The Unknown of Multiple Sclerosis

Multiple Sclerosis (MS) is a disease that occurs in the central nervous system (CNS). Within the CNS, the immune system attack myelin which is the fatty substance that protects the nerve fibers. The immune system also attacks the nerve fibers themselves. The myelin then forms scar tissue, and the damaged nerve fibers can no longer send normal nerve impulses to and from the brain and spinal cord. Experts consider this disease to be an immune-mediated disease rather than an autoimmune disease because the target of the immune cells is still unknown. There is still so much that is unknown about why this disease occurs. However, there are many ideas of why this disease occurs, but it is believed that there are several interactions of many different factors. These factors can include immunologic, environmental, infectious, and genetic.

Immunologic: Researchers have been able to identify which immune cells are attacking the myelin, the factors that cause them to attack, and the sites that appear to be "more attractive" for the cells to attack.

Environmental:

1. MS seems to be more frequent further away from the equator.
2. People born in an area with higher risk of MS rather than lower risk, but move to the area of lower risk before the age of 15 bring about the idea that someone exposed to some environmental agent before puberty may predispose them to develop MS. 
3. Higher levels of naturally-produced vitamin-D helps support immune function and could help protect against an immune-mediated disease.
4.  Smoking increases the risk of MS. 

Infectious: Exposure to bacteria, viruses, and other microbes at a young age could increase chances of getting MS because viruses are well known for inflammation or the destruction of myelin.

Genetic: MS is not hereditary, but having a family member with MS can increase the chances of getting developing the disease.

There are so many different ideas and theories behind MS, and studies are still being done. MS is most commonly diagnosed in ages 20 to 50 and is more common in women as well. The more that is understood, the closer we are to finding a cure for MS or a way to get it under control. Hopefully, sometime soon, this disease will have a known cause and someway to cure it.


Citation: 
What Is MS? (n.d.). Retrieved September 28, 2017, from https://www.nationalmssociety.org/What-is-
       MS

Rabies Podcast: Rodney Versus Death

Radiolab: Rodney Versus Death


This podcast which talks about the 15 year old girl, Jeanna, who became the world's first known survivor of rabies (without vaccination) and the protocol that was developed from her treatment. I highly recommend it; the science behind it is really fascinating and it's only 30 minutes.

It explains rabies in simplest terms- how it travels from a bite wound site into your nervous system, and its neurologic manifestations, including behavior changes, convulsions, inability to drink, and eventually complete system shut down. The actual physiology of the disease is not very well known.

Dr. Rodney Willoughby at Children's Hospital of Wisconsin, in a last-ditch effort, developed a treatment which essentially put the patient in a coma to "ride out" the disease. Once Jeanna arrived to Children's, Dr. Willoughby started going through dozens of case reports, and began to hypothesize that rabies causes excito-toxicity. In other words, there is no physical damage to the brain, but the neurons become overstimulated, and therefore shut down because they are overwhelmed. He suggested putting Jeanna in a coma to allow her immune system time to fight the virus.

Such a treatment had never been done, or even formally considered/suggested, and Dr. Willoughby discusses the ethical dilemma of potentially "locking the patient in," or causing brain damage but having the patient remain in a coma, leaving her "trapped" in her body. With the fatality rate of rabies being 100%, Dr. Willoughby was more concerned with this notion, saying he might "be doing worse than death."

The treatment worked, and they named it The Milwaukee Protocol. It has since been implemented for others infected with rabies, but its efficacy has come under question. The role of immune system is discussed and critics of the protocol suggest that this patient had the ability to fight the disease regardless of implemented treatment. According to an article by New Scientist, only six of the 35+ who have undergone treatment have survived.


Here are some links discussing the protocol:

Critical Appraisal of the Milwaukee Protocol for Rabies: This Failed Approach Should Be Abandoned

The "Milwaukee protocol" (MP) hope does not succeeds for rabies victim

An unlikely remedy for brain cancer: Zika virus

An unlikely remedy for brain cancer: Zika virus

When people think of treating brain cancer, or any other cancer for that matter, most people think of chemotherapy, radiation, or surgery as standard treatment options. There are very few people who would think to utilize a virus to treat brain cancer, especially the Zika virus. However, a team of researchers have now found that Zika virus can be used to treat cancer, more specifically, glioblastoma. If glioblastoma sounds familiar, that is because Senator John McCain was recently diagnosed with this type of cancer (Mohney, 2017). Glioblastoma is the most common brain cancer in adults with a survival rate of only two years (Roberts, 2017; Zhu et al., 2017). The glioblastoma is usually removed with surgery; however, tumorous stem cells cause the cancer to grow back. In addition, glioblastomas do not metastasize outside of the central nervous system (CNS), meaning the cancer tends to stay localized (Zhu et al., 2017).  It is for these reasons that researchers have been hoping to utilize a virus, such as Zika, to fight the cancer (Mohney, 2017).   

Zika virus is an RNA virus of the flavivirus genus that also includes dengue, West Nile virus, and yellow fever viruses (Zhu et al., 2017). Zika virus made headlines for causing microcephaly in infants and was linked to birth defects in 30 countries. The virus is spread through infected mosquitoes (Roberts, 2017). Zika primarily attacks the CNS, mainly stem and progenitor cells, which are prominent in the developing infant brain (Zhu et al., 2017) 

Because Zika targets the CNS, Zhu et al. (2017) wanted to study the effects of Zika virus on glioblastoma stem cells in mice. The researchers found that Zika virus killed glioblastoma stem cells but not normal cells. This is in contrast to the West Nile virus that killed both tumor and normal cells. Furthermore, when mice were inoculated with a mouse strain of Zika virus, they had significantly longer survival rates compared to a wild-type virus. However, the researchers are still unsure of the exact mechanisms by which the virus works.

Zhu et al. (2017) point out that safety is still a concern with utilizing this virus because of some of the unknown factors, but the results of the mouse studies are promising for glioblastoma treatments. In addition, the researchers acknowledge that the virus would be used with other conventional therapies. There is also work being done on other viruses for treating glioblastomas. These studies are exciting because they offer new therapies for patients with a type of cancer that significantly reduces their life spans. These are also targeted therapies that could potentially reduce unwanted side effects associated with more conventional therapies. Although more studies need to be done, there is progress being made in finding alternative treatments for patients with these types of cancers.     

References:

Mohney, G. (2017). Researchers Hope Zika Virus Can Treat Deadly Brain Cancer. Retrieved September 23, 2017, from https://www.healthline.com/health-news/zika-virus-can-treat-brain-cancer

Roberts, M. (2017). Zika virus used to treat aggressive brain cancer. Retrieved September 23, 2017, from http://www.bbc.com/news/health-41146628

Zhu, Z., Gorman, M. J., Mckenzie, L. D., Chai, J. N., Hubert, C. G., Prager, B. C., . . . Chheda, M. G. (2017). Zika virus has oncolytic activity against glioblastoma stem cells. The Journal of Experimental Medicine,1-15. doi:10.1084/jem.20171093

            

Mary Jane and IBD

With public perception of marijuana use becoming increasingly more positive, its physiological effects, social implications, and potential benefits have continued to be widely debated. In this article, researchers were interested in assessing the therapeutic role of marijuana use on inflammatory bowel disease (IBD). The article bases its research on previous knowledge that two cannabinoid receptors have been isolated. It notes that CB1 receptors are located all throughout the gastrointestinal tract while CB2 receptors have been expressed in the ileum. These endocannabinoid receptors may participate in a variety of responses such as secretion, gut motility, and inflammation.  Marijuana contains the active ingredient, tetrahydrocannabinol (THC), which bind these receptors potentially mediating the therapeutic roles. With this research, a cross-sectional survey and questionnaire was administered to 291 patients with IBD to assess characteristics such as their diagnosis, the need for conventional IBD medication, analgesics for abdominal pain, their overall quality of life, and cannabis use. Overall, the study demonstrated that a significant portion of the patients used cannabis to relieve their IBD-related symptoms, particularly those with a lower rated quality of life and a history of chronic abdominal pain and surgery. Unfortunately, this research (like many other marijuana research) lacks evidence for the drug’s direct impact on disease activity. This brings to mind a conversation that I had with Dr. Hutchison at CU Boulder in regards to the limits of marijuana in health research. First, it is a class 1 drug that makes it difficult to obtain for academic researchers. When it is finally obtained, its external validity is lacking because its THC levels are not representative of what is available to the population making any type of this research lacking. Meanwhile, there is still some negative public perception that is prevalent socially and politically and is preventing any possibility of demonstrating marijuana’s efficacy. Since marijuana research is lacking in many domains, there will always be this cycle that presents marijuana in a negative light further limiting the potential to demonstrate its pros and cons. While the particular article discussed in this blog is a bit older, progress of marijuana research is still very slow even to this day. Hopefully with the years to come, more valid research will come out and maybe it can be decided, once and for all, whether marijuana is helpful or harmful. The CU school of medicine has a news article that discusses these ideas as well. 

The Resurgence of Tuberculosis

When many people think of tuberculosis (TB) they imagine an archaic or even eradicated disease. Unfortunately, this is far from reality. In the World Health Organization's 2016 Global Tuberculosis Report, it was estimated that in 2015, 10.4 million new TB cases emerged worldwide. Of note, people living with HIV accounted for 1.2 million (11%) of all new TB cases. The resurgence of TB is a cause of serious concern for global health monitoring organizations and it may be attributed to several factors including a comorbidity with immunosuppressive diseases and antibiotic resistance (World Health Organization, 2016).

TB is an infection primarily of the lungs caused by a mycobacteria, predominantly Mycobacterium tuberculosis. TB is a communicable disease that is usually acquired by inhalation of the bacteria as it spreads through the air from the cough, sneeze, or spit of an individual with an active infection. When the bacteria invades the lungs, the immune response causes the pathogens to be isolated in a tubercle. As the disease progresses, caseous necrosis results in the tissue within the tubercle (Huether and McCance 86). Symptoms of an active infection include coughing, bloody sputum, extreme weight loss, and fatigue. The mycobacterium is an opportunistic pathogen and it preys on the immunocompromised. In people with healthy immune systems, the pathogen is defeated 90% of the time without the host every knowing he/she was infected (Tortora, Funke, and Case 687). Up to 95% of those infected do not have any symptoms of the disease. This is called a latent TB infection. Without treatment, the remaining 5-10% of people infected by the bacteria will develop active and contagious TB (CDC.gov).

Tuberculosis is comorbid with many diseases that depress the immune system such as malnutrition, diabetes, malaria, and HIV. The immunodeficiency that manifests in people living with HIV leaves them susceptible to the initial TB infection. Additionally, those with HIV who are infected with the mycobacterium, are much more likely to rapidly develop active and contagious TB over those who are not HIV positive. The higher prevalence of active TB in HIV positive patients significantly attributes to the resurgence of TB, especially in sub-Saharan Africa and Asia (CDC.gov). Antimicrobials are used to treat TB, usually a combination of antimicrobials for a minimum of 6 months and up to 130 doses of the antibiotic cocktail. Some patients fail to finish the full course of treatment which results in mycobacterium resistance to the antibiotics. There are now multi-drug-resistant (MDR) strains which are resistant to isoniazid and rifampin, two first-line antimicrobials. Additionally, there are emerging strains that are resistant to all first and second-line treatments called extensively drug-resistant (XDR) strains. These XDR strains are almost untreatable with current drug-therapies and have also contributed to the resurgence of TB (Tortora, Funke and Case 684-687).

TB is usually spread through aerosols and therefore susceptible populations in very close quarters contribute to the prevalence of the disease. Overcrowded correctional facilities, homeless shelters, and refugee camps are breeding grounds for TB. Additionally, extensive international travel or immigration also contribute to the rise of the disease as individuals can contract TB in another country and carry it to less infected populations (CDC.gov). The mycobacteria that cause TB are different from other bacteria primarily in their cell wall composition. The cell wall of mycobacteria contain a high lipid content and mycolic acids. Two first-line treatments against the mycobacteria that cause TB are isoniazid and ethambutol which both act on mycolic acid. Isoniazid can effectively penetrate the tubercles or macrophages that hold the bacteria inside the host. Isoniazid then inhibits the synthesis of mycolic acids, disrupting the bacterial cell wall and causing cell death. Ethambutol prevents mycolic acid from being incorporated into the cell wall, causing cell death. It is less effective at penetrating tubercles but is used as a secondary drug to prevent drug resistance. Both isoniazid and ethambutol are used worldwide (Tortora, Funke and Case 559). Fluoroquinolones in combination with other antimicrobials can be used especially against drug resistant strains. Fluoroquinolones work by inhibiting bacterial DNA gyrase during DNA replication. Fluoroquinolones are used primarily in less developed countries where TB is prevalent and drug-resistant strains are spreading (Tortora, Funke and Case 562).

References

Bates, Matthew, Ben Marais, and Alimuddin Zumla. “Tuberculosis Cormorbidity with Communicable and    

          Noncommunicable Diseases.” Cold Spring Harb Perspect Med (2015): 5:a017889. Retrieved from      

          Perspectivesinmedicine.cshlp.org. 
Huether, Sue, and Kathryn McCance. Understanding Pathophysiology. St. Louis: Mosby, Inc, 2012. Print.

Tortora, Gerard, Berdell Funke, and Christine Case. Microbiology: An Introduction. United States of America: 

          Pearson, 2016. Print.

“Tuberculosis (TB) Fact Sheets.” CDC.gov. Centers for Disease Control and Prevention, n.d. Web. Retrieved from   
          www.cdc.gov.
World Health Organization (2016). Global Tuberculosis Report 2016. Retrieved from http://apps.who.int/ 
          iris/bitstream/10665/250441/1/9789241565394-eng.pdf

What the study of inner speech tells us about neurologic studies overall

Psychological and neurological studies often run into the same problem over and over again: Many thought patterns and behaviours can be elicited on demand, yet the underlying mechanism in the brain that causes the thought may be altered from what may happen if the thought occurs naturally. In the article referenced, researchers were interested in the cause of "self talk", or inner speech occurring in the mind. Almost everyone experiences this, be it psyching oneself up for a sports match, or going over an argument and wondering what could have been said differently after the fact. The researchers in the referenced study used fMRI to monitor subject's brains while they were first prompted to start an internal monologue, and then start an internal conversation. The brains behaved as predicted; the monologue caused the areas affiliated with speech to light up, whereas the dialogue caused the areas affiliated with both speech and monitoring the speech of others activated. However, the experimenters designed an alteration to the study, where the subjects were not prompted to have any sort of inner speech and instead were monitored constantly in the machine, and prompted by random beeps to transcribe what they were thinking. This resulted in discovering a completely different area of the brain associated with inner speech.
This study demonstrates one of the key failings of studying human psychological experience. While fMRI provides useful information, it doesn't always capture the whole picture of how we think, since lying very still inside of a large and very loud metal tube is not the most natural setting. Yet there doesn't seem to be much alternative. Survey studies about mental experience are indeed possible, but often people are not inclined to share their deepest thoughts with a strange researcher. We also do not have the technology to monitor brain function at the level of an fMRI while people are just walking around. Morally, would that even be something we would want to do? In order to map natural brain function, necessity demands that some sort of portable monitor be developed, yet is that too much of an invasion into what is usually considered the most private of places, the mind?
I apologize for the formatting, the original article was from Scientific American and was only accessible in a paid format online, so I scanned my print copy.

Emerging Role for IL-1α Inhibition in Cancer Therapeutics

TNFα is an inflammatory cytokine and anti-TNFα therapy has been used for a variety of ailments. Since IL-1 is upregulated by TNFα signalling, researchers have began to hone in on IL-1’s role to look more specifically at which particular action of TNFα has the most therapeutic promise. This article, IL-1 blockade, discusses the aspects of the research leading up to the discovery of IL-1’s (both IL-1α’s and β’s) role in aiding tumorigenesis and chronic inflammation. It’s often difficult to conduct clinical trials on humans that involve a placebo, especially with cancer patients, due to ethical reasons. When cancer patients are enrolled in clinical trials, the control group always gets chemotherapy and the variable group gets chemotherapy on top of the experimental treatment. Dr. Charles Dinarello used correlative data based on a longitudinal clinical trial for an experimental heart medication, when the researchers followed up the patients at various time points years later. They found that the people who had received the IL-1 inhibitor were over 50% less likely to die from lung cancer than the people in the control group who received a different medication. The age range of the study was in an older population and so Dr. Dinarello suspected that the increase of lung cancer incidence wasn’t due to prevention of tumor initiation, but rather, the participants in the study were in early stages of lung cancer and the group that received IL-1 inhibitors had remission of the cancer without being aware of it (Immunology Conference, 2017). Since this wasn’t an official study on cancer, it didn’t have the same restrictions as it otherwise would have and therefore serves as strong preliminary data to start researching how this could could become a potential therapy for cancer patients. Another study published in Nature found that certain cancers, such as breast cancer, demonstrated a decrease in tumor growth and metastasis when inflammasome activity was decreased. The inflammasome is responsible for converting pro-IL-1β into its mature form after cleavage by caspase-1. Anti-IL-1β therapy has demonstrated promise in Multiple Myeloma and other cancers. Inflammatory stimuli act through TLR and IL-1R signal transduction pathways to upregulate mRNA transcription of the pro-IL-1β as well as the inflammasome. An example of such a stimuli is IL-1α which is released by necrotic cells such as cancer cells that run out of nutrients in their microenvironment. This leads to production of IL-1β in certain cells, but separate from its role in increasing IL-1β production, IL-1α also contributes to induction of chemokines and local inflammation prior to IL-1β’s arrival.  There is ideally a temporally distinct two-step process in inflammatory induction in response to infection or tissue damage. This includes the initial inflammatory response which involves the recruitment of various immune cells as a result of chemokines released by cells that are stimulated with IL-1α. The second step is to heal the “wound” and this is mediated by IL-1β. Based on this model, inhibiting IL-1α may prove to be a more specific therapy in certain cancers since inflammation can lead to angiogenesis, metastasis, and immunosuppression. Current drugs used in anti-IL-1 treatments have a higher specificity for inhibiting IL-1β and so clinical trials are currently being conducted to test the efficacy of monoclonal IL-1α antibodies.