Immunodepression Greatly Increases Risk for Either Stroke

As we continue to discuss and become informed about stroke, it is quite evident that the immune system plays a role in both pre stroke and post stroke conditions.  As discussed last week by specialist Juliet, we have been able to demonstrate that induced immunodepression after an ischemic stroke event has both positive and negative effects in rodents.  While it increases susceptibility to infection, it can potentially suppress autoagressive responses catalyzed by inflammation that are very possible to occur with the formation of lesions after an ischemic brain infarction.  Diving into that article really got me wondering about the potential connection between our immune systems and stroke.  One of the best ways to see this connection is to take a look at a study done by the University of Kentucky's Department Neurology in which they review "Stroke in HIV Infection and AIDS".  If we take away the immune system, do stroke risk-factors change?

In this study, the doctors from the University of Kentucky analyzed multiple cohort and case-control studies that were completed from the United States, Europe, Asia, Australia, and most importantly, Africa.  With the analysis of each study, it has been made statistically significant that advanced HIV infection and AIDS lead to "opportunistic infections, intracranial malignancies, marantic endocarditis, cachexia & dehydration, and coagulation abnormalities" which lead to significantly increased risk for either type of stroke in younger populations (50 and younger) not otherwise significantly affected by stroke (Dobbs 1263).  The researchers crunched numbers from these cohort studies and point out (just to name a few) that the prevalence of HIV in young stroke patients from KwaZulu Natal, Africa is 16% while it is around 6% (lower yet still significant) in Cape Town, South Africa (Dobbs 1264).  In addition to the significant prevalence of HIV/AIDS in these young stroke populations, the researchers very animately declare that instead of the "typical risk factors for ischemic stroke [hypertension, diabetes, hyperlipdemia, and smoking]" we see significant levels of infectious meningitis/vasculitus (28%), coagulopathy (19%), cardioembolism (14%), and multiple etiologies (11%) as risk factors for stroke (Dobbs 1264).

So now we can see the difference in the dynamic that HIV/AIDS both bring to induce similar results in young stroke patients that typical stroke patients experience from a completely different set of risk factors.  The researchers bring to light that these similar results come from HIV-associated vasculopathy:  Small-vessel vasculopathy as well as medium/large vessel vasculopathy to vessels in the Central Nervous System (Dobbs 1266-1267).  In short, altered (deficient) levels of CD4 cells and Protein S help to set the table for conditions that promote alternative vasculopathy which leads to "small-vessel-wall thickening, perivascular space dilation, rarefaction and pigment deposition" as well as "medium-vessel occlusion or significant stenosis of the extracranial carotid artery" (Dobbs 1267).  To bring all of these findings together, the researchers point out that the mean age of HIV-infected stroke patients is 33.4 years (19-74 range) while non HIV-infected stroke patients averaged the age of 64 years (17-96 range), (Dobbs 1267).

In previous discussions we've seen and defined typical risk factors for both ischemic and hemorrhagic strokes.  Now we see what happens when the immune system is pretty much eliminated from the equation.  What do you think about these findings?  More importantly, what other links can be found between either type of stroke, inflammation, and the immune system?

Dobbs, Michael, and Joseph Berger. "Stroke in HIV Infection and AIDS." Expert Reviews. 7.10 (2009): 1263-1271. Web. 6 Oct. 2013. <http://www.osuem.com/downloads/resources/AIDSandstroke.pdf>.

C-Reactive Protein: A Simple Test to Help Predict Risk of Heart Attack and Stroke

The major topic of this article is discussing C-Reactive Protein (CRP) and its relationship to stroke.  In order to determine whether a patient is at high risk for stroke, physicians have started to measure their CRP levels.  This test is simple and inexpensive and should be used along with cholesterol evaluation.  An individual is at low risk for stroke if their CRP results are less than 1mg/L.  However, an individual is at a moderate risk if CRP levels are between 1 to 3 mg/L, and at high risk if greater than 3mg/L.   

Everyone’s body produces CRP, but the amount produced depends on a variety of factors.  Several factors include genetics, lifestyle habits, weight, and nutrition. Someone that is overweight and has high blood pressure will exhibit higher levels of CRP than someone that is fit and has lower levels of blood pressure.

 CRP plays a role in inflammation, wound healing, and warding off bacteria and viruses.  Studies show that too much inflammation can affect the blood vessels that carry oxygen and nutrients to all the tissues of the body, leading to stroke or heart attack.  In addition, not only can levels of CRP determine your risk for stroke, it can also be used to determine your risk of developing type-2 diabetes.  The authors mention, “Individuals with CRP levels greater than 3mg/L have a risk of getting diabetes 4 to 6 times higher than individuals with lower levels of CRP.” (Ridker)

As I mentioned in class, I do not believe that measuring CRP levels is a good indicator of stroke because CRP levels can also be influenced by other factors. However, I do believe that people should have their CRP levels checked in order to maintain relatively low levels of CRP, as high levels can be detrimental to overall health.  Also, the authors state, “Elevated CRP levels predict risk over the next 30 to 40 years.” (Ridker)

Ridker, Paul M. "Circulation." C-Reactive Protein: A Simple Test to Help Predict Risk of Heart Attack and Stroke 108 (2003): E81-85. Web. 4 Oct. 2013. <http://circ.ahajournals.org/content/108/12/e81.full.pdf+html>.  

Location, Location, Location!

Our environment can have a profound effect upon our systemic health, but our enteric environment, and its flora may have even greater effects. Intestinal microflora is heavily regarded for its impact upon systemic health and contribution to inflammation.  "Resident luminal bacteria seem to be an important factor in the development of IBD [irritable bowel disease] and its chronicity," (1).  In ulcerative colitis, germinated barley foodstuff, or GBF, is found to exhibit a therapeutic-level effect.  GBF is a glutamine-rich protein made from certain fractions of malt, milled and sieved after beer production.  GBF was found in this study to reduce the inflammatory epithelial response on colitis.  Stat-3 expression and NFKB binding activity were found to be inhibited possibly by reducing bile concentrations.  The action of GBF is thought to be its conversion to lactate and acetate by bifidobacterium and lactobacterium which help to preserve the enteric environment.  GBF is considered a "prebiotic."

1. Germinated barley foodstuff, a prebiotic product, ameliorates inflammation of colitis through modulation of the enteric environment. Osamu Kanauchi, Journal of Gastroenterology

February 2003, Volume 38, Issue 2, pp 134-141

Gluten Glutton Beware!

Biopharmacy will soon predominate treatment once the genome is mapped and DNA packets are linked to specific diseases.  Even within diseases there are disease subtypes, or immunogenotypes.  One disease whose HLA (human leukocyte antigen) has been immunogenotyped, irritable bowel syndrome with diarrhea with HLA-DQ/8-positive, was found to be particularly vulnerable to mucosal permeability.  Although the effects of gluten intake have not been widely studied, in this study, "It is plausible that the link between gluten or gliadin and inflammation may be the increase in intestinal permeability, which is well established in celiac disease," (1).  Looking also to the role of gluten in metabolic syndrome with the contribution of obesity to inflammatory sequelae, another study found, that "gluten-free animals showed a reduction in body weight gain and adiposity, without changes in food intake or lipid excretion.  These results were associated with up-regulation of PPAR-alpha, LPL, HSL and CPT-1, which are related to lipolysis and fatty acid oxidation," (2).   Between these two studies an alert is sounded to the likely role of gluten in inflammation.

1. Association of HLA-DQ gene with bowel transit, barrier function, and inflammation in irritable bowel syndrome with diarrhea  Maria I. Vazquez-Roque, et al American Journal of Physiology - Gastrointestinal and Liver PhysiologyDec 2012,303(11)G1262-G1269;DOI: 10.1152/ajpgi.00294.2012

2.  http://dx.doi.org/10.1016/j.jnutbio.2012.08.009

A Toast for High-Cholesterol Foods--Red or White Wine?

The auto-oxidation of cholesterol leaves oxysterols in its wake, causing intestinal mucosal damage.  Interleukin-6 and interleukin-8 are found to be upregulated by the presence of these oxysterols (1).  The inflammatory aspect appears dependent upon redox inequilibrium and causes reactive oxygen species to increase as a function of NADPH-oxidase NOX1 activation.  Phenolic compounds extracted from selected Sardinian wines was found to partially inhibit NOX1, while a Vermintino white wine, containing a smaller fraction of phenols, demonstrated lesser efficacy.  Cannonau red wine; however, was seen to completely inhibit NOX1 activation.  Cannonau red wine is not only abundant with higher levels of phenols than the Sardinian wine, but also contains flavonoids.  

1.Biasi, Fiorella, Tina Guina, Marco Maina, Barbara Cabboi, Monica Deiana, Carlo I. Tuberoso, Simone Calfapietra et al. "Phenolic compounds present in Sardinian wine extracts protect against the production of inflammatory cytokines induced by oxysterols in CaCo-2 human enterocyte-like cells."Biochemical pharmacology (2013).

The Darker Side of Chocolate

Although chocolate, especially the darker variety known to contain higher levels of cocoa, is attributed with characteristics of anti-inflammatory flavanols, a recent article, cited below (1) separates the cytokines for which it favorably decreases expression, and those for which it does not.  In this study, healthy subjects are found to experience an increase in the incidence and severity of acne with chocolate consumption.  The culprit? interleukin-1beta and interleukin-10 is stimulated by chocolate consumption.  In chocolate's defense, however, interleukin-22 was downregulated.  The role of chocolate in inflammation continues to vacillate, although its cardioprotective attribute is seldom overlooked by those of us seeking little excuse to enjoy a "healthy nib."

1. Cytokine, Volume 62, Issue 1, Pages 40-43
Stejara A. Netea, Sam A. Janssen, Martin Jaeger, Trees Jansen, Liesbeth Jacobs, Gosia Miller-Tomaszewska, Theo S. Plantinga, Mihai G. Netea, Leo A.B. Joosten

The Latest Look at Curcumin

Pursuing my interest in curcumin, I searched for more recent information regarding its role in inflammation and pharmacology.  More specifically, I have learned that the cytokine TNF-alpha blockers are approved for use by the U. S. Food and Drug Administration for a range of inflammatory conditions.  "TNF dysregulation has been linked to a wide variety of diseases including cancer, obesity, cardiovascular diseases, pulmonary diseases, metabolic diseases, neurological diseases, psychological diseases, skin diseases and autoimmune diseases," (1). Pharmacologic drugs approved include  infliximab, a chimeric TNF antibody; Humira, a humanized TNF-alpha antibody, and Enbrel, which is a soluble TNF recepter-II.  Despite their inflated costs and administration by injection, these drugs have severe adverse effects.  "Some of the important adverse effects most extensively associated with TNF blockers include lymphoma, infections, congestive heart failure, demyelinating disease, a lupus-like syndrome, induction of auto-antibodies, injection site reactions and systemic adverse effects," (2).  These effects are significant to the point of being given a black label warning by the FDA.  By contrast, the study cited below by G. Garwal (1), lends support for the use of curcumin, the inexpensive, natural, and safe component of tumeric, as a natural TNF-alpha blocker.  Curcumin inhibits the production and cell signalling pathways which are activated by TNF-alpha.  Reporting on curcumin's role:  "...curcumin can inhibit TNF-mediated NF-KB action in variety of cell types, (3)...TNF-mediated expression of various cell surface adhesion molecules in endothelial cells is down-regulated by curcumin(4)...A wide variety of cell signalling pathways activated by TNF have been shown to be down-regulated by curcumin; these include JNK, MAPK, PI3K/Akt...In addition, curcumin has also been shown to modulate TNF-alpha by directly binding to the ligand,(5)." 


1.  ggarwal, B. B., Gupta, S. C. and Sung, B. (2013), Curcumin: an orally bioavailable blocker of TNF and other pro-inflammatory biomarkers. British Journal of Pharmacology, 169: 1672–1692. doi: 10.1111/bph.12131
2.  http://onlinelibrary.wiley.com/doi/10.1111/bph.12131/full#bph12131-bib-0198
3.  http://onlinelibrary.wiley.com/doi/10.1111/bph.12131/full#bph12131-bib-0210
4.  http://onlinelibrary.wiley.com/doi/10.1111/bph.12131/full#bph12131-bib-0127
5.  http://onlinelibrary.wiley.com/doi/10.1111/bph.12131/full#bph12131-bib-0084