Hemolytic uremic syndrome (HUS) in history–part 2

As I mentioned yesterday, the epidemiology of hemolytic uremic syndrome (HUS) was murky for several decades after it was first defined in the literature in 1955. In the ensuing decades, HUS was associated with a number of infectious agents, leading to the general belief that it was a “multifactorial disease”–one that had components of genetics and environment, much like we think of multiple sclerosis today, for example.

Several HUS outbreaks made people think twice about that assumption, and look deeper into a potential infectious cause. A 1966 paper documented the first identified outbreak of HUS, which occurred in Wales. The researchers examined a number of possible environmental factors the patients may have had in common–including food, water, and various toxins–but came up empty. They sum up:

Since it is almost invariably preceded by a gastrointestinal or respiratory illness, it seems probable that it represents a response to an infection. Although Gianantonio et al. (1964) have identified one possible causative virus, it may be that various infective agents can initiate the syndrome.

This idea held throughout the next 20-odd years, as numerous studies looked at both environmental and genetic effects that may be leading to HUS. A 1975 paper examined HUS in families, suggesting that there may be two types of HUS (which we now know to be true–the genetic form is less often associated with diarrhea, and tends to have a worse prognosis as I mentioned yesterday). But still, no definitive cause for either.

There were also a number of studies testing individuals for many different types of pathogens. A 1974 paper enrolled patients in the Netherlands between 1965 and 1970, but one of the inclusion criteria was a “history of a prodromal illness in which gastrointestinal or respiratory tract symptoms were present.” The respiratory tract symptoms are mentioned in a number of papers, and were probably a red herring that sent people in search of the wrong pathogens for awhile. In this particular paper, they examined children for infection with a number of viral and bacterial pathogens, using either culture or serological methods (looking for antibodies which may suggest a recent infection). In that portion of the paper, they note a possible association with adenoviruses, but state that the data don’t support a bacterial infection–a viral etiology was deemed more likely. Regarding basic epidemiology, they did note a few small clusters of cases in families or villages, as well as a peak in cases in spring/summer–as well as an increasing number of cases from the first year of their study to the last. The epidemiology of HUS was starting to become clearer, and the syndrome appeared to be on the rise.

Even as additional case reports occasionally targeted foods as a precursor to HUS outbreaks, it wasn’t until the late 1970s and early 1980s that HUS really started to come into focus. In 1977, a paper was published identifying the “Vero toxin”–a product of E. coli that caused cytotoxicity in Vero cells (a line of African green monkey kidney cells, commonly used in research). Researchers were closing in.

Malignant Mesothelioma and Simian Virus 40 (SV40)

Student guest post by Andrew Behan

Malignant Mesothelioma (MM) is a rare type of cancer which manifests itself in the thin cells lining the human body’s internal organs. There are three types of MM; pleural mesothelioma, peritoneal mesothelioma, and pericardial mesothelioma, affecting the lining of the lungs, abdominal cavity, and lining of the heart, respectively (1). Pleural mesothelioma is most common, consisting of about 70% of all MM cases and has a poor prognosis; patients live a median time of 18 months after diagnosis. (Note: for the purposes of this article, MM will be used to represent pleural mesothelioma exclusively.) Despite its discovery in the mid-1800’s, MM was not linked to asbestos until the late 1900’s, when case reports of fast-growing lung cancers, different from previously described lung cancers, motivated investigators to uncover undisputed evidence linking asbestos to MM. Measures to reduce/eliminate asbestos from buildings reduced exposure to the cancer-causing agents found within the material, and public health officials remained confident by the year 2000 MM cases would decline in the U.S. and parts of Europe. Despite these predictions, MM cases have not declined. In fact, the incidence of MM is on the rise (1). Consequently, investigators have focused their attention on other factors to explain the steady incidence of MM in the U.S., eventually naming Simian Virus 40 (SV40) as a potential cause of MM.

You might be asking, “SV40? What’s that?” SV40 is a virus originally discovered in 1960 in kidney cells of rhesus monkeys. SV40 is dormant and asymptomatic in rhesus monkeys, but was later found to cause kidney disease, sarcoma, and other cancers in animal models. Later on, it was found SV40 attacks p53 gene (a tumor suppressor) and can interrupt the cell’s ability to perform apoptosis, or cell death. This makes the cells immortal, leading to tumor formation, or cancer (2). Controversy arose when the discovery of SV40 was found in the rhesus monkey kidney cells because these same cells were being utilized to form the polio vaccine. Consequently, many polio vaccines were contaminated with SV40 and when the vaccine was used to inoculate humans, SV40 was passed to humans along with the inactive form of the polio virus. It was estimated over 98 million Americans received the vaccine from 1955-1963, when a proportion of the vaccine was contaminated with SV40. Of the 98 million vaccinated during this time period, it was estimated 10-30 million of those individuals were exposed to SV40. Naturally, people who received contaminated forms of the vaccine were afraid they would develop cancer from exposure to SV40.

Since the controversy began in 1960, research has been devoted to confirming its role in cancer development in humans, as well as many animal models. As I mentioned above, presence of SV40 in animals has led to tumors and other cancers, and a few studies have found presence of SV40 in humans who have developed MM. For example, Carbone et al. found SV40 in mesothelial cells of humans who had developed MM, but not in the surrounding tissue (3). They did not find SV40 in patients who had other lung cancers, possibly reinforcing the specificity of their findings (3). Overall, 54% of MM cases were found to have SV40 infection within the mesothelial cells (3). The investigators determined more research needed to be done to see if SV40 infection alone could cause MM, or if other factors, such as immunosuppression or exposure to asbestos, were necessary for development of MM.

Other studies were not as convincing. For example, Lopez-Rios et al. reported that initially they detected SV40 in about 60% of MM specimens, and then they determined that most of the positive results were caused by plasmid PCR contamination, and that only 6% of the initially positive samples were confirmed to contain SV40 DNA (4). However, studies have shown the presence of SV40 in human specimens by using several other techniques besides PCR, including Southern blotting, immunostaining, RNA in situ hybridization, microdissection, and electron microscopy” (5).

Thus, the question remains: does SV40 cause MM, or does SV40 infection, in conjunction with asbestos exposure, generate a greater risk for the development of MM? This is a tough question to answer, because although asbestos is no longer mined in the U.S., it is still being imported; workers are still continually being exposed to asbestos. However, the use of asbestos has nearly ceased, decreasing from 813,000 metric tons in 1973, to 1700 metric tons in 2007 (6). The other problem in teasing out SV40 as a cause of MM from asbestos lies in the latency period between asbestos exposure and MM clinical diagnosis. According to the CDC, the latency period for someone who is first exposed to asbestos and clinical disease is 20-40 years. It may be, given asbestos still remains in many buildings, and exposure to it is inevitable when removal is completed, in addition to the long latency period between exposure and disease, that we have not yet come to the dramatic decrease in MM health officials have predicted. Or, is SV40 infection the culprit and the increase in incidence of MM will continue to rise? According to the SV40 Foundation, “SV40 is a problem that federal government authorities have not addressed responsibly because the government’s own vaccine programs are responsible for the spread of the virus throughout the western world”.(2) It is no question the public has not forgotten, even after almost 50 years, and much more research into this area is needed, to attempt to confirm SV40’s causal role, if any, in the development of MM.

References

(1) Mesothelioma. Retrieved April 2010.

(2) “Treating SV40 Cancers.” Retrieved April 2010.

(3) Carbone, M. “Simian virus 40 and human tumors: It is time to study mechanisms.” Retrieved from PubMed April 2010.

(4) López-Ríos F, Illei PB, Rusch V, et al. “Evidence against a role for SV40 infection in human mesotheliomas and high risk of false-positive PCR results owing to presence of SV40 sequences in common laboratory plasmids”. Lancet. 2004;364:1157-1166.

(5) Yang, Haining et al. “Mesothelioma Epidemiology, Carcinogenesis, and Pathogenesis.” http://www.ncbi.nlm.nih.gov.proxy.lib.uiowa.edu/pmc/articles/PMC2717086/. Retrieved from PubMed April 2010

(6) CDC. “Mesothelioma.” Retrieved from PubMed April 2010.

Schizophrenia: is it preventable?

Student guest post by Zainab Khan

Schizophrenia has puzzled and often times scared not only the scientific community, but also the general public since its emergence. Cases of schizophrenia-like behavior have been well documented in history. As this disease has been studied, factors such as genetics, environment, and even personal habits have all been associated to some degree with schizophrenia. However, evidence in past years has mounted showing an association between infectious agents and schizophrenia. The three main infections associated/studied with schizophrenia have been toxoplasmosis gondii, herpes family viruses (namely herpes simplex virus and cytomegalovirus), and retroviruses. [1]

When discussing schizophrenia it is important to have a grasp on some of the basics about this disorder. Schizophrenia is a mental disorder in which an individual faces many mental and functionality problems including hallucinations, paranoia, and poor speech and organizational skills. Schizophrenia usually appears when people are in their twenties, but it can occur at any age (men tend to get it earlier and women a bit later). [2] People diagnosed with this disorder typically have elevated dopamine activity in their brains. There is no actual test for schizophrenia; all diagnosis is based on what the patient tells the doctor, leaving a lot of room for misclassification. Schizophrenia shares its symptoms with diseases like bipolar disorder, multiple personality disorder, just to name a few. Treatment for schizophrenia usually involves antipsychotic medications in combination with counseling. These patients are much more prone to develop drug dependency, have shorter lifespan, and are much more likely to be unemployed, depressed, and homeless. [3]

Toxoplasmosis gondii is a parasite that is most commonly found in rats and cats. Cats are the reservoir for this parasite to reproduce and infect humans. It is well known that the majority of people in the world have been infected with this parasite and never have any signs or symptoms. This parasite becomes dangerous typically for immune compromised patients and pregnant woman (as it can cause birth defects). However, studies have also linked this parasite with an increased chance of schizophrenia. In one study individuals who have a schizophrenic episode and have never been treated with antipsychotic medications have higher antibodies against both toxoplasmosis gondii and CMV. [4] Further evidence in this study shows that when these people are treated with antipsychotic medicines these medicines also inhibit toxoplasmosis and CMV in patients. Toxoplasmosis is also known to increase dopamine distribution in the brain which strengths the idea that it does contribute to an individual becoming schizophrenic. [4]

Another infectious cause associated with schizophrenia is a retrovirus, specifically human endogenous retroviruses. HERV are viruses that during replication the reverse transcriptase copies its retroviral RNA into the DNA of the host (it forms a haploid DNA provirus). This provirus can be integrated in the germ line of the host, and is therefore transmitted to the following generation [5] Many of these HERV have had mutations or deletions which cause the majority of them not be active, but a small amount do remain active. It has been shown that people who have recently been diagnosed with schizophrenia have about a 29% increased chance of having the retroviral pol RNA in their cerebral spinal fluid. Conversely, none of the control patients had this nucleotide sequence in their CSF. [6]

Schizophrenia is a devastating disease that can not only ruin an individual’s life, but also his or her families. There is no precise answer for what is the cause of schizophrenia, so there is no way of knowing how to prevent it. More than likely this is a disease that occurs when the perfect mixture of environmental-genetic-infectious agents all come into play together. It does seem possible that if one of these factors were taken away the disease may not occur; there is no way to ‘fix’ the genetics of an individual, and similarly environmental stressors are a part of routine life. Therefore the easiest (easiest being a relative term) factor to try to take away is the infectious agent. More time and money should be placed in finding the connection between schizophrenia and its infectious causes and how to prevent these agents.

References

1. Harrison Catherine (January 2008) “What Causes Schizophrenia?” About.com

2. “Mental Health and Schizophrenia” WebMD

3. “Schizophrenia” Wikipedia

4. F.Markus Leweke, Christoph W. Gerth, Dagmar Keothe, Joachim Klosterkotter, Inna Ruslanova, Bogdana Krivogorsky, E. Fuller Torrey, Robert H. Yolken (2004) “Antibodies to infectious agents in individuals with recent onset schizophrenia” Eur Arch Psychiatry clin Neurosci 254: 4-8

5. Lewis David (2000) “Retroviruses and the Pathogenesis of Schizophrenia” Neuron 28:325-334

6. Hakan Karlsson, Silke Bachmann, Johannes Schro dert, Justin McArthus, E. Fuller Torrey, Robert Yolken (January 2001) “Retroviral RNA Identified in the Cerebrospinal Fluids and Brains of Individuals with Schizophrenia” Stanley Division of Developmental Neurovirology