost ball in the woods, or finding some impromptu private thicket in order to take care of "business." Suddenly, a glance down and thoughts of concern course through your mind: was that...poison ivy?!? Did I step in it? Is that a rash? Do I feel itchy? I feel a little itchy, I must have touched it!

Poison Ivy enacts its damage by a chemical called urushiol, which is a catechol molecule that is part of the oily sap. This oil is in all parts of the plant: leaves, stems, roots, and berries. When human skin is exposed to the oil the catechols may combine with skin proteins and the response is the typical itching rash from a mechanism called a type IV hypersensitivity reaction. Understanding this is crucial to understanding what is, and what isn't, caused by a brush with poison ivy, oak, or sumac.

A type IV hypersensitivity reaction, also called a delayed type hypersensitivity reaction, is a type of allergic reaction that is mediated by the T cells of your immune system rather than antibodies, the mediator of other allergic reactions. This is important because an adverse response requires two encounters with the offending agent, be it a chronic bacteria (such as tuberculosis) or an environmental contact like poison ivy. During the first encounter, macrophages engulf the invading agent and present this to your T cells, which become sensitive to that specific antigen. When you are re-exposed, the T cells can interact directly with the antigen (the urushiol in this case) and elicit an aggressive immune response.

Basically, the first time you see the poison ivy you educate your T cells, which takes roughly three weeks. Then, the second time you are exposed, the memory T cells are ready in waiting and can immediately start responding. This isn't the fastest of allergic responses: since actual cells are responding, and not just an antibody, it takes time for them to divide and signal for others to go to the site of the lesion. The peak response will be 2 days following encounter with the antigen (the same reason a PPD test for TB takes 2 days to read); therefore if you are in the woods and suddenly get a poison ivy-like rash, you must have touched the plant 2 days prior.

Poison ivy will cause a rash, or contact dermatitis, that often starts as little red bumps and later blisters and may crust or ooze. Keep in mind that leakage of blisters does NOT spread the rash, only lingering oils on skin and clothing or tools. If you have been exposed the best treatment is to try and remove the oil within 10 minutes; rubbing alcohol can break it up and help in this process. The FDA recommends you first use rubbing alcohol, and then rinse generously with water; don't use soap yet because it may spread the oil. After this, take a shower with soap and water if possible. Of course, avoiding poison ivy in the first place is the best medicine: if you see "leaves of three, let it be."

Antibiotic Resistance

Botox and Botulism and Celebrity Crazes

As a medical student free time can be scarce. Except, of course, when you have access to celebrity gossip. One week a tummy-tuck, the next week rhinoplasty, all topped off with a face-lift, there are ample excuses to read about the stars as part of my "medical education." Of all these "enhancements," one of the most commonplace is the Botox injection; speculation about the use of which is constantly attributed to various celebs. There are also questions about the safety of the use of this treatment, which may be clearer after learning how it works.

Botox is a medical and cosmetic form of a toxin produced by Clostridium botulinum, a spore-forming bacteria. The Clostridia family of bacteria are gram positive and are obligate anaerobes; they cannot survive in the prescence of oxygen. They have worked around this weakness, however, and can coat themselves in a thick coat to make an environmentally resistant spore. When they find an anaerobic environment, such as the GI tract, the bacteria can uncoat and proliferate.

It is not this proliferation that you need to worry about, at least not directly. The bacteria enacts its damage by releasing an A-B toxin, a two subunit toxin where the B subunit binds a cell and the A subunit is the active agent. In this case, the B subunit binds motor neurons and the A subunit cleaves a protein involved in synaptic vesicle release. Basically, the neurotransmitter acetylcholine, which signals for your muscles to contract and is inside the vesicle, is no longer released and you succumb to flacid paralysis, in a disease process called botulism. This is why Botox is known to smooth wrinkles; it paralyzes that area of the face and so the skin becomes relaxed. It also becomes immobile, and you often see Botox parodied for making patients expressionless.

One of the things to keep in mind is that botulinum toxin is one of the most potent and deadly toxins known to man. Just one picogram (1x10^-12g) of this toxin per kilogram (roughly 2.2lbs) that you weigh is the lethal dose in humans. Incidence of botulinum poisoning is fairly rare; in adults, it is most often seen when someone eats home-canned foods, which provide that anaerobic environment needed for proliferation and toxin release. Interestingly, infants tend to be affected not by ingesting the toxin, but by getting infested with the bacteria in their guts. Infants lack the normal flora that would otherwise occlude the GI surfaces, and so C. botulinum can proliferate when eaten, commonly from honey (spores are in 10% of honey). Botulinum toxin can also be an agent of bioterrorism: since it is so potent, a small amount can be released and incapacitate thousands of people.

In spite of this, botulism is no longer always fatal; affected individuals can be placed on a ventilator and make it through the paralysis. Its diluted relative, Botox, is used both medically and cosmetically and can have a positive role in many treatment plans. Clearly there can be concern with using this extremely potent toxin, but with proper regulation it has a role, as seen in the New York Times article on the business of Botox from last week. While it may be all the rage among the stars, be sure to be safe about any treatment you may seek and consult your physician.

Avandia, Type II Diabetes, and Heart Attacks

I happened to be watching television earlier this afternoon when I noticed a trend in the commercials: at least two of the commercials during each of the breaks were asking for people who have recently experienced a cardiac event and who were taking Avandia for their type II diabetes. Now, these advertisements were to seek plaintiffs for a suit against the maker of Avandia, but they also highlight the process by which medications are scrutinized following distribution. For Avandia, a widely prescribed medication for type II diabetes, this scrutiny most recently comes from an article published in the New England Journal of Medicine on June 14, 2007.

Avandia, or by its generic name Rosiglitazone, is a member of the thiazolidinedione class of anti-diabetic drugs. It is indicated for type II diabetes, which is, basically, an acquired state of insulin insensitivity. A better description of insulin is given by my co-contributor below, but as a brief refresher this hormone regulates your blood glucose level. When you have eaten a high sugar meal, insulin is released from the pancreas and makes tissues, especially the liver and your muscles, take up glucose. This is important because a chronic high blood glucose level can cause the morbid complications of diabetes, including neuropathy, renal failure, eye damage, and damage to your circulatory system and heart, relevant to this study.

Key to understanding how thiazolinediones (TZDs) work is this idea of type II diabetes stemming from decreased tissue sensitivity to insulin. Essentially, the tissues no longer take in as much sugar from the blood when insulin is secreted. Thiazolinediones act by activating transcription of genes that would normally be activated by an insulin signal. Basically, this means that they amplify the signal to the DNA in the nucleus to make proteins, and these proteins do the actions that insulin tells the cell to do. They act on the peroxisome proliferator-activated receptor (PPAR gamma) signal pathway, which are nuclear receptors part of the insulin response that increase lipid synthesis and carbohydrate metabolism. Giving a TZD boosts a response to insulin by activating this additional route of gene transcription.

In the study published by Nissen and Wolski in the NEJM, they found that patients had a significant increase in deaths from heart attacks, or myocardial infarction, and a borderline significant increase in risk of death from other cardiovascular consequences. Already GlaxoSmithKline, the maker of Avandia, has responded to the article and cited several other studies, including the ADOPT, DREAM, and RECORD trials which followed Avandia users and all failed to find any increase in cardiac events. Moreover, the FDA issued a statement acknowledging both the previous studies and this new finding, and does not recommend drastic treatment changes or new warnings for Avandia use yet. Ironically, changing your diabetes medications can also increase your risk for cardiac events, and so discontinuing Avandia may be worse than a possible side effect.

Whether or not the drug carries an increased risk for cardiac events, the mechanism by which rosiglitazone affects the heart remains uncertain. The NEJM article highlights some of the possible ways this might occur. One is that the drug appears to be detrimental to the lipids in your serum, or blood. There is an increase in LDL cholesterol, the so-called "bad" cholesterol, by 18.6% over 26 weeks, which may contribute to a poor cardiovascular outcome, such as the increased death from heart attacks seen here. Another proposal is that Avandia, and other TZDs, have been shown to precipitate congestive heart failure, which would place greater stress on the heart wall and thereby increase oxygen demand. There is also data showing that TZDs reduce hemoglobin, the protein in your blood that holds oxygen, which could provoke the ischemia, or lack of blood supply, that causes the heart attack.

Whatever the mechanism, I think it is safe to say the jury is still out on Avandia's role in adverse cardiac events, and further investigation is certainly needed. Nonetheless, as the FDA recommends, concerns with medication should be directed to your physician, to ensure individualized treatment.

Lyme Disease

Summertime is upon us here in New England, and you know what that means. Trips to the beaches of Cape Cod or the islands, backyard barbeques with friends and neighbors, and, as some of us know far too well, a sharp increase in bug bites. Mosquitoes might be the more frequent agitators, but around these parts they pose a much smaller medical risk than the other major arthropod: the tick population.

Of import, Lyme disease is carried by ticks, as well as other illnesses, and is especially prevalent along the east coast between Maryland and Boston. It is an interesting disease, as its discovery was one of the great victories of epidemiology. In 1975, in the small town of Lyme, Connecticut, there was an outbreak of juvenile rheumatoid arthritis, a fairly rare disease. This prompted the CDC to do further investigation, and they discovered that the arthritis was a result of a tick-borne agent, Borrelia burgdorferi. Here in Rhode Island there are about 80 cases per 100,000 people, Connecticut is at 133, New York about 30, and the highest incidence was Columbia County, NY, with 1,583 cases per 100,000. And it is becoming more prevalent; Connecticut recently noted that cases are underreported, and even across the Atlantic in England concerns of Lyme disease are mounting.

Borrelia burgdorferi is an interesting type of bacteria. Instead of having the typical oval-rod shape that we think of with bacteria, borrelia is a spirochete, and it looks almost exactly like it sounds it might. It likens a corkscrew, and is so thin that it is very hard to see with most standard microscope techniques. The spirochete has two membranes, and between these inner and outer membrane is a series of 7 to 11 endoflagella, which are basically like little tails that make the spirochete undulate and move around, somewhat akin to a snake.

With Lyme disease, the spriochete is carried in Ixodes scapularis, the common deer tick. The deer tick has an interesting life cycle. It feeds three times in its life: first as a larvae, on a white footed mouse where it gains the spirochete; then as a nymph it bites and infects a human or dog; and finally as an adult it bites its namesake, the deer.

Disease commonly presents with three stages. First, you present with erythema migrans, a bulls eye rash around the initial bite that is caused by the spirochetes moving within the skin centrifugally around the wound. You may also have generic flu symptoms, which don't tell much about the disease, or neurologic symptoms from the migration of the spirochetes. This stage lasts a few weeks and 50% don't recall a tick bite. The infection then goes underground, only to resurface weeks to months later. Here you commonly get meningitis, and an interesting neurological symptom called Bell's Palsy, where the infection irritates the facial nerve and half of your face becomes paralyzed and "droops." Patients can have heart complications that vary in severity; rarely they may also see eye involvement. This stage will also subside, and in another 6 months to a year the end-stage complications of the infection will manifest. These include frank arthritis, which is thought to be an autoimmune disease initiated because the spirochete may mimic a cellular antigen. The majority of patients will also have neurologic involvement, with difficulty concentrating, symptoms that may appear like multiple sclerosis or a progressive encephalitis, and an incapacitating fatigue.

The good news is that we can treat the illness rather effectively if we catch it early. Some of the late effects cannot be reversed, and the arthritis often remains because it is an autoimmune reaction that persists after the spirochete is gone. Moreover, the tick needs to bite for more than 24 hours to transmit a high enough dose of spirochetes to infect. If you find a tick on you, pull it out slowly but firmly with some tweezers perpendicular to your skin. Of course, if you are going to be out in the woods, prevention is the best cure, and using DEET or tucking your pants into your socks can help avoid the deer ticks in the first place. Above all, have some fun this summer, and don't let a bug bite make you miss a barbeque!

Diabetes and Stem Cells