Inflammatory Bowel Disease: An Overview

Inflammatory bowel disease (IBD) consists of two primary inflammatory disorders – Crohn’s disease (CD) and ulcerative colitis (UC). Given that family history is a major risk factor for the development of IBD, genetics are thought to play an imperative role in establishment of disease phenotypes. On a basic level, IBD is caused by an inappropriate and long-term immune response to commensal microbes. The reality is much more multifaceted, however, with the pathobiology including interaction of genetic factors “with microbial and environmental cues within tissue-specific contexts, the biological checkpoints involved, the selective decisions made during the course of disease and how plasticity of the biological response results in the capacity for different phenotypes” [1].

Due to the complexity of IBD, both CD and UC are currently labeled as idiopathic. Evidence exists that, in addition to genetic susceptibility, environmental factors such as sanitation, hygiene, smoking, and geography can yield mucosal inflammation. Infectious microbes and ethnic origin have also been reported to uniquely affect immune dysregulation and inflammation [2]. UC is distinguished by inflammation that is localized to the colon. Beginning the in the rectum, it spreads proximally. CD is distinct in that inflammation can occur in any part of the gastrointestinal tract, with the most common affected areas being the terminal ileum or the perianal region. Unlike ulcerative colitis, the spread is non-continuous and is frequently associated with “strictures, abscesses, and fistulas” [1].

Through the use of transcriptional profiling of circulating T cells derived from UC or CD patients, Lee et al. was able to identify CD8+ T cell transcriptional signatures that divvied patients into 2 distinct subgroups. UC and CD patients in these subgroups suffered from higher incidences of frequently relapsing disease and had elevated expression of genes involved in antigen-dependent T cell responses. Interestingly, no equivalent correlation was observed for CD4+ T cell gene expression [3].

Numerous other genes have been reported to play paramount roles in mediating these diseases. Given that abnormal intestinal permeability has been observed in IBD patients (as well as their immediate relatives), candidate genes involved in barrier integrity were investigated. Candidate genes that may regulate this process include CDHI, GNA12, and PTPN2. Truncated forms of E-cadherin (encoded by CDH1) have been associated with CD, with intestinal biopsies of CD patients showing inappropriate protein localizeationand cytosolic accumulation. Myriad transcription factors, such as HNF4A (regulates crypt cell proliferation), have been also been associated with IBD [1].

Autophagy, the catabolic process by which a cell degrades its own compartments, contributes both to the recycling and degradation of cytosolic contents and organelles. It also contributes to the removal of intracellular microbes and thus resistance against infection. ATG16LI, a gene essential for all forms of autophagy, appears to play a role in CD. Humans with the coding mutation T300A have an increased risk of Crohn’s disease and mouse models possessing defects in autophagy show abnormalities consistent with CD. Together these data all suggest an important role for autophagy in IBD [1].

In sum, perturbations of the host-commensal relationship caused by environmental and genetic factors lead to the pathogenesis of IBD. Consisting of CD and UC, IBD is marked by inappropriate immune responses to otherwise benign microbes and has been reported to involve alterations in intestinal permeability, autophagy, T cell gene regulation, and many other factors.

Citations:

1) Khor et al. Genetics and pathogenesis of inflammatory bowel disease. Nature 474: 307-217. 2011.

2) Baumgart et al. Inflammatory bowel disease: cause and immunobiology. Lancet 369: 1627-1640. 2007.

3) Lee et al. Gene expression profiling of CD8+ T cells predicts prognosis in patients with Crohn disease and ulcerative colitis. J Clin Invest. 121 (10): 4170-4179. 2011

Ability to Distinguish a Stroke?

I found this article particularly interesting. The article is entitled “Ethnic Disparities in Stroke Recognition in Individuals with Prior Stroke”. The researchers basically asked if people were able to recognize a stroke when it happened in front of them. The researchers also asked if a person who had suffered a stroke could identify a stroke themselves. Therefore, the concentration of the study was to see if further stroke education was necessary in communities. 2,970 subjects were taken as a sample for the study. These individuals were all placed into groups of age, race/ethnicity, income, education, and health. Several other characteristics were taken into account in the study. Health for example was considered just in case if the subject has diabetes, hypertension, or cardiovascular disease.

The study took place through phone completed surveys. The subjects were asked if certain symptoms pertained to stroke. Researchers had previously characterized five symptoms as being central to stroke. They also asked if they would call for emergency assistance or wait for someone else to do so. Surprisingly, the results indicated that only 32% of the subjects correctly identified the five symptoms of stroke (Ellis and Egede, 2008). Then of those 26% would have also called or emergency assistance (Ellis and Egede, 2008).

This study striking with its findings. How could these people not have wanted to call for emergency assistance? This goes to show that further education in stroke is necessary in communities. The basic though and instinct of being a good samaritan would also go far. At an early age, these symptoms could be taught in order to further inform the people. This way people who suffer from stroke can be taken to the hospital and treated faster. It's common sense that your brain needs blood. The more time these people have the more likely they will recuperate from the stroke.

Source Citation

Ellis, Charles and Egede, Leonard E. Ethnic Disparities in Stroke Recognition in Individuals with Prior Stroke. Association of Schools of Public Health Vol. 123: 518-522, 2008.

Types of Stroke

Stroke can be categorized into several different groups. These groups are more commonly known as the types of stroke. By listing this serious topic, it becomes simpler to follow the symptoms and the disease itself. The different types of stroke include ischemic stroke, hemorrhagic stroke, and watershed strokes. There is also another type most commonly referred to as a mini-stroke or transient ischemic attack. Stroke can be defined as a disease characterized by improper perfusion of blood to the brain. Each type is separated by how it causes the improper perfusion. Instinctively, several of these methods can be thought of through the vasculature. The methods that come to mind may include clotting, vessel ruptures, or a clot far from the brain. These methods can all be considered correct.

Ischemic strokes can be characterized by clots and occlusion in a blood vessel of the brain. The clots are mostly caused by atherosclerosis or constant fatty acid deposits. When the clots form they can cause an occlusion in the vessel which disrupts perfusion of blood to that part of the brain. Clots themselves are specific since they can form into a thrombus or an embolism. Think of a thrombus as a clot in the vessel while an embolism is a broken piece of a clot that moves. Embolisms are particularly dangerous since they can stop in the brain or anywhere else in the body through the circulation. Most cases of stroke are ischemic strokes. Hemorrhagic strokes represent blood vessel ruptures. In the brain, high blood pressure can cause swelling of the blood vessels. If the vessels swell far enough they can burst causing hemorrhage. The ruptured vessel no longer works properly and perfusion of blood has been disrupted. These swollen blood vessels are called aneurysms while others are referred to as arteriovenous malformations. Hemorrhage is common in two regions intracerebral or in the subarachnoid space. Watershed strokes are caused by improper perfusion to the brain caused by occlusion far away from the brain. Most often a clot forms in the carotid artery in the neck. The blood would consequently not be able to reach the farther ends of the brain due to lack in pressure.

A transient ischemic attack is commonly referred to as a mini-stroke. These types of stroke are called mini because they are related to ischemic strokes. Like in an ischemic stroke, a TIA is caused by a clot formed in a vessel of the brain which causes occlusion. The difference between these strokes is the time length. A TIA only last a couple of minutes because the clot has been removed and the occlusion stopped. Fortunately, TIA's don't leave permanent damage to the brain.

Although there are several different types of stroke, the symptoms appear similar across the board. Symptoms such as confusion, dizziness, loss of balance, trouble walking, problems speaking, vision problems, and numbness in the face are common in all strokes. Stroke is a serious condition that should not be taken lightly. Knowledge of the types of strokes can assist with a faster diagnosis and faster treatment to the patient.

Sources

http://www.strokeassociation.org/STROKEORG/AboutStroke/TypesofStroke/Types-of-Stroke_UCM_308531_SubHomePage.jsp

http://www.stroke.org/site/PageServer?pagename=TYPE

http://www.neurosurgery.ufl.edu/patients/stroke.shtml

Aspirin Therapy

An article was published in the Journal of the American Heart Association suggesting that early aspirin therapy in stroke patients could be crucial in preventing a second stroke in the following days and weeks. Aspirin is an antiplatelet medication which works to thin the blood and therefore is excellent at preventing clots. The controversy surrounding this treatment is that only ischemic strokes are caused by clotting, hemorragic strokes are caused by uncontrollable bleeding which could worsen if the patient were given aspirin. When it comes to treating a stroke patient it is obviously beneficial to begin treatment as soon as possible and dianosing which kind (ischemic or hemorragic) of stroke has occurred could take a little time. Although the majority of strokes that occur are ischemic, it is extremely important to weigh the risks and benefits of acute aspirin therapy before the treatment of a stroke.

Additionally, long term aspirin therapy has also been proven to thin the blood preventing stroke and heart attack. If a person is at high risk for a blood clot they may be prescribed to take a low dose of aspirin everyday to reduce their risk. Because aspirin is an antiplatelet medication, this therapy may cause increased bruising and complications for people with stomach ulcers or asthma. Abruptly stopping this treatment can cause a rebound effect and potentially cause a stroke or heart attack.

http://www.sciencedaily.com/releases/2000/06/000602073156.htm

http://www.ncbi.nlm.nih.gov/pubmed/9186381

http://www.webmd.com/stroke/news/20000601/aspirin-after-stroke-helps-prevent-another

South Park Tackles the Anti-Vaccine Movement

For those of us in need of a break from this weeks studies, check out last week's episode of South Park in which the plot has some relevance to what will be brought up in lecture this week, the anti-vaccine movement.

Being the first episode for season 15 after the summer hiatus, they continue the story line from the June 8th episode. In it, Stan's continual negativity calls him to the school counselor's office where he gets diagnosed with Asperger's syndrome after it is revealed he was immunized for the flu the year prior. Stan becomes the first confirmed case of Asperger's syndrome caused by a vaccine, and a law is made to ban mandatory vaccines. The planned HPV vaccine for all the school girls at South Park Elementary is assumed to have been canceled, and Cartman tries to cash in on the lawsuits by claiming to also have Asperger's (he thinks it is a condition where burgers grow out of your ass). Mayhem ensues.

Anti-social behavior is a symptom of Asperger's and it is one of several disorder's being blamed on vaccinations by the anti-vaccine movement. Those opposed to mandatory vaccines believe it will cause unknown consequences such as autism and Asperger's. In recent news, one debate among the Republican presidential candidates has been over the imposition of mandatory HPV vaccines to young girls. While there is no science to back the anti-vaccine agenda, the HPV controversy has more to do with parents not wanting to believe their daughters will ever partake in sexual interaction required to contract HPV. The benefits of mandatory vaccines far outweigh the possible consequences, if any even exist.

http://www.southparkstudios.com/full-episodes/s15e08-ass-burgers

Leukotrienes and Asthma

It has long been known that leukotrienes play an important role in the inflammatory effects of asthma. Evidence for their effects have come from studies of inhaled LT4. Inhaled aerosol of LTC4 and LTF4 from a nebulizer in concentrations as low as 10micron have shown to decrease maximal expiratory airflow by as much as 30%. The bronchoconstrictor effects of leukotrienes are as much as 1000 fold more potent than that of histamine. Elevated LTC4, LTD4, and LTE4 have been identified in serum and urine of asthma patients. These findings have led to many experiments over the last 3 decades for antileukotriene therapy. Leukotrienes are synthesized from arachidonic acid by the 5-lipoxygenase pathway. CysLT1 is a leukotriene receptor on the surface of structural and inflammatory cells that mediates bronchoconstriction, mucus secretion, and edema in the airways. CysLT1 receptors are influenced at the transcriptional level by TH2 helper cell cytokines. Select drug antagonists for this receptor block the pro-inflammatory effects. Researchers have been developing drugs aimed at blocking synthesis of chronic levels of leukotrienes and their binding to receptors. The drug Zileuton was developed to inhibit 5-lipoxygenase pathway of leukotriene synthesis. This drug is a powerful blocker of leukotrienes, but it appears that it also causes hepatic toxicity. Two other drugs, Montelukast and Zafirlkukast, were developed and are used as CysLT1 antagonists. All of these drugs have been shown to increase pulmonary function. Montelukast has also been shown to be quite effective in treating exercise induced asthma. The discovery of leukotrienes and their role in bronchoconstriction have uncovered many possible avenues of treatment. Further investigation into the synthesis, receptor binding and effects of leukotrienes in the future may provide even more detailed and focused treatment of asthma that may be tailored to the individual patient.

http://universityofarizona.worldcat.org.ezproxy1.library.arizona.edu/title/leukotrienes

Boron W., Boulpaep E., Medical Physiology: A Cellular and Molecular Approach. 2nd ed., Elsevier 2009.

Breathing insulation and having asthma attacks

I thought it would be a good time to talk about asthma since I have recently been reminded of what it feels like to have frequent asthma attacks. I grew up with very severe asthma and I would like to think that lifestyle changes including eating a better diet and getting more exercise have led to me not having attacks on a daily basis. I have been asthma symptom free for several years until recently. The shop I work in was hit by a so called "microburst" which basically destroyed the shop and the insulation covering all of the interior walls. We have continued to work in the shop and my lungs have been paying the price. The torn insulation has exposed large amounts of fiberglass and when the wind blows there is tiny fiberglass particles floating through the air that inevitably make their way into my respiratory system. Now I have asthma attacks on a daily basis, increased amounts of sputum, and persistent airway obstruction when I am in the presence of the airborne particulates. These events are a stark reminder of the inflammatory processes that are plaguing my ability to breathe normally. When an irritant is inhaled it first enters the nasal turbinates and mouth where it contacts mucus, saliva, and the mechanical action of the tongue. Larger particles are usually trapped there and smaller particles enter the conducting airways where they cause release of cytokines and recruitment of large numbers of inflammatory cells like eosinophils. The particles that reach distal regions of the conducting airways (generation 16) are approximately greater than 5 micrometers. Only particles that are ultrafine, <0.1 micron, can reach the alveolus (generation 17-23). This leads to the development of mucus, buildup of proteins, edema, and sloughing of epithelium, all which contribute to bronchial lumen occlusion. It is cytokines such as IL-4, IL-13 and TNF-alpha released by mast cells and TH2 cells that can upregulate the expression of leukocyte and endothelial adhesion molecules ICAM-1, E-selectin, VCAM-, and LFA-1. These processes facilitate transendothelial migration into the lung tissue, which can be a good thing for trapping inhaled particulates and to cough them out, but when this process is over reactive as is the case in people with asthma then too much edema causes airway obstruction. The good thing about airway hyperreactivity as seen in asthma is that it is generally reversible. I am really hoping that my the exposed insulation situation is rectified quickly and that the mucociliary escalator of my conducting airways can carry out this annoying inhaled irritant from my lungs so that I may return to normal breathing.