Before I forget, I did not get a chance to mention in class today that I thought it was interesting that TLRs can recognize and differentiate specific types of lipids. We know that TLRs recognize the LPSs found on bacterial membranes, but it is interesting that TLRs can scout out similar fatty acids from adipose tissue (secretion of fatty acids in droplet form?). AND they can differentiate between saturated and unsaturated fats. AND they can elicit different immune responses upon independent recognition.
This innate response/reaction from TLRs seems (to me) to be what could be happening when lean mice become overweight after they are exposed directly (dermatological/topical) to the waste products of obese rats.
Thoughts before bed....I am proud to say I am a nerd.
Jennifer
07 February 2011
Obesity is so interesting...'cause it's scary!
Hello!
I hope in class we are able to discuss not only the physiological aspect of obesity, but also the sociological and psychological aspects. I read this article in The Atlantic (at the Dr.'s office). And it had a great commentary about a research article in Obesity. The commentary stated in large print: “it will take less than 30 years for all black women to become overweight or obese.”AHHH! So that means that If I have a baby today, in 30 years it will be overweight or obese! (That won't happen to MY kid, but this is the overall trend in America).
I know that we talked about how bogus articles scare people into becoming borderline hypochondriacs, but some people need to be tricked into getting healthy. Is this statement too bold? This information was developed from data that just so happened to be tested scientifically...but if it wasn't, it would have still empowered me! What do yall think?
Another point I wanted to make was that disease prevention (vs treatment) strategies have become vital to clinicians and medical researchers. It is far too easy to simply call for implementation of a more nutritious diet and exercise in a person’s life; therefore, looking deeply into the reasons people eat the way they do could provide better ways to intervene and combat epidemic obesity. I am sure there are immuno-neuro-endocrine linkages that many researchers have not even thought about. Or have they...? That is what I meant by social and psychological aspects of obesity.
See ya!
Jennifer
I hope in class we are able to discuss not only the physiological aspect of obesity, but also the sociological and psychological aspects. I read this article in The Atlantic (at the Dr.'s office). And it had a great commentary about a research article in Obesity. The commentary stated in large print: “it will take less than 30 years for all black women to become overweight or obese.”AHHH! So that means that If I have a baby today, in 30 years it will be overweight or obese! (That won't happen to MY kid, but this is the overall trend in America).
I know that we talked about how bogus articles scare people into becoming borderline hypochondriacs, but some people need to be tricked into getting healthy. Is this statement too bold? This information was developed from data that just so happened to be tested scientifically...but if it wasn't, it would have still empowered me! What do yall think?
Another point I wanted to make was that disease prevention (vs treatment) strategies have become vital to clinicians and medical researchers. It is far too easy to simply call for implementation of a more nutritious diet and exercise in a person’s life; therefore, looking deeply into the reasons people eat the way they do could provide better ways to intervene and combat epidemic obesity. I am sure there are immuno-neuro-endocrine linkages that many researchers have not even thought about. Or have they...? That is what I meant by social and psychological aspects of obesity.
See ya!
Jennifer
20 December 2010
Happy Solstice, Eclipse, and New Year!
There is an eclipse of the moon tonight, but it starts at around 11:15 PM and runs until 2 AM, so good for night owls. If the sky is clear it should be spectacular.
A very happy holiday to all, and best wishes for a terrific New Year!
A very happy holiday to all, and best wishes for a terrific New Year!
16 December 2010
BCG, why still excluded in US?
This is a question I have at the end of our course: Given that the BCG is used in cancer treatment (both to boost the CTL function and increase the angry macrophages and to kill bladder tumors being the innocent bystander or battlefield), then how come it is not even included in the list of recommended childhood vaccines?
I can understand that TB is uncommon in US but since immune deficient people (eg AIDS patietnts) can develop the disease and be possible foci for its' spread, wouldn't that mean that an outbreak may occur ?
I can understand that TB is uncommon in US but since immune deficient people (eg AIDS patietnts) can develop the disease and be possible foci for its' spread, wouldn't that mean that an outbreak may occur ?
15 December 2010
HIV trials and tribulations - a new prophylactic treatment?
I've been meaning to blog about the following for a while, and it came up in one of the past posts, but here is some information on an exciting new trial for the use of Truvada as a prophylactic measure for HIV transmission:
Recently (week of November 23rd), I read/heard on www.newyorktimes.com and NPR about a recent trial that was conducted using Truvada (a two drug combination nucleoside reverse transcriptase inhibitor) prophylactically. The article itself (on NEJM.org) gives a 44% increase in protection from HIV infection with the prophylactic use of Truvada. The other sources, where I originally heard this news, quoted other percentages, ranging from 44% to 90% efficacy, depending on the subject's reported pill use, as well as laboratory results of measured blood medication levels. I haven't had time to read the article as carefully as I would like to in order to try and discern these numbers for myself (woohoo, winter break!), but it seems like this prophylactic use of an NRTI could be promising...check out the articles below when you have time.
http://www.npr.org/blogs/health/2010/11/23/131536422/pill-cuts-hiv-infection-risk-significantly-for-a-price
http://www.nytimes.com/2010/11/24/health/research/24aids.html?_r=1&ref=research
Grant, R.M., Lama J.R., Anderson P.L., et al. (2010 November 23). Preexposure Chemoprophylaxis for HIV Prevention in Men Who Have Sex with Men. The New England Journal of Medicine 10 (1056). Retrieved 13 December 2010 from http://www.nejm.org/doi/full/10.1056/NEJMoa1011205#t=articleTop
Recently (week of November 23rd), I read/heard on www.newyorktimes.com and NPR about a recent trial that was conducted using Truvada (a two drug combination nucleoside reverse transcriptase inhibitor) prophylactically. The article itself (on NEJM.org) gives a 44% increase in protection from HIV infection with the prophylactic use of Truvada. The other sources, where I originally heard this news, quoted other percentages, ranging from 44% to 90% efficacy, depending on the subject's reported pill use, as well as laboratory results of measured blood medication levels. I haven't had time to read the article as carefully as I would like to in order to try and discern these numbers for myself (woohoo, winter break!), but it seems like this prophylactic use of an NRTI could be promising...check out the articles below when you have time.
http://www.npr.org/blogs/health/2010/11/23/131536422/pill-cuts-hiv-infection-risk-significantly-for-a-price
http://www.nytimes.com/2010/11/24/health/research/24aids.html?_r=1&ref=research
Grant, R.M., Lama J.R., Anderson P.L., et al. (2010 November 23). Preexposure Chemoprophylaxis for HIV Prevention in Men Who Have Sex with Men. The New England Journal of Medicine 10 (1056). Retrieved 13 December 2010 from http://www.nejm.org/doi/full/10.1056/NEJMoa1011205#t=articleTop
14 December 2010
Immunization vs Autism
While reading up on papers about vaccinations, I found out that some vaccines contain thimerosal which is a compound well known for its antiseptic and anti-fungal usages. Thimerosal contains toxic ethyl mercury. Thimerosal was used as a preservation component for some vaccines used for children and pharmaceutical products to avoid bacterial and fungal growth. Thimerosal has been found as a possible risk factor for autism. In the United State, the Centers for Disease Control and Prevention estimates that the current prevalence of Autism Spectrum Disease (ASD) to be 1 in 110 children (Centers for Disease Control and Prevention 2010).
In another paper I read through, a total of 109,863 children from the United Kingdom were exposed to thimerosal based on the number of DTP (diphtheria-tetanus-pertussis) and DT (diphtheria-tetanus) vaccinations. The study kept track of subjects’ gender, year of birth, month of birth, but not for other potentially confounding variables. Also, there was no apparent association seen between thimerosal and autism in the control numbers. In addition, a recent study done by Hertz-Picciotto shows that the level of mercury concentration in blood was not elevated or reduced. Therefore, there is no relationship between ASD and the mercury level in blood.
In conclusion, both studies show that thimerosal does not cause ASD or neurological disease. They do suggest that the topic requires more study in the near future. It will be interesting to see if thimerosal really does have any correlation with autism.
Andrews N, Miller E, Grant A, Stowe J, Osborne V, Taylor B (2004) Thimerosal exposure in infants and developmental disorders: a retrospective cohort study in the United Kingdom does not support a causal association. Pediatrics 114: 584–591.
Hertz-Picciotto I, Green PG, Delwiche L, Hansen R, Walker C, Pessah IN (2010) Blood mercury concentrations in CHARGE. Study children with and without autism. Environ Health Perspect 118: 161–166.
13 December 2010
TRALI – Two hits and some bad luck…
TRALI or Transfusion Related Acute Lung Injury is the most common cause of transfusion-associated death in the US. As a critical care physician, TRALI is a diagnosis we commonly consider but rarely diagnose and its pathogenesis befuddled me until now. Newly armed with new immunologic background I retackled the topic – and it is fascinating!
The clinical phenomenon
Within hours of receiving blood products, approximately one in 20,000-50,000 patients develops shortness of breath, low oxygen levels and a chest X ray with diffuse patchy consolidation (too much whiteness!). This is TRALI, a form of non-cardiogenic pulmonary edema (a life-threatening leak of fluid into the airspaces or alveoli.) Between 5-25% of patients with TRALI die as a consequence. TRALI can occur after transfusion with any product derived from blood (such as packed red cells, platelets, cryoglobulin) but risk is higher with products that contain greater proportions of plasma.
Why does TRALI occur?
TRALI appears to be due to due to donor antibodies to three major recipient leukocyte antigens. In up to 90% of cases donor antibodies to recipient MHC I, MHC II and human neutrophil antigens have been identified.
The proposed mechanisms are a bit different for each type of antigen:
• Anti-neutrophil antibodies – the donor antibody directly binds to antigen on the neutrophil surface. Activation of complement and release of neutrophil vasoactive peptides damages the pulmonary endothelium and leads to “capillary leak.”
• Anti-MHC I antibodies – the donor antibody is thought to bind to pulmonary endothelium. As neutrophils squeeze through the tiny pulmonary vessels, neutrophils bind via their Fc receptors and cross link.
• Anti-MHC II antibodies – this mechanism was a mystery until recently because neither endothelial cells nor neutrophils have MHC II! A recent article suggested the mechanism is indirect. Circulating monocytes (which do display MHC II) are activated by when bound by specific anti-MHC antibodies. The supernatant from these activated monocytes stimulates neutrophils to produce reactive oxygen species (ROS). The ROS produced by neutrophils disturbs the pulmonary endothelial barrier resulting in greater permeability and fluid leakage.
Is one hit alone sufficient?
The above mechanisms are pretty neat, but experimentally antileukocyte antibodies alone are not sufficient to result in TRALI. For rats to develop TRALI with infusion of antileukocyte antibodies, the pulmonary endothelium must first be “primed” with lipopolysaccharide (LPS) an intensely immunogenic component of the cell wall of gram negative bacteria. This experimental data is consistent with the observation that critically ill patients appear to be at greater risk of developing TRALI than otherwise healthy patients. Presumably critical illness is associated with pulmonary microvascular injury that provides the first hit. The transfusion of antileukocyte antibodies is the second hit.
But why would blood donors have anti-MCH or anti-neutrophil antibodies anyway?
Almost always the donor has been alloimmunized during pregnancy. In recent study of 5,000 US woman, alloimmunization rates were directly correlated with parity. Antileukocyte antigens were identifiable in 1.7% of nulliparous women but rose to 29.8% among woman with three or more pregnancies.
You feeling lucky?
The bad luck part comes in receiving a blood product from a donor who has been alloimmunized by a person who has MCH or neutrophil antigens that match yours. Recall that despite the fact that antileukocyte antibodies are relatively common, TRALI is rare because the antibodies only cause disease if there is a specific cognate antigen.
What can be done to prevent TRALI?
Traditionally, blood banks have attempted to identify donor who are “responsible” for TRALI and prevent them from donating again. This means that once TRALI has occurred, blood bank staff must investigate to identify the donor. The problem with this approach is that TRALI can be difficult to identify definitively as these patients often have other reasons for having diffuse lung problems.
A more effective strategy would be to use only male donors for plasma donation. The UK implemented this approach and reports of TRALI fell by 75%. The challenge is that this is one more restriction that compromises an already stretched blood supply.
Sachs UJ, et al Mechansim of transfusion-related acute lung injury induced by HLA class II antibodies. Blood 2010 [Epub ahead of print]
Triulzi DJ. Transfusion-related Acute Lung Injury: Current concepts for the clinician. Anesthesia and Analgesia. 2009; 108: 770-6.
Stafford-Smith M. Many, but not all, outcome studies support exclusion of female plasma from the blood supply. Expert Reviews in Hematology. 2010;3:551-8.
The clinical phenomenon
Within hours of receiving blood products, approximately one in 20,000-50,000 patients develops shortness of breath, low oxygen levels and a chest X ray with diffuse patchy consolidation (too much whiteness!). This is TRALI, a form of non-cardiogenic pulmonary edema (a life-threatening leak of fluid into the airspaces or alveoli.) Between 5-25% of patients with TRALI die as a consequence. TRALI can occur after transfusion with any product derived from blood (such as packed red cells, platelets, cryoglobulin) but risk is higher with products that contain greater proportions of plasma.
Why does TRALI occur?
TRALI appears to be due to due to donor antibodies to three major recipient leukocyte antigens. In up to 90% of cases donor antibodies to recipient MHC I, MHC II and human neutrophil antigens have been identified.
The proposed mechanisms are a bit different for each type of antigen:
• Anti-neutrophil antibodies – the donor antibody directly binds to antigen on the neutrophil surface. Activation of complement and release of neutrophil vasoactive peptides damages the pulmonary endothelium and leads to “capillary leak.”
• Anti-MHC I antibodies – the donor antibody is thought to bind to pulmonary endothelium. As neutrophils squeeze through the tiny pulmonary vessels, neutrophils bind via their Fc receptors and cross link.
• Anti-MHC II antibodies – this mechanism was a mystery until recently because neither endothelial cells nor neutrophils have MHC II! A recent article suggested the mechanism is indirect. Circulating monocytes (which do display MHC II) are activated by when bound by specific anti-MHC antibodies. The supernatant from these activated monocytes stimulates neutrophils to produce reactive oxygen species (ROS). The ROS produced by neutrophils disturbs the pulmonary endothelial barrier resulting in greater permeability and fluid leakage.
Is one hit alone sufficient?
The above mechanisms are pretty neat, but experimentally antileukocyte antibodies alone are not sufficient to result in TRALI. For rats to develop TRALI with infusion of antileukocyte antibodies, the pulmonary endothelium must first be “primed” with lipopolysaccharide (LPS) an intensely immunogenic component of the cell wall of gram negative bacteria. This experimental data is consistent with the observation that critically ill patients appear to be at greater risk of developing TRALI than otherwise healthy patients. Presumably critical illness is associated with pulmonary microvascular injury that provides the first hit. The transfusion of antileukocyte antibodies is the second hit.
But why would blood donors have anti-MCH or anti-neutrophil antibodies anyway?
Almost always the donor has been alloimmunized during pregnancy. In recent study of 5,000 US woman, alloimmunization rates were directly correlated with parity. Antileukocyte antigens were identifiable in 1.7% of nulliparous women but rose to 29.8% among woman with three or more pregnancies.
You feeling lucky?
The bad luck part comes in receiving a blood product from a donor who has been alloimmunized by a person who has MCH or neutrophil antigens that match yours. Recall that despite the fact that antileukocyte antibodies are relatively common, TRALI is rare because the antibodies only cause disease if there is a specific cognate antigen.
What can be done to prevent TRALI?
Traditionally, blood banks have attempted to identify donor who are “responsible” for TRALI and prevent them from donating again. This means that once TRALI has occurred, blood bank staff must investigate to identify the donor. The problem with this approach is that TRALI can be difficult to identify definitively as these patients often have other reasons for having diffuse lung problems.
A more effective strategy would be to use only male donors for plasma donation. The UK implemented this approach and reports of TRALI fell by 75%. The challenge is that this is one more restriction that compromises an already stretched blood supply.
Sachs UJ, et al Mechansim of transfusion-related acute lung injury induced by HLA class II antibodies. Blood 2010 [Epub ahead of print]
Triulzi DJ. Transfusion-related Acute Lung Injury: Current concepts for the clinician. Anesthesia and Analgesia. 2009; 108: 770-6.
Stafford-Smith M. Many, but not all, outcome studies support exclusion of female plasma from the blood supply. Expert Reviews in Hematology. 2010;3:551-8.
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