For those of you that did not get a chance to read about the so-called "aspartame poisoning," please see Dr. Cohen's post above for the link if you're interested. For those of you that did get the chance to read the lengthy claim, the following was noted at the bottom:
~ The origin of this article does not allow for a list of references for the above claims. In other words, believe at your own discretion. ~
Although this warning was included at the end of my post, I should have conducted some research prior to posting, to ensure the claim's validity. In reading and posting the article I did, I mistakenly fell into the trap that many writers create - I became a member of the lay public, shocked by the possibility that the words I had just read could actually be true! I have recently been enlightened, however, and the article I posted is a hoax. I urge you all to use this incident as an example: many of the articles that you read via the Internet or e-mail do not come with an attached list of references, so next time you read one, ask yourself why the information isn't referenced...it's probably because there's a good chance that the information did not arise from research attributable to various sources. Nevertheless, I found this article to be personally beneficial: it caused me to think about the positive and negative effects of artificial ingredients, about the possibilities of misdiagnoses, and also about the junk that isn't filtered before it reaches the community. I suppose we can't go wrong in being skeptical until we've researched to find the truth.
My apologies,
JessicaR495
24 September 2007
Hygiene Hypothesis
Hygiene Hypothesis: Are higher living standards and hygienic conditions responsible for an increasing prevalence of allergies?
I knew there was a reason I ate mudpies (as a kid)! I’ve even heard this connection thrown out in conversations between friends outside the field of science, and often wondered about the explanation according to immunology. As many of us may know, immunology is a literature base where few of us travel, unless necessary. But this feels like the perfect time to finally check it out.
The ‘hygiene hypothesis’ was first proposed by Strachan in 1989 to explain the relationship between modern healthcare and living practices that have reduced exposure to bacterial, viral or fungal components and increased risk for developing allergic disease. In his proposal, Strachan states that without the presence of these potentially allergy-preventing microbes, the immune system becomes imbalanced and this leads to predisposition to allergies.
Now, without the aid of our future lectures on T-cells and allergies, I will try to explain the details of this hypothesis. The major player of the adaptive immune cells in the initiation and perpetuation of allergies is the Th2 cell (T-helper cell type 2). Th2 cells contribute to the allergic immune response through release of cytokines IL4, IL5, IL9 and IL13 which promote three of the characteristic mechanisms of allergy. These include the shift toward IgE immunoglobulin production, the activity of eosinophils (proliferation, differentiation, recruitment and survival), and mucus production in the airways or gut. Th1 cells (T-helper cell type 1) can abrogate Th2 development and activity by producing the cytokine IFN-gamma. Tregs (regulatory T-cells) can also suppress Th2 activation. Romagnani et al. (2004) suggest that increased Th2 activities (specifically allergic immune responses) result from a decrease in the suppressive activities of Th1 and Treg cells.
Further, dendritic cells of the innate immune response aid in activating T-cells, and have also been implicated in the initiation and perpetuation of allergic immune responses. The types and activation status of the dendritic cell/antigen-presenting cell determines the type of T-cell response. For example, antigens presented in the presence of IL12 lead to Th1 development while antigens presented in the presence of IL4 lead to a Th2 response. Of note, dendritic cells that express surface marker CD11 have been shown as necessary and sufficient for induction of a Th2-driven allergic response. Also relevant to the hygiene hypothesis is that stimulation of antigen-presenting cells through Toll-like receptors (TLRs) leads mostly to induction of a Th1-driven immune response. Remember TLRs bind to pathogen-associated molecular patterns (PAMPs) that are characteristic of bacteria, viruses and fungi. These are the microbes that are missing in our highly hygienic modern environment. So the idea is that exposure at young ages (even in utero) to these microbes primes or activates the immune system in a way (Th1-driven) that prevents allergic sensitization (Th2-driven) later in life.
There are numerous animal studies that have shown this exact phenomena, that exposure to specific microbes (single bacterial strains like Mycobacterium bovis, whole cell vaccines like Bordetella pertussis, and LPS from bacteria, yeast and mycoplasma) exerts allergy-protective effects. Plus several very interesting connections between decreased microbe exposure and increased allergy production have been shown in human data studies (epidemiology). I was more interested in describing the immunologic mechanism for the hygiene hypothesis in this blog entry. However, I suggest reading the terrific review from Garn and Renz (2007), entitled “Epidemiological and immunological evidence for the hygiene hypothesis” for more engaging details.
I knew there was a reason I ate mudpies (as a kid)! I’ve even heard this connection thrown out in conversations between friends outside the field of science, and often wondered about the explanation according to immunology. As many of us may know, immunology is a literature base where few of us travel, unless necessary. But this feels like the perfect time to finally check it out.
The ‘hygiene hypothesis’ was first proposed by Strachan in 1989 to explain the relationship between modern healthcare and living practices that have reduced exposure to bacterial, viral or fungal components and increased risk for developing allergic disease. In his proposal, Strachan states that without the presence of these potentially allergy-preventing microbes, the immune system becomes imbalanced and this leads to predisposition to allergies.
Now, without the aid of our future lectures on T-cells and allergies, I will try to explain the details of this hypothesis. The major player of the adaptive immune cells in the initiation and perpetuation of allergies is the Th2 cell (T-helper cell type 2). Th2 cells contribute to the allergic immune response through release of cytokines IL4, IL5, IL9 and IL13 which promote three of the characteristic mechanisms of allergy. These include the shift toward IgE immunoglobulin production, the activity of eosinophils (proliferation, differentiation, recruitment and survival), and mucus production in the airways or gut. Th1 cells (T-helper cell type 1) can abrogate Th2 development and activity by producing the cytokine IFN-gamma. Tregs (regulatory T-cells) can also suppress Th2 activation. Romagnani et al. (2004) suggest that increased Th2 activities (specifically allergic immune responses) result from a decrease in the suppressive activities of Th1 and Treg cells.
Further, dendritic cells of the innate immune response aid in activating T-cells, and have also been implicated in the initiation and perpetuation of allergic immune responses. The types and activation status of the dendritic cell/antigen-presenting cell determines the type of T-cell response. For example, antigens presented in the presence of IL12 lead to Th1 development while antigens presented in the presence of IL4 lead to a Th2 response. Of note, dendritic cells that express surface marker CD11 have been shown as necessary and sufficient for induction of a Th2-driven allergic response. Also relevant to the hygiene hypothesis is that stimulation of antigen-presenting cells through Toll-like receptors (TLRs) leads mostly to induction of a Th1-driven immune response. Remember TLRs bind to pathogen-associated molecular patterns (PAMPs) that are characteristic of bacteria, viruses and fungi. These are the microbes that are missing in our highly hygienic modern environment. So the idea is that exposure at young ages (even in utero) to these microbes primes or activates the immune system in a way (Th1-driven) that prevents allergic sensitization (Th2-driven) later in life.
There are numerous animal studies that have shown this exact phenomena, that exposure to specific microbes (single bacterial strains like Mycobacterium bovis, whole cell vaccines like Bordetella pertussis, and LPS from bacteria, yeast and mycoplasma) exerts allergy-protective effects. Plus several very interesting connections between decreased microbe exposure and increased allergy production have been shown in human data studies (epidemiology). I was more interested in describing the immunologic mechanism for the hygiene hypothesis in this blog entry. However, I suggest reading the terrific review from Garn and Renz (2007), entitled “Epidemiological and immunological evidence for the hygiene hypothesis” for more engaging details.
Leptin: Anti-Obesity or Immune System Secret?
Leptin: Anti-Obesity Hormone or well-kept Secret to the Immune System?
The discovery of leptin (Greek root leptos, meaning thin) (1), the “anti-obesity hormone,” (2) raised hope that there might actually be a simple cure for obesity. Though the hormone was first documented in 1958 (1), an explosion of research through the 1990s to the present has revealed that this hope was premature. Obesity is undeniably a complex condition that is closely intertwined with biology/genetics, environmental conditions, and social/behavioral factors. Thus, there is no “simple” cure for obesity, and unfortunately, leptin’s role in any “cure” at all remains speculative. While the neurohormonal role of leptin in human metabolism and adipose tissue biology is now fairly well established, a less well-known role of leptin in human physiology appears to be rooted in the immune system. This article will provide a short overview of leptin, emphasizing on its role in immunity.
Leptin is expressed in white adipose tissue, the stomach, placenta, and possibly the mammary gland, with receptors throughout human tissues (2). It is best known as a cytokine-like hormone produced by adipose tissue (3). There is a positive relationship between levels of leptin and level of adiposity (1), and in this way, it is able to communicate information on energy availability (4). Leptin activates specific areas in the central nervous system, particularly the hypothalamus, to decrease food intake, increase energy expenditure, influence metabolism of fat and glucose, and alter neuroendocrine function. It was originally thought that obesity could be a leptin-deficient state, and that peripheral or central administration of the hormone could induce satiety, thus decreasing food intake. However, it has since been documented that persons who are leptin-deficient represent only a small minority of obese individuals (2). Beyond its role in energy homeostasis, leptin plays a role in angiogenesis, bone formation, and reproduction (3), demonstrating a wide range of biological responses.
Recent investigation over the last decade has confirmed that leptin plays an essential role in 3 critical phases of immune response, including in B-cell ontogeny, and in both innate and adaptive immune responses. Leptin’s part in immunity was recently highlighted through the clinical observation that children with congenital leptin-deficiency manifested aberrant immune function through their high incidence of infections and infection-related deaths. In fact, leptin administration in these children has now been shown to correct many abnormalities of the immune system (Farooqi, 2002 in (3)). On the level of B-cell ontogeny, human bone marrow stromal cells have been shown to express leptin, and leptin is now understood to directly enhance the creation and distribution of hematopoeic stem cells and lymphoid precursor cells. In innate immunity, leptin acts upon antigen-presenting (dendritic) cells (DC), natural killer (NK) cells, and neutrophils. For example, human studies have shown that leptin signaling promotes DC maturation and enhances their survival (3). In NK cells, leptin is involved with all phases of cell development, proliferation, and death (4). Leptin also enhances macrophage migration to wound sites, and stimulates chemotaxis in neutrophils. In adaptive immunity, leptin appears to modulate T-cell immune responses, and it attenuates apoptosis in both T and B lymphocytes, promoting a longer survival for these cells (3). Leptin may also modulate autoimmune conditions. It is currently being studied in the context of rheumatoid arthritis and multiple sclerosis (3;4).
In conclusion, while leptin’s neuroendocrine function remains intriguing because of its association with eating and satiety, its critical role in the immune system is only just beginning to be understood. In the context of obesity and its associated immune functions, leptin poses a particular paradox since the majority of obese persons have plentiful levels of leptin, yet they tend to be more susceptible to infections and impaired wound healing (4). Instead of its potential as the “anti-obesity” hormone, it is possible that leptin may instead be therapeutic for immune disorders in the future. TLH, RN
(1) Caro JF, Sinha MK, Kolaczynski JW, Zhang PL, Considine RV. Leptin: the tale of an obesity gene. Diabetes 1996; 45(11):1455-1462.
(2) Mantzoros CS. The role of leptin in human obesity and disease: a review of current evidence. Ann Intern Med 1999; 130(8):671-680.
(3) Lam QL, Lu L. Role of leptin in immunity. Cell Mol Immunol 2007; 4(1):1-13.
(4) Matarese G, Moschos S, Mantzoros CS. Leptin in immunology. J Immunol 2005; 174(6):3137-3142.
The discovery of leptin (Greek root leptos, meaning thin) (1), the “anti-obesity hormone,” (2) raised hope that there might actually be a simple cure for obesity. Though the hormone was first documented in 1958 (1), an explosion of research through the 1990s to the present has revealed that this hope was premature. Obesity is undeniably a complex condition that is closely intertwined with biology/genetics, environmental conditions, and social/behavioral factors. Thus, there is no “simple” cure for obesity, and unfortunately, leptin’s role in any “cure” at all remains speculative. While the neurohormonal role of leptin in human metabolism and adipose tissue biology is now fairly well established, a less well-known role of leptin in human physiology appears to be rooted in the immune system. This article will provide a short overview of leptin, emphasizing on its role in immunity.
Leptin is expressed in white adipose tissue, the stomach, placenta, and possibly the mammary gland, with receptors throughout human tissues (2). It is best known as a cytokine-like hormone produced by adipose tissue (3). There is a positive relationship between levels of leptin and level of adiposity (1), and in this way, it is able to communicate information on energy availability (4). Leptin activates specific areas in the central nervous system, particularly the hypothalamus, to decrease food intake, increase energy expenditure, influence metabolism of fat and glucose, and alter neuroendocrine function. It was originally thought that obesity could be a leptin-deficient state, and that peripheral or central administration of the hormone could induce satiety, thus decreasing food intake. However, it has since been documented that persons who are leptin-deficient represent only a small minority of obese individuals (2). Beyond its role in energy homeostasis, leptin plays a role in angiogenesis, bone formation, and reproduction (3), demonstrating a wide range of biological responses.
Recent investigation over the last decade has confirmed that leptin plays an essential role in 3 critical phases of immune response, including in B-cell ontogeny, and in both innate and adaptive immune responses. Leptin’s part in immunity was recently highlighted through the clinical observation that children with congenital leptin-deficiency manifested aberrant immune function through their high incidence of infections and infection-related deaths. In fact, leptin administration in these children has now been shown to correct many abnormalities of the immune system (Farooqi, 2002 in (3)). On the level of B-cell ontogeny, human bone marrow stromal cells have been shown to express leptin, and leptin is now understood to directly enhance the creation and distribution of hematopoeic stem cells and lymphoid precursor cells. In innate immunity, leptin acts upon antigen-presenting (dendritic) cells (DC), natural killer (NK) cells, and neutrophils. For example, human studies have shown that leptin signaling promotes DC maturation and enhances their survival (3). In NK cells, leptin is involved with all phases of cell development, proliferation, and death (4). Leptin also enhances macrophage migration to wound sites, and stimulates chemotaxis in neutrophils. In adaptive immunity, leptin appears to modulate T-cell immune responses, and it attenuates apoptosis in both T and B lymphocytes, promoting a longer survival for these cells (3). Leptin may also modulate autoimmune conditions. It is currently being studied in the context of rheumatoid arthritis and multiple sclerosis (3;4).
In conclusion, while leptin’s neuroendocrine function remains intriguing because of its association with eating and satiety, its critical role in the immune system is only just beginning to be understood. In the context of obesity and its associated immune functions, leptin poses a particular paradox since the majority of obese persons have plentiful levels of leptin, yet they tend to be more susceptible to infections and impaired wound healing (4). Instead of its potential as the “anti-obesity” hormone, it is possible that leptin may instead be therapeutic for immune disorders in the future. TLH, RN
(1) Caro JF, Sinha MK, Kolaczynski JW, Zhang PL, Considine RV. Leptin: the tale of an obesity gene. Diabetes 1996; 45(11):1455-1462.
(2) Mantzoros CS. The role of leptin in human obesity and disease: a review of current evidence. Ann Intern Med 1999; 130(8):671-680.
(3) Lam QL, Lu L. Role of leptin in immunity. Cell Mol Immunol 2007; 4(1):1-13.
(4) Matarese G, Moschos S, Mantzoros CS. Leptin in immunology. J Immunol 2005; 174(6):3137-3142.
23 September 2007
Do Vaccines Cause Autism?
For about the last decade, a debate has been raging between researchers, health professionals, parents, and the government about whether vaccines cause autism. Autism is a developmental disability that causes impairments with social interaction and communication, and also marked by unusual or repetitive behaviors and interest. Children are usually diagnosed around ages two to four, when social interaction becomes more complex and children start preschool. There is no laboratory test for autism – it is diagnosed by observation, interaction, and psychological tests.
Statistics differ slightly, but in the 1970s approximately 1 in 10,000 children was diagnosed with autism. Today, about 1 in 500 children is diagnosed with autism.
The causes for autism are complex. Autism has been shown to have both genetic and environmental components. The apparent rise in autism rates have led some to suspect vaccines may be the cause, in particular the MMR (measles, mumps, and rubella) vaccine. Parents report that an otherwise normally developing baby or toddler suddenly shows the signs of autism 1-2 months after receiving a vaccine. Vaccines contain mercury and other substances known to cause neurological defects. In fact, the ingredient list for a vaccine is downright scary. Parents are very worried that something which is designed to protect the health of their child is instead causing developmental problems.
References: Centers for Disease Control and Prevention website: "Autism and Vaccines Theory"; Institute of Medicine of the National Academies website: "Immunization Safety Review: Vaccines and Autism"; "Vaccines and Autism" article by Dr. Paul Offit of the Vaccine Education Center, Children's Hospital of Philadelphia published by the Immunization Action Coalition
20 September 2007
I've been shot
As the threat of bioterrorism grows, the military must keep pace by protecting their soldiers against potential biological agents such as Anthrax. Currently, the US military uses an injectable form of vaccine to immunize its soldiers against the threat of anthrax spores. This vaccine requires six does and annual boosters to remain effective (http://www.msnbc.msn.com/id/20323558/). As any individual who has been immunized by the fine staff of the UCHSC mouse colonies can tell you, even a single immunization can be painful and traumatic. Recently, a more effective, inhalation vaccine has been discovered and brought to market by a company called NanoBio Corporation of Ann Arbor, MI.
This new vaccine relies on technology discovered at the University of Michigan in James Baker’s lab that uses a new adjuvant/delivery method to increase the uptake efficiency of antigens by dendritic cells, increasing the vaccine’s overall effectiveness. An adjuvant is a substance that elicits an immune response and activates the innate immune system, resulting in inflammation and enhancing the action of the vaccine (http://en.wikipedia.org/wiki/Immunologic_adjuvant). In this new technology, protective antigen (PA) of B anthracis, is presented to dendritic cells in a “nanoemulsion”. These nanoemulsion particles lyse viruses and retain some of their antigenic determinants. Due to the small size of these particles, endocytosis by antigen presenting cells becomes a more efficient process, resulting in an enhanced adaptive immune response. This in turn leads to better immunological memory cell formation and a more complete protective immunity to Anthrax (Bielinska et al. 2007. “Mucosal Immunization with Novel Nanoemulsion-Based Recombinant Anthrax Protective Antigen Vaccine Protects against Bacillus anthracis Spore Challenge.” Infection and Immunity 75:4020-4029)
In contrast, conventional adjuvants include aluminum potassium sulfate or aluminum hydroxide. These along with biological pathogen associated molecular patterns (PAMPs) elicit a weaker immune response than this nanoemulsion technology. Furthermore, current vaccines carry the risk of toxicity and other side effects, whereas the NanoBio Corporation swears up and down on their website that this is an impossibility with their product (http://www.nanobio.com/Products/Mucosal-Vaccines.html). If their claims are accurate and this product completes clinical trials successfully, it could signal a time when the military no longer pokes and prods its recruits with needles.
This new vaccine relies on technology discovered at the University of Michigan in James Baker’s lab that uses a new adjuvant/delivery method to increase the uptake efficiency of antigens by dendritic cells, increasing the vaccine’s overall effectiveness. An adjuvant is a substance that elicits an immune response and activates the innate immune system, resulting in inflammation and enhancing the action of the vaccine (http://en.wikipedia.org/wiki/Immunologic_adjuvant). In this new technology, protective antigen (PA) of B anthracis, is presented to dendritic cells in a “nanoemulsion”. These nanoemulsion particles lyse viruses and retain some of their antigenic determinants. Due to the small size of these particles, endocytosis by antigen presenting cells becomes a more efficient process, resulting in an enhanced adaptive immune response. This in turn leads to better immunological memory cell formation and a more complete protective immunity to Anthrax (Bielinska et al. 2007. “Mucosal Immunization with Novel Nanoemulsion-Based Recombinant Anthrax Protective Antigen Vaccine Protects against Bacillus anthracis Spore Challenge.” Infection and Immunity 75:4020-4029)
In contrast, conventional adjuvants include aluminum potassium sulfate or aluminum hydroxide. These along with biological pathogen associated molecular patterns (PAMPs) elicit a weaker immune response than this nanoemulsion technology. Furthermore, current vaccines carry the risk of toxicity and other side effects, whereas the NanoBio Corporation swears up and down on their website that this is an impossibility with their product (http://www.nanobio.com/Products/Mucosal-Vaccines.html). If their claims are accurate and this product completes clinical trials successfully, it could signal a time when the military no longer pokes and prods its recruits with needles.
Cytokine Storm and Avian Influenza
Cytokine Storm and Avian Influenza
In class, Dr. Cohen referenced the cytokine storm in association with Multiple Sclerosis on Tuesday [1]. Interestingly enough, cytokine storm is associated with many conditions.
The term “Cytokine Storm” has been used more or less romantically with regard to the hot topics of Emergency Preparedness in a Post 9/11 world. A particular scientist, Dr. Michael Osterholm (http://www.cidrap.umn.edu/),[1, 2] has been one of the loudest voices (many consider him quite controversial – Look at this clip from the Oprah Show - http://www2.oprah.com/tows/pastshows/200601/tows_past_20060124.jhtml) in putting the possible “natural” biological threats like Avian Influenza (H5N1) in the popular media.
Specifically, the threat from bird flu is considered different from the seasonal flu from public health standpoint, in part, because young, healthy individuals might be most at risk. The reason for this – the “Cytokine storm”. It is believed that healthy, young individuals could over respond immunologically. Typically, in the public health community, the oldest and youngest individuals are the target of influenza vaccine programs because they are considered most at risk for death from the seasonal influenza outbreaks. This release of literally hundreds of pro-inflammatory cytokines simultaneous could result in sepsis, or septic shock syndrome, and put younger individuals at most risk. (SSS) (http://www.cytokinestorm.com/). In addition, there is some evidence that inhibition of this response would not protect an individual from the lethality of the infection [3], that the H5N1 infection might have a dual mechanism for causing death.
There is some historical precedent and justification for this - the Spanish Flu of 1918. This world wide Pandemic from the Type A H5N1 Influenza strain resulted in an estimate in upwards of 50 million deaths worldwide. Younger individuals ( e.g. military men, college students, etc.) seemed to be disproportionately affected.
References
1. Link H. The cytokine storm in multiple sclerosis. Mult Scler 1998;4:12-5.
2. Osterholm MT. Preparing for the next pandemic. N Engl J Med 2005;352:1839-42.
3. Salomon R, Hoffmann E, Webster RG. Inhibition of the cytokine response does not protect against lethal H5N1 influenza infection. Proc Natl Acad Sci U S A 2007;104:12479-81.
In class, Dr. Cohen referenced the cytokine storm in association with Multiple Sclerosis on Tuesday [1]. Interestingly enough, cytokine storm is associated with many conditions.
The term “Cytokine Storm” has been used more or less romantically with regard to the hot topics of Emergency Preparedness in a Post 9/11 world. A particular scientist, Dr. Michael Osterholm (http://www.cidrap.umn.edu/),[1, 2] has been one of the loudest voices (many consider him quite controversial – Look at this clip from the Oprah Show - http://www2.oprah.com/tows/pastshows/200601/tows_past_20060124.jhtml) in putting the possible “natural” biological threats like Avian Influenza (H5N1) in the popular media.
Specifically, the threat from bird flu is considered different from the seasonal flu from public health standpoint, in part, because young, healthy individuals might be most at risk. The reason for this – the “Cytokine storm”. It is believed that healthy, young individuals could over respond immunologically. Typically, in the public health community, the oldest and youngest individuals are the target of influenza vaccine programs because they are considered most at risk for death from the seasonal influenza outbreaks. This release of literally hundreds of pro-inflammatory cytokines simultaneous could result in sepsis, or septic shock syndrome, and put younger individuals at most risk. (SSS) (http://www.cytokinestorm.com/). In addition, there is some evidence that inhibition of this response would not protect an individual from the lethality of the infection [3], that the H5N1 infection might have a dual mechanism for causing death.
There is some historical precedent and justification for this - the Spanish Flu of 1918. This world wide Pandemic from the Type A H5N1 Influenza strain resulted in an estimate in upwards of 50 million deaths worldwide. Younger individuals ( e.g. military men, college students, etc.) seemed to be disproportionately affected.
References
1. Link H. The cytokine storm in multiple sclerosis. Mult Scler 1998;4:12-5.
2. Osterholm MT. Preparing for the next pandemic. N Engl J Med 2005;352:1839-42.
3. Salomon R, Hoffmann E, Webster RG. Inhibition of the cytokine response does not protect against lethal H5N1 influenza infection. Proc Natl Acad Sci U S A 2007;104:12479-81.
Inflammation and Infection in Clinical Stroke
A major cause of most coronary artery disease and the majority of ischemic stroke among humans is Atherosclerosis. Atherosclerosis is the process in which fatty acid deposits build up in the inner lining of arteries. Accumulation of fatty acid buildup results in a plaque that can significantly reduce blood flow and possibly even rupture. If they rupture they can cause blood clots to form which may block blood flow or travel to other parts of the body. Several studies suggest that there are several inflammatory mechanisms involved with the development and progression of Atherosclerosis. The cytokines IL-1 beta, IL-6 and TNF-alfa, nitric oxide synthase (NOS), cylcooxygenase-2 (COX-2) intrcelular adhesion molecule-1 (ICAM-1), matrix metalloproteinases, C-reactive protein and leukocytes are all involved with ischemic stroke. Studies suggest IL-6 and TNF alfa can have antiinflammatory, neuroprotective, and proinflammatory effects on ischemic stroke. Nitric oxide synthase produced early may be beneficial to vasodilation whereas if it is produced later may contribute to ischemic injury. Reactive oxygen species are a product of COX-2 reactions and are thought to increase tissue damage during cerebral ischemia. Adhesion molecules such as ICAM-1 are involved with leukocyte infiltration into the brain. Matrix metalloproteinases increase tissue damage and aide in the opening of the blood brain barrier. C-Reactive protein has received a lot of attention since its levels can be measured using a blood test and the protein levels increases during systemic inflammation. It is possible that this test can determine cardiovascular disease risk, and may help predict cardiovascular events such as heart attack and stroke. There are several studies which account for all of these inflammatory factors however little is still known of their actual effects on ischemic stroke. Some studies show the effects to be beneficial and some detrimental. What is known is that there seems to be a strong correlation with inflammation both before and after stroke, it is just unclear as to whether these processes are providing protective effects or further damaging cells and tissue.
Stroke also has a strong correlation with inflammatory conditions and infection. Studies have shown the bacteria Chlamydia pneumoniae may be a risk factor to stroke however it is still unclear. Chronic and recurrent respiratory infections, herpes viruses, periodontal disease and meningitis are just a few of the many conditions that may also cause an increased risk of ischemic stroke. Similar to the inflammatory factors and mechanisms of stroke, the connection of stroke to infections and inflammatory disorders is still unknown. Further scientific research is needed in the both of these areas to increase our knowledge and hopefully eliminate the numerous negative implications of stroke.
Stroke also has a strong correlation with inflammatory conditions and infection. Studies have shown the bacteria Chlamydia pneumoniae may be a risk factor to stroke however it is still unclear. Chronic and recurrent respiratory infections, herpes viruses, periodontal disease and meningitis are just a few of the many conditions that may also cause an increased risk of ischemic stroke. Similar to the inflammatory factors and mechanisms of stroke, the connection of stroke to infections and inflammatory disorders is still unknown. Further scientific research is needed in the both of these areas to increase our knowledge and hopefully eliminate the numerous negative implications of stroke.
tPA and the Time Frame of Administration
In one of the lay articles posted, it mentioned a treatment for strokes called tPA, or tissue plasminogen activator. Out of curiosity, I did some more research to find out more about it.
tPA is a serine protease that converts the proenzyme plasminogen to plasmin, which is an enzyme that breaks down the clotting factor fibrin. When fibrin is inactivated, the clots that normally cause the occlusion of blood flow in the cerebral blood vessels are broken down and the risk is minimized considerably. Like the article stated, the tPA must be administered intravenously within three hours of the initial symptoms of a stroke (in this case, it treats ischemic stroke which constitute about 80% of all strokes) in order to be used to its full potential and possibly prevent the serious long-term effects of ischemic stroke. A major issue surrounding the usage of tPA is that due to this short time period of effectiveness, only a small fraction of ischemic stroke patients are able to put it to use, approximately 3%.
But due to advances in imaging technology, researchers are beginning to find out that there are still some advantages to administering the tPA up to eight hours after the initial symptoms. The reason for this is that the neurons that are damaged by the lack of blood flow may not all be dead in this three hour time period. Newer CT scans and MRI's can now show us which of the affected neural tissue is dead so we can see if it is still beneficial to inject the tPA to salvage some of the tissue. And just as importantly, these scans can also tell us which patients are more susceptible to bleeding when given tPA; a problem that prevents the treatment for some patients even within the initially determined three-hour time period.
These advances in the research of tPA are very beneficial to the well-being of stroke patients, and hopefully researchers will continue to build upon the treatment methods for strokes.
tPA is a serine protease that converts the proenzyme plasminogen to plasmin, which is an enzyme that breaks down the clotting factor fibrin. When fibrin is inactivated, the clots that normally cause the occlusion of blood flow in the cerebral blood vessels are broken down and the risk is minimized considerably. Like the article stated, the tPA must be administered intravenously within three hours of the initial symptoms of a stroke (in this case, it treats ischemic stroke which constitute about 80% of all strokes) in order to be used to its full potential and possibly prevent the serious long-term effects of ischemic stroke. A major issue surrounding the usage of tPA is that due to this short time period of effectiveness, only a small fraction of ischemic stroke patients are able to put it to use, approximately 3%.
But due to advances in imaging technology, researchers are beginning to find out that there are still some advantages to administering the tPA up to eight hours after the initial symptoms. The reason for this is that the neurons that are damaged by the lack of blood flow may not all be dead in this three hour time period. Newer CT scans and MRI's can now show us which of the affected neural tissue is dead so we can see if it is still beneficial to inject the tPA to salvage some of the tissue. And just as importantly, these scans can also tell us which patients are more susceptible to bleeding when given tPA; a problem that prevents the treatment for some patients even within the initially determined three-hour time period.
These advances in the research of tPA are very beneficial to the well-being of stroke patients, and hopefully researchers will continue to build upon the treatment methods for strokes.
19 September 2007
stroke and brain ischemia
Stroke is the third most common cause of death in the United States and the leading cause of serious, long-term disability. Recent work in the area of stroke and brain ischemia have a significant inflammatory response (early responses) accompanying necrotic injury. Although later responses may be beneficial in recovery and repair, future studies are attempting to address the timing of inflammation responses. What this article does is discuss roles of specific cells types (leukocytes, endothelium, microglia, the extracellular matrix) as well as the intracellular inflammatory pathways. As well as discussing the mediators produced by inflammatory cells (cytokines, ROS, etc.) and then linking everything together in the process of inflammation following stroke.
This is an overview of inflammation following stroke beginning with brain ischemia which then triggers inflammatory responses in the presence of necrotic cells. This then generates ROS (reactive oxidative species) and produces inflammatory cytokines with neurons which initiate microglial activation that produces more cytokines causing upregulation of adhension molecules in the cerebral vasculature. At the same time chemokines lead to inflammatory cell chemotaxis to the ischemic brain. The adhesion molecules modulate adhesion of circulating leukocytes to the vascular endothelia and infiltration into the brain parenchyma. When in the brain, the activated leukocytes and microglia produce a diverse amount of inflammatory mediators such as matrix metalloproteinases, inducible nitric oxide synthase (generates nitric oxide), cytokes and more ROS. All which leads to brain edema, hemorrhage and eventually cell death.
When future studies are concluded about later responses playing a important role in recovery and repair, we will be able to reduce the risk of stroke and brain ischemia.
This is an overview of inflammation following stroke beginning with brain ischemia which then triggers inflammatory responses in the presence of necrotic cells. This then generates ROS (reactive oxidative species) and produces inflammatory cytokines with neurons which initiate microglial activation that produces more cytokines causing upregulation of adhension molecules in the cerebral vasculature. At the same time chemokines lead to inflammatory cell chemotaxis to the ischemic brain. The adhesion molecules modulate adhesion of circulating leukocytes to the vascular endothelia and infiltration into the brain parenchyma. When in the brain, the activated leukocytes and microglia produce a diverse amount of inflammatory mediators such as matrix metalloproteinases, inducible nitric oxide synthase (generates nitric oxide), cytokes and more ROS. All which leads to brain edema, hemorrhage and eventually cell death.
When future studies are concluded about later responses playing a important role in recovery and repair, we will be able to reduce the risk of stroke and brain ischemia.
17 September 2007
Dengue virus infection: Don't get it
Dengue virus infection-an interesting immunological explanation why you do not want to get it.
Dengue fever is a mosquito-borne (Aedes aegypti) tropical disease that is caused by any of the four serotypes of the Dengue virus (DV). (A “serotype” is a specific microorganism as characterized by serologic typing-aka, testing for recognizable antigens on the surface of the microorganism.)
There are an estimated 50-100 million cases of Dengue fever (DF) per annum worldwide, 500000 of which result in the severe form of the disease, Dengue hemorrhagic fever (DHF) marked by abnormal vascular permeability.
Humans, mosquitos and some primates can be infected through the bite of infected A. aegypti that breed in domestic and peridomestic water containers.
DV causes an acute infection that is effectively controlled after 3 to 7 days. Individuals that have recovered from DV infection are immune to re-challenge with the same type but not with other serotypes of DV. Sequential infection with a second serotype usually results in the severe form of disease, DHF. In short, this virus can and will cause a very painful death in most people who get infected again, but this time with a different serotype.
If you think about this, the question that arises is the following:
What makes the secondary infection with the virus much worse than the first?
Interestingly, this phenomenon has little to do with the direct activation of immune cells through antigen expressed by the infecting virus.
Studies have lead to the hypothesis that infection with a second dengue virus serotype results in antibody-mediated immune enhancement. Antibodies generated against the first infecting serotype (#1) will bind the second (#2). Unfortunately, these antibodies are not able to neutralize serotype #2 and they will facilitate FC-receptor mediated and complement-mediated virus-uptake and replication in phagocytic cells (ADE-antibody-dependent enhancement). This means that the same antibody that works well to decrease the number of the first infecting virus does the exact opposite to the second infecting virus. By helping it to enter phagocytic cells it helps more viral particles to grow and more viral offspring will infect new cells. In the end, the virus will take over and the patient’s immune system will not be able to fight it anymore.
This increased severity of a secondary infection has been observed in different virus infections in vitro (aka, in a test tube) and one can imagine that it could potentially be a problem when new vaccines are created. For example, imagine giving a vaccine against serotype 1 of the HIV virus and the person is getting infected with serotype 2. This means that the person’s immune system has already created antibodies against serotype 1 (this is the whole idea behind vaccinations) that –unfortunately- can help to enhance viral entry of serotype 2 into the host cell. As a result, the infectivity of serotype 2 increases.
Selected references
Dengue fever is a mosquito-borne (Aedes aegypti) tropical disease that is caused by any of the four serotypes of the Dengue virus (DV). (A “serotype” is a specific microorganism as characterized by serologic typing-aka, testing for recognizable antigens on the surface of the microorganism.)
There are an estimated 50-100 million cases of Dengue fever (DF) per annum worldwide, 500000 of which result in the severe form of the disease, Dengue hemorrhagic fever (DHF) marked by abnormal vascular permeability.
Humans, mosquitos and some primates can be infected through the bite of infected A. aegypti that breed in domestic and peridomestic water containers.
DV causes an acute infection that is effectively controlled after 3 to 7 days. Individuals that have recovered from DV infection are immune to re-challenge with the same type but not with other serotypes of DV. Sequential infection with a second serotype usually results in the severe form of disease, DHF. In short, this virus can and will cause a very painful death in most people who get infected again, but this time with a different serotype.
If you think about this, the question that arises is the following:
What makes the secondary infection with the virus much worse than the first?
Interestingly, this phenomenon has little to do with the direct activation of immune cells through antigen expressed by the infecting virus.
Studies have lead to the hypothesis that infection with a second dengue virus serotype results in antibody-mediated immune enhancement. Antibodies generated against the first infecting serotype (#1) will bind the second (#2). Unfortunately, these antibodies are not able to neutralize serotype #2 and they will facilitate FC-receptor mediated and complement-mediated virus-uptake and replication in phagocytic cells (ADE-antibody-dependent enhancement). This means that the same antibody that works well to decrease the number of the first infecting virus does the exact opposite to the second infecting virus. By helping it to enter phagocytic cells it helps more viral particles to grow and more viral offspring will infect new cells. In the end, the virus will take over and the patient’s immune system will not be able to fight it anymore.
This increased severity of a secondary infection has been observed in different virus infections in vitro (aka, in a test tube) and one can imagine that it could potentially be a problem when new vaccines are created. For example, imagine giving a vaccine against serotype 1 of the HIV virus and the person is getting infected with serotype 2. This means that the person’s immune system has already created antibodies against serotype 1 (this is the whole idea behind vaccinations) that –unfortunately- can help to enhance viral entry of serotype 2 into the host cell. As a result, the infectivity of serotype 2 increases.
Selected references
- Tirado SM, Yoon KJ. 2003. Antibody-dependent enhancement of virus infection and disease. Viral Immunol 13(6): 387
- Takada A, Kawaoka Y. 2003. Antibody-dependent enhancement of viral infection: molecular mechanisms and in vivo implications. Rev Med Virol 16(1): 69
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