C-sections, allergies, and probiotics

Student guest post by Shylo Wardyn

I recently read the book ‘Good Germs, Bad Germs’ by Jessica Snyder Sachs. I became intrigued by parts of her book that discussed how babies become colonized with bacteria during birth. The most interesting part was the differences between vaginally-delivered and Caesarean-delivered babies. It was not something I had ever thought of before. With my interest piqued, I did a Google scholar search to see what kind of research was being done on this topic. I stumbled upon an article looking at C-sections and risk of childhood allergies, namely asthma. I realized this would be the perfect topic for this assignment!

A little background information:

Asthma is a chronic inflammatory disorder of the airways that affects both children and adults. It is not known why some people develop asthma and others don’t. Rates of asthma have more than doubled from 1980 to 2004 in children <18, but since 2001 have held steady. It is noteworthy to mention that the definition of asthma was altered in 2001, as well (Moorman, et al., 2007). A Caesarean section (C-section) is a surgical procedure in which an incision is made through the mother's abdomen and uterus to deliver one or more babies. While C-sections are traditionally done when a vaginal delivery poses risk to the mother or baby, women can also elect to have a C-section instead of a normal delivery. C-section delivery rates account for 31.8% of all births in the United States; 2007 marked the 11th consecutive year of increase and a record high for the US (Hamilton B.E., 2009). The neonatal period is critical for bacterial colonization of the intestines. Infants delivered vaginally acquire their intestinal flora from their mother's vaginal and fecal flora, generally species of Bacteroides, Lactobaccilus and Bifidobacteria. This intestinal flora colonization is delayed in Caesarean delivered infants; consequently, their gut flora is abnormal for weeks to months. One study found that in Caesarean delivered infants at the age of 6 months, the colonization rate of Bacteroides was half that of infants in the vaginally delivered group (Grölund, 1999). The research: Gut normal flora has a significant impact on the immune system; normal flora strains have been shown to induce the production of IL-10, which has an important regulatory role in the development of the allergic immune response (Kalliomaki & Isolauri, 2003). This is the biological hypothesis behind the proposed association between C-sections and asthma. This issue has been studied, but results are conflicting. I found two meta-analyses that looked at the research to date. Thavagnanam (S. Thavagnanam, 2007) found a 20% increase in the risk of asthma in children who had been delivered by Caesarean. While Bager et al. also found a moderate increase in the risk of asthma after Caesarean, they did not attribute this to the increasing rates of C-sections (Bager, Wohlfahrt, & Westergaard, 2008). They felt that for this to be the case, C-section deliveries should be associated with all allergic outcomes, not just some of them. I felt that they discredited their study by stating this; they still found a biologically plausible and significant association between C-section delivery and asthma. A more recent Norwegian population-based cohort study confirmed a moderate association between C-section and asthma (Tollanes, Moster, Daltveit, & Irgens, 2008). Probiotics and general remarks: While there clearly needs to be more research about the exact role of gut flora in the development of allergies, an interesting area of research is in probiotics. Probiotics are cultures of beneficial bacteria of the normal gut flora. Studies have shown that probiotics administered to pregnant women and their newborns lead to lower rates of development of allergic diseases (including asthma). However, these studies looked at high-risk children; those that had a first degree relative or parent with any allergic disease (Kalliomaki, et al., 2001; Kuitunen, et al., 2009). I couldn't find any randomized placebo-controlled trials with babies delivered by C-section as the group of interest. I think that would be a great study and would answer a lot of questions. While it seems this is still a new area of research, I think the studies speak for themselves. If this information was more widely disseminated, maybe some women would think twice before electing to have a C-section. Maybe in the future, parents will be advised to give their newborns that were delivered by C-section probiotics. Or maybe everyone will be prescribed probiotics after taking broad-spectrum antibiotics....but that is for another blog! Bager, P., Wohlfahrt, J., & Westergaard, T. (2008). Caesarean delivery and risk of atopy and allergic disease: meta-analyses. Clin Exp Allergy, 38(4), 634-642. Grölund, M.-M. L., Olli-Pekka; Eerola, Erkki; Kero, Pentti. (1999). Fecal Microflora in Healthy Infants Born by Different Methods of Delivery: Permanent Changes in Intestinal Flora After Cesarean Delivery. Journal of Pediatric Gastroenterology & Nutrition, 28(1), 19-25. Hamilton B.E., J. A. M., S.J. Ventura. (2009). Births: Preliminary Data for 2007. Kalliomaki, M., & Isolauri, E. (2003). Role of intestinal flora in the development of allergy. Curr Opin Allergy Clin Immunol, 3(1), 15-20. Kalliomaki, M., Salminen, S., Arvilommi, H., Kero, P., Koskinen, P., & Isolauri, E. (2001). Probiotics in primary prevention of atopic disease: a randomised placebo-controlled trial. Lancet, 357(9262), 1076-1079. Kuitunen, M., Kukkonen, K., Juntunen-Backman, K., Korpela, R., Poussa, T., Tuure, T., et al. (2009). Probiotics prevent IgE-associated allergy until age 5 years in cesarean-delivered children but not in the total cohort. J Allergy Clin Immunol, 123(2), 335-341. Moorman, J. E., Rudd, R. A., Johnson, C. A., King, M., Minor, P., Bailey, C., et al. (2007). National surveillance for asthma--United States, 1980-2004. MMWR Surveill Summ, 56(8), 1-54. S. Thavagnanam, J. F., A. Bromleyz, M. D. Shields and C. R. Cardwell. (2007). A meta-analysis of the association between Caesarean section and childhood asthma. Clinical and Experimental Allergy, 38, 629-633. Tollanes, M. C., Moster, D., Daltveit, A. K., & Irgens, L. M. (2008). Cesarean section and risk of severe childhood asthma: a population-based cohort study. J Pediatr, 153(1), 112-116.

The role of beta-HPVs in skin cancer development

Student guest post by Desiré Christensen

Human papillomaviruses (HPVs) are small DNA viruses that infect epithelial cells. There are well over 100 subtypes of HPV. The subtypes that infect cutaneous epithelia are termed beta-HPVs and those that infect the mucosal epithelia are termed alpha-HPVs. Some alpha-HPVs have received attention as strong risk factors for the development of cervical cancer. Less public awareness has been generated over the role of HPVs in the development of other cancers such as vulvar, vaginal, anal, head and neck, and penile cancers. Only recent research has focused on an association between HPV infection and skin cancer development.

Infection with beta-HPVs and development of skin cancer was first identified in patients with a rare inherited disorder called epidermodysplasia verruciformis (EV)(1). Roughly 50 percent of EV patients develop premalignant skin lesions and squamous cell carcinomas (SCCs) by the time they are 40 (2). Lesions and carcinomas mainly develop in sun-exposed regions, but HPV DNA has also been detected.3 Based on these findings, an interactive carcinogenesis between HPV and UV radiation has been suggested.

Immunocompromised patients are at increased risk of developing SCCs and other skin lesions, supporting the hypothesis that an infectious agent may play a role in skin cancer development. Organ-transplant recipients are at increased risk of developing warts and other skin lesions often followed by the development of SCC. The prevalence of beta-HPV DNA nears 100 percent in premalignant lesions and SCC in these immunocompromised individuals (4,5). In comparison, beta-HPVs have been detected in 30 to 60 percent of SCCs from immunocompetent patients (6).

A study by Karagas et al (7) aimed to describe the association between beta-HPVs and squamous cell carcinomas by testing for anti-HPV antibodies. Anti-HPV antibodies were found 60 percent more often in cases of squamous cell carcinomas compared to controls. A significant association between basal cell carcinoma and beta-HPVs was not observed. Beta-HPVs were associated with squamous cell carcinomas even after adjusting for smoking, drinking, medical and family history, and sun exposure (7).
Mechanisms for the role of HPVs in skin cancer are currently under investigation.

Recent research supports the biologic plausibility of a causal pathway from HPV infection to the development of skin cancer. The E6 and E7 proteins in high-risk types of HPV are known to modify and interact with cellular proteins leading to uncontrolled cell growth. In response to UV damage, the E6 protein from several beta-HPVs effectively inhibits cell apoptosis (8). The promoter of beta-HPV types 5 and 8 is also stimulated by UV exposure (9). Disruption of UV-induced thymine dimer repair has been demonstrated in cells expressing beta-HPV type 5 E6 protein, but has not been shown in cells expressing the E6 protein from other beta-HPVs (10).

The interaction between E6 and Bak, a proapoptotic effector, has been studied as a possible oncogenic pathway. Bak is degraded by the beta-HPV E6 protein resulting in protection from apoptosis in UV damaged cells. The degradation of Bak by beta-HPVs can occur without affecting regulators of Bak. The ability of the E6 protein to degrade Bak was not different between beta-HPV subtypes, suggesting other mechanisms should be studied to explain differential carcinogenesis (11).

More mechanistic studies are needed to determine the carcinogenic properties of beta-HPVs and their potential role in skin cancer development. More epidemiologic studies are needed to determine causality. Most studies have demonstrated an association between beta-HPVs and skin cancer through detection of HPV antibodies or DNA in cancer tissue and the sample sizes used have been small. The presence of HPVs in cancer tissue encourages further investigation but does not prove causation.
UV exposure is known to be a strong risk factor for the development of skin cancer, but recent research has indicated a potential role of HPV infection in skin cancer. It is possible that HPV interacts with UV exposure in oncogenic pathways. There is increasing evidence supporting the biologic plausibility of an interactive effect. Beta-HPVs are ubiquitous in the population and present in both normal and cancer tissues, making it difficult to conduct a prospective study. HPV detection methods have improved over time and should be combined with a strong epidemiologic study design to demonstrate causation (6).

References

1. Lutzner, M. A., C. Blanchet-Bardon, and G. Orth. (1984) Clinical observations, virologic studies, and treatment trials in patients with epidermodysplasia verruciformis, a disease induced by specific human papillomaviruses. J Invest Dermatol 83:18-25

2. Orth, G., S. Jablonska, M. Jarzabek-Chorzelska, S. Obalek, G. Rzesa, M. Favre, and O. Croissant. (1979) Characteristics of the lesions and risk of malignant conversion associated with the type of human papillomavirus involved in epidermodysplasia verruciformis. Cancer Res 39: 1074-82

3. Pfister, H. (1992) Human papillomaviruses and skin cancer. Semin Cancer Biol 3:263-71

4. Bouwes Bavinck JN, Plasmeijer EI, Feltkamp MC. (2008) Beta-papilloma- virus infection and skin cancer. J Invest Dermatol 128:1355-8

5. Pfister H. (2003) Human papillomavirus and skin cancer. J Natl Cancer Inst Monogr 31:52-6.

6. Asgari MM, Kiviat NB, Critchlow CW, Stern JE, Argenyi ZB, Raugi GJ et al. (2008) Detection of human papillomavirus DNA in cutaneous squamous cell carcinoma among immunocompetent individuals. J Invest Dermatol 128:1409-1417

7. Karagas MR, Nelson HH, Sehr P, Waterboer T, Stukel TA, Andrew A et al. (2006) Human Papillomavirus Infection and Incidence of Squamous Cell and Basal Cell Carcinomas of the Skin Journal of the National Cancer Institute 98:389-395

8. Jackson, S., and A. Storey. (2000) E6 proteins from diverse cutaneous HPV types inhibit apoptosis in response to UV damage. Oncogene 19:592-8

9. Akgul, B., W. Lemme, R. Garcia-Escudero, A. Storey, and H. J. Pfister. (2005) UV-B irradiation stimulates the promoter activity of the high- risk, cutaneous human papillomavirus 5 and 8 in primary keratinocytes. Arch Virol 150:145-51

10. Giampieri, S., and A. Storey. 2004. Repair of UV-induced thymine dimers is compromised in cells expressing the E6 protein from human papillomaviruses types 5 and 18. Br J Cancer 90:2203-9

11. Underbrink MP, Howie HL, Bedard KM, Koop JI, and Galloway DA. (2008) The E6 proteins from multiple beta HPV types degrade Bak and protect keratinocytes from apoptosis after UVB irratiation. J Virol 82:10408-17

Enteroviruses and Type I Diabetes Mellitus

Student guest post by Andrew Behan

Type I Diabetes Mellitus (T1DM) is a disease most affecting children (previously named juvenile-onset diabetes). However, adults can still develop this life-threatening illness. Research in the genetic arena has provided evidence this disease is partially due to inheritance, leaving a portion of causality yet to be determined. More specifically, a look at certain viruses which attack the beta cells of the pancreas, the cells responsible for producing insulin, have provided new information regarding etiology of T1DM. Some recent research aimed at enteroviruses as pathogens for triggering T1DM has sparked the interest of scientists and general public alike.

First, a quick overview of enteroviruses. Enteroviruses are second only to rhinovirus in terms of incidence worldwide (2). When a susceptible falls victim to an enterovirus, most will never know they contracted the virus. A minority will experience influenza-like illness (ILI), presenting with symptoms such as headache, malaise, stomach cramps, diarrhea, vomiting, or fever. A small percentage of that minority will have major complications, such as pericarditis or myocarditis, and possibly sudden death (1). Interestingly, the CDC reports enteroviruses are responsible for almost 50% of sudden deaths in the U.S. In regards to cost of healthcare and loss of productivity due to enteroviruses, the CDC states $132 billion dollars is spent yearly as a result of enteroviruses, with about $90 billion due to direct healthcare costs and the remaining $42 billion lost as a result of loss in productivity (2). With this point in mind, it is no wonder research has been targeted at this nasty group of viruses in hopes of finding vaccines to prevent premature death.

Enteroviruses have only recently been studied in relation to T1DM, due to improvements in diagnostics. The technology to detect enteroviruses enabled researchers in England to study its possible link to T1DM, especially in children. One such study, “Enteroviruses May Play Role in Type 1 Diabetes,” appeared in the March issue of the leading European Diabetes journal, Diabetologia. The team, funded by the Juvenile Diabetes Research Foundation (JDRF), studied the pancreases from 72 people under age 18 who died after recently being diagnosed with T1DM. The team found evidence of enterovirus infection in the beta cells of over 60% of pancreases (3). The collaborators also studied pancreases of 50 individuals without T1DM and found that hardly any of the beta cells had any signs of an enterovirus infection (3).
Keep in mind these findings do not suggest T1DM is caused by enterovirus infection alone. The study aforementioned merely points out children who already have genetic predisposition to T1DM when infected with enterovirus “may start the process where the immune system identifies beta cells as ‘foreign’ and rejects them” (3).

The study did have a second component, whereby researchers found infection of enteroviruses in over 40% of pancreases of adults, compared to 13% of the non-diabetics of the same age group (3). The evidence for linkage of enteroviruses to type 2 diabetes mellitus is not as strong, but a possible conclusion suggests infection of beta cells causes them to be less able to produce insulin. This factor, combined with obesity and, subsequently, a much larger demand for insulin, could contribute to progression of the disease.

These findings could cause one to think proactively; i.e. vaccination. However, there are over 100 different strains of enteroviruses (2), and researchers have not narrowed exactly which of the 100 strains are more likely associated with the development of diabetes, either type 1 or 2. The only strain named to date is the coxsackievirus B4 (4), but, like similar studies, did not find an absolute causal relationship between the infection and development of T1DM. Instead, the study did solidify the argument enterovirus infection does cause beta-cell lysis, molecular mimicry, ‘bystander activation’ and viral persistence (4).

Having not yet found the cause and, more importantly, the cure for this life-threatening chronic disease, JDRF and the rest of the scientific world remain hopeful future research into enteroviruses and their role in T1DM development may eventually provided definitive answers. When asked about the study, “Enteroviruses May Play Role in Type 1 Diabetes” Karen Addington, Chief Executive for JDRF, commented “JDRF passionately believes that research such as this brings us a step closer to improving treatment and eventually curing this condition” (3). Hopefully, research may continue to make large strides, as diabetes diagnosis continues to rise on a global scale at an alarming rate.

Works cited

(1) Maze, S. S.; R. J. Adolph (February 1990). “Myocarditis: unresolved issues in diagnosis and treatment”. Clinical Cardiology 13 (2): 69-79.

(2) CDC. Feb 2010.

(3) “Enteroviruses May Play Role in Type 1 Diabetes.” Feb 2010.

(4) Enterovirus and Type 1 Diabetes. “Role of Coxsackievirus B4 in the Pathogenesis of Type 1 Diabetes.” Retrieved from PubMed Feb 2010.

Reviewing the big P…Prions!

Student guest post by Rajeshwari Nair

Discussion on consumption of meat products is a common occurrence in my household. Hailing from India, I have always relished meat dishes that my mom cooks up, hot and spicy! However, there is always a nagging guilt on eating animals. People have tried convincing me that we are all part of the food-chain in this ecosystem, so either eat or be eaten. However, in recent times one thought crosses my mind when I stuff that yummy piece of meat in my salivating mouth, will this karma get to me soon? Will my brain dissolve as I chew on the brain of this mute four-legged creature? All this began not very long after my first lecture on ‘Prion diseases’. I sit in class thinking, ‘Hey we are built of protein matter, we eat forms of protein daily, we digest proteins daily and look at what a tiny solitary protein can do to us.’

Prions (pronounced pree-ons) are an acronym for proteinacious infectious particles. A normal prion protein, designated as PrPc is produced by every cell in a human body. This protein is encrypted by a highly conserved gene PrP in the human genome (chromosome 20) [5]. Okay all this sounds just fine, so what about this protein? Well believe it or not, it has a life of its own. Yes, superior to viruses and bacteria and it does not need a DNA or RNA to survive or infect other living forms.
Prion protein has a beautiful structure made of alpha helix sheets. This protein can be digested by enzymes generally used to breakdown proteins. However, something goes awry and this awe-inspiring protein changes to a structure with several beta sheets. What transpires here is really not well understood. However, there have been several hypotheses, what we know better as educated guess! The protein gets misfolded (PrPsc) and leads to further misfolding of normal PrPc. Thus there is a school of thought that the ‘first misfolded prion protein’ may be the infectious agent [1]. However, propagation process does not stop at this. These misfolded proteins form plaques and thus begins the destruction of a thinking organ, the brain. Hey, but why did the first prion protein misfold. It could be due to something you inherited from your parents, something you ate at your favorite food joint, a mutation or just like that…research is ongoing!

Abnormal prion proteins cause a spectrum of diseases known as transmissible spongiform encephalopathy or TSE. Prion diseases are progressive, neurodegenerative disorders that affect animals as well as humans. The disease spectrum includes gory sounding conditions in humans such as true Cruetzfeld-Jakob Disease (CJD), Kuru (spread by ritualistic cannibalism), Fatal Familial Insomnia, and Gerstmann-Sträussler-Scheinker syndrome [4]. Remember the ‘Mad Cow disease’ which caused chaos in England way back in 1986. Farmers back then fed their cattle soybean. However soybean did not grow well, so these farmers found an alternative. They fed their cattle animal byproducts, brain, blood, bones from other cattle and sheep. Hmm…I am thinking ‘animal cannibalism’. Anyways, these infected cows found their way to markets in England, either as fuel (food) or fertilizer (manure). People who came in contact with these infected animals soon took ill, and contracted what is known as Variant form of CJD (vCJD). At least 157 people were infected and killed till 2004. United States has not been oblivious to this disease. Holman et al., reported an analysis of death certificates of US residents which estimated 6,917 deaths with CJD, 1979-2006. Most of these deaths were among people 65 years and older and mostly whites. At least three patients have died of vCJD since 2004 [2]. Occurrence of prion diseases could be familial (inheritance of mutated prion genes), just out of the blue with no known cause (sporadic), ingestion of infected material, and even through transplant of infected organs such as the brain, ocular tissue or human pituitary growth hormone [4]. Signs and symptoms depend on part of the brain infected and age at infection. Disease symptoms can be easily mistaken for other neurological conditions such as Alzheimer’s, Parkinson’s or even just depression. Prions can turn our brain into a complete mush which may not be diagnosed until an autopsy is performed. Something to ponder about may be…increase in mental health conditions such as Alzheimer’s, dementia and others. Ever speculate there may be a prion disease since above mentioned conditions are often clinically diagnosed.

It is time to further investigate this situation and fill in existing gaps in knowledge. Various forms of therapy are under investigation with focus on preventing structural changes to the normal prion, thus preventing disease. Drugs which can cross the blood brain barrier are being considered to combat prions. Some antimalarial drugs such as Mepacrine, an anti-tumoral drug Iododoxorubicin and even Tetracycline are being considered potential for anti-prion therapy. Some of these drugs have been tested on animal models and cell cultures, and have shown robust effects. Even a vaccine was being tested by clinical trial as a method to slow disease progression [3].

Even though all these facts sound alarming, one may be lead to think why should we care. There are hardly any cases occurring, there are several other battle to be fought. This one can be laid to rest for now. On the contrary, in today’s world with new emerging and re-emerging diseases prions could be a significant assault on living forms. Also, globalization and environmental interactions could act as fuel to this fire. We hear of diseases being transmitted from animals to human (zoonotic) and the reverse. Is there a chance that prion diseases could add to this list?

References:

1. Gains MJ, LeBlanc AC. (2007). Canadian Association of Neurosciences Review: Prion protein and prion diseases: The good and the bad. The Canadian Journal of Neurological Sciences, 34: 126-145.

2. Holman RC, Belay ED, Christensen KY, Maddox RA, Minino AM, Folkema AM, et al. Human prion diseases in the United States. PLoS ONE. 5;1:e8521.

3. Caramelli M, Ru G, Acutis P, Forloni G. Prion Diseases Current understanding of epidemiology and pathogenesis and therapeutic advances. CNS Drugs. 20;1:15-28.
4. Pedersen NS, Smith E. Prion diseases: Epidemiology in man. Acta Pathologica, Microbiologica et Immunologica Scandinavica. 110:14-22.

5. Glatzel M, Stoeck K, Seeger H, Lührs T, Aguzzi A. Human prion diseases:molecular and clinical aspects. Archives of Neurology. 2005;62:545-52.

Getting the whole story- attempting to make sense of disease through evolutionary medicine

Student guest post by Anne Dressler

The idea of evolutionary medicine is new to me and my understanding is quite shallow but it has piqued my interest. Currently, the book “Why We Get Sick” by Randolph M. Nesse and George C. Williams has been satisfying my curiosity during the 15 minutes of intellectual thought I have left at the end of the day while reading before bed. From what I’ve read, I’m finding how useful it can be to consider disease in light of evolution and I’m left wondering how I haven’t heard of it before. I’m guessing I’m not the only one interested, so let’s talk evolutionary medicine, starting with some of the basics and finishing with why I find this particularly interesting for the nexus between infectious and chronic disease.

If basic biology and traditional medicine make up the plot of our disease “stories”, evolutionary medicine would be somewhat like the moral. My roommate is a medical student and when asked, she can tell you how just about anything in the human body works and what is happening when things go wrong. When asked why things go wrong, her answer will refer to a proximate cause, such as certain foods leading to plaque build up which can lead to heart disease. If the question of why is rephrased, as in why does the disease even exist at all, then she’s stumped. This is the question considered by evolutionary medicine. Why aren’t our bodies able to repair clogged arteries? Why are we prone to infections? Why are our bodies so good at some things but so inept at others? At first I found theses questions strange- after studying epidemiology’s risk factors for the past year, I had started viewing them as the sole reason for the existence of disease. And that kind of makes sense…if you completely ignore evolution. Enter famous and ubiquitous Dobzhansky quote:

“Nothing in biology makes sense except in the light of evolution.”
-Theodosius Dobzhansky

It is through the perspective of evolution that one can consider why a disease exists beyond the obvious.

In their book, Nesse and Williams propose six categories for evolutionary explanations of disease: infection, novel environments, genes, design compromises, evolutionary legacies, and defenses. The basis for all these explanations is evolution through natural selection thus I think it is wise to keep in mind some key points. First, natural selection occurs when survival and reproduction are affected by genetic variation among individuals. Genes are only passed on by the organisms that survive to reproduce. Note, surviving to reproduce doesn’t necessarily have anything to do with health or survival later in life nor does it necessarily mean good health before reproduction either.

“If tendencies to anxiety, heart failure, nearsightedness, gout, and cancer are somehow associated with increased reproductive success, they will be selected for and we will suffer even as we ‘succeed,’ in the purely evolutionary sense.”
-Randolph M. Nesse and George C. Williams, Why We Get Sick

Also, think Richard Dawkins and “selfish genes”- selection doesn’t consider populations, but rather benefits genes. With this in mind, let’s go over one of the proposed categories for explaining disease- infection (even if it is just skimming the surface).

Infectious agents have long been a cause of human disease. As we have evolved means to avoid infection, pathogens have evolved means to counter us leaving us prone to infection. Due to their relatively rapid reproduction, pathogens can evolve much more quickly than we can. One way we attempt to make up for this deficiency is by using antibiotics. Interestingly, by using antibiotics we are essentially taking advantage of the evolutionary advantages of another organisms. Toxins produced by fungi and bacteria are a result of millions of years of selection to combat pathogens and competitors. Dangerously, many believed that with antibiotics we would finally be in control of infections. Unfortunately, that was an underestimation of evolutionary forces and while almost all staphylococcal strains were susceptible to penicillin in 1941, today nearly all are resistant. This pattern is standard for most newly introduced antibiotics

The concept seems simple enough, but it’s not the only thing we’ve misunderstood about the evolution of pathogens. A common misperception is that a pathogen will evolve from being virulent to being more and more benign in order for the host to live long enough for the pathogen to pass on offspring to new hosts. This makes sense, yet doesn’t fully take into account the need to pass on offspring. Being able to disperse offspring to new hosts may mean it is most beneficial to the pathogen for the host to be sneezing, coughing, or laying prostrate. Another force behind pathogens evolving increased virulence is within-host selection. Simply, if there is more than one strain of a pathogen within a host, the one that uses the host’s resources most effectively will be the one to disperse the most offspring.

So if infections are one evolutionary explanation for disease, what’s an example? I recently came across an interesting article about infection and it’s relation to premenstrual syndrome. In the article Premenstrual Syndrome: an evolutionary perspective on its causes and treatment, Doyle et al. propose premenstrual syndrome is due to an exacerbation of a set of infectious diseases during cyclic changes of immunosuppression by estrogen and progesterone. While genetics and non-infectious environmental influences have been examined and found largely unable to explain PMS, infectious causes have been overlooked. However, it is know how immune function varies throughout the menstrual cycle in such a way that there could be less effective control of fungi, viruses, and intracellular bacteria, so making the leap to a persistent infection contributing to PMS doesn’t seem too difficult. Supporting this hypothesis is a long list of chronic diseases with suspected infectious causes that are exacerbated premenstrually including Crohn’s disease with Mycobacterium avium and juvenile onset OCD with Streptococcus pyogenes.

I think the most important point to take from this article is that there may be many other chronic diseases we don’t yet fully understand that are caused by infectious agents.

Yet even while the who, what, when, and where of some diseases may already be understood, the why of a disease is usually ignored. With an evolutionary perspective, we can try to answer the question of why diseases arise and persist under the forces of selection. These insights could help answer some old questions, such as those regarding unknown causes of chronic diseases, and ask some new ones, such as how could PMS be treated if it’s cause really is infectious. Finally, while guiding health care practices to improve health is the ultimate goal, at the very least evolutionary medicine reminds us to keep thinking about things in new ways.

Sources:

Doyle, C., H. A. Ewald, and P. W. Ewald. “Premenstrual Syndrome: An Evolutionary Perspective on its Causes and Treatment.” Perspectives in biology and medicine 50.2 (2007): 181-202.

Gammelgaard, A. “Evolutionary Biology and the Concept of Disease.” Medicine, health care, and philosophy 3.2 (2000): 109-16.

Nesse, Randolph M., and George C. Williams. Why we Get Sick. New York: Vintage Books, 1994.

Nesse, R. M. “How is Darwinian Medicine Useful?” The Western journal of medicine 174.5 (2001): 358-60.

Stearns, S. C., and D. Ebert. “Evolution in Health and Disease: Work in Progress.” The Quarterly review of biology 76.4 (2001): 417-32.

Williams, G. C., and R. M. Nesse. “The Dawn of Darwinian Medicine.” The Quarterly review of biology 66.1 (1991): 1-22.

A Rule Worth Keeping?

Student guest post by Jay Watson

We’ve all been there at some point before: a hot summer day, your delicious ice cream cone or tasty treat, and that uneven sidewalk. After taking about ten steps away from the vendor, you mistakenly put your foot into a gigantic fault in the sidewalk and accidentally toss your tasty treat face-down into the pavement. For many of us, “what now?” is actually a deliberation of a bunch of different, yet seemingly important questions: Who is watching me? How hungry am I? How much did it cost? Does this thing look dirty? Can I salvage most of it? But perhaps what unites us all more than any of these ponderings is the underlying question that our clumsiness has begged numerous times before: “Is this thing safe to eat?”

The answer to this question (much like our own consideration as to whether or not we actually pick up that double fudge delight now complete with grit and germ topping) is that ‘it depends.’ Though all of us are probably familiar with the 5-second rule from elementary school days, in actuality, only a few have tested its validity with science. The first person to inquire about the topic was a senior high school student who was working through an internship at the University of Illinois in 2003 [3]. In her experiment, Jillian Clarke dropped gummi bears and fudge-striped cookies onto tiles of E. coli (with pre-established organism counts) to see how many microbes would be transferred in 5 seconds or less. The results of her experiments showed that organisms can be transferred within 5 seconds [5]. In addition, she dispersed surveys and found that significant proportions of people (70% of women and 56% of men) she sampled were guilty of pick-it-up behavior [1]. In order to further test this myth, researchers at Clemson University (using Salmonella as their organism and bread and bologna as their test food) used similar methods to test surfaces including tile, wood flooring, and nylon carpet. Among their findings, they discovered that the survival times for some of the organisms on each of the surfaces were several hours, even days [5]. Like Clarke, they also noted that organisms are definitely transferred to food items within five seconds, with actual counts increasing with an increasing duration of time (for instance, there was a notable ten-fold increase in bacteria between five seconds and one minute) [4].

Granted, minimal research has been done in this area, but with consideration of the outcomes of these few inquiries, and perhaps with a little bit of common sense, we might best leave anything that lands on something other than our tongue for the birds or for the trash. However, I believe that there’s more to this matter than just how many germs or how fast they transfer. While many of us may have considered eating something off of the ground, it is less likely that we’ve considered eating it because it might be ‘dirty.’ Though it may sound like a ridiculous idea, perhaps there are more aspects to this issue than it would seem. While I’m certainly not promoting that we pick up garbage off the street and chow down, perhaps throwing out the 5-second rule wouldn’t be in our best interest.

Why? Maybe we need a little more dirt; a little less antibacterial hand cream. According to Wikipedia, the hygiene hypothesis states that “the lack of early childhood exposures to infectious agents, symbiotic microorganisms, and parasites has increased our susceptibility to allergic diseases by modulating immune system development” [2]. Simply put, our immune systems may have gone awry because we’ve eliminated many of the challenges for it. This has several implications today: are we ‘too’ clean? Have we developed environments that disrupt our child’s health? There are certainly others as well [6]. Many of these questions are definitely worth considering, but my point is that perhaps our immune systems need a little more in order to keep them in check. Now I would be the first to acknowledge that there are extenuating circumstances in all of this. After all, some floors (or any other germ-harboring surface for that matter) are dirtier than others; some materials are more absorbent and promote growth of organisms better, etc. Likewise, I’m not arguing that we should stop taking baths or eat our dinners off the floor. Common sense and a healthy lifestyle should by no means go by the wayside either. But next time, when you drop your lifesaver on the ground at work and run through that list of questions, you might consider whether or not “a little dirt don’t hurt.”

Works cited

[1] Clark, AS. 2006. Dry Floors Cleaner than Expected, but Existing Pathogens will Transfer. CBS News.

[2] Hygiene hypothesis. 2010. Wikipedia.

[3] Five-second rule. 2010. Wikipedia.

[4] Franko, M. Does the five second rule really work? 2010. HowStuffWorks, Inc.

[5] McGee, H. 2007. The Five-Second Rule Explored, or How Dirty is that Bologna? The New York Times.

[6] The Hygiene Hypothesis: Are Cleanlier lifestyles Causing More Allergies for Kids? 2007. Science Daily.

A Look into Obesity and Gut Microbiota

Student guest post by Liz Stepniak

In the United States, the obesity epidemic is rapidly spreading. Since 1980 the prevalence of obesity has increased over 75%. Currently, over half the population is overweight, and nearly 1 in every 3 adults is clinically obese. Research has also been proliferating, exploring a plethora of possibilities to better understand and treat this growing epidemic. One of the recent trends in obesity research has been investigating the role of the microbiota in the gut and differences in the composition of these bacteria between obese and non-obese individuals. Could this be a potential treatment for obesity? Like many things in research, not all studies come to the same conclusion that there is an important role of gut microbiota in obesity.

Obesity is a result of alterations in the body’s regulation of energy intake, expenditure, and storage. During a time when a large portion of the population worked in manual labor and it was necessary to conserve calories for long periods of time; this was an efficient mechanism. Currently, the majority of people do not have manual labor positions, so our energy expenditure is much lower but our bodies are still conserving those calories leading to an imbalance in regulating energy intake and expenditure and an overall increase in weight gain.

An important site to explore the regulation of energy intake and storage is the digestive system, specifically: the gut. The human gut has over 5,000 species of bacteria. There are three main phyla found in the gut: Firmicutes, Bacteriodetes, and Actinobacteria. One of the roles that bacteria plays in the gut is to help extract calories from what we eat, help store these calories for later use, and provide energy and nutrients for the production of new bacteria to continue this job. So, it is biologically plausible that if this was the primary job of one of these groups of bacteria or a certain bacteria phyla were more proficient in this job; that this could help explain a possible link to obesity.

The field of understanding metabolic balance and its role in obesity expanded with a December 2006 paper which discovered that an obesity-associated gut microbiome had an increased capacity for energy harvest. This study demonstrated overt differences between microbiomes of obese and non-obese mice and also indicated that this trait was transmissible among mice. Research has also shown that maintaining a proper ratio between Firmicutes and Bacteriodetes is necessary to maintain good health. Another study found that obese people have higher amounts of Firmicutes and lean people had higher amounts of Bacteriodetes. This study also found that the composition of bacteria shifted as the obese subjects lost weight. Enter: the probiotics push. An attempt to alter the composition of the microbiota in the gut.

This idea was spread further in April of 2008, when the Mayo Clinic published a paper which examined the role that bacteria play in the human gastrointestinal tract for regulating weight and obesity. Through experiments using mouse models, the investigators suggested that the manipulation of gut microbiota could be a useful strategy for regulating energy balance in obese people. They clearly state that this would not be a substitute for proper diet and exercise; this was to be approached as a novel tactic to treating obesity.

However, not all research has agreed upon a link between gut microbiota and obesity. A group of investigators at the University of Aberdeen Rowett contradicted this research and claimed there was no link between gut bacteria and a person’s BMI level. This was a small study, only 33 obese participants and 14 participants of average weight and they only changed the carbohydrate portion of the diet. They further comment on this finding to say that they’re not ruling out the possibility that a more detailed analysis of the gut bacterial community may reveal differences between obese and normal weight people in some different bacteria species that make up the Bacteroides and Firmicutes groups, which is directly linked to the diet. Essentially, the authors question whether there is an important difference linked to obesity in the composition of gut microbiota or if the composition is merely altered by diet.

Recently, I have seen several mentions of probiotics in the news, articles on maintaining proper digestive health, and frequent literature regarding gut microbiota and obesity. Although there have been multiple studies showing an association between gut microbiota and obesity, there is a significant amount of research needed to confidently classify the link between the role of gut bacteria and obesity. The big question remains whether this is just another short-lived trend in obesity treatment or if it has the ability to be sustained and make a positive impact in the obesity epidemic.

Maybe one day the answer to solving the obesity epidemic will be uncovered….

Until then… in the words of Michael Pollan: “Eat Food. Not Too Much. Mostly Plants.” And exercise!!

Works Cited:

CDC: Obesity and Overweight.

Mayo Clinic (2008). Could Changing The Bacteria In Your Digestive System Be An Obesity Treatment? ScienceDaily.

Duncan SH et al. (2008). Human colonic microbiota associated with diet, obesity and weight loss. International Journal of Obesity 32, 1720-1724

Turnbaugh PJ et al. An obesity-associated guy microbiome with increased capacity for energy harvest. Nature 444, 1027-1021.

Grimes M. Jan 26, 2010 NaturalNews.com: Bacteria in the Gut Shown to Reduce Obesity

DiBaise JK et al (2008). Gut microbiota and its possible relationship with obesity. Mayo Clin Proc 83: 460-469.

Cytomegalovirus and Heart Disease

Student guest post by Dayna Groskreutz

Heart disease is the leading cause of death in adults in the United States. Acute coronary syndrome (ACS) is a term which includes both heart attacks and unstable angina. ACS occurs, in part, due to atherosclerosis, or plaque accumulation leading to narrowing of the artery. Some known risk factors for atherosclerosis and ACS include smoking, family history, high blood pressure, and high cholesterol. Recently, the role of inflammation in the development of atherosclerosis and ACS has been an area of intense study. Proposed causes of inflammation include bacteria and viruses, including Cytomegalovirus (CMV).

CMV is a common virus, with most people being infected by age 40. For healthy individuals, infection symptoms are minor, but CMV poses a particular threat to immunosuppressed patients and to pregnant woman and their unborn babies. CMV has been associated with heart transplant rejection, but there are conflicting data as to whether CMV is an important pathogen in the development of atherosclerosis and ACS. Thus far, associations have been demonstrated but no clear causative role has been determined.

Basic research studies demonstrated that CMV infection puts individuals at risk for clot formation (1). CMV became a pathogen of interest to cardiologists in 1996 when Zhou et al. reported that a previous CMV infection increased the rate of recurrent clots after clot/plaque removal during a heart catheterization (2). A subsequent study by Neumann and colleagues investigated the effect of previous CMV infection on the risk of complications for 30 days following stent placement. A positive CMV IgG antibody titer (indicating a previous infection with CMV) was found in 62% of the 551 patients included in the study, and 10 of them experienced death (2), infarction (4), or urgent re-intervention (4). No patients with a negative CMV IgG titer had any of these events, even when the data was corrected for potential confounders. A follow-up study by Smieja et al. found a lower prevalence of 17.3% of circulating CMV DNA in the blood (indicating active infection) using polymerase chain reaction (PCR) technique (4). Further, the study demonstrated that the processes of angiography and angioplasty do not increase circulating CMV.

The idea that an infection plays a role in atherosclerosis is intriguing, but Liu and colleagues attempted to determine the role of CMV in the acute coronary syndrome (heart attacks and unstable angina) (5). Coronary plaque specimens from 38 patients who underwent a heart catheterization were divided into an ACS group (21) and a non-ACS group (17). Using special stains to detect CMV, the ACS group was found to have a higher number of CMV-infected cells. The authors concluded that CMV in the coronary plaque is involved with the development of blockages in the heart arteries.

Another study investigated the same association of CMV and ACS but with distinct advantages: they used the more sensitive technique of RT-PCR to detect CMV rather than the less sensitive staining method, and they included a control group (6). In this study, Gredmark et al. studied the prevalence of active CMV infection in 40 patients with ACS, 50 patients with stable angina and coronary artery disease previously proven by catheterization, and 50 healthy controls. White blood cells were obtained from the blood, and RT-PCR was performed to detect CMV. The prevalence of acute CMV infection was significantly higher in ACS patients (15%) and in patients with stable angina (10%) than in healthy controls (2%). Whether CMV is a cause of the ACS and atherosclerosis or whether their ACS and atherosclerosis put these patients at risk for CMV reactivation is uncertain.

Another study compared actual biopsy specimens for the presence of CMV infection (7). 33 patients undergoing heart bypass surgery and 10 control patients underwent biopsy of the aorta and internal mammary artery. Contrary to previous studies, CMV was not detected by real time PCR in either the internal mammary artery or aortic biopsies of both groups.

A later study examined aortic biopsy specimens from 40 patients with three-vessel coronary artery disease undergoing bypass surgery, and 20 control patients undergoing aortic valve replacement (8). CMV was detected by polymerase chain reaction and was found in 55% of the bypass group and 50% of the control group. The authors concluded that the similar frequency of CMV in both groups did not support a role of CMV in atherosclerosis. A potential confounding variable is that many patients requiring a valve replacement also have atherosclerosis, and this confounder may have blunted the differences between the coronary and control groups.

Finally, a study done last fall by Xanaki and colleagues again attempted to quantify CMV DNA in specimens from coronary plaques vs. normal vessels of 26 patients undergoing bypass surgery (9). CMV DNA was detected in 34.6% of patients (9 of 26), but there was no difference between the amount of viral DNA detected in the normal and the diseased vessels. The authors concluded there was no causative role of CMV in the development of atherosclerotic plaques.

There are conflicting data as to whether CMV is an important pathogen in the development of atherosclerosis and the acute coronary syndrome. Several questions remain. Does CMV cause heart disease, or does heart disease put patients at risk for reactivation of CMV? Are the local effects of the virus in the plaque important, or is the systemic response of the body to the infection playing a role? Thus far, associations have been demonstrated but no clear causative role has been determined. Further well-designed studies are needed to clarify the role of this ubiquitous virus in this common disease.

References

1. Vercellotti, G. M. (1998) Blood Coagul Fibrinolysis 9 Suppl 2, S3-6
2. Zhou, Y. F., Leon, M. B., Waclawiw, M. A., Popma, J. J., Yu, Z. X., Finkel, T., and Epstein, S. E. (1996) N Engl J Med 335, 624-630
3. Neumann, F. J., Kastrati, A., Miethke, T., Pogatsa-Murray, G., Seyfarth, M., and Schomig, A. (2000) Circulation 101, 11-13
4. Smieja, M., Chong, S., Natarajan, M., Petrich, A., Rainen, L., and Mahony, J. B. (2001) J Clin Microbiol 39, 596-600
5. Liu, R., Moroi, M., Yamamoto, M., Kubota, T., Ono, T., Funatsu, A., Komatsu, H., Tsuji, T., Hara, H., Nakamura, M., Hirai, H., and Yamaguchi, T. (2006) Int Heart J 47, 511-519
6. Gredmark, S., Jonasson, L., Van Gosliga, D., Ernerudh, J., and Soderberg-Naucler, C. (2007) Scand Cardiovasc J 41, 230-234
7. Iriz, E., Cirak, M. Y., Engin, E. D., Zor, M. H., Erer, D., Imren, Y., Turet, S., and Halit, V. (2007) Acta Cardiol 62, 593-598
8. Reszka, E., Jegier, B., Wasowicz, W., Lelonek, M., Banach, M., and Jaszewski, R. (2008) Cardiovasc Pathol 17, 297-302
9. Xenaki, E., Hassoulas, J., Apostolakis, S., Sourvinos, G., and Spandidos, D. A. (2009) Angiology 60, 504-508

Post Polio Syndrome Week – No Presidential Proclamation Required

Student guest post by Ron Bedford.

The first week of February 2010 must have been some sort of Post Polio Syndrome (PPS) week. The New York Times ran a story about PPS on February 2nd.
On the following Saturday, during the broadcast of the 2009 AKC/Eukanuba National Championship dog show, a Labrador Retriever named Benton was honored with an AKC Humane Fund Award for Canine Excellence (ACE) in the service category for his work as an assistance dog for his owner, Margo Dietrich, a polio survivor who “lives with physical limitations due to experiencing adult-onset Post Polio Syndrome”.

Since the mid 1950s polio has been characterized as a chronic disease caused by infection with poliovirus, which was all but eradicated from the developed world through mass immunization campaigns and routine vaccination of infants. During the 1980s and 1990s, clinicians and researchers identified PPS among polio survivors who, after 10 or more years of stability, had experienced significant deterioration of their neuromuscular functioning. The Polio Today website of the Salk Institute for Biological Studies describes PPS as “a serious neuromuscular condition … Characterized by extreme fatigue and further weakness or paralysis in the limbs.” Since the onset is typically gradual with symptoms similar to other neurodegenerative diseases, PPS is not easily diagnosed. It is not uncommon for PPS to arise in people that had such a mild case of polio that they were not even aware of the infection.

This is where things start to get interesting and frustrating. Since the last great polio pandemics occurred during the 1950s and 1960s, the numbers of polio survivors are diminishing. In a study prepared for the Board of Directors of Post-Polio Health International, Lawrence C. Becker estimates that there were approximately 426,000 polio survivors living in the U.S. in 2006, 53% of whom were over the age of 65.

The cost/benefit analyses may not work in favor of those afflicted to fund the research necessary to understand the disease mechanisms and find effective treatment modalities, but polio and PPS won’t disappear any time soon. Despite the efforts of the WHO to eradicate polio worldwide, the virus remains endemic in parts of sub-Saharan Africa and the Indian subcontinent. This WHO webpage lists the countries where cases of polio have been diagnosed recently and the accompanying map shows locations of outbreaks of wild poliovirus in the last 6 months. The WHO currently estimates that there are “10 to 20 million polio survivors worldwide … one of the largest groups with physical disabilities in the world.”

There are also reports of sporadic outbreaks elsewhere, such as among communities that discourage routine vaccination of infants and among people with compromised immune systems, such as the cases described in this 2009 blog by virology Professor, Vincent Racaniello.

Whether the virus is wild type or vaccine associated, the approximately one percent of individuals infected with polio who develop paralytic symptoms will continue to suffer with the chronic phase of the disease long after being “cured” of the infection. Since the mechanism of PPS occurrence is not well understood, it should be assumed that the syndrome will continue to manifest in 20-80% of polio survivors, the current range of prevalence estimates, though Polio Today puts the estimate at 40-50%.

Recent research projects report evidence of potential immune system involvement leading to nerve tissue damage due to inflammatory processes. The causes of the inflammation are as yet unknown, but Susan Perlman, M.D., Clinical Professor of Neurology at UCLA and Ask the Expert columnist on the Polio Today website reports encouraging results in clinical trials, European studies, and her own treatment of a handful of patients with intravenously administered immunoglobulin (IVIG) to “flush out bad antibodies attacking neuromuscular junctions.”

A study by Gonzalez et al. in the Journal of Proteomics reported identification of potential protein biomarkers for PPS which, according to the authors, would aid in the diagnosis of PPS, but would also also support hypotheses of possible immune mediated inflammation and nerve damage causing the observed neurodegeneration. The researchers examined cerebrospinal fluid of PPS patients, healthy controls, negative controls with other non-inflammatory diseases, and subjects with secondary progressive multiple sclerosis. The protein expression profiles clearly distinguished the PPS patients from other subjects in the study. The authors interpret their findings to support studies with IVIG such as those referred to by Dr. Perlman. One stated potential limitation of this study is that no polio survivors without PPS were included, so it is impossible to say whether the proteomic aberrations would be specific to PPS or would be expected to identify subjects with stable neuromuscular conditions after paralytic polio as well (Gonzalez et al., 2009).

Both of these areas of study identify potentially beneficial treatments for PPS. Both are also deserving of further research and funding to find and treat the causes of this debilitating late onset consequence of an infectious cause of a chronic disease.

References

Gonzalez, H., Ottervald, J., Nilsson, K. C., Sjogren, N., Miliotis, T., Von Bahr, H., et al. (2009). Identification of novel candidate protein biomarkers for the post-polio syndrome – implications for diagnosis, neurodegeneration and neuroinflammation. Journal of Proteomics, 71(6), 670-681.

What might have caused my cousin’s nasopharyngeal carcinoma

Student guest post by Anh To.

When I found out my only non-smoking cousin had nasopharyngeal carcinoma (NPC), I was puzzled. With all the hype about cigarette smoking associated with various kinds of cancers in the media, I did not understand why none of my smoking cousins had NPC but the one who didn’t smoke did. At first, I thought it must be due to the second hand smoke. Now, I understand that the picture is very complex.

Before I go into what I have learned over the past several months, I need to make a disclaimer. I am not an expert in NPC. I am an average college student. This is what I have learned.

Back to my story, the first thing I did when I heard the news was to do a search on what NPC is and what are some of the current risk factors associated with it. According to the American Cancer Society (ACS), NPC arises from epithelial cells of the nasopharynx. There are three types of NPC, keratinizing squamous, non-keratinizing and undifferentiated. Keratinizing is more common in the US, whereas undifferentiated is more common in Asia (1). My cousin is in SE Asia, it made sense that he had undifferentiated carcinoma.

Unsurprisingly, I found that NPC has both genetic and environmental contributing factors. In genetic factors, there are strong associations with a family history of NPC and being male (1); there are also some associations with certain Human Leukocyte Antigen (HLA) types and/or the CYP2E1 gene (1, 2). HLA is the name for major histocompatibility complex (MHC) in humans. MHC is part of the immune system. Thus, certain HLA makes people vulnerable to all kind of diseases, including NPC. CYP2E1 is a member of the cytochrome P450 superfamily of enzymes which metabolizes many substances (6). Homozygous for certain allelic version of CYP2E1 was associated with NPC in a case-control study (2). It is proposed that CYP2E1 metabolizes nitrosamine, which is converted from nitrites and secondary amines from proteins, into a carcinogenic form inside the body (5). In environmental factors, the strongest associations are Epstein-Barr Virus (EBV) infection and consumption of “salted fish”, which was a common dish in Southern China, where one of the highest incidences of NPC occurred.

My cousin is a man, and we have a family history of NPC. Genetically, he was out of luck. However, I have many male cousins, but not all of them got NPC, therefore environment must have a big role in the causation. My other reason for learning more about environmental contributing factors was that I want to know what I can do to reduce my risks. I can’t change my genes, but I can modify my environment.

The two commonly accepted environmental contributions of NPC are EBV infection and consumption of “salted fish”. First, let’s focus on EBV. EBV is a member of the herpes family, which means it has a lysogencic (resting) and a lytic (active) phase. EBV infection prevalence is very high all over the world. As an infectious disease agent, it is associated with mononucleosis (kissing disease). As a chronic disease agent, EBV has been associated with nasopharyngeal carcinoma, Burkitt’s lymphoma and is being investigated for association with multiple sclerosis.

According to the CDC website, as many as 95% of adult American (between the ages of 35-40) has EBV, I’m not that old yet, but the chance that I already have or will have EBV infection is really high. Since I can’t do much to change my risk of exposure to EBV, let see if I can reduce my consumption of “salted fish”.

I didn’t know what this “salted fish” is and what makes it a contributing factor for NPC. The first evidence I found that links it to NPC was two papers written by Xi Zheng et al. The first indicated that EBV is the most important factor for NPC with “salted fish” in second place (3). The second suggested that there is interaction between EBV and something in “salted fish” that induced tumor growth since higher proliferation in non-tumorigenic human keratinocyte line in vitro (culture cells) was observed in cells infected with EBV that is incubated with “salted fish” extract than without(4).
Later study indicated that the something in “salted fish” was nitrosamine, a known carcinogen in many animal models (2). This is where second-hand cigarette’s smoking came into play. While I didn’t find any study that stated that cigarette smoking is a significant contribution to NPC, there is nitrosamine in cigarettes. I believe that my cousin’s NPC was partially caused by his being around my smoking cousins. Of course, I have no epidemiology evidence for it. I also realize that this is just a tiny part of the whole picture.

So far, I have learned that HLA, CYP2E1, EBV, and nitrosamine, are some of the contributing factors, I still don’t know the rest of the contributing factors or how they all interact with each other. However, now I know that while I can’t do much about HLA, CYP2E1, or EBV, I can certainly reduce my exposure to nitrosamine through checking labels and selecting food with low nitrosamine as well as avoiding cigarette smoke.
As for my cousin, he finished his chemo and radiation therapy. His cancer is in remission. However, I don’t know if or when it will come back.

References

1. Detailed Guide: Nasopharyngeal Cancer. American Cancer Society. Accessed on 2/16/2010 Link

2. Ward, Mary and et al. Dietary Exposure to Nitrite and Nitrosamines and risk of Nasopharyngeal Carcinoma in Taiwan. Int. J. Cancer: 86, 603-609 (2000).

3. Zheng, Xi, Luo Yan, Bo Nilsson, Gunnar Eklund and Borje Drettner. Epstein-Barr Virus Infection, Salted Fish and Nasopharyngeal Carcinoma. Acta Oncologica Vol. 33, No. 8, 867-872 (1994).

4. Zheng, Xi and et al. Studies on Etiological Factors of Nasopharyngeal Carcinoma. Acta Otolaryngol (Stockh) 113, 455-457 (1993).

5. Hildesheim, A. et al. CYP2E1 genetic polymorphisms and risk of nasopharyngeal carcinoma in Taiwan. J. Natl Cancer Inst 89, 1207-1212 (1997)

6. Cytochrome P450, family 2, subfamily E, polypeptide 1. Accessed on 2/16/2010 Link