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INTRODUCTION
Considerable progress in blood purification
techniques over the years has not
yet ended the ongoing discussion regarding
the exact place and most convenient
mode of blood purification in patients
with septic shock (1,2). Septic shock indeed
remains a leading cause of mortality
in intensive care patients (3), and sepsis
research focuses on developing
methods to improve outcome of this devastating
disease. Unfortunately, attempts
to decrease mortality in septic shock by
using pharmacological (4) and blood purification
(5,6) approaches have been disappointing.
Therefore, every effort to improve
the understanding of rationale of
blood purification can be seen as a key
process to succeed in therapy—an elegant
description is in the report by
Namas et al., published in this issue (7).
Despite growing insight into key
physiological aspects and valuable incentives
on technical issues, therapeutic
targeting and more adequate dose determination
(8), the rationale of blood purification
as part of treatment in severe
sepsis and septic shock is still questioned.
Sepsis is a complex and multifaceted
inflammatory condition (9) initiated
and rekindled by stimulated host immune
effector cells. The intensity of the
inflammation is determined by a myriad
of biologically active substances such as
cytokines, chemokines and reactive
oxygen/nitrogen species. This process
functions properly when mediators remain
restricted to specific tissues, inducing
a well-controlled inflammatory response
to local injury or infection.
However, any “overflow” of mediators
in the bloodstream may generate a relentless
and harmful systemic inflammation.
Sustained elevation and/or uncontrolled
production of pro- and
antiinflammatory cytokines may finally
turn into a toxic self-propagating cascade
reaction that causes remote organ
damage, multiorgan failure and, in some
patients, ultimately death (9).
THE “OLD” CYTOTOXIC APPROACH
For almost three decades, researchers
have invested in strategies that involved
removal of excess inflammatory media-
M O L M E D 1 8 : 1 3 6 3 - 1 3 6 5 , 2 0 1 2 | H O N O R E E T A L . | 1 3 6 3
Moving from a Cytotoxic to a Cytokinic Approach in the
Blood Purification Labyrinth: Have We Finally Found Ariadne’s
Thread?
Patrick M Honore,1 Rita Jacobs,1 Olivier Joannes-Boyau,2 Willem Boer,3 Elisabeth De Waele,1
Viola Van Gorp,1 Jouke De Regt,1 and Herbert D Spapen1
1Intensivist University Hospital, Vrije Universiteit Brussel (VUB), Brussels, Belgium; 2Haut Leveque University Hospital of Bordeaux,
University of Bordeaux 2, Pessac, France; and the 3Department of Anesthesiology and Critical Care Medicine, Hospital East Limburg,
Genk, Belgium
For almost three decades, researchers have invested in strategies that involved removal of excess inflammatory mediators from
the circulation (that is, the “cytotoxic” approach). Blood purification techniques using an extracorporeal device can indeed nonspecifically
remove a wide array of inflammatory mediators from the circulation. In animal models, this multimediator targeting or
pleiotropic approach was shown to downregulate systemic inflammation and to restore immune homeostasis. In this issue, Namas
et al. seriously challenge this cytotoxic hypothesis and propose to replace it by a cytokinic approach. In a rodent model of sepsis,
these authors elegantly demonstrate that hemoadsorption using a large surface-area polymer could reduce and, more importantly,
relocalize and reprogram sepsis-induced acute inflammation, while simultaneously lowering infectious burden and liver
damage. Although challenging, this new theory can be considered complementary to the existing cytotoxic hypotheses by coupling
reduced endothelial damage at the interstitial level (cytotoxic approach) with the concept of reprogramming leucocytes
and mediators toward infected tissue, thus emptying the bloodstream of important promoters of remote organ damages (cytokinic
approach).
Online address: http://www.molmed.org
doi: 10.2119/molmed.2012.00300
Address correspondence to Patrick Honore, ICU Department, University Hospital, Vrije
Universiteit, Brussels, 101, Laarbeeklaan, B-1090 Brussels, Belgium. Phone: +32-2-4749097;
Fax: +32-2-4765253; E-mail: patrick.honore@uzbrussel.be.
Submitted June 7, 2012; Accepted for publication August 9, 2012; Epub
(www.molmed.org) ahead of print September 25, 2012.
tors from the circulation (that is, the “cytotoxic”
approach). Blood purification
techniques that an extracorporeal device
can indeed nonspecifically remove a
wide array of inflammatory mediators
from the circulation (10,11). In animal
models, this multimediator targeting or
pleiotropic approach was shown to
downregulate systemic inflammation
and to restore immune homeostasis (12).
In this issue, Namas et al. (7) seriously
challenge this cytotoxic hypothesis and
propose to replace it with a “cytokinic”
approach. They used the word cytokinic,
meaning that cytokines are attracting inflammatory
cells and in fact are messengers
between cells. Every technique that
can relocalize cytokines will also in itself
relocalize inflammation toward the infected
tissue and emptying secondary to
the blood compartment. In a rodent
model of sepsis, these authors elegantly
demonstrated that hemoadsorption
using a large surface-area polymer could
reduce and, more importantly, relocalize
and reprogram sepsis-induced acute inflammation
while simultaneously lowering
infectious burden and liver damage.
Read full study here:
https://molecularhub.org/forum/topics/default-category/37/37/cytokinic.pdf
CytoSorbents Corporation Announces Additional Data From European Sepsis Trial
Wednesday September 7, 2011
"As expected, there is also a good correlation between CytoSorb™ cytokine reduction and outcome in patients with highly elevated IL-6 levels (greater than or equal to 1,000 pg/mL) or IL-1ra (greater than or equal to 16,000 pg/mL) which are both known, independent predictors of mortality in sepsis. In these patients, CytoSorb™ treatment showed positive trends to benefit in 28-day all-cause mortality (0% vs 62.5% control, n = 14), fewer patients on mechanical ventilation at 28 days (33% vs 88% control), and fewer days in the ICU (23.8 vs 27.5 days control).
CytoSorbents had previously reported that the primary endpoint of the study had been achieved with an average IL-6 reduction of 49.1% (p = 0.01) across the 7-day treatment period. Analysis of other important cytokines demonstrated similar patterns of reduction including MCP-1 (-49.5%, p = 0.002), IL-1ra (-36.5%, p = 0.001) and IL-8 (-30.2%, 0.002) with additional cytokine analysis ongoing. These data further confirm the effectiveness of CytoSorb™ as a broad cytokine filter and its ability to reduce cytokine storm in patients with sepsis. Treatment was well-tolerated across more than 300 treatments without serious device related adverse events."
http://www.cytosorbents.com/news46.htm
D. Early Induced Innate Immunity
Early induced innate immunity begins 4 - 96 hours after exposure to an infectious agent and involves the recruitment of defense cells as a result of pathogen-associated molecular patterns or PAMPS (def) binding to pattern-recognition receptors or PRRs (def). These recruited defense cells include:
• phagocytic cells: leukocytes such as neutrophils, eosinophils, and monocytes; tissue phagocytic cells in the tissue such as macrophages (def);
• cells that release inflammatory mediators: inflammatory cells in the tissue such as macrophages and mast cells (def); leukocytes such as basophils and eosinophils; and
• natural killer cells (NK cells (def)).
Unlike adaptive immunity, innate immunity does not recognize every possible antigen. Instead, it is designed to recognize molecules shared by groups of related microbes that are essential for the survival of those organisms and are not found associated with mammalian cells. These unique microbial molecules are called pathogen-associated molecular patterns or PAMPS (def) and include LPS from the gram-negative cell wall, peptidoglycan and lipotechoic acids from the gram-positive cell wall, the sugar mannose (a terminal sugar common in microbial glycolipids and glycoproteins but rare in those of humans), bacterial and viral unmethylated CpG DNA, bacterial flagellin, the amino acid N-formylmethionine found in bacterial proteins, double-stranded and single-stranded RNA from viruses, and glucans from fungal cell walls. In addition, unique molecules displayed on stressed, injured, infected, or transformed human cells also act as PAMPS. (Because all microbes, not just pathogenic microbes, possess PAMPs, pathogen-associated molecular patterns are sometimes referred to as microbe-associated molecular patterns or MAMPs.)
Most body defense cells have pattern-recognition receptors or PRRs (def) for these common PAMPS and so there is an immediate response against the invading microorganism. Pathogen-associated molecular patterns can also be recognized by a series of soluble pattern-recognition receptors in the blood that function as opsonins and initiate the complement pathways. In all, the innate immune system is thought to recognize approximately 103 of these microbial molecular patterns.
We will now take a closer look at inflammation.
________________________________________
7. Inflammation (def)
The inflammatory response is an attempt by the body to restore and maintain homeostasis (def) after injury and is an integral part of body defense. Most of the body defense elements are located in the blood and inflammation is the means by which body defense cells and defense chemicals leave the blood and enter the tissue around the injured or infected site. Inflammation is essentially beneficial, however, excess or prolonged inflammation can cause harm.
1. The Mechanism of Inflammation
Esentially, three occurrences make up the inflammatory mechanism:
a. Smooth muscles around larger blood vessels contract to slow the flow of blood through the capillary beds at the infected or injured site. This gives more opportunity for leukocytes to adhere to the walls of the capillary and squeeze out into the surrounding tissue.
b. The endothelial cells (def) that make up the wall of the smaller blood vessels contract. This increases the space between the endothelial cells resulting in increased capillary permeability. Since these blood vessels get larger in diameter as a result of this, the process is called vasodilation. (see Fig. 1 and Fig. 2).
c. Adhesion molecules are activated on the surface of the endothelial cells on the inner wall of the capillaries. Corresponding molecules on the surface of leukocytes called integrins (def) attach to these adhesion molecules (def) allowing the leukocytes to flatten and squeeze through the space between the endothelial cells. This process is called diapedesis (def) or extravasation.
d. Activation of the coagulation pathway causes fibrin clots to physically trap the infectious microbes and prevent their entry into the bloodstream. This also triggers blood clotting within the surrounding small blood vessels to both stop bleeding and These four events are triggered and enhanced by a variety of chemical inflammatory mediators. We will now divide the inflammatory response into two stages: early inflammation and late inflammation.
1. Early Inflammation and Diapedesis (def)
Most leukocyte diapedesis (extravasation) occurs in post-capillary venules because hemodynamic shear forces are lower in these venules. This makes it easier for leukocytes to attach to the inner wall of the vessel and squeeze out between the endothelial cells. We will look at this process in more detail below.
a) During the very early stages of inflammation, stimuli such as injury or infection trigger the release of a variety of mediators of inflammation such as leukotrienes, prostaglandins, and histamine. The binding of these mediators to their receptors on endothelial cells leads to vasodilation, contraction of endothelial cells, and increased blood vessel permeability. In addition, the basement membrane surrounding the capillaries becoming rearranged so as to promote the migration of leukocytes and the movement of plasma macromolecules from the capillaries into the surrounding tissue.
Mast cells in the connective tissue as well as basophils, neutrophils and platelets leaving the blood from injured capillaries, release or stimulate the synthesis of vasodilators (def) such as histamine (def), leukotrienes (def), kinins (def), and prostaglandins (def). Certain products of the complement pathways (def) (C5a and C3a) can bind to mast cells and trigger their release their vasoactive agents. In addition, tissue damage activates the coagulation cascade and production of inflammatory mediators like bradykinins (def).
b) The binding of histamine to histamine receptors on endothelial cells triggers an upregulation of P-selectin molecules (def) and platelet-activating factor (def) or PAF on the endothelial cells that line the venules.
c). The P-selectins then are able to reversibly bind to corresponding P-selectin glycoprotein ligands (PSGL-1) on leukocytes. This reversible binding enables the leukocyte to now roll along the inner wall of the venule.
d) The binding of PAF to its corresponding receptor PAF-R on the leukocyte upregulates the surface expression of an integrin (def) called leukocyte function-associated molecule-1 (LFA-1) on the surface of the leukocyte.
e) The LFA-1 molecules on the rolling leukocytes can now bind firmly to an an adhesion molecule (def) called intercellular adhesion molecule-1 (ICAM-1) found on the surface of the endothelial cells forming the inner wall of the blood vessel (see Fig. 4).
f) The leukocytes flatten out, squeeze between the constricted endothelial cells, and use enzymes to breakdown the matrix that forms the basement membrane surrounding the blood vessel. The leukocytes then migrate towards chemotactic agents such as the complement protein C5a and leukotriene B4 generated by cells at the site of infection or injury (see Fig. 5).
2. Late Inflammation and Diapedesis
a. Usually within two to four hours of the early stages of inflammation, activated macrophages and vascular endothelial cells release inflammatory cytokines (def) such as TNF and IL-1 when their toll-like receptors bind pathogen-associated molecular patterns (def) - molecular components associated with microorganisms but not found as a part of eukaryotic cells. This enables vascular endothelial cells of nearby venules to increase their expression of adhesion molecules such as P-selectins (def), E-selectins, intercellular adhesion molecules (ICAMs), and chemokines (def).
b) The binding of TNF and IL-1 to receptors on endothelial cells triggers an maintains the inflammatory response by upregulation the production of the adhesion molecule (def) E-selectin and maintaining P-selectin expression on the endothelial cells that line the venules.
c). The E-selectins on the inner surface of the endothelial cells can now bind firmly to its corresponding integrin (def) E-selectin ligand-1 (ESL-1) on leukocytes (see Fig. 4).
d) The leukocytes flatten out, squeeze between the constricted endothelial cells, and move across the basement membrane as they are are attracted towards chemokines such as interleukin-8 (IL-8) and monocyte chemotactic protein-1 (MCP-1) generated by cells at the site of infection or injury (see Fig. 5). Leakage of fibrinogen (def) and plasma fibronectin (def) then forms a molecular scaffold that enhances the migration and retention of leukocytes at the infected site.
3. Benefits of Inflammation
As a result of this increased permeability:
a. Plasma (def) flows out of the blood into the tissue.
Beneficial molecules in the plasma (see Fig. 2) include:
1. Clotting factors. Tissue damage activates the coagulation cascade causing fibrin clots to form to localize the infection, stop the bleeding, and chemotactically attract phagocytes.
2. Antibodies (def). These help remove or block the action of microbes through a variety of methods that will be explained in Unit 5. 3. Proteins of the complement pathways (def). These, in turn: 1) stimulate more inflammation (C5a, C3a, and C4a), 2) stick microorganisms to phagocytes (C3b and C4b), 3) chemotactically attract phagocytes ( C5a), and 4) lyse membrane-bound cells displaying foreign antigens (membrane attack complex or MAC).
4. Nutrients. These feed the cells of the inflammed tissue.
5. Lysozyme (def), cathelicidins (def), phospholipase A2 (def), and human defensins (def). Lysozyme degrades peptidoglycan. Cathelicidins are cleaved into two peptides that are directly toxic to microbes and can neutralize LPS from the gram-negative bacterial cell wall. Phospholipase A2 hydrolizes the phospholipids in the bacterial cytoplasmic membrane. Human defensins put pores in the cytoplasmic membranes of many bacteria. Defensins also activate cells involved in the inflammatory response.
6. Transferrin (def). Transferrin deprives microbes of needed iron.
b. Leukocytes enter the tissue through a process called diapedesis (def) or extravasation, discussed above under early inflammation and late inflammation.
Benefits of diapedesis (def) include (see Fig. 2):
1. Increased phagocytosis. Neutrophils, monocytes that differentiate into macrophages when they enter the tissue, and eosinophils are phagocytic leukocytes.
2. More vasodilation. Basophils, eosinophils, neutrophils, and platelets enter the tissue and release or stimulate the production of vasoactive agents that promote inflammation.
3. Cytotoxic T-lymphocytes (CTLs) (def), effector T4-cells (def), and NK cells (def) enter the tissue to kill cells such as infected cells and cancer cells that are displaying foreign antigens (def) on their surface (discussed in Unit 5).
Cytokines called chemokines (def) are especially important in this part of the inflammatory response. They play key roles in diapedesis -enabling white blood cells to adhere to the inner surface of blood vessels, migrate out of the blood vessels into the tissue, and be chemotactically attracted to the injured or infected site. They also trigger extracellular killing by neutrophils.
Finally, within 1 to 3 days, macrophages release the cytokines interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-alpha). These cytokines stimulate NK cells and T-lymphocytes to produce the cytokine interferon-gamma. (IF-gamma). The IF-gamma then binds to receptors on macrophages causing them to produce fibroblast growth factor and angiogenic factors for tissue remodeling. With the proliferation of endothelial cells and fibroblasts, endothelial cells (def) form a fine network of new capillaries into the injured area to supply blood, oxygen, and nutrients to the inflammed tissue. The fibroblasts (def) deposit the protein collagen in the injured area and form a bridge of connective scar tissue to close the open, exposed area. This is called fibrosis or scarring, and represents the final healing stage.
Inflammation is normally carefully regulated by cytokines (def). Inflammatory cytokines such as interferon-gamma and interleukin-12 enhance the inflammatory response whereas the cytokine interleukin-10 inhibits inflammation by decreasing the expression of inflammatory cytokines.
So as can be seen, acute inflammation is essential to body defense. Chronic inflammation, however, can result in considerable tissue damage and scarring. With prolonged increased capillary permeability, neutrophils (def) continually leave the blood and accumulate in the tissue at the infected or injured site. As they discharge their lysosomal contents and reactive oxygen species or ROS (def), surrounding tissue is destroyed and eventually replaced with scar tissue. Anti-inflammatory agents such as antihistamines or corticosteroids may have to be given to relieve symptoms or reduce tissue damage.
For example, as learned in Unit 2, during severe systemic infections with large numbers of microorganisms present, high levels of pathogen-associated molecular patterns (PAMPs) (def) are released resulting in excessive cytokine production by macrophages and this can harm the body. In addition, neutrophils (def) start releasing their proteases (def) and toxic oxygen radicals (def) that kill not only the bacteria, but the surrounding tissue as well. Harmful effects include high fever, hypotension (def), tissue destruction, wasting, acute respiratory distress syndrome or ARDS (def), disseminated intravascular coagulation or DIC (def), damage to the vascular endothelium, hypovolemia (def), and reduced perfusion (def) of blood through tissues and organs resulting to shock (def), multiple system organ failure (MOSF), and often death. This excessive inflammatory response is referred to as Systemic Inflammatory Response Syndrome or SIRS or the Shock Cascade.
Chronic inflammation also contributes to heart disease, Alzheimer's disease, diabetes, and cancer.
• In the case of cancer,it is proposed that when macrophages (def) produce inflammatory cytokines (def), such as TNF-alpha (def), these cytokines activate a gene switch in the cancer cell that turns on the synthesis of proteins that promote cell replication and inflammation while blocking apoptosis (def) of the cancer cell.
• In heart disease, it is thought that macrophages digest low density lipoprotein or LDL, the bad cholesterol, and are then encased in a fibrous cap that forms arterial plaque.
• With diabetes, it is thought that the metabolic stress of obesity triggers innate immune cells and fat cells to produce cytokines such as TNF-alpha that can interfere with the normal function of insulin.
• In the case of Alzheimer's disease, microglial cells, macrophage-like cells in the brain, interact with the beta-amyloid proteins that build up in neurons of those with Alzheimer's and subsequently produce inflammatory cytokines and free radicals that destroy the neurons.
http://faculty.ccbcmd.edu/courses/bio141/lecguide/unit4/innate/inflammation.html
Why Trauma Makes People Sick: Inflammation, Heart Disease and Diabetes in Trauma Survivors
Cytokines are proteins that regulate immune response and proinflammatory cytokines help the body heal wounds and fight infection. But there can be too much of a good thing; chronic inflammation is a likely cause of a wide range of illnesses including heart disease, diabetes, and Alzheimer’s disease.
Trauma survivors have higher than average rates of serious illness including heart disease, diabetes and metabolic syndrome, the precursor to type 2 diabetes (Batten et al., 2004; Felitti et al., 2001; Kendall-Tackett & Marshall, 1999). The intriguing question is why this is so. One possible explanation is the connection between disease and inflammation— specifically, elevated levels of proinflammatory cytokines. Cytokines are proteins that regulate immune response and proinflammatory cytokines help the body heal wounds and fight infection. But there can be too much of a good thing; chronic inflammation is a likely cause of a wide range of illnesses including heart disease, diabetes, Alzheimer’s disease, and even cancer (Batten et al., 2004; Robles et al., 2005; Suarez, 2006).
So why would proinflammatory cytokines to be elevated in trauma survivors? Low levels of cortisol, which are common in trauma survivors, can allow inflammation to go unchecked since cortisol generally regulates the inflammatory response. Another possibility is that cytokines increase in the wake of two common trauma sequelae-- depression and hostility. Depression and hostility act as stressors, and increase inflammation and subsequent risk of disease. These can affect survivors’ health long after the trauma has ended.
Depression, Inflammation and Health
Depression is one of the most commonly occurring sequela of trauma (Kendall-Tackett, 2003). But it’s one we tend to think of it as an outcome—an endpoint we measure in the wake of traumatic events. Yet depression can also be a mechanism that leads to poor health. The negative impact of depression is well known in the cardiovascular literature. Patients who become depressed after a heart attack are two to three times more likely to have another one and are three to four times more likely to die (deJong et al., 2006; Lesperance & Frasure-Smith, 2000). And inflammation is the likely culprit (Kiecolt-Glaser et al., 2007).
In depressed people, there are several biomarkers of increased inflammation including acute-phase proteins, such as C-reactive protein (CRP; Kop & Gottdiener, 2005; Robles, Glaser, & Kiecolt-Glaser, 2005), and proinflammatory cytokines. The proinflammatory cytokines that have been identifi ed in most studies of depressed people are interleukin-1ß (IL-1ß), interleukin-6 (IL-6), tumor necrosis factor-a (TNF-a) and more recently, interferon-? (IFN-?; Kiecolt-Glaser et al., 2007; Robles et al., 2005). Researchers hypothesize that chronic inflammation increases the risk of heart disease by damaging blood vessels, reducing the stability of plaque, and increasing the risk of acute episodes (e.g., Kop & Gottdiener, 2005).
In summary, depression raises inflammation and is generally bad for people’s health. It alone could explain many of the health effects of trauma. But unfortunately, depression is not the only mental state that increases the risk of disease. Hostility is another common sequela of trauma that leads to poor health. Its effects are described below.
Hostility and Trauma
For people with a hostile world view, life is not benign. People high in trait hostility don’t trust others, are suspicious and cynical about human nature, and tend to interpret the actions of others as aggressive (Smith, 1992). And hostility is a common response among trauma survivors. In a sample from primary care, 52% of female sexual abuse survivors indicated that they could not trust others compared with 17% of the nonabused women (Hulme, 2000). In a community sample, approximately half of sexual abuse survivors indicated that their views of themselves and others were very negative. And in a sample of 90 women veterans (Butterfield, Forneris, Feldman, & Beckham, 2000), women with PTSD reported significantly higher levels of hostility and had poorer health than women without PTSD.
The Health Effects of Hostility
Hostility is a reaction that may have been adaptive at one point, and served to protect the survivor from further danger. However, hostility has a well-documented negative impact on health. Hostility increases physiological arousal because of the way hostile people interpret the world (Kiecolt-Glaser & Newton, 2001). This reaction increases both the risk of cardiovascular disease and diabetes. In their review, Smith and Ruiz (2002) noted that people who are high in trait hostility are more prone to ischemia and constriction of the coronary arteries during mental stress. Trait hostility predicted new coronary events in previously healthy people. And for patients who already have coronary heart disease, hostility sped-up progression of the disease.
Hostility also increased levels of proinflammatory cytokines (IL-1a, IL-1ß, IL-8 and TNF-a) in a study 44 healthy, non-smoking, premenopausal women (Suarez et al., 2004). The combination of depression and hostility was especially deleterious, and there was a dose-responsive effect: the more severe the depression and hostility, the greater the production of cytokines. A study with men had similar results (Suarez, 2003). The author noted that increased levels of IL-6 predicted both future risk of cardiac events and all-cause mortality, and hypothesized that IL-6 may mediate the relationship between hostility and these health problems.
Hostility also increases the risk of metabolic syndrome. In a three-year follow-up of 134 white and African American teens, hostility at Time 1 predicted risk factors for metabolic syndrome at Time 2 (Raikkonen, Matthews, & Salomon, 2003). These risk factors were at the 75th percentile for age, gender and race and included BMI, insulin resistance, ratio of triglycerides to HDL cholesterol, and mean arterial blood pressure.
More recently, Suarez (2006) studied 135 healthy patients (75 men, 60 women) with no symptoms of diabetes. He found that women with higher levels of depression and hostility, and who had a propensity to express anger, had higher levels of fasting insulin, glucose, and insulin resistance. These findings were not true for men and they were independent of other risk factors for metabolic syndrome including BMI, age, fasting triglycerides, exercise regularity, or ethnicity. The author indicated that these findings were significant since pre-study glucose levels were in the non-diabetic range. The author noted that inflammation, particularly elevated IL-6 and C-reactive protein, may mediate the relationship between depression and hostility, and risk of type 2 diabetes and cardiovascular disease, possibly because they increase insulin resistance.
Anti-Inflammatory Treatment Approaches
The studies cited above indicate that two common trauma sequelae—depression and hostility—appear to increase inflammation and impair health. The inflammation health connection raises at least the possibility that reducing inflammation may help lessen the severity of symptoms. The depression literature already indicates that many of the effective treatments for depression are also anti-inflammatory, and this may be another mechanism for their efficacy. For example, the selective serotonin reuptake inhibitor (SSRI) class of antidepressants have been found to lower levels of C-reactive protein in cardiac patients with major depression (O’Brien et al., 2006). This anti-inflammatory effect was independent of whether depression resolved in these patients.
Even cognitive therapy, a treatment with well-established efficacy, is arguably anti-inflammatory (Rupke et al., 2006). Two recent studies have demonstrated that negative beliefs, such as hostility, can increase the levels of proinflammatory cytokines—especially IL-6 (Kiecolt-Glaser et al., 2005; Suarez et al., 2004). The primary goal of cognitive therapy is to reduce negative cognitions. Since negative cognitions increase inflammation, reducing their occurrence should reduce inflammation.
Omega-3 Fatty Acids, Inflammation and Health
In my view, some of the more promising work, with potential application to trauma survivors, is research on the health effects of long-chain Omega-3 fatty acids: EPA and DHA. EPA and DHA are anti-inflammatory and lower levels of proinflammatory cytokines. A recent large population study found that people with high blood levels EPA and DHA had low levels of IL-6, IL-1, TNF-a and lower levels of C-reactive protein. The opposite was true for people with low EPA/DHA in their blood (Ferrucci et al., 2006). Another study of older adults found that the combination of depressive symptoms and low blood levels of Omega-3s enhanced production of IL-6 and TNF-a (Kiecolt-Glaser et al., 2007). These are the same cytokines that are high in depression and hostility and that likely have a relation to heart disease and diabetes.
EPA and DHA may also protect mental health. High levels of EPA and DHA increased resilience to laboratory-induced psychological stressors in college students and attenuated the proinflammatory response (Maes et al., 2000). In population studies, populations with higher levels of EPA and DHA in their diets (usually from eating fatty fish) had lower levels of major depression (Tanskanen et al., 2001), postpartum depression (Hibbeln, 2002), bipolar disorder (Noagliul & Hibbeln, 2003), and even future suicide risk (Sublette et al., 2006).
Similar findings have been noted in randomized clinical trials, where researchers have given either EPA/DHA supplements or a placebo to people currently receiving treatment for unipolar or bipolar depression. Two recent studies added EPA to patients’ normal regimen of antidepressants and found that EPA made the antidepressants more effective in treating depression than the placebo (Nemets et al., 2002; Peet & Horrobin, 2002). Similarly, in a study of childhood depression, children who received EPA and DHA in addition to their medications had significantly improved depression compared with children who received their meds and a placebo (Nemets et al., 2006). And EPA also helped stabilize symptoms of bipolar disorder in a 12-week double-blind trial (Frangou et al., 2006).
Although these findings are preliminary, treatments that are anti-inflammatory show promise as primary or adjunct treatments in trauma survivors. Although cognitive therapy and antidepressants have been used successfully with trauma survivors (Kendall-Tackett, 2003), to my knowledge, EPA and DHA have not been tried. But this may prove to be an effective addition to our treatment regimens and would be a fruitful avenue to explore.
Overall Summary
Depression and hostility are common sequelae of trauma and violence. In addition to their negative impact on day-to-day functioning, they can also act as chronic stressors in trauma survivors. Both of these can have a profound impact on health, in part, by raising levels of proinflammatory cytokines. Treatments that reduce inflammation show promise in alleviating depressive and trauma symptoms, and also in decreasing the risk of subsequent health problems.
Bestthinking.com/articles/medicine/psychiatry_and_neurology/why-trauma-makes-people-sick-inflammation-heart-disease-and-diabetes-in-trauma-survivors
Competition?
BERKELEY, Calif.--(BUSINESS WIRE)--
ExThera Medical announced today that its President and CEO, Bob Ward, will present ExThera Medical’s opportunity at ‘OneMedForum 2013.’ Dr. Ward’s presentation will be at The Sir Francis Drake Hotel beginning at 2:40 p.m. PST on Tuesday, Jan. 8th.
ExThera’s Seraph™ (Selective Removal by Apheresis) Microbind™ Affinity Blood Filter has received enthusiastic scientific scrutiny for its potential to bind a wide range of pathogens, toxins and pro-inflammatory cytokines to thwart bacteremia and viremia in the prevention of sepsis.
While other medical treatments of bacteremia caused by S. aureus or MRSA (Methicillin-Resistant S. Aureus) rely on antibiotics with failure rates up to 40%, the Seraph™ apheresis device capitalizes on the affinity of the bacteria in an infected patient’s blood to attach to immobilized heparin—a natural anticoagulant, with many other biological attributes. Seraph™ is designed to be a biomimetic adjunct to antibiotic therapy that reduces bacterial load and duration of bacteremia while lowering levels of pro-inflammatory cytokines in a patient’s blood, thereby preventing complications such as endocarditis, osteomyelitis, and sepsis.
Although presently aimed at its prevention, another critically important application of Seraph™ is expected to be the treatment of sepsis within intensive care units (ICU). Seraph™ consists of a specially designed cartridge packed with a novel bioactive polymer substrate that acts as a hemofilter. By incorporating immobilized heparin, and supplemental ligands the cartridge’s high-surface-area may safely and selectively reduce pro-inflammatory cytokines such as TNF-alpha and remove many toxins and pathogens such #$%$. aureus including MRSA, from a patient’s blood before the blood is (re)infused.
About ExThera Medical
Privately held ExThera Medical, based in Berkeley, Calif., is targeting the clinical treatment of blood-borne diseases including bacteremia and sepsis, as well as the removal of harmful substances present in banked human blood.
CAUTION: ExThera Medical’s products are for investigational use only. Less
Dialysis Like Therapeutics
Continuous Blood Sensing, Scrubbing, and Therapy
Integration Technology Exchange
March 29, 2012
Timothy Broderick, MD
Program Manager, Microsystems Technology Office
Approved for Public Release, Distribution Unlimited
Program impact
May save at least 43,000 US lives and $3.3B annually
http://websearch.darpa.mil/search?q=cache:RHZIL46bc28J:www.darpa.mil/WorkArea/DownloadAsset.aspx%3Fid%3D2147485152+Aethlon&access=p&output=xml_no_dtd&ie=UTF-8&client=default_frontend&site=default_collection&proxystylesheet=default_frontend&oe=UTF-8
Good Aethlon Article, Journal of Translational Medicine (Circa.27 June 2012)
Long Article Good Read
Conclusions:
Exosomes have emerged as being important vehicles for intercellular communication and for modulating immune responses, owing to their content of proteins and genetic material that mirror their cells of origin. Whereas exosomes from activated lymphocytes can possess immune stimulatory functions, there are many physiologic examples of exosomes exerting tolerogenic functions during dampening of immune responses, oral tolerance and pregnancy. In cancer, the tolerogenic activities of exosomes represent pathological responses whereby tumor cells secrete vast amounts of immune inhibitory exosomes that hinder anti-cancer immune responses. Tumor-derived exosomes are involved in the fundamental aspects of cancer pathogenesis including growth, metastasis, angiogenesis, and immune suppression. Therefore, to address the unmet need for a strategy to target tumor-secreted exosomes, one possible option involves a therapeutic hemofiltration approach, the Aethlon ADAPT™ system, which is designed to selectively capture and remove target particles such as exosomes from the entire circulatory system. This technology consists of hollow fiber plasma filtration cartridges constructed with affinity agents that are fitted for existing dialysis machines. The ADAPT™ system has the potential to address a variety of types and stages of cancer since it can incorporate diverse affinity agents for capturing cancer-specific exosomes on the basis of their display of surface proteins (using antibodies) and/or glycoproteins (using lectin affinity agents). The emerging evidence that tumor-secreted exosomes are involved in mediating resistance to therapies provides an impetus for exploration novel therapeutic options for addressing the immune inhibitory and tumor growth-promoting effects of cancer exosomes.
http://www.translational-medicine.com/content/10/1/134
I think everyone is forgetting the guidance already provided during the initial phases of the trial. Everyone complained primary endpoint was not updated but the following guidance was:
Seven of these patients were treated with CytoSorb? and standard of care therapy, while six others were in the control group receiving standard of care therapy alone. We are encouraged that an analysis of the data demonstrates improvements in many of the secondary and exploratory endpoints of the trial in the treatment group compared to the control group including:
· 28-day and 60-day all cause mortality
· Ventilator free days
· Pace of ventilator weaning
· Organ failure scores
· Vasopressor use
· Days in the intensive care unit
These objective endpoints in the treatment of severe sepsis are important. First, improvements in these key outcomes are difficult to accomplish but are directly associated with improved patient outcome and survival. Secondly, these are parameters used by critical care physicians to judge how patients are doing and are predictors of length of stay and cost of stay in the intensive care unit. Lastly, improvements in these criteria are consistent with how CytoSorb? is intended to work.
Add the primary data we received with CE mark approval to this data to get a clearer picture.
http://02c390e.netsolhost.com/news21c.ht...
I think everyone is forgetting the guidance already provided during the initial phases of the trial. Everyone complained primary endpoint was not updated but the following guidance was:
Seven of these patients were treated with CytoSorb? and standard of care therapy, while six others were in the control group receiving standard of care therapy alone. We are encouraged that an analysis of the data demonstrates improvements in many of the secondary and exploratory endpoints of the trial in the treatment group compared to the control group including:
· 28-day and 60-day all cause mortality
· Ventilator free days
· Pace of ventilator weaning
· Organ failure scores
· Vasopressor use
· Days in the intensive care unit
These objective endpoints in the treatment of severe sepsis are important. First, improvements in these key outcomes are difficult to accomplish but are directly associated with improved patient outcome and survival. Secondly, these are parameters used by critical care physicians to judge how patients are doing and are predictors of length of stay and cost of stay in the intensive care unit. Lastly, improvements in these criteria are consistent with how CytoSorb? is intended to work.
Add the primary data we received with CE mark approval to this data to get a clearer picture.
http://02c390e.netsolhost.com/news21c.htm
FDA Prioritys
PRIORITY 4. PROACTIVELY FACILITATE INNOVATION AND ADDRESS UNMET PUBLIC HEALTH NEEDS
http://www.fda.gov/AboutFDA/CentersOffic...
Put these two goals together...
By June 30, 2011, provide a progress report on at least 2 pilot programs developed to address unmet public health needs identified by the Council on Medical Device Innovation and provide an updated list of the top 5 unmet public health needs that could be cured, significantly improved, or prevented by the development or redesign of a medical device.
By July 31, 2011, begin to utilize mechanisms for the routine exchange of medical device information with foreign regulatory authorities.
By September 30, 2011, establish a forum for global medical device regulators to address the implementation of harmonization efforts, facilitate the exchange of information, and foster collaboration.
Goal 1.1.4.2. By January 31, 2012, CDRH will make use of Quality Systems Inspections conducted by other countries.
Subject: RE: Cytosorbent Patents Vs Appliction Number 12/306670 recorded 3/2010
From: "Phillip Chan" <pchan@cytosorbents.com>
To: XXXXXXX
Thank you XXXXXXXXXXX,
Although I can't comment in detail on this, please understand that the concept of using blood purification to remove "evil humors" is not new. In fact, some have likened it to "21st century bloodletting". However, modern blood purification returns "purified" blood to the body. You will likely find many technologies claiming to remove substances from blood and treating similar diseases. The real test is whether or not they can perform in a real world setting.
In this particular case, the technology appears to be a ligand-based technology - very different from our hemocompatible porous polymer technology. One of the greatest challenges of the former is in the manufacturing and sterilization of such products. That being said, it is interesting, but let me know when you see the technology in the clinic.
Best,
Phillip
--------------------------------------------------------------------------------
From: XXXXXXXXXXXXXXXXXXXXXXX
Sent: Tuesday, April 19, 2011 3:33 PM
To: Phillip Chan
Subject: Cytosorbent Patents Vs Appliction Number 12/306670 recorded 3/2010
Dr Chan,
Let me start this email with congratulatory remarks for the work you have accomplished with the EU approvals; your leadership has been spot on in regards to financing and execution. I have followed CTSO for the past two years and slowly invested moneys into what I see as a world class product and operation. With that being said I have a question relating to our patents. Yesterday in my research I found an approved patent issued to Asahi Kasei Kabushiki Kaisha in Japan. After reviewing the details it seams it closely resembles our products. The three main area of concern are as follows: (excerpt taken from this http://www.freepatentsonline.com/20100069815.pdf)
1. The material of the substrate may be either an inorganic compound or an organic compound as long as it is capable of stably immobilizing at least a predetermined amount of the recognition molecule, although it is preferably a safe material for use as a medical material which can be processed into various forms, which is capable of chemically binding to the recognition molecule either directly or indirectly, and which produces little eluted matter when being contacted with a biological fluid such as blood. Examples thereof can include inorganic materials such as glass, kaolinite, or bentonite, polysaccharide-based compounds of plant origin such as cellulose, natural polymers such as dextran, chitin, chitosan, starch, agarose, protein (collagen etc.), or natural rubber, polypropylene, polystyrene, polyamide, polyethylene, polyurethane, polyvinyl alcohol, ethylene-vinylalcohol copolymer, polymers and copolymers of polymethacrylic ester, polyacrylic ester, polyacrylic acid, polyvinyl alcohol, other vinyl-based compounds, or derivatives thereof, polyamide-based compounds such as Nylon 6 or Nylon 66, polyester-based compounds such as polyethylene terephthalate, synthetic polymers such as polyamino acids, and activated carbon.
2.The term “biorelated substance” among the target substances refers to a biologically produced protein, nucleic acid, lipid, saccharide, low molecular chemical compound, or the like. Further, the term “biorelated substance” used herein can include even an artificial matter such as an endocrine disrupter which seriously affects living bodies. The biorelated substance also includes harmful matters. The term “harmful matter” means, for example, LDL, ß2 microglobulin, drugs, bilirubin, bile acid, amino acids, creatinine, endotoxin, an anti-A antibody, an anti-B antibody, an anti-acetylcholine receptor-antibody, IgG, anti-cardiolipin antibody, anti-DNA antibody, immune complexes, coma-inducing substances, rheumatoid factors, and other plasma components. Abnormal prions are also included therein. In addition, various mediators such as inflammatory cytokines can also serve as harmful matters depending on the pathologic condition. As to inflammatory cytokines, IL-1, IL-6, IL-8, IL-18, TNF-a, GM-CSF, and RANTES/SIS cytokine families are known. Moreover, mediators involved in inflammation include prostaglandin, thromboxane, leukotriene and other products which is produced from arachidonic acid in vivo, platelet activating factors, histamine, bradykinin, and a complement factor C5a.
3. The aforementioned device for biological fluid treatment can be used for the treatment against a disease associated with at least one target substance, selected from a biorelated substance, a bacterium, a cell, a cell aggregation, a virus, or a virus-infected cell. Examples of the disease associated with such target substance(s) can include, but not limited to: (1) acute renal failure, chronic renal failure, and the like; (2) fulminant hepatitis, acute hepatic failure, arteriosclerosia obliterans, myasthenia gravis, Guillain-Barre syndrome, multiple sclerosis, myeloma, drug poisoning, pemphigus, and the like; (3) septic shock, familial hyperlipemia, arteriosclerosia obliterans, focal glomerular sclerosis, dialytic amyloidosis, and the like; and (4) ulcerative colitis, chronic rheumatoid arthritis, multiple sclerosis, dermatosis, and immunological disease.
The target substance in an aqueous solution or blood can be adsorbed or removed by treating this aqueous solution or blood containing the target substance by flowing the aqueous solution or blood through the aforementioned device for biological fluid treatment. Such a treatment method of an aqueous solution and a treatment method of blood are also included in the scope of the present invention.
It seems like the mentioned everything except Cytosorbents: Can you shead some light on the differences and similarities?
I am a long time holder of CTSO stock and have accumulated XXX,XXX shares.
Thank you for all you do,
XXXXXXXXX
XXXXXXXXX
XXXXXXX, XXXXXXXXX
Does the use of a cytokine 'filter' during cardiopulmonary bypass make sense?
G Clermont1, J Kellum1, J Bartels2, S Chang2, C Chow1 and Y Vodovotz1
1 University of Pittsburgh, Pennsylvania, USA
2 Immunetrics, Inc., Pittsburgh, Pennsylvania, USA
From 24th International Symposium on Intensive Care and Emergency Medicine
Brussels, Belgium. 30 March – 2 April 2004
Critical Care 2004, 8(Suppl 1):P149doi:10.1186/cc2616
Published: 15 March 2004
Objective
Very high or sustained high levels of the inflammatory cytokines tissue necrosis factor (TNF) and interleukin (IL)-6 are believed to be responsible for adverse clinical effects in patients undergoing cardiopulmonary bypass (CPB). We explored, using a mathematical model, whether modulation of this response might be beneficial.
Methods
We developed a mathematical model of the acute inflammatory response that was calibrated from rat endotoxemia and hemorrhagic shock data. The model accommodates a variety of initiators of acute inflammation, provides a dynamic profile of serum markers of inflammation over time, and expresses outcome in as global tissue dysfunction. Irreversible dysfunction is interpreted as death. We constructed a population of 100,000 cases that differed by level of initial stress and propensity to mount an inflammatory response. Initial stress was chosen to result in 4% cohort mortality and to last less than 6 hours, such as CPB. The intervention consisted of the removal of circulating TNF, IL-6 and IL-10 over a period of 6 hours, during which stress was inflicted and acute inflammation triggered. We equated the degree of removal of cytokines to that observed with the application of a biocompatible adsorbent polymer hemoperfusion column in endotoxemic rats.
Results
Death correlated to serum IL-6 and to a lesser degree TNF cumulative levels. Patients with the highest levels of IL-6 6–24 hours after the insult are those that will go on to die (Fig. 1). Examination of the results show that, if the IL-6 levels were decreased by > 60% and TNF levels by > 50% in the period at or shortly after the CPB, over 99% of all patients would survive, compared with 96% in the control arm.
Conclusions
Global, nonspecific, reduction of inflammation improves outcome in simulations of an acute inflammatory challenge such as CPB.
http://ccforum.com/content/8/s1/p149