Relationship Between Sleep and Fibromyalgia

I just did a little exercise for myself and I want to share the results, and then share a new way of looking at the relationship between sleep and fibromyalgia. The exercise was to ask, “if I wanted to learn about the current thinking about fibromyalgia in the scientific and medical community, where would I look?” What field of study would be the best source of information about fibromyalgia? I don’t know much about fibromyalgia other than it has something to do with chronic pain. Because of the association with pain, I figured Neurology would be a good place to start. So I went to one of my favorite sources, Nature Reviews Neurology. I did find a few references, but I was also directed to Nature Reviews Rheumatology, which I would not have expected. My point is this. Conditions like fibromyalgia are very complex, and many times, controversial. The information you need might not be found in the most obvious places, but you have to know when to keep digging and where to dig in order to find the information you need.

Illustration of a nerve cell
Photo: Illustration of a nerve cell
Andrej Vodolazhskyi, Shutterstock

Sleep and Fibromyalgia

Fibromyalgia is a disease or condition characterized by chronic pain. Fibromyalgia sufferers have increased sensitivity to pain such that pain sensation may be triggered by stimuli that don’t normally cause pain. Light touch or even simple movements can cause the person to feel pain. To make matters worse, the diagnosis of fibromyalgia is not completely accepted within the medical community, kind of like adding insult to injury. As you might imagine, fibromyalgia suffereers are pretty miserable and often depressed. Many fibromyalgia sufferers have difficulty sleeping which exacerbates the feelings of exhaustion, pain, and depression.

New Development

Here’s the kicker–the new development. The association between fibromyalgia and sleep has been known for a long time. It has been assumed that suffering from fibromyalgia resulted in a disruption of normal sleep. Now it turns that we might have had this backward. Some investigators now believe that sleep disruption, or insomnia, may be one of the triggers of fibromyalgia, not the other way around. I know from personal experience that not being able to sleep is very serious and can lead to a variety of real and psychosomatic physical consequences. It is not surprising to me that some people could experience chronic pain sensations as a result of prolonged sleep deprivation and the anxiety that accompanies it. If you read this post, and you know someone who suffers from fibromyalgia, find out if they are able to sleep. Find out if they started having trouble sleeping BEFORE they began to suffer from fibromyalgia. This might provide some additional treatment options to explore, if you haven’t explored this possibility already.

Reference

Choy EH. 2015. The role of sleep in pain and fibromyalgia. Nat Rev Rheumatol. 2015 Apr 28. doi: 10.1038/nrrheum.2015.56. [Epub ahead of print]

Dr. Choy is in the Section of Rheumatology, Institute of Infection and Immunity, Cardiff University School of Medicine, Tenovus Building, Heath Park, Cardiff CF14 4XN, UK.

Immunotherapy for Rheumatoid Arthritis

Rheumatoid Arthritis is an autoimmune disease that results in pain swelling the joints. An autoimmune disease is a condition where your immune system attacks your own tissues, in this cells and tissues lining the joints. RA involves both T cells, which directly attack other cells, and B cells which produce antibodies—in this case “auto-antibodies. RA is antigen specific, meaning that certain proteins (antigens) are targeted by the immune system. Learning which proteins these are helps us combat the disease. Over 70% of RA patients (70% is a very high proportion when it comes to disease correlation) make antibodies against a group of proteins called citrullinated proteins. The two main types of antibodies are anti-citrullinated peptide antibodies (ACPA) and anti-cyclic citrullinated peptides (anti-CCP).

Preparation and delivery of Rheumavax to a patient with rhematoid arthritis.
Preparation and delivery of Rheumavax to a patient with rhematoid arthritis. Sketch, S. Anderson.

Immunotherapy is a form of treatment where cells of the immune system are used as “drugs” to treat the disease. In present study an immunotherapy preparation called “Rheumavax” was tested for safety and effects on the immune response in small group of patients. Rheumavax is prepared by drawing blood from each patient, culturing the dendritic cells with citrullinated peptides, and then injecting back into the patient. Dendritic cells are a specialized kind of cell that present antigens to T cells in order trigger an immune response. If conditions are right (or wrong) when the dendritic cells are exposed to antigen they will turn off the immune response instead of turning it on, which is what the investigators are trying to do here. The purification and preparation of the dendritic cells takes about 2 days in tissue culture. The patients were divided into three groups. One group (9 patients) got a single low dose of Rheumavax cells (1 million), a second group (9 patients) got a single high dose of Rheumavax cells (5 million), and the third group (16 patients) got no Rheumavax cells. Both doses of cells were well-tolerated.

After 1 month the patients were evaluated for the state of their arthritis symptoms and for the number of autoimmune cells they had. The results showed the patients receiving Rheumavax showed at least some clinical improvement, which correlated with a decrease in active autoimmune T cells in their bodies. Reduced T cell responses were observed in both the low dose and high dose patient groups. This is exactly what the investigators had hoped for.

Even though this trial was a small one, with a simple design and outcome measurements, the results are very promising and suggest that this kind of immunotherapy with dendritic cells is worth pursuing in future trials.

Immunotherapy like this represents one form of so-called “personalized medicine” in which each individual patient is treated with a tailored therapy regimen based on their own physiology and disease conditions.

Reference

Benham H, Nel HJ, Law SC, Mehdi AM, Street S, Ramnoruth N, Pahau H, Lee BT, Ng J, G Brunck ME, Hyde C, Trouw LA, Dudek NL, Purcell AW, O’Sullivan BJ, Connolly JE, Paul SK, Lê Cao KA, and Thomas R. 2015. Citrullinated peptide dendritic cell immunotherapy in HLA risk genotype-positive rheumatoid arthritis patients. Sci Transl Med. Jun 3;7(290):290ra87. doi: 10.1126/scitranslmed.aaa9301.

University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Woolloongabba, Queensland, Australia.

Blood Cell Primer

This post contains some fun facts about the cells found in our blood. It’s presented in a slightly disorganized way—part table and part text. All the information comes from Wikipedia or MedLine. I hope you will find it interesting and informative. This post illustrates a couple of other points  I would like to make. All of this information is very basic and very easy to find—if you (1) know what to look for, (2) know when you’ve found the right (accurate) information, (3) know what the information means, and (4) understand how you can use it.

Composition of Whole Blood
Composition of Whole Blood centrifuged to show volume of plasma, WBCs, and RBCs (Hematocrit). Wiki Commons.

Total blood volume in an adult human: 5 Liters = 5,000 mL = 5.25 quarts = 10.5 pints.

1 Unit of blood is 500 mL = 0.5 qt, = 1 pint, about 10% of your total blood volume.

Red Blood Cells (RBCs, Erythrocytes): 4,000–6,000 x106 (106 =1 million) per milliliter (mL)

Photo of RBCs and platelets
Photomicrograph of RBCs also showing platelets. Photo: UCSF School of Medicine

 

Platelets: 150–400 x106 per mL

White Blood Cells (WBC, Leukocytes): 4.0–11.0 x106/mL

About 40-45% of your total blood volume is RBCs. That number is your Hematocrit.

There are 5 major types of WBCs. They are named for either their morphology (physical appearance under the microscope), or where they were first found. The ratio of these cells to each other is called the Differential Count, or “Diff”.

Micrograph of Neutrophils.
Micrograph of Neutrophils. Wiki Commons.

Neutrophils: 40%–60% of all WBCs in the blood

Micrograph of monocytes.
Micrograph of monocytes. Wiki Commons

Lymphocytes: 20%–40%

Monocytes: 2%–8%

Micrograph of an eosinophil.
   Micrograph of an eosinophil. Wiki Commons.
Micrograph of a basophil.
Micrograph of a basophil. Wiki Commons.

Eosinophils: 1%–4%

Basophils: 0.5%–1%

Interestingly, WBCs in the blood are only about 0.1% of all the WBCs in the body. The body has approximately 1×1012 total WBCs. The remainder are found in the lymphatic system, including the lymph nodes, and dispersed throughout our tissues, especially in the gut, liver, spleen, and skin.

Micrograph of a lymphocyte.
  Micrograph of a lymphocyte. Wiki Commons.
Scanning electron micrograph of a lymphocyt
  Scanning electron micrograph of a lymphocyte. Wiki Commons.
Transmission electron micrograph of a lymphocyte.
Transmission electron micrograph of a lymphocyte. Photo: UCSF School of Medicine.

 

Each WBC has a specific job to do.

Neutrophils, the most abundant WBCs, are our first line of defense against bacteria and other foreign invaders, especially those that enter the body through cuts, scrapes, and other injuries.

Monocytes are phagocytic cells that eat dead cells, debris, bacteria, and foreign substances. Together with another type of cell called Dendritic Cells, they alert helper T cells (below) that they need to jump into action.

Eosinophils are a primary attacker of parasites and worms.

Basophils release histamine when they are activated. When they are over-stimulated, like when you have an allergic reaction, they are the culprits. It’s a good thing we don’t have more of them, huh?

Platelets are actually small cell fragments. They are activated in response to tissue injury. When they are activated they become sticky and become trapped in webs of fibrin to form what we call clots. Platelets are also activated by fatty plaques that form in your arteries which leads to atherosclerosis. Not good.

Lymphocytes. All lymphocytes look relatively the same under the microscope, but with special techniques and technology such as flow cytometry we now know that there are several different kinds of lymphocytes with highly specialized functions.

There are CD4 T lymphocytes (CD4 T cells) also called T helper cells, and CD8 T cells called cytotoxic T cells or CTLs. CD8 T cells attack and kill other cells like cancer cells and virus-infected cells. T helper cells are necessary to initiate and support the function of other lymphocytes. As you may know, HIV, the AIDS virus, specifically infects and kills CD4 T cells, thus taking down your immune system and leaving you essentially defenseless. Those suffering from AIDS often die from a variety of unusual infections and/or cancer.

B lymphocytes or B cells, when activated by antigens and helper T cells, become plasma cells, which are the cells that make antibodies. If you have no B cells, you will have no antibodies.

Natural Killer cells. There is another type of lymphocyte that is close to being a T cell, but is not quite the same. They are called Natural Killer cells, or NK cells. NK cells circulate through the body looking for bad cells to kill. They are one of our primary defense mechanisms against cancer.

There are even more sub-types of T cells, B cells, and monocytes that I will not describe here. Just know that the immune system is highly specialized, and highly complex.

References

Wikipedia: look up each cell type by name

MedlinePlus: http://www.nlm.nih.gov/medlineplus/ency/article/003657.htm

Photo Credits

Hematocrit

By MesserWoland [GFDL (http://www.gnu.org/copyleft/fdl.html), CC-BY-SA-3.0 (http://creativecommons.org/licenses/by-sa/3.0/) or CC BY-SA 2.5-2.0-1.0 (http://creativecommons.org/licenses/by-sa/2.5-2.0-1.0)], via Wikimedia Commons

SEM Lymphocyte

By Unknown photographer/artist (False color modifications made by myself–DO11.10) (Dr. Triche National Cancer Institute) [Public domain], via Wikimedia Commons

Lymphocyte (sang humain, normal). Coloration de May-Gründwald Giemsa, Gc = 1000. Février 2006.

TEM Lymphocyte

UCSF School of Medicine Prologue Histology Resource

http://missinglink.ucsf.edu/lm/ids_101_histo_resource/blood_cells.htm

RBCs

UCSF School of Medicine Prologue Histology Resource

http://missinglink.ucsf.edu/lm/ids_101_histo_resource/blood_cells.htm

Monocytes

By Dr Graham Beards [CC BY-SA 3.0 (http://creativecommons.org/licenses/by-sa/3.0)], via Wikimedia Commons

Neutrophils

By Dr Graham Beards (Own work) [CC BY-SA 3.0 (http://creativecommons.org/licenses/by-sa/3.0)], via Wikimedia Commons

Eosinophil

By Bobjgalindo (Own work) [GFDL (http://www.gnu.org/copyleft/fdl.html) or CC BY-SA 4.0-3.0-2.5-2.0-1.0 (http://creativecommons.org/licenses/by-sa/4.0-3.0-2.5-2.0-1.0)], via Wikimedia Commons

Basophil

By User CS99 at German Wikipedia (German Wikipedia) [Public domain], via Wikimedia Commons

 

 

 

Can Zoloft Protect Us Against Ebola Virus Infection?

Repurposing drugs already approved by the FDA for different applications is highly attractive because these drugs have known pharmacology and toxicity profiles, as well as established manufacturing and formulation methods. That’s why thousands of existing drugs, those currently in use, are being screened by pharma companies for efficacy in other diseases of conditions. Some of these results are very surprising. Recently it was found that two known drugs that are already being used for other conditions might offer protection against infection by Ebola Virus. These findings are really significant since there is currently no effective treatment for Ebola infection. Vascor (Bepridil), a calcium channel blocker used to treat angina, and interestingly, Zoloft (Sertraline), a selective serotonin reuptake inhibitor (SSRI) used to treat anxiety and depression, were recently shown to inhibit virus replication in cells in tissue culture, and also to protect mice from virus infection.

First drugs were tested for their ability to prevent the virus from replicating/reproducing in cells in tissue culture. The cells were also tested for viability to make sure the drugs weren’t simply killing the cells. Several known drugs showed anti-virus activity in these experiments. The authors selected drugs with proven track records for safety in man as candidates for further studies. Two of the most promising were Vascor (Bepridil) and Zoloft (Sertraline).

Micrograph of ibroblasts in culture
Fibroblasts in culutre. Micrograph. Photo: Shutterstock.
Adding samples to an ELISA plate.
Adding samples to an ELISA plate. Photo: Shutterstock.

Next, the drugs were tested for their ability protect mice from infection with the virus. One hour after the mice were infected with the virus, drug treatment was started. Drugs were given to the mice for 10 days, and then the mice were observed for another 18 days. Zoloft treatment resulted in 70% survival (7/10) of the infected mice. Vascor (Bepridil) treatment resulted in 100% survival (10/10). In the Control groups, that is, mice infected with virus but not treated with a drug, no mice survived until day 10 post-infection (0/10, 0/10).

In a previous paper it was reported that two compounds that interfere with estrogen receptors also protected mice from infection with Ebola Virus. Clomiphene (brand names Clomid and Serophene) is used to treat female infertility due to anovulation. Toremifene (brand name Fareston) is approved for the treatment of advanced metastatic breast cancer. Treatment of mice with Clomiphene resulted in 90% (9/10) survival of the infected mice, while Toremifene resulted in 50% survival (5/10). Again, in the Control groups no mice survived until day 10 (0/10, 0/7).

Harvesting cells with a cell scraper.
Harvesting cells with a cell scraper. Photo: Shutterstock.

Finally, another in vitro (tissue culture) test was performed on artificially produced virus-like particles (VLPs) to study the mechanism by which the drugs inhibited the virus. From these experiments it was determined that both compounds inhibited the transport of virus components into the cells’ internal machinery, despite the fact the neither compound inhibited the ability of the intact virus particles to get into the cells. Although the exact mechanisms by which these drugs work in blocking Ebola Virus infection of cells, it seems likely that they are NOT working by the same molecular mechanisms that they use for their “real” jobs.

Thus, it is well worth the effort to continue to study known drugs for unexpected activity in situations other than those for which they are currently in use. Repurposing drugs will also save us lots of time and money with regard to drug development. Who can forget that the little blue pill, Viagra (Sildenafil) was originally developed to treat angina. To my knowledge it hasn’t been tested against Ebola yet, but if Vascor works, why not?!

References

Johansen LM, DeWald LE, Shoemaker CJ, Hoffstrom BG, Lear-Rooney CM, Stossel A, Nelson E, Delos SE, Simmons JA, Grenier JM, Pierce LT, Pajouhesh H, Lehár J, Hensley LE, Glass PJ, White JM, Olinger GG. 2015. A screen of approved drugs and molecular probes identifies therapeutics with anti-Ebola virus activity. Sci Transl Med. 7(290): 290ra89. doi: 10.1126/scitranslmed.aaa5597.

Johansen LM1, Brannan JM, Delos SE, Shoemaker CJ, Stossel A, Lear C, Hoffstrom BG, Dewald LE, Schornberg KL, Scully C, Lehár J, Hensley LE, White JM, Olinger GG. 2013. FDA-approved selective estrogen receptor modulators inhibit Ebola virus infection. Sci Transl Med. 5(190):190ra79. doi: 10.1126/scitranslmed.3005471.

Seppa, N. 2015. An antidepressant may protect against Ebola: Zoloft and another drug keep most mice alive after infection with the virus. Science News, Magazine of the Society for Science and the Public. JUNE 3, 2015.  https://www.sciencenews.org/article/antidepressant-may-protect-against-ebola

 

What is Scarlet Fever?

I had heard of Scarlet Fever, but to be honest I didn’t know what it was. A faded memory from microbiology classes long past. Recently, a friend of mine got it so I decided to look it up. Scarlet Fever, it turns out, is a sequela (plural = sequelae) of Strep Throat. A sequela is a complication of another disease or condition, kind of like a side effect.

My friend’s young son got Strep Throat, and like a good parent, he got it too. Then he developed Scarlet Fever. Scarlet Fever is a rough, red rash on the skin. You can also get red bumps on your tongue that make it look like a strawberry.

 

Scarlet fever rash on the torso
Body Rash of Scarlet Fever. Wikimedia Commons.

 

Strawberry tongue of Scarlet Fever.
Strawberry tongue of Scarlet Fever. Wikimedia Commons.

That’s called—you guessed it–Strawberry tongue. It’s usually seen in young children, but my friend is one of the lucky adults to come down with it. Only a small percentage of people who get Strep Throat or another streptococcal disease develop Scarlet Fever. This suggests to me that there may be a host (or genetic) factor or factors that play a role in developing Scarlet Fever, but I don’t know that for sure.

Strep Throat is caused by a bacteria called Streptococcus pyogenes, or Strep pyogenes. Strep pyogenes is a member of a family of bacteria called Group A Strep. Strep pyogenes bacteria are commonly found on our skin. These bacteria cause a number of nasty diseases, such as Toxic Shock Syndrome, Rheumatic Fever, and necrotizing fasciitis, the flesh eating disease.

Long strings of spherical bacteria are characteristic of Streptococci.
Illustration of Streptococcus bacteria based on a photomicrograph. S. Anderson. Long strings of spherical bacteria are characteristic of Streptococci. Strepto = twisted chain; Coccus = spherical.

Strep pyogenes bacteria produce several toxins that help them cause disease. These toxins are known as virulence factors. The virulence factors that lead to Scarlet Fever are three toxins called SPE-A, SPE-B, and SPE-C. SPE stands for Streptococcal Pyrogenic Exotoxin. “Pyrogenic” means they cause fever. SPE-A, B, and C were formerly called erythrogenic toxins. “Erythrogenic” means “causing redness”, as seen in Scarlet Fever.

Strep Throat and Scarlet Fever are not normally serious or life-threatening, and can be treated with antibiotics like penicillin. However, if left untreated, they can lead to some serious sequelae (see what I did there) such as Rheumatic Fever, kidney disease, even lung infection, and arthritis. So if you think you or your child or loved one might have Strep Throat–GET TO THE DOCTOR!

References

Todar, K. Todar’s Online Textbook of Bacteriology www.textbookofbacteriology.net. Streptococcus pyogenes and Streptococcal Disease, p. 2. http://textbookofbacteriology.net/streptococcus_2.html. Accessed June 7, 2015.

Centers for Disease Control and Prevention (CDC). Scarlet Fever: A Group A Streptococcal Infection. http://www.cdc.gov/features/scarletfever/. Accessed June 7, 2015.

Streptococcus pyogenes. http://en.wikipedia.org/wiki/Streptococcus_pyogenes. Accessed June 7, 2015.

Images

Strawberry tongue of Scarlet Fever. Attribution: 6 Mar 2006: Erdbeerzunge Himbeerzunge Scharlach. Foto von Martin Kronawitter, Kellberg; 22 July 2013, color adjust by Jbarta; via Wikimedia Commons.

Body Rash of Scarlet Fever. Attribution: By The original uploader was Estreya at English Wikipedia (Transferred from en.wikipedia to Commons.) [CC BY 2.5 (http://creativecommons.org/licenses/by/2.5), via Wikimedia Commons.

Leukemias and Lymphomas Come From Normal Blood Cells

This article was inspired by a paper I read as graduate student. I was fascinated by the observation that leukemia and lymphoma cells could be matched to a specific type of normal cell, and that they retained some of the functions of the normal cells. As an immunologist we use leukemia and lymphoma cells from patients to study the functions of normal cells and to develop specific treatments for these types of tumors. I’m happy to share these ideas with you and I hope that my article provides you with some useful and valuable information. Please let me know if you find the information useful or if you have any comments or suggestions for future topics you would like to learn about.

Cancers of the cells of the blood and immune system are called leukemias or lymphomas depending on where and in what kind of cell they originate. Leukemias originate in stem cells in the bone marrow, while lymphomas originate in mature cells in peripheral tissues such as lymph nodes. Leukemias and lymphomas arise from normal cells at a certain stage of maturation or differentiation. The leukemia and lymphoma cells retain many of the characteristics of the normal cells from which they are derived. The cells’ lineage, the kind of normal cell it started as, can tell us what kind of prognosis to expect. In some cases the cells’ physical and molecular characteristics can form the basis of specialized treatments aimed at one or more of these characteristics.

Leukemias and Lymphoas represent normal developing cells

Leukemias and Lymphomas Begin As Normal Cells

Leukemia and Lymphoma cells come from normal cells at a certain stage of differentiation. The type of cell the cancer comes from determines your diagnosis. Knowing what cell type leukemia or lymphoma cells look like allows us to place them on the map of normal blood cell development. Most leukemias come from immature cells in the bone marrow or thymus, while lymphomas usually come from mature T cells or B cells that have been reactivated in lymph node germinal centers.

Abbreviations: ALL, Acute Lymphocytic Leukemia; T-ALL, ALL with characteristics of T lymphocytes; B-ALL, ALL with characteristics of B lymphocytes; CLL, Chronic Lymphocytic Leukemia; CML, Chronic Myelogenous Leukemia; AML, Acute Myelogenous Leukemia; HL, Hodgkin’s’ Lymphoma; NHL, Non-Hodgkin’s Lymphoma; MM, Multiple Myeloma.

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