I found the article entitled "Leukocyte Accumulation and Hemodynamic Changes in the Cerebral Microcirculation During Early Reperfusion After Stroke" very interesting. It was one of the first studies done on the effect of leukocyte contribution to cerebral ischemia-reperfusion injury by examining both in vivo behavior and microvascular rheology. One thing that i noticed when reading the article was that there were noticeable differences between the leukocyte accumulation in venules versus arterioles. It seems that in the study that was conducted, there was noticeable leukocyte adhesion to the venules in the pial microcirculation of the cortex, but this was rarely observed to happen in the arterioles and capillaries.
The reason this caught my mind is because the study used a technique called MCAO-R, which stands for Middle Cerebral Artery Occlusion and Reperfusion. If the middle cerebral artery is occluded, then why is it that there is only significant leukocyte accumulation in the venules of the microcirculation? After reading the study, I noticed that it commented on the fact that others have gotten similar results, but it did not go on to explain why this happens the way it does. I could just be completely overlooking something really obvious...but i figured i would just put the question out there and see if anybody could come up with an explanation.
27 September 2007
Leukocyte-Platelet Aggregates in Rat Peripheral Blood After Ischemic Stroke and Reperfusion
The events which follow a cerebral ischemia-reperfusion injury are complex but are mediated by an inflammatory response involving the activation of leukocytes and platelets. The formation of leukocyte-platelet aggregates (LPA) may amplify immunologic functions and increase the severity of reperfusion injury following ischemic stroke. However prior to this study it was unknown whether LPA could be detected in peripheral blood following ischemic stroke and reperfusion (ISR).
Using a rat model LPA in peripheral blood was detected following ischemic stroke and early reperfusion, and also the effect that LPA inhibitors have on LPA formation was studied. Separate groups used tirofiban and fucoidan. Tirofiban is a platelet GPIIb/IIIa inhibitor and fucoidan is a selectin adhesion molecule inhibitor. Since there is also little known about nonadhered polymorphonuclear neutrophilic (PMN) leukocytes following ISR, PMN CD11b adhesion molecule expression and ROS were measured. Following 4 hours of ischemia and 1 hour of reperfusion there was an increase in LPA following ISR, and both tirofiban and fucoidan decreased LPA formation. CD11b showed a small nonsignificant increase and ROS had a significant increase during both ischemia and reperfusion in the SHAM animals. (SHAM animals were the control group that did not undergo placement of the occluding filament.) This may have resulted due to the PMNs in the ISR group being rapidly activated and unable to produce ROS.
Although this study provides evidence that LPA are increased in peripheral blood during early reperfusion following an acute ischemic stroke, there is still very little known of LPA occurence and significance. However the findings of this study may lead to future developments in therapies that target decreasing leukocyte-platelet aggregates to avoid reperfusion injury following ischemic stroke.
Using a rat model LPA in peripheral blood was detected following ischemic stroke and early reperfusion, and also the effect that LPA inhibitors have on LPA formation was studied. Separate groups used tirofiban and fucoidan. Tirofiban is a platelet GPIIb/IIIa inhibitor and fucoidan is a selectin adhesion molecule inhibitor. Since there is also little known about nonadhered polymorphonuclear neutrophilic (PMN) leukocytes following ISR, PMN CD11b adhesion molecule expression and ROS were measured. Following 4 hours of ischemia and 1 hour of reperfusion there was an increase in LPA following ISR, and both tirofiban and fucoidan decreased LPA formation. CD11b showed a small nonsignificant increase and ROS had a significant increase during both ischemia and reperfusion in the SHAM animals. (SHAM animals were the control group that did not undergo placement of the occluding filament.) This may have resulted due to the PMNs in the ISR group being rapidly activated and unable to produce ROS.
Although this study provides evidence that LPA are increased in peripheral blood during early reperfusion following an acute ischemic stroke, there is still very little known of LPA occurence and significance. However the findings of this study may lead to future developments in therapies that target decreasing leukocyte-platelet aggregates to avoid reperfusion injury following ischemic stroke.
Low Levels of IL-10 Detect Neurological Worsening
This weeks article investigated the concentration levels of anti-inflammatory molecules IL-10 and IL-4 and their role in neurological worsening in acute ischemic stroke, both are able to block proinflammatory action. IL-1o is known to inhibit monocyte/marophage synthesis and tumor necrosis factor-alpha by blocking gene transcription and downregulates release of intercellular adhesion molecules-1 and matrix metalloproteinase, and may have neuroprotectant activities resulting from non-anti-inflammatory action.
The results of this study proved that levels plasma concentrations of IL-10 does play a significant role in neurological worsening, whereas IL-4 was less important. Low plasma concentration of IL-10 provided an association with neurological deterioration in subcortical and lacunar infarts. These findings give further support from past experiments linking cytokines with early motor impairment with lacunar stroke.
Although studies have proved that IL-1o may be markers of neorolgical deterioration, work needs to be done to provide effects of cytokines on late worsening. A comparison can be made between concentration levels of early and late worsening to get more accurate results. But with the current findings in this study, it give evidence that IL-10 may have a potential role as neuroprotectants in acute vascular syndromes. The study mentions if there is a relationship between low concentration levels of IL-10 and risk of stroke and mortality when strokes occur, perhaps an exogenous injection of IL-10 to increase concentration can prevent stroke and clinical worsening in acute stroke.
The results of this study proved that levels plasma concentrations of IL-10 does play a significant role in neurological worsening, whereas IL-4 was less important. Low plasma concentration of IL-10 provided an association with neurological deterioration in subcortical and lacunar infarts. These findings give further support from past experiments linking cytokines with early motor impairment with lacunar stroke.
Although studies have proved that IL-1o may be markers of neorolgical deterioration, work needs to be done to provide effects of cytokines on late worsening. A comparison can be made between concentration levels of early and late worsening to get more accurate results. But with the current findings in this study, it give evidence that IL-10 may have a potential role as neuroprotectants in acute vascular syndromes. The study mentions if there is a relationship between low concentration levels of IL-10 and risk of stroke and mortality when strokes occur, perhaps an exogenous injection of IL-10 to increase concentration can prevent stroke and clinical worsening in acute stroke.
25 September 2007
Careful what you read
Just a comment to all our bloggers (but mostly 495K!!!)...you are posting to a site that can be read by anybody, so it's our responsibility to make sure that we are putting accurate information out there (so that we are not like some of the lay articles we read!!)
JessicaR put up an interesting (but WAY too long) article which has been shown over and over to be a HOAX
http://www.trendmicro.com/vinfo/hoaxes/hoaxDetails.asp?HName=ASPARTAME+HOAX
We need to be better at: 1) paraphrasing our articles-they should be snippets, educational but brief
2) referenced! (7630 is really good at this, we're not as good)
3) checked for accuracy
Thanks!!!
JessicaR put up an interesting (but WAY too long) article which has been shown over and over to be a HOAX
http://www.trendmicro.com/vinfo/hoaxes/hoaxDetails.asp?HName=ASPARTAME+HOAX
We need to be better at: 1) paraphrasing our articles-they should be snippets, educational but brief
2) referenced! (7630 is really good at this, we're not as good)
3) checked for accuracy
Thanks!!!
24 September 2007
Interesting E-mail to Lay Public..."A Sweet Poison"
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
~ 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
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
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