Stroke Pathophysiology

            I thought this would be a nice play by play of the cascade of things that occur in the event of a stroke. First, a little background of the types of strokes again:
            There are two types of stroke, ischemic and hemorrhagic. 80 percent of strokes are ischemic in nature where "decreased or absent circulating blood deprives neurons of necessary substrates," whereas hemorrhagic stroke (15-20 percent) causes "disrupting of connective pathways" leading to "localized pressure injury." Ischemia can affect the brain rapidly because the brain does not have an independent supply of glucose and does not anaerobically metabolize. In the case of a hemorrhage, this becomes a much slower process because the effect on the brain is prolonged. However, both types induce a release of factors that in turn play major roles in the destruction of brain tissue.
            In class I presented that there were two subtypes of ischemic stroke, either focal or global, which led into one of the reasons why the model for the study done by Leslie Ritter was highly valuable. Global ischemia is just caused by "profound reduction in systemic blood pressure due to any reason," also known as hypotension (found on page 7 where hypotensive stroke is discussed) Focal ischemia normally happens as a result of a thrombus or an embolus. A thrombus is a "solid mass of platelets and/or fibrin (and other components of blood) that forms locally in a vessel" and an embolus is "often a piece of a thrombus that has broken free and is carried toward the brain by the bloodstream" (refer to #2 in references for more info). whether it be caused by a thrombus or embolus, injury to the brain is determined by parameters such as rate of onset and duration, collateral circulation, health of systemic circulation, hematologic factors, temperature, and glucose metabolism. For further understanding of these parameters look to page 2 of the article under Focal Ischemic Injury. No matter the source of the stroke (ischemic, hemorrhagic, focal, or global), the following changes happen in attempt to reach homeostasis:
            The reduction in cerebral blood flow causes vasodilatation of the surrounding vessels as a compensatory mechanism, but if the rate of flow is too low (less than 20 ml/100g/min) then electrical output is skewed to save energy. This leads to neuronal injury, which can be initiated through several excitotoxic mechanisms that the paper highlights in detail ranging from prolonged opening of calcium channels to the inflammatory response. There was great emphasis on the endothelial response at all levels of organization in regards to its promotion of inflammation. This reminded me of the necessity to know timing of post-ischemic events for optimization of treatment talked about in both mine and Carl's articles.
            We briefly covered what a penumbral region was with Dr. Cohen in class, but the section called Ischemic Penumbra (IP) elaborates upon what constitutes this region. It is generalized by ineffective autoregulation, meaning there are no compensatory measures in this area. This is due to the reduction in cerebral blood flow that falls to a quarter or half of what is physiologically normal.
            The IP is the primary region that experiences cell death by one of two known processes in regards to stroke. The first is Coagulation Necrosis (described on the bottom of page 4 in the article) where the cells are severely damaged and basically condense to nothing. The second, we all should be familiar with- Apoptosis in which the cells are programmed for death by the inflammatory response. Apoptosis by inflammatory targeting was shown to occur within the hour after ischemia, whereas coagulation necrosis did not begin until six hours after.  Once I read this, the importance of understanding the relationships between inflammation and stroke became apparent to me. If the cell programming could be rewired to hinder or slow the inflammatory response by modification or inhibitory measures, then neuronal injury could be greatly reduced or at best case avoided.
            Sid Shah created an outstanding schematic of the pathophysiology of stroke by the collaborative knowledge he obtained from 50 scholarly articles. This was such a great help at grasping the concepts and mechanisms behind how stroke is initiated, what happens during, and terminal effects post-ischemia. If you happen to read it, or even just my blog, please let me know your thoughts.

References:

1) Shah, Sid. "Stroke Pathophysiology." Foundation for education and research in neurological emergencies [FERNE]: 1-14. web. 13 october 2013. http://tigger.uic.edu/com/ferne/pdf2/saem_0501/shah_stroke_saem_0501.pdf

2) http://www.umassmed.edu/strokestop/module_one/thrombus_embolus.html

IBD IS NOT IBS!

After being assigned this topic, it came to my attention that Inflammatory Bowel Disease, aka IBD, is not the same as Irritable Bowel Syndrome, aka IBS. First and foremost, IBS is not a disease, it is a syndrome, as it's name suggests. The difference between a syndrome and a disease is that a syndrome is a set of symptoms that occur together, and can increase one's chances of developing a disease. A disease on the other hand is a diagnosed impairment of one's health. The commonalities between IBD and IBS are that they both share symptoms of abnormal bowel functions such as pain and/or discomfort in the abdominal area. Irritable Bowel Syndrome does not, however, exhibit any structurally abnormalities that are associated with Inflammatory Bowel Disease such as the existence of Polyps. Also, IBD is associated with inflammation and ulcerations of the mucosa layers of the colon whereas IBS does not exhibit these characteristics. Furthermore, IBD is subdivided into two categories: Ulcerative Colitis and Crohn's Disease.

Another distinguishing factor between IBD and IBS is that IBS is not limited to a homogenous group of individuals, meaning that anybody can develop the clustering symptoms associated with IBs. Whereas IBD is typically seen in individuals of Caucasian and Jewish descent, in women who have a family history of IBD, in higher socioeconomic status, and of individuals in well developed countries.

What intrigues me most is that IBD is common in individuals of higher socioeconomic status. What do you think a reason for this is?


1.) Bradesi, Sylvie, James A. McRoberts, Peter A. Anton, and Emeran A. Mayer. "Inflammatory Bowel Disease and Irritable Bowel Syndrome: Separate or Unified?" Medscape Multispeciality (2003): n. pag. Medscape Log In. Web. 13 Oct. 2013. <http://www.medscape.com/viewarticle/457728>.
2.) "Difference Between Syndrome and Disease." Difference Between Similar Terms and Objects. DifferenceBetween.net, n.d. Web. 13 Oct. 2013. <http://www.differencebetween.net/science/health/difference-between-syndrome-and-disease/>.

Intracerebral Hemorrhage Triggers Interleukin-6 and Interleukin-10 Release in Blood

            Recently cytokine levels and its relationship to stroke has been an area of interest for researchers.  “The goal for this study was to determine the serum level of interleukin-6, interleukin-10, and interleukin 13 in patients with intracerebral hemorrhage and to correlate cytokine concentrations with stroke severity.” (Dziedzic, et.al)  From previous studies, it has shown that systemic anti-inflammatory response may be induced by acute brain injuries.  To test their hypothesis, researchers tested 30 patients (17 men, 13 women) that had supratentorial, intraparenchymal cerebral hemorrhage.  In addition, researchers also contained a control group with 16 patients.  For this study patients with cardiac, renal, hepatic, autoimmune, or cancerous diseases were excluded.  As we mentioned in class, it is important to remove these patients because it will minimize factors influencing cytokine levels. 

            Under the “subjects and methods” portion of this article, it discusses the various tests the patients underwent.  Within 24 hours after stroke, all patients were required to have a brain CT scan.  “To estimate the magnitude of brain injury, they used 2 parameters: volume of hematoma and mass effect.” (Dziedzic, et.al)  As for neurological deficit, researchers used the Glasgow Coma Scale (GCS).  “The GCS is a neurological scale that aims to give a reliable, objective way of recording the conscious state of a person for initial as well as subsequent assessment.” (Wikipedia)  The blood of both patients and controls were drawn on the second day at 10AM via the antecubital vein.  I thought it was a good idea that both groups had their blood tested at the same time and day, because it allows for more accurate results that can be compared. 

            From this study, researchers recognized that IL-6 and IL-10 levels were higher in patients with intraparenchymal hemorrhage than the control group.  Even though the mechanism of how these increased cytokines are released is unknown, we can see that IL-6 and IL-10 levels are correlated with brain damage.  In addition, based off this article, we can see that elevated concentrations of anti-inflammatory cytokines may increase the patient’s risk for an infection.     

Dziedzic, Tomasz, Stanislaw Bartus, Aleksandra Klimkowicz, Maciej Motyl, Agnieszka Slowik, and Andrzej Szczudlik. "Intracerebral Hemorrhage Triggers Interleukin-6 and Interleukin-10 Release in Blood." (n.d.): n. pag. Stroke, 2012. Web. <http://stroke.ahajournals.org/content/33/9/2334.full.pdf+html>.

"Glasgow Coma Scale." Wikipedia. Wikimedia Foundation, 10 Mar. 2013. Web. 13 Oct. 2013. <http://en.wikipedia.org/wiki/Glasgow_Coma_Scale>.

            

Crohn's Disease

A Crohn's disease is a inflammatory bowel disease that about 700,000 people in the US have and follow them in their life time. The disease is mainly affecting any tissues running from the mouth to anus making them inflamed. During these times the inflamed tissue would not be able to function normally. Many cases have patients come with with just the disease affecting the small intestine and the beginning of the colon. The symptoms that comes with this disease are stomach pain, diarrhea and rectal bleeding, etc. The best way to know if you have this disease is to have a colonoscopy performed.

The causes of Crohn is that the immune system starts attacking the bacteria that are already in our bodies that help us digest food. Mainly is this a genetic disorder that runs in families and the symptoms will start to happen as lowest as the age of 13 years old. The people who have this disease can watch their diets and life habits to manage their symptoms from getting worse like spicy food and drinking could trigger the symptoms of the disease to worsen.

Sadly for those people who have this disease there is no cure as of right now. There are treatments for Corhn's disease, which is to take medication to reduce the symptoms and sometimes the medication doesn't help the patient, so surgery is performed to remove the diseased section of the intestine. About 70 % of the people who have the Crohn's disease will undergo surgery some point in their life because of the symptoms worsening and medication couldn't help at all.

I thought the article was pretty helpful on understanding the basics of the Crohn's disease. For the general public this would be a good article to get a broad description of what Crohn's disease is and what are the causes of the disease along with testings to identify if one has such disease or not. If I was an average person reading this it would give me insights of this disease and what my choices could be for treatment if I happen to have such disease, so I would not be going into the doctors blind. 

Zanni, Guido R. "Crohn's Disease: Symptoms and Treatment." US News. U.S.News & World Report, 03 Aug. 2013. Web. 13 Oct. 2013.

The Impact of IL-6 on Future Aging Phenotypes

The Impact of IL-6 on Future Aging Phenotypes

Interelukin-6 is a proinflammatory cytokine. It is also known that IL-6 stimulates other downstream inflammatory markers like C-reactive protein and fibrinogen. A recent study has determined that chronically elevated levels of IL-6 are associated with unhealthy aging phenotypes and a decreased likelihood of successful aging.

This study was conducted over 10 years. I now appreciate this length of time more after reading previous research articles and comparing the span of this study to others. Additionally, the researchers included 3,044 participants in their study. I believe this is a substantial number of human participants and that this contributes to the credibility of their findings. The 3,044 included had no history of stroke, cancer, or myocardial infarction.

IL-6 was measured in the participants by using high sensitivity enzyme linked immunosorbent assay every five years for a period of 10 years. Health behaviors such as smoking status and activity level were also taken into consideration. Sociodemographic data on the participants’ age, sex, socioeconomic status was collected. At the 10 year follow up the patients were classified as one of four aging phenotypes: successful aging, normal aging, fatal or nonfatal cardiovascular disease (CVD) event, or non-CVD death.

There were 721 participants that were classified as successful aging, 321 had CVD events, 147 died from non-CVD events, and 1,855 were classified as normal aging. The IL-6 levels were compared between the four phenotypes. It was found that participants with high IL-6 at the baseline were significantly less likely to achieve successful aging, an increased risk of a CVD event, or death from a non-CVD cause over the 10 year follow up period. Additionally, participants with high IL-6 once or twice over the 5-year evaluation periods were less likely to achieve successful aging, increased risk of a CVD event, and increased risk of death from a non-CVD cause. High IL-6 levels measured twice over the 5-year exposure period were associated with half the odds of successful aging. The associations found were independent of socioeconomic factors, health behaviors, health conditions, and the use of inflammatory drugs. More simply, the results suggest that maintaining low IL-6 levels reduce the likelihood of impaired musculoskeletal and respiratory functioning and increase the likelihood of remaining diabetes free.

I thought the study was interesting and verified the relationship between IL-6 and chronic inflammation that we have discussed with previous articles. However, one important limitation of this study that the researchers noted is that elevated IL-6 levels at the beginning and end of a 5-year exposure period should not necessarily be regarded as an indicator of chronic inflammation, because repeated short-term inflammatory responses are also possible.

Sources:

Akbaraly, Tasnime N., Mark Hamer, Jane E. Ferrie, Gordon Lowe, G. Batty, Gareth Hagger-Johnson, Archana Sing-Manoux, Martin J. Shipley, and Mika Kivimaki. "Chronic Inflammation as a Determinant of Future Aging Phenotypes." Canadian Medical Association Journal (2013): n. pag. 16 Sept. 2013. Web. 11 Oct. 2013.

INFLAMMATORY BOWEL DISEASE: IMMUNOBIOLOGY AND PATHOPHYSIOLOGY

This is a review of the upcoming presentation upon "Inflammatory Bowel Disease:  Cause and Immunobiology," being posted in two parts due to the size of the article, cited below.  Here I will cover the second part, immunobiology and pathophysiology.

Immunobiology -- A healthy enteric immune state has, at its foundation, the capacity to prevent inflammatory cytokine release and mediate damage.  The gut is an exernal environment assaulted with high loads of antigens but also harbors the largest and most diverse microbiota of over 500 species of bacteria.  In a healthy immune state, no inflammatory response is activated, whereas the pathophysiology of IBD results in a hyperactive immune state and subsequent alignment of histamine and neurokinin and leads to mesenteric pain. Commensal bacteria modulate gene expression in nutrient absorption, mucosal barrier reinforcement and postnatal intestinal maturation.  The symbiotic relationship is established during the first two to three years of life.  During colonization, the mucosal immune system matures and oral tolerance is established. Intestinal epithelium serves as a defensive barrier.  Defective mucus production is part of the pathophysiology of people with Crohn's and UC.  

Specialized Paneth cells produce antimicrobial proteins against gram positive and gram negative baceteria which regulate microbial density and protects nearby stem cells.  Pattern-recognition receptors identify microbe-associated molecular patterns.  NOD proteins are located in the cytoplasm of antigen-presenting cells that have been exposed to peptidoglycans.  They are usually little present in intestinal epithelium but NOD 1 and 2 rise upon insult by inflammation and inflammatory cytokines.  NOD 2 is found in Paneth cells and stimulate NF Kappa B.  

Mucosal lymphoid tissues contain T cells, B cells, granulocytes, mast cells, NKCs and NK T cells.  Highly-specialized enterocytes reside between the epithelium and lymphoid tissue.  By their structure and function, villi cells channel antigens to Peyers patches, lymphocyte clusters where antigen-presenting cells are present. Of these, dendritic cells open tight junctions between epithelial cells and directly sample bacteria without compromising the barrier.  In this way, immunity is maintained against pathogens and tolerance toward commensals.  

Pathophysiology -- IBD results from inappropriate response of a defective mucosal immune system to normally-existing flora and antigens.  Several interacting pathways may trigger inflammatory cascades.  Seven system malfunctions are identified in the pathophysiology of IBD:

• People with IBD have leaky epithelial barriers and these precede disease onset.  The mechanism is hypothesized to be a result of T cell disruption of tight junction proteins to enteric neuron dysfunction.
• The innate immune mechanism of the epithelial layer is also disturbed, with different TLR expression patterns than those in healthy subjects.
• Dendritic cells may not recognize commensal bacteria and thereby cause a proinflammatory response.
• Non-professional antigen-presenting cells which normally produce inaction become potent effector T cell activators in people with IBD.
• Activated T cells persist rather than undergo apoptosis.
• The balance of regulatory and effector T cells is disturbed in IBD to the favor of effector T cells.
• Psychological stress triggers through the vagus nerve an inflammatory response that induces cytokine production.  In UC, stress causes paracellular permeability.

The article is very well written, provides excellent and fine detail in special blocks, pros and cons, hypothetical information and clearly understood figures.  I do hope you will take the time to look into the article.  I look forward to your questions and comments.

Baumgart, Daniel C., and Simon R. Carding. "Inflammatory bowel disease: cause and immunobiology." The Lancet 369.9573 (2007): 1627-1640.

INFLAMMATORY BOWEL DISEASE - CAUSES

This is a review of the upcoming presentation upon "Inflammatory Bowel Disease:  Cause and Immunobiology," being posted in two parts due to the size of the article, cited below.  Here I will cover the first part, causes.

Two main inflammatory bowel diseases (IBD), Crohn's disease and ulcerative colitis (UC) are idiopathic.  Environmental factors, infectious microbes, ethnic origin, genetic susceptibility, and a dysregulated immune system result in mucosal inflammation.  What events initiate and perpetuate this inflammation?  In part two I will discuss immunobiology and pathophysiology.

Epidemiology -- High risk groups for both diseases include northern Europe, the UK, and North America, which is stabilizing.  The growth rate in low-incidence areas of southern Europe, Asia and developing countries is on the rise.  Disease location and extraintestinal complications are seen to co-localize for disease type, pattern, and extaintestinal disease dependent upon race and ethnic origin.

Genetics -- IBD subtype susceptibilities range from IBD1-9.  Currently 12 chromosomes have been identified as being affected.  Family history is the largest risk factor, with Crohn's patients have a first degree relative in 2.2-16.2% of cases and IBD in 5.2-22.5% of cases.  When a sibling has Crohn's, the risk is even higher.  Monozygotic twins demonstrated 37.3% concordance and dizygotic twins 7% for Crohn's.  Ulcerative colitis patients demonstrate similar familial distribution patterns with lower percentages.  Overall, Crohn's is demonstrated to have more of a genetic contribution than UC, with multiple gene products contributing to the risk.

Biochemistry -- Polymorphisms on chromosome 16 may affect signal transduction, epithelial-cell integrity and carnitine transport in lipid metabolism.  Two types of pattern-recognition receptors are TLR and NOD.   TLR and NOD interactions with different cell types produce events that are either anti-inflammatory or proinflammatory.  Across all populations and diseases, IBD3 is found on chromosome 6.  Some mutations may even be protective of Crohn's development. NOD has a CARD domain that interacts with adapter molecules to activate NF Kappa B.  TLRs also activate NF Kappa B.  NF Kappa B is involved in apoptosis.

Environmental Factors and Lifestyle -- Variation in access to and quality of healthcare, sanitation and hygiene may impair mucosal immune system function and induce immune tolerance, both of which compromise immune tolerance.  Psychological stress may impact IBD by involving the nervous system.  Typical North American diets, consisting of excess carbs and polyunsaturated fats is associated primarily to Crohn's and contrasts to Asia's low rates where sugar consumption is low.  Smoking accelerates the need for surgery in Crohn's while being protective of UC.  Bacterial infection has unknown impact upon Crohn's, but impairs handling of microbial antigen.  Even appendectomy was shown in epidemiological studies to be protective against UC.  

The article is very well written, provides excellent and fine detail in special blocks, pros and cons, hypothetical information and clearly understood figures.  I do hope you will take the time to look into the article.  I look forward to your questions and comments.

Baumgart, Daniel C., and Simon R. Carding. "Inflammatory bowel disease: cause and immunobiology." The Lancet 369.9573 (2007): 1627-1640.