Efficacy of Arthritis Supplements

Osteoarthritis is one of the most common forms of arthritis, and currently affects more than 20 million Americans. Osteoarthritis is caused by the degradation of cartilage, enabling the bones within the joint to rub against each other. This causes stiffness and pain, and subsequent inflammation can further aggravate these symptoms. Supplements such as fish oil, vitamins, turmeric and white willow have been suggested as possible alternative compounds that may relieve the pain and inflammation associated with the disease. Glucosamine and chondroitin are by far the most used supplements, with sales around $700 million each year. Glucosamine and chondroitin are thought to alleviate joint pain because they both contribute to cartilage structure.

The GAIT study (Glucosamine/chondroitin Arthritis Intervention Trial) looked at the effectiveness of glucosamine, chondroitin, a mixture of both, Celecoxib (NSAID) and a placebo on pain management in osteoarthritis patients. They found that while glucosamine and chondroitin did seem to slightly decrease the pain, the difference was not significant relative to placebo. (NEJM, 354(8):795-808, 2006)

Conversely, what are the effects of these supplements on rheumatoid arthritis? Because rheumatoid arthritis is thought to be an autoimmune disease that causes inflammation of the joints, the use of these supplements may alleviate the symptoms but will probably not stop degeneration. Multiple studies have looked at the efficacy of glucosamine or chondroitin on alleviating rheumatoid arthritis pain and inflammation, but have shown that neither was significantly more effective than placebo. (Biosci. Biotechnol. Biochem, 73(2):288-292, 2009; Rheumatol Int, 27:213-218, 2007)

The most intriguing aspect of all these studies is the ability of the placebo to alleviate some pain and discomfort in both rheumatoid and osteoarthritis patients. Which pathways or mechanisms do you think are being activated by the placebo? Do you think there are any benefits to the placebo effect, and if so, how could we manipulate it to benefit us?

Social Implications of IDB

Last week was a long week. A stress-filled week. I went with a friend to BJs to try their new pumpkin ale, ate their margarita pizza, and thought about some dessert. Afterward, I went with a group of friends to Tucson's Fall Club Crawl. They have alcohol served on the streets, loud bars, and greasy foods (sonoran hot dogs ftw!). Just another college weekend. But why am I telling you this? I'm blogging about my weekend because this was my stress outlet and my social life. Consider someone with IBD. Which of these activities would that individual have to restrict because of their disease? We take for granted some of the normal, every day activities because we enjoy them without consequence.

Northwestern University's division of Gastroenterology emphasizes patient care and patient education. They are located in Chicago and accept a multitude of health plans. They have an inflammatory bowel disease clinic as well as GI laboratory. More importantly for this blog, the division offers extensive "pyshcosocial services." As we read in the article "Population-based Controlled Study of Social Support, Self-perceived Stress, Activity and Work Issues, and Access to Health Care in Inflammatory Bowel Disease," there are certain social implications for those with Inflammatory Bowel Disease. The first of which they consider, is stress:
In this study, there is evidence that, while work is the number one cause of stress, IBD patients more often marked personal, physical problems as a source of stress than the control group. The surprising trend found among those with IDB that is in remission feel LESS stressed than the control group. The researchers propose that this is due to their relieved symptoms after pushing through years of disease symptoms.
The next item addressed is social support: an patient with IBD is less likely to say they feel understood by another than the control group. Although this would seem to be a downturn in the lifestyle of patients with IDB, these patients, more often than the control group, had tangible, affective, and emotional support.

The IBD Center of Northwestern U describes "pyschosocial therapy" as their first alternative treatment for IBD. "Patients with IBD often have psychosocial concerns directly or indirectly associated with their disease. Coping with a chronic, unpredictable disease can be extremely difficult for patients and their loved ones." The center offers a health psychologist for patients with the disease to help individuals manage their relationships, employment, and educational goals. Interestingly enough, the study found that patients with IDB were often more educated than the control group AND more of them had a significant other in their lives. The Northwestern U program also emphasizes that their psycho-social treatment includes stress management because it is often involved in irritation of the GI system.

The program also offers "dietary therapy." As the research article mentions, there are a large number of IBD patients that consume alcohol. While the article does not cover dietary factors entirely, there are implications of sugary and greasy foods, as well as alcohol, that can irritate the bowels and can intensify symptoms (See other blog posts). The dietary therapies recommended are:
-Eat five small meals every 3 to 4 hours
-Limit your consumptions of milk or dairy products if you are lactose intolerant
-Reduce the amount of greasy or fatty foods in your diet
-Reduce certain high fiber foods such as nuts, seeds, popcorn, and some vegetables
Many websites provide information about IBD friendly diets.
One of the larger irritants is alcohol. As we know, long term alcohol use can have severe effects on the liver just by itself. As chronic liver disease is already a serious complication of the disease (affects 5-15% of people with IBD) the addition of alcohol to the diet can be detrimental. There is also evidence of alcohol having irritating effects on the GI tract epithelium that can cause nausea, vomiting, diarrhea, and bleeding. A common complication of alcohol is its interference with medications. All in all, alcohol can sound like a dangerous irritant of the disease. So just stop drinking, right?! Well wait a minute. What about those 20-30 year old patients with IBD? Do you think they should just stop drinking, save themselves the pain??? What are the social implications that follow??? No, really, I want to hear what you think!!! What about the positive effects of alcohol? There are studies that indicate (as discussed in Dr. Cohen's cardiology class) that 1 drink a day for women and 2 drinks a day for men can have positive effects on the coronary system, perhaps even preventing CAD. And consider the psychological and social benefits of having a drink at a party.

It is interesting to me that even the choice of having a drink at a party would add more stress to my life. Just once more thing to consider while enduring the disease. So last weekend, what choices would I have needed to make? What would this disease prevent me from doing? Would my friends understand my reason for making these choices? These are all interesting questions to consider when looking at the social implications of IBD. To learn more about Northwestern University's
Inflammatory Bowel Disease Center, please visit their website @ http://www.ibdcenter.org/index.html

Suppressed and Exposed: A Clinical Dilemma

A student in Pharmacy wrote with this question she's facing, which offers a good opportunity for you 7630'ers to comment. A grandmother has been taking care of her young grandkids, one of which has just developed chicken pox. Grandma is on long-term low-dose prednisone (a glucocorticoid steroid) for her rheumatoid arthritis. It is known that chicken pox can be severe, even deadly, in the immunosuppressed. She cannot remember if she ever had chicken pox, but has heard that there is a vaccine against the virus just for older people. She wonders if she should get that vaccine right away, or, because it's live virus and she's on prednisone, avoid it. What do you (or your sources) recommend?

Autism: Maternally derived antibodies specific for fetal brain proteins

Previous studies have been suggested the role of maternal autoantibodies on the development of autism. To further these studies, a research has been done by the University of California at Davis to examine the influence of maternal antibodies on human fetal and adult brain proteins. The subjects comprised of 61 mothers of children with autism (AU) and 102 mothers of children without autism (non-AU) as a control group. Western blot was used to compare the reaction of antibodies (proteins) from AU mothers and from (non-AU) mothers against fetal and adult brain proteins.

The analysis from western blot showed reactivity of antibodies of (AU) mothers, which was presence as two protein bands approximately at 37kD and73kD, against fetal brain but not adult brain. The control group, (non- AU) mothers’ antibodies, showed no reaction against fetal brain. When the result was compared from (AU) mothers with (non-AU) mothers, more than a quarter of AU mother’s protein (antibodies) bands were different than the control group. The reason why all (AU) mothers’ antibodies did not show bands is due to heterogeneity of autism.

Since maternal IgG is the only antibody that can be transferred from mother to child via placenta, it can be detected in the fetal circulation after 18 weeks of gestation. Immunoblot from fetal brain has shown the heavy and light bands of IgG, which supports the notion that maternal IgG is transported to fetal brain during gestation. The gestation period is a critical time for fetal early neurodevelopment therefore; the transport of maternal IgG to fetal brain interferes with this period. Despite benefits that majority of maternal IgG offer to fetal, some pathogenic maternal IgG are responsible for autoimmune diseases like lupus syndrome, abnormal thyroid function and etc.

The data from this study provides evidence that there is an association between biomarkers present in maternal immune system and diagnosis of autism. “The presence of specific anit-fetal brain antibodies in the plasma of mothers during pregnancy may be a potential trigger that, when paired with genetic susceptibility, is sufficient to induce a downstream effect on neurodevelopment leading to autism.” Although other studies have shown similar findings as this study, however further research is needed to identify the protein targets of these maternal antibodies, which will help us in understand the mechanisms in interaction of proteins and maternal antibodies.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2305723/

Alochol and Crohn's Disease

After reading the basic article, Smoking and sugar intake are separate but interactive risk factors in Crohn’s disease, I wanted to look and see if alcohol had been researched in affecting Crohn’s disease.

I found an article from Health Central called, Alcohol Consumption and Crohn’s Disease. This article was written explaining the research and results done by Scandinavian researches who had been published in the Scandinavian Journal of Gastroenterology (2007). The research supported the hypothesis that drinking alcoholic drinks can increase abdominal pain in people living with Crohn’s disease. Another finding that the study discovered was that the amount of sugar in the alcoholic drink made a difference in if the participants’ system tolerated the drink.

The researches asked patients who were in remission to drink 5 different alcoholic drinks at different and random times. These drinks included red wine, white wine, Smirnoff Ice, Elephant Beer, and pure ethanol. Their findings were supported because the findings showed that abdominal pain was worse when the patient had consumed Smirnoff Ice or Elephant beer. Both of these drinks have higher sugar amounts compared to the other drinks.

The study also supported the finding that diseases are individualized, while most patients’ symptoms were worse when the consumed alcoholic beverages, especially when they had a high amount of sugar, some patients did not have negative effects after consuming alcohol.

The article from Health Central can be found at the following URL:

http://www.healthcentral.com/ibd/c/17824/40351/alcohol-consumption

Double role of Inflammation in Stroke

Much research has been done on the role of inflammation during ischemic stroke, but there have been many contradicting results. Inflammation can have bother damaging and protective effects after stroke depending on what phase it starts. According to the review article, The Inflammatory Response to Stroke, an earlier inflammatory response can increase the damage and a late response is needed for protective and restorative purposes. There are many transcriptional factors that regulate inflammation to work in this way.

Nuclear factor kB is involved in regulating the transcription of inflammatory factors such TNF-alpha, IL-6 and ICAM-1. NF-kB is activated by the phosphorylation of IkB. By blocking IkB phosphorylation, the transcription of inflammatory factors can be blocked. This showed a reduced infarct size in mouse models soon after the stroke but in other cases it showed an increased infarct size. The same discrepancies were seen in other transcription regulatory factors such as Mitogen-activated protein kinase and Activator Protein-1. MAPK plays an important role in transducing stress-related signal cascades. During ischemic stroke it plays a role in activating three different pathways: the stress-activated protein kinases, the p38MAPK’s and extracellular signal-regulated kinases. The activation of these pathways in increased at 30 min and 3 days after ischemia. The inhibition of this pathway can have a protective effect on ischemic injury. Activator Protein-1, on the other hand can promote proliferation of neuronal precursor cells which enhance neurogenesis after ischemia.

These contradicting results go to show that these factors can have damaging and protective effects. The authors of the article state that the effect of these factors depends on the time of release. Early inflammation after stroke can increase the infarct volume and injury where as late inflammation can have protective help with injury repair. More research needs to be done on this switch which could lead to finding the optimal timing of interventions to decrease stroke injury.

Restoring the Intricate Balance

As indicated in the article "Translational Research in Inflammatory Bowel Disease," the key to putting immunological diseases into remission lies in the restoration of the delicate balance of the immune system. Both Crohn's Disease (CD) and Ulcerative Collatis (UC) are diseases that arise when the immuno-scales are skewed. Patients with CD often display a Th-1 cytokine profile, implying hyperactivity of Th-1 mediated immunity. UC patients commonly show a Th-2 cytokine profile, implying a Th-2 mediated response. In real life, though, it is not as black and white as that. There is a lot of gray when looking at these diseases and it is because of the interrelatedness of the T-cell mediated immunity. While seemingly bad, all of the interconnectedness actually allows a lot of opportunity for intervention. Some of the proposed treatments for CD and UC include:
1. Blocking downstream effects such as cytokines
2. Inhibiting the T-cell
3. Inhibiting the migration of immune cells


1. Infliximab
Infliximab is a monoclonal antibody to TNF-a. TNF-a is a Th1-mediated cytokine. Based on the information, one would assume that Infliximab would be particularly useful for patients with CD. Interestingly enough, Infliximab also has its successes with the remission of UC. This effect reinforces the interconnectedness of T-cell mediated immunity. In a randomized trial for remission of Crohn's Disease upon 1 treatment of Infliximab, it was found that patients who have initial decline in disease will be likely to continue disease remission with continued Infliximab treatment. A study of Infliximab and UC patients showed that moderate to severe UC could be sent into remission with treatments of Infliximab. Results showed showed that 44-45% of patients treated with infliximab for a year maintained a response to the medication, compared with 21% of patients who were treated with placebo medication. At 2 months, the response was 61-69% for patients treated with infliximab, and 31% for those who were treated with placebo.
There is similar success with anti-cytokine drugs for INF-g and IL-12. Based on our knowledge of these cytokines, what are the advantages to developing drugs like these? What are the disadvantages?

2. Visilizumab
Visilizumab is a drug that binds the CD3 receptor on activated T cells without affecting the resting T cells. The current trials with this drug are being used in the more severe cases of IBD. More specifically, Visilizumab is an IgG2 non FcGR. This receptor is expressed on >95% of circulating, resting T cells and on activating T cells that are actively involved in inflamed tissues. The company, BioPharma, which produces the drug, has also produced similar versions of this drug that have been used for imaging lymphocytes, type 1 diabetes, and multiple myeloma. (, , , respectively)
PDL BioPharma's "Nuvion" is currently in its Phase 2/3 clinical trials and is used in patients with steroid-resistance UC and CD. Knowing that the drug is an immunosuppresant, what complications can arise from this drug? Does the benefit outweigh the cost?

3. Natalizumab
Natalizumab is an anti-adhesion monoclonal antibody drug. It is an anti alpha-4 integrin, a cellular adhesion molecule. Alpha-4 integrin is required for white blood cells to move in to organs. It is believed that Natalizumab blocks this interaction, preventing white blood cells from leaving the blood stream. The drug Natalizumab has historically been used in treating CD and MS (multiple sclerosis). The article "Translational Research in Inflammatory Bowel Disease" alludes to the dangers and risks associated with this drug. There are complications with the drug both in the intestine and blood brain barrier. There is an association of patients taking this drug and the disease PML. PML is a neurological condition involving and opportunistic virus. Currently the drug has been pulled off the European market, but is available to patients in the US with severe cases. The question again becomes does the benefit outweigh the cost? The FDA in the USA has made the decision that it does and leaves the drug available to patients.

The Confusing Inflammation Response

The more we continue to learn about the inflammatory process the more we realized how complicated it is. A good example is the research that has been done on the inflammatory process and its affects on stroke. The article The Inflammatory Response in Stroke written by Wang reviews all the finding in the research that has been done so far. There are so many different players and many are reviewed in the article. First they review the cellular processes which include leukocytes, microglia the macrophages of the brain, and astrocytes. Secondly it goes over the adhesion molecules which include selectins, immunoglobulin family and integrins. The inflammatory markers are gone over commenting on cytokines, chemokines, arachidonic acid metabolites through two different pathways, nitric oxide, reactive oxygen species and matrix metalloproteinase. Lastly the transcriptional regulation through nuclear factor kB, mitogen activated protein kinase and activator protein-1.
In this review you get lost in all the details since there are so many different components to the inflammatory response. Which also is hard for researchers because there can be so many variables in an experiment. When reviewing each component they go into how each can be either beneficial and detrimental to the the outcome of strokes. This depends on when the events happen either right away or later into recovery. It also depend on the severity of the inflammation response and how the components affect it. For example there are cytokines that heighten inflammation process for example IL-6 and also ones that decrease it, IL-10. That is why it is so hard for researches to zoom into one specific factor that can be the culprit and it continues to be as confusing and intricate.

Treating cancer with irony (375 mg/m2 qweek x 8 weeks).

Clinical cancer research is my area, so in sync with all of our discussion about antibodies, complement and such, this seemed like an appropriate topic. I'm not trying to be a drug rep for Genentech here; I just find such an ironic treatment for cancer pretty interesting.

Imagine you, the esteemed Inflammablog4 contributor, have been having a string of very bad luck. First, you felt a lymph node in your neck get inflamed. The node didn’t go down and you had it removed, pathology came back and said they want to see your bone marrow. You oblige, and have a bone marrow biopsy (not as painful as you thought, but still not pleasant); you also have a CT scan. Now you’re in your oncologists office, and he just dropped the ‘C’ word. Cancer.

Doc: You have cancer, more specifically, follicular CD20+ B-cell lymphoma.

You: What does that mean?

Doc: Well, you’re making to many B-Cells. They’re invading your lymph nodes, and making a mess.

You: You mean those cells that make antibodies? What’s the treatment for this?

Doc: We can treat you with antibodies.

You: Wait, what?!?!

Now, there are many types of lymphomas. Not just Hodgkins or Non-Hodgkins. There’s a monoclonal antibody (rituximab) that is used to treat many types of lymphomas (It’s also used for leukemia, rheumatoid arthritis, and many other diseases). To keep things focused, let’s just focus on follicular CD20+ B-Cell lymphoma.

The diagnosis of follicular CD20+ B-cell lymphoma can be broken down word by word. Lymphoma is a disease of lymphocytes. Follicular means that the disease involves areas of lymph nodes that are packed full of b-cells that form a round-ish area. CD20+ B-cell describes that your cancer involves b-cell lymphocytes that express the CD20 receptor.

Rituximab is an IgG monoclonal antibody (mAb) that specifically targets CD20. The IgG will bind to your CD20+ b-cells and activate complement. Bye, bye malignant b-cells. The good news: you have a targeted therapy for your cancer (along with a cyclphosphamide, vincristine, and prednisone chemotherapy regimen). The drug has been shown to improve overall progression free survival by more than double that of CVP alone (2.67 years vs. 1.25 years) (Marcus m39021 trial; The terminology used by Genentech in the later stages of this clinical trial is actually under fire by the FDA, check it out).

The bad news: pretty much all of your b-cells (malignant or not) express CD20, as do some other types of lymphocytes, so you may become immune compromised. Also, you may need to take out a second mortgage to afford it.

So, in essence, we are using the product of b-cells to kill b-cells. Interesting, no?

Yogurt a treatment for IBD

We discussed the lay article from Newsweek, Friendly Infections, about probiotics in yogart and other fermented dairy products being helpful for our digestive tracts to include people with IBD. While this article simply stated the author's opinion on the matter of probiotics and bacterial flora being helpful to our digestive tracts, it had no research referenced.

In the British Society for Immunology there was an article published about probiotics in IBD, Anti-inflammatory effects of probiotic yogurt in inflammatory bowel disease patients. In this article they researched the effects of probiotics on T cells, monocytes and DC, serum and stool cytokines. The results of this study showed that consumption of the probiotic yogurt resulted in increased levels of CD4+ CD25+ T-reg cells in the peripheral blood of IBD patients. Looking at a short term yogurt consumption of yogurt supplemented with probiotics, Lactobacillus strains GR-1 and RC-14 promoted the desirable anti-inflammatory environment in peripheral blood of IBD patients and showed no ill effects. They went over the methods and results in depth and their conclusion was that further research still needed to be conducted but that there were many potential applications of the nutritional supplement.

One of the applications they felt was a good candidate are HIV/AIDs patients with chronic diarrhea and in a preliminary study of its use the patients showed a decline in diarrhea within 2 days. Do you think that we should all consumed yogurt or other producted with probiotics to help our digestive systems? Do you think that having manufactured increased probiotics in yogurts could be a potential widespread treatment for IBD?

Below is the URL to the article. http://www.ncbi.nlm.nih.gov/sites/ppmc/articles/PMC2219330/

Two Seperate Risks Might Operate Similarly

In the article "Smoking and Sugar Intake are Separate but Interactive Risk Factors in Crohn's Disease," observations were made on individuals who subjected themselves to known risks of Crohn's disease. The paper questions whether smoking and additional processed sugar intake affect each other as risks for Crohn's disease. For many diseases such as the metabolic syndrome which was brought up earlier this year, risk factors can build additively or exponentially to greatly increase chances of developing a chronic disease. This study showed that these two risk factors do not additively increase risk for IBD. The suggestion is that these two risks might operate at the same root cause and activate the same pathway for disease development. This is a significant finding because if the mechanism can be traced using smoking of sugar intake, then perhaps a root cause for the disease can be treated and not just one possible risk factor. By searching for a multifunctional pathway, this disease would be easier to treat because eliminating every possible risk which would be unfavorable for the patient, perhaps an easier method which could simultaneously fix many areas can be discovered. Presently, one of the major areas of concern involving treating IBD is localizing it to affected areas only.

The Basics of IBD

So far we have discussed topics in the class that focus on diseases and problems which are known by most of the population as very major problems in our society. Obesity, insulin resistance, and stroke are talked about publicly and easily recognized as major issues amongst the average American. Most people associate all of these problems with chronic disease, cardiac stresses, lifestyle problems, and other common terms tossed around by the media. while this only scratches the surface concerning the root of these diseases, at least the big picture is broadcasted to the average person. this week's topic of discussion, inflammatory bowel disease (IBD) is not quite as popular but just as debilitating.

Inflammatory bowel disease can be split into two categories, Crohn's disease and ulcerative colitis. Generally, ulcerative colitis is restricted to the colon and large intestine. Crohn
s disease can occur anywhere form the mouth to the anus. Both forms of IBD have similar symptoms such as bloody stools, diarrhea, abdominal pain and extreme discomfort. Historically, these two forms of IBD were not differentiable. While ulcerative colitis and Crohn's disease are similar, they each have unique pathways by which the disease develops. Typically, they overlap and cause a mixture of both diseases. Some of the articles show how a specific risk factor such as added dietary sugar or smoking can affect one disease and not necessarily the other. IBD is still under research and cures for this disease hove not yet been established. Many tests have shown to be promising, but stopping the mechanism by which ulcerative colitis and Crohn's disease forms and localizing it to these diseases only is still under the works.

On the Topic of IFN Gamma....

My research area is in cancer biology, and I wanted to learn more about the role the immune system plays in cancer suppression. I found what turned out to be a seminal article in the field, about what plays a role in tumor immunogenicity. IFN gamma and lymphocytes prevent primary tumour development and shape tumor immunogenicity (Nature 410, 1107-1111 26 April 2001) talks about the fundamentals we learned in class in the context of cancer biology.
It was previously a school of thought that cancer was "surveillanced", and that this protected a host against tumor development. It was later discovered however, that there were no differences in primary tumor development among athymic nude mice and syngeneic wild type mice. What's more, is that later on it was discovered that nude mice do not actually have completely nonfunctional T cells, but that IFN gamma and perforin play a role in tumor suppression. Now enter Shankaran et al.....
The researchers of this study really defined the details about the roles IFN gamma and lymphocytes play in tumor suppression. The details are really neat.
Two classes of mice (one class was wild type, the other was immunodeficient) were exposed to a chemical carcinogen, and tumor formation was observed. For this study, immunodeficient was defined as individuals who did no express the RAG2 gene, which exists in lymphocytes and plays a role in the recombination of VDJ regions that code for immunoglobins and t-cells. Immunodeficient mice developed more tumors, and developmed them faster. To assess the extent of suppression mechanisms, other classes of mice were compared to the first two- those individuals ranging in different types of deficiencies. The most telling, were the mice which were immunodeficient, AND insensitive to IFNgamma. Those mice had the highest percentage of tumor formation accumulation over everyone.
Other parts of the study included discovering that tumors in immunodeficient mice were more immunogenic than those with normal immune systems. Combined this with the fact that through more experimentation from tumor transplantation, that IFN gamma responsiveness by the tumor cells is critical for immune response, the researchers were able to show that that IFN gamma and STAT1 signaling pathway cooperates to form the immune response.
In a final experiment, researchers wanted to determine the link between lymphocytes and IFN gamma/STAT1 processes. To do this, IFN gamma insensitive tumour cells were expressed in the MHC1 processing components to allow it to be presented so IFN gamma could be upregulated (this part started to go over my head though, sorry if this gets confusing!). These cells were challenged with a virus. Cells which were IFN gamma insensitive required participation of CD4 and CD8 presenting T cells, and those rejected virus and not wild type (please see the paper for clarification on this part). Those cells were also immune to later challenges.
There is a little more to the paper, but I think this is the bulk of it. I found it a very interesting read!

Ischemic Stroke and Immunodepression: The Downside.

Since we have looked at some of the many classified correlations between post-stroke immunosuppression and increased recovery from an ischemic brain attack, I thought a post that put immunodeficiency in a different light was warranted. Post-stroke infection is a very crippling problem as about 85% of all stroke patients have some sort of infectious complications. Infection is also the most relevant complication during recovery from stroke, and it is the number one cause of death day 1 post-stroke. (Dirnagl et al.) It has been relatively controversial whether stroke caused immunosuppression or if it simply was a correlation. Recently, it has been realized that CNS injury is likely responsible for induced immunodepression.

One study looked into this controversy:

"Infection After Acute Ischemic Stroke" Angel Chamorro, et al. Stroke: 2007.

They observed that stroke patients would usually develop infections shortly after acute stroke regardless of the quality of care and treatment received. Furthermore, the mortality risk from infection increases with the severity of the stroke. It is recently discovered that the brain and immune system are linked through neural and humoral mechanisms, and so this is one of many experiments seeking a mechanistic answer. They found that in experimental brain ischemia (in mice), infections were associated with the activation of the ANS (autonomic nervous system) and neuroendocrine pathways, which ultimately increased the strength of anti-inflammatory signals. Also observed was a cytokine-mediated anti-inflammatory response in stroke patients with high infection risk.

This study gives some insight on what is causing the high infection rate in stroke patients. However, the authors admit that although a connection exists between an anti-inflammatory response and bran ischemia, more needs to be understood about the cross-talk between brain and the immune system. It is also still unclear whether infection is independently detrimental in stroke patients' recovery of brain tissue.

Fortunately, more has been done on this subject. From this same journal that the above study was found in, a review article did a wonderful job of organizing recently studies into assembled hypotheses:

"Stroke-Induced Immunodepression. Experimental Evidence and Clinical Relevance" Dirnagl et al. Stroke: 2007.

Not only does the review article describe how the immunodepression is acquired, it also explains what causes it. They show that it is known that the SNS and HPA axis are key players in the progression to immunodepression in brain ischemia. They also propose a few mechanism for what stimulates these systems after ischemia. This review was very useful for understanding the current knowledge of post-stoke immunodepression.

There is much research being done to attempt to understand the complicated workings of the immune system post-ischemia, but unfortunately the mechanisms are still not clearly understood. Moreover, the results from studies are really only relevant in mice! Nonetheless, progress is still happening and someday we will be more competent.

I Wish I Had SCID...

With all the papers we have been discussing, it seems that the worst thing to have after a stroke is a good adaptive immune system. Of course, I don't really want SCID (Severe Combined Immune Deficiency- A congenital disease where the person lacks the ability to produce functioning T and B cells), but all this research is enticing!

After discussing on Monday the effects of T and B cells on post-stroke infarction size, I decided to look for more research on stroke and immunosuppression. This article is very interesting:

"Immunosuppression promotes endogenous neural stem and progenitor cell migration and tissue regeneration after ischemic injury" Anna Erlandsson, et al. Experimental Neurology: 2010.

The article first describes how recent work has shown that growth factor infusion post stroke can increase repair in the brain by activating endogenous neural precursor cells that will aid in new tissue formation and functional recovery. This paper investigated whether or not immunosuppression would mirror the effects of growth factor infusion. They used both a drug induced (Cyclosporine A) immunosuppressed model and a SCID model (in mice). They found that immunodeficiency (drug induced and SCID) had near the exact same effect as the growth factors. However, there was a physical difference. The immunodeficient mice had their cortical cavity formed with tissue containing glial cells and subependyma derived neural stem and progenitor cells, but NO new neurons. The growth factor model had the stem cells, progenitor cells, AND new neurons. Surprisingly, both the growth factor treated and immunodeficient mice displayed the same functional behavioral recovery despite the lack of neurons. (Neural precursor cells migrate from lateral ventricle lining)

This is exciting search, and could have powerful clinical manifestations. I invite anyone that is interested to take a look at the article and the figures. There are some very good pictures of the brain infarct sizes and clear immunocytochemistry pictures.

E-selectin a vaccine for stroke..

Research had been done to show that tolerance to E-selectin in rats can have a preventative and protective effects on ischemic stroke. But can this research lead to a possible vaccine against stroke in humans? E- selectin is a cytokine inducible adhesion molecule that is expressed when the endothelium is activated by inflammatory stimuli such as IL1 or tumor necrosis factor. In the research article “Mucosal tolerance to E-selectin provides cell-mediated protection against ischemic brain injury,” the researchers investigated wether E-selectin tolerance in spontaneously hypertensive-genetically stroke prone rats could decrease ischemic stoke injury. They suggested that E-selectin tolerance could lead to redirecting regulatory T-cells to activating blood vessels and releasing anti-inflammatory factors and thereby decreasing stoke injury.

To support this, the researchers created 7 groups of SRH-SP rats. The first two groups were the control single and booster groups, given PBS. The next two groups were the single and booster active tolerization groups that were given E-selectin intranasaly. The last three groups were the adaptive tolerization groups that were given cells from the active groups. The single tolerization groups were given E-selecting every other ay for 10 days and the booster groups followed the same schedule but it was repeated after 11 days. After tolerization, the middle cerebral artery was surgically occluded and 6 to 48 hours later the rats were killed to be examined.

As a result, they found that infract volume was significantly decreased in booster rats, but not much in single tolerization group and no difference was found in the PBS control groups. In the active booster group, a 45% decrease was observed and in the adoptive booster groups a 35% decrease was found. They also found an increased concentration of IL 10, an anti-inflammatory factor released by T cells. Since the same effect was found in active and adoptive groups, it supports the idea at this protection is most likely cells mediated.

This and other studies shows that tolerizing for E-selectin can have a protective effects after stroke in rats but claiming it to be a possible vaccination for stroke is a far stretch. First, this study is done on rats and a human study may not have the same results. This time of tolerance is very difficult to create in humans and therefore this would not be successful. Also, this type of intervention that takes place before a stroke has occurred is hard to implement since we do not normally know who and when a person is going to have a stroke. More research needs to be done to establish effects of this therapy in humans.

Babies benefit from their mother's getting flu shots!

In a study published in the Archives of Pediatric and Adolescent Medicine, U.S researchers found that unborn children benefit from their mothers getting their flu vaccination. The study population was obtained from the Navajo and White Mountain Apache Indian Reservations- whose children are more prone to experience severe upper respiratory infections than the general population. Over three flu seasons, it was found that babies whose mother had been vaccinated were 41% less likely to get the flu, and were 39% less likely to be hospitalized for flu-like illness. The most important finding to back up these statistics, was that those babies had higher levels of flu antibodies at birth at 2 to 3 months, compared with babies whose mothers did not get a flu shot.
As we have learned in class, this time period of 2 to 3 months occurrs during the time that is critical when babies start to make their own IgG at 3 months (mom's is declining), and when babies begin to be most vulnerable to illness. Now pregnant mom's know they can protect themselves from the flu, as well as their child. A two for one!

Let's play doctor!

I was a huge fan of the TV show, Dr. House. Actually, while living in the dorm my freshman year, it was the traditional gathering time of many physiology dorks in our room (we were the first to get a big TV). I always loved, that it played out like a terribly convoluted and unfortunate case study. And, in the days when the disease was the antagonist, Dr. House played an unlikeable, static, yet ultimately pitiable protagonist it made for rather compelling TV. I began thinking the other day, we are all unique, so when we get sick truly no two cases will ever be identical. So, I bring this up for everyone to ponder for a bit.

An otherwise healthy, young, athletic Type I diabetic goes to the ER with abdominal pain. The patient has not eaten for two days, has a fever over 101 and the pain is in the RLQ. Having the most advanced (read expensive) medical system in the country where this occurred, the ER doctor orders blood work, X-ray, and ultrasound. The blood work shows elevated CRP, and a slightly elevated leukocytes, the X-ray shows nothing interesting, and the ultrasound shows a hard mass in the appendix. So, the surgeons are called and are more than happy to extract the troublesome vestigial organ.

Imagine you are an internist, considering the following what challenges might this patient face while going into surgery? What steps would you take before the patient goes to the OR?
Remember:

• The patient hasn't eaten for two days, and after the surgery it will be at least three.
• The patient's diabetes is under control with an insulin infuser (pump), and shows no secondary complications from the disease.
• Due to the infection, there is a marked increase in pro-inflammatory factors.

Immune Reconstitution Illness

I was consulted on a patient with lymphoma, who developed a lobar pneumonia-an infection that affected about 1/5 of his lung tissue. His immune system had been weakened by the lymphoma, and chemotherapy, but his bone marrow was recovering, and his white blood cell count was improving. He was treated with antibiotics, and was slowly improving. His hematologist found that his blood levels of IgG were very low-a common finding in lymphoma. He wanted to treat the patient with intravenous immune globulin, but the patient refused, because he is a Jehovah’s witness (a religion that proscribes transfusion of any human cells, products, or tissues, including IVIG). His team really wanted to help him get better, so they asked if he would accept treatment with filgrastim, a molecule that stimulates neutrophil production. Since this did not come from another human, he accepted. Two days later his lungs became inflamed, filled with water, and he had to be placed on a ventilator.
What happened?
Most of the clinical signs and symptoms of infections are due to the inflammatory response to the infection. When his neutrophil count increased suddenly and massively, neutrophils attacked his infected lungs. There are other examples of this that are well described. The most well known occurs in patients with AIDS. When patients with advanced AIDS are treated with antiretroviral therapy, a few will develop immune reconstitution illness-a reaction to organisms that were already present, but not clinically apparent because there was no inflammatory response to them. Zidovudine, (AZT) was the first drug we had to treat HIV infection, in 1988. It was a pretty weak antiretroviral, but in a small number of patients, after it was started, an immune reconstitution illness was observed. They developed local soft tissue abscesses with mycobacterium avium complex, a bacterium that usually affects the bloodstream and liver, and is manifested mostly by fever. In these cases, immune function improved somewhat, and attempted to localize the bacteria in a soft tissue abscess. In the early 1990s, when this occurred, the number of cases was small, and little was made of the observations. Later, when we developed really potent antiretroviral therapies, immune reconstitution inflammatory syndrome (IRIS) was seen in many cases, and became scientifically accepted.
Leukemia patients sometimes will have fevers when their white blood cell counts are low, but no identifiable iinfection source. When their bone marrow recovers from chemotherapy, candidal abscesses appear in the liver. The candida (fungus) was there all along, but we could only “see” it when their neutrophils responded to it with inflammation.
So, did my patient have an immune reconstitution illness? Maybe-it is hard to say in a single case, but it seems plausible.
The follow-up? The patient recovered, the ventilator was removed, and he was discharged from the hospital.

Cytokines in stroke

Many studies have been done with the relationship of cytokines and the neurological worsening of stroke, but it seems there is never a final conclusion. Cytokines are shown to be released after an ischemic stroke takes place, they can either be pro or anti inflammatory markers. One study, by Nicolas Vila M.D., showed the potential benefit of the cytokine Interlukin-10. IL-10 is an anti-inflammatory marker that shows to have a correlation with stable or improving neurological damage after stroke. The patients that experience worsening symptoms have lower IL-10 levels in their plasma as compared to those who were stable or improved. This article seems like it could come to a good conclusion, until you look further into the details. Like many articles written, variables in the experiment are not fully noted and when not mentioned give a false sense of conclusion.

This study took patients plasma upon entry, but in detail this time lapse was very large. Patients plasma was taken from 80% of the patients with in 12 hours. Although 80% seems like a great number, what about 12 hours, could that potentially lead to false data from the degeneration of those cytokines. Secondly the plasma was frozen "immediately" after, for them this means there could have been a delay of up to 14 hours. These 14 hours many things could change the composition of the blood. Once they finally got the blood into the freezer it stayed there for 5-7 years. Again, change in composition is very likely in that time period.

Not only does the issue of plasma arise in this article but the main characteristics for the population studied shows significant flaws. The average age of the worsening patients was 8.5 compared to stable being 68.2. This mean age is very significant and is not at all mentioned in the actual text. Not to mention the systolic and diastolic blood pressure of worsening group was 60/1.7, obviously experiencing a lot more severe of a stroke than those with the blood pressure of 160.9/92.1 of those that remained stable. Along with this the mean temperature for those that worsened was 7.8 degrees Celsius compared to 36.8 degrees Celsius in those that were stable. Since these patients have mean numbers of a person that is in a coma or dead. So no wonder there has been no conclusion drawn about cytokines if studies like this are being produced.