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inflammation and disease
To determine if a patient has inflammation in their body, doctors use what is called a biomarker.

A biomarker, or biological marker, generally refers to a measured characteristic which may be used as an indicator of some biological state or condition. The term occasionally also refers to a substance whose presence indicates the existence of living organisms.

Biomarkers are often measured and evaluated to examine normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention. Biomarkers are used in many scientific fields.

A biomarker can be chemical, physical or biological. In molecular terms biomarker is "the subset of markers that might be discovered using genomics, proteomics technologies or imaging technologies. Biomarkers play major roles in medicinal biology. Biomarkers help in early diagnosis, disease prevention, drug target identification, drug response etc. Several biomarkers have been identified for many diseases.

A simple example of a biomarker would be if you had a swollen and darkly bruised ankle. Even though you can't see the actual cause of the swelling and darkness, you can safely assume that some sort of trauma has occured in the ankle area - either a break or sprain. The bruising and swelling are biomarkers pointing to this condition.

When it comes to testing for inflammation, the two most common biomarkers are C-reactive protein (CRP) and AA/EPA Ratio.

Biomarker (medicine) From Wikipedia, the free encyclopedia http://en.wikipedia.org/wiki/Biomarker_%28medicine%29


Restless Legs as a Biomarker

As I've discussed on the page WED/RLS is NOT a disease, it's a blessing in disguise, I believe that Restless Legs Syndrome is actually a biomarker for chronic inflammation. If your legs are twitching, that's a sign that you have inflammation. It's just a matter of time before this is proven.

A recent study by neurologist Sanford H. Auerbach, MD. of the Boston Medical Center strongly supports this belief.


Restless Legs Syndrome May Signify Bigger Health Problems
from Medical Xpress / Neurology, March 5, 2014

A nationally-recognized sleep expert has published an editorial describing Restless Legs Syndrome (RLS) as a possible biomarker for underlying disease. The editorial appears in the March 5, 2016 issue of Neurology the medical journal of the American Academy of Neurology and was authored by Boston Medical Center neurologist Sanford H. Auerbach, MD.

RLS is a disorder of the nervous system. Patients with RLS have uncomfortable sensations in their legs which lead to an overwhelming urge to move them – most often at night or whenever the patient is resting.

The editorial was in response to an analysis of 12,556 men who were followed over time by the Health Professionals Follow-Up Study, published in the same issue of Neurology, which showed multiple disease associations with RLS.

“Patients with RLS had a higher mortality rate than similar men, and showed an especially strong tendency toward cardiovascular disease and hypertension,” said Auerbach, associate professor of neurology and psychiatry at Boston University School of Medicine. In earlier analyses of the same data, men with RLS were more likely to be diagnosed with lung disease, endocrine disease, diseases of nutrition and metabolism and immune system problems.

Auerbach suggests that restless leg syndrome is a meaningful biomarker for serious disease, and that RLS screening may become more common as a tool for primary care providers to identify patients at risk.


http://medicalxpress.com/news/2014-03-restless-legs-syndrome-signify-bigger.html


inflammation and disease
This unique test measures the ratio of arachidonic acid (AA) to eicosapentaenoic acid (EPA) in plasma. This ratio of the principle omega-3 and omega-6 fatty acids is a measure of the body's eicosanoid balance. Balancing the eicosanoids in the body is an excellent way for managing heart disease and other chronic and inflammatory processes.

A lower AA/EPA ratio indicates a better balance of "good" and "bad" eicosanoids in your body. An AA/EPA ratio of less than 3 but not less than 1.5 is considered to be ideal. It is no longer considered "well" to have a ratio greater than 10. Anything exceeding 15 means a high level of inflammation in the blood (Toxic Fat Syndrome) and requires immediate dietary attention.

PGE2 is known to cause overall inflammation in your body causing DNA mutation and cell damage when you have too much of it. As a result of this cell damage (think cells of your cardiovascular system, lymph system, cartilage, muscles, nervous system, etc) it has been linked to chronic pain, cancer, heart disease, and many other diseases that plague our nation and drive our healthcare costs through the roof. However inflammation is what gives your body the ability to fight infection and disease so you do need it, so the ratio of AA to EPA is the key, just as the ratio of total cholesterol to HDL is more meaningful than just total cholesterol.

There are no drugs that can change the AA/EPA ratio. This is because AA/EPA ratio is a consequence of the diet. One method of lowering the AA/EPA ratio is to increase the intake of high-purity omega-3 fatty acid concentrates rich in EPA. This will increase the EPA content in the blood (2). This represents the fastest way to reduce the AA/EPA ratio. However, the best long-term method is to reduce the AA levels in the blood. This is best achieved by following a strict anti-inflammatory diet, such as the Zone diet (3-5). The Zone diet was designed to reduce elevated levels of both insulin and omega-6 fatty acids so that the production of AA is significantly reduced. The combination of an anti-inflammatory diet coupled with high-purity omega-3 concentrations represents the most powerful dietary approach to reach and maintain a low level of cellular inflammation for a lifetime.

Humans evolved on a diet of approximately 1:1 AA to EPA. The average North American diet consists of over 10 to 1 of AA to EPA. In other words, most people consume more than 10 times more inflammatory omega 6 fatty acids than they require.

The average American male has a dangerously high ratio of 16.2, whereas the maximum recommended AA/EPA ratio is 5.18 By contrast, Japanese men, whose diets are rich in omega-3s through fish consumption, generally possess AA/EPA ratios of 1.7, reflecting a substantially lower risk of chronic inflammation.

Supplementation with EPA can have a powerful effect on the important AA/EPA ratio, in one study dropping it from a concerning 23.7 at baseline in people with coronary artery disease to a remarkable 4.9.40 And a falling AA/EPA ratio was strongly correlated in reduction in gene expression of the inflammatory mediator IL-1b in patients with coronary artery disease.

Good quality fish oil supplement restores the balance between Omega 3 and Omega 6. Look for products that meet International Fish Oil Standards (IFOS). Amounts from 2 to greater than 10 grams may be required. Testing can determine whether healthy ratios and percentages have been achieved.


Dr. Barry Sears, Official Science Site of the Zone Diet, www.drsears.com

"Anti-Inflammatory Medicine: Dietary Modulation of Eicosanoids" Inflammation Research Foundation, Marblehead, MA www.inflammationresearchfoundation.org

"Measuring Your Future Wellness" DrSears.com http://www.drsears.com/DesktopModules/EngagePublish/printerfriendly.aspx?itemId=68&

"Optimize Your Omega-3 Status Personalized Blood Test Reveals a Novel Cardiac Risk Factor" by Julius Goepp, MD, Lfe Extension Magazine http://www.lef.org/magazine/mag2010/may2010_Optimize-Your-Omega-3-Status_02.htm

"Essential Fatty Acid Status" Eyes on Health http://www.eyesonhealth.com/services/labratory_testing/essential_fatty_acid

"Do you know your AA/EPA Ratio?" by Dr. Sean Miller D.C. http://seanmillerhealth.com/do-you-know-your-aaepa-ratio



inflammation and disease
C-reactive protein (CRP) is a substance produced by the liver that increases in the presence of inflammation in the body. An elevated CRP level is identified with blood tests and is considered a non-specific "marker" for disease. Data from a large number of studies suggest that over time chronic, imperceptible, low-level internal inflammation can lead to many serious, age-related diseases including heart disease, some forms of cancer and neurodegenerative conditions such as Alzheimer's and Parkinson's disease.

CRP is used mainly as a marker of inflammation. Apart from liver failure, there are few known factors that interfere with CRP production.

A C-reactive protein test to check for heart disease is not right for everyone. According to the American Heart Association, having a C-reactive protein test isn't recommended for the general population to screen for heart disease risk. And it might not be helpful in determining your heart attack risk, depending on your health and lifestyle choices.

CRP levels don't appear to help predict the risk of heart disease in patients already being treated for risks such as high blood pressure or high LDL ("bad") cholesterol. A 2010 analysis of British data on 4,853 patients found that CRP levels didn't yield any more information about the risk of heart disease than LDL ("bad") cholesterol levels or high blood pressure in patients who already were being treated with a cholesterol-lowering statin drug or with medication to lower blood pressure.

Your C-reactive protein level can be checked with a simple blood test. Some researchers think that by treating people with high C-reactive protein levels, it's less likely they might have a heart attack or stroke.

A C-reactive protein (CRP) test checks for inflammation. Your doctor may order a CRP test to monitor:

  • Coronary artery disease risk
  • Damage from a heart attack
  • Inflammatory bowel disease
  • Some forms of arthritis
  • Pelvic inflammatory disease
  • Lupus
  • Infection after surgery

CRP may be a risk factor for heart disease. It's thought that as coronary arteries narrow, you'll have more CRP in your blood. A CRP test can't tell your doctor exactly where the inflammation is, though, so it's possible that a high CRP level could mean there's inflammation somewhere in your body other than your heart.

According to the American Heart Association, a CRP test is most useful for people who have an intermediate risk (a 10 to 20 percent chance) of having a heart attack within the next 10 years. This risk level, called the global risk assessment, is based on lifestyle choices, family history and current health status. People who have a low risk of having a heart attack are less likely to benefit from having a CRP test, and people who have a high risk of having a heart attack should seek treatment and preventive measures regardless of how high their CRP level is.


"The physiological structure of human C-reactive protein and its complex with phosphocholine." Thompson, D; Pepys, MB; Wood, SP (February 1999). Structure 7 (2): 169–77. doi:10.1016/S0969-2126(99)80023-9. PMID 10368284.

"C-reactive protein: a critical update." Pepys, MB; Hirschfield, GM (June 2003). J Clin Invest 111 (12): 1805–12. doi:10.1172/JCI18921. PMC 161431. PMID 12813013.

"Adipokines: molecular links between obesity and atheroslcerosis." Lau, DC; Dhillon, B; Yan, H; Szmitko, PE; Verma, S (May 2005). Am J Physiol Heart Circ Physiol 288 (5): H2031–41. doi:10.1152/ajpheart.01058.2004. PMID 15653761.

"C reactive protein." Wikipedia en.wikipedia.org/wiki/C-reactive_protein

"C-reactive protein test" The Mayo Clinic http://www.mayoclinic.org/tests-procedures/c-reactive-protein/basics/definition/prc-20014480

"Elevated C-reactive Protein (CRP)" DrWeil.com http://www.drweil.com/drw/u/ART03424/Elevated-Creactive-Protein-CRP.html



inflammation and disease
Since cellular inflammation is confined to the cell itself, there are few blood markers that can be used to directly measure the levels of systemic cellular inflammation in a cell. However, the AA/EPA ratio in the blood appears to be a precise and reproducible marker of the levels of the same ratio of these essential fatty acids in the cell membrane.

The leukotrienes derived from AA are powerful modulators of NF-kB. Thus a reduction in the AA/EPA ratio in the target cell membrane will lead to a reduced activation of NF-kB by decreased formation of inflammatory leukotrienes. The cell membrane is constantly being supplied by AA and EPA from the blood. Therefore the AA/EPA ratio in the blood becomes an excellent marker of the same ratio in the cell membrane. Currently the best and most reproducible marker of cellular inflammation is the AA/EPA ratio in the blood as it represents an upstream control point for the control of NF-kB activation.

The most commonly used diagnostic marker of inflammation is C-reactive protein (CRP). Unlike the AA/EPA ratio, CRP is a very distant downstream marker of past NF-kB activation. This is because one of inflammatory mediators expressed in the target cell is IL-6. It must eventually reach a high enough level in the blood to eventually interact with the liver or the fat cells to produce CRP. This makes CRP a more long-lived marker in the blood stream compared to the primary inflammatory gene products (IL-1, IL-6, TNF, and COX-2) released after the activation of NF-kB.

As a consequence, CRP is easier to measure than the most immediate inflammatory products generated by NF-kB activation.

However, easier doesn’t necessarily translate into better. In fact, an increase AA/EPA ratio in the target cell membrane often precedes any increase of C-reactive protein by several years. An elevated AA/EPA ratio indicates that NF-kB is at the tipping point and the cell is primed for increased genetic expression of a wide variety of inflammatory mediators. The measurement of CRP indicates that NF-kB has been activated for a considerable period of time and that cellular inflammation is now causing systemic damage.


"Clinical Measurement of Cellular Inflammation" by Dr. Barry Sears, http://zonediet.com/blog/2012/01/what-is-cellular-inflammation


inflammation and disease

Silent Inflammation

Silent inflammation is the first sign that your body is out of balance and you are no longer well. You can't feel it, but it is affecting your heart, your brain, and your immune system.

There are three underlying hormonal changes that are linked to silent inflammation. They involve the overproduction of three distinct types of hormones:
  • Eicosanoids
  • Insulin
  • Cortisol

"A Silent Killer in Our Midst" Dr. Barry Sears, Zone Health.com www.zoneliving.com (2005)


Eicosanoid

A lipid mediator of inflammation derived from the 20-carbon atom arachidonic acid (20 in Greek is "eicosa") or a similar fatty acid. The eicosanoids include the prostaglandins, prostacyclin, thromboxane, and leukotrienes. eicosanoids can be considered "super-hormones" capable of modulating the immune system either by turning on the inflammatory response ("bad" eicosanoids) or turning off the inflammatory response ("good" eicosanoids) depending on which type of an eicosanoid a cell produces. Unlike typical hormones that are produced by a particular gland, every cell in your body is capable of producing eicosanoids. In essence, you have about 100 trillion eicosanoid glands, and the goal of anti-inflammatory medicine is to maintain an appropriate balance of the "good" and "bad" eicosanoids by controlling the levels of their molecular building blocks in the membranes of each cell in the body.

Here are some examples of chronic diseases that result from an excess production of "bad" eicosanoids.
  • Heart disease
  • Stroke
  • Hypertension
  • Arthritis
  • Cancer
  • Asthma
  • Depression
  • Alzheimer's

Eicosanoids form the command center of your immune system. Knock them out completely, and the immune system gets knocked out as well. This occurs in those who have immune-deficiency diseases, such as AIDS.

Long-chain omega-3 fatty acids reduce pro-inflammatory eicosanoids, whereas omega-6 fatty acids increase the production of pro-inflammatory eicosanoids.


Dr. Barry Sears, Official Science Site of the Zone Diet, www.drsears.com

MedicineNet www.medterms.com/script/main/art.asp?articlekey=25922

"Anti-Inflammatory Medicine: Dietary Modulation of Eicosanoids" Inflammation Research Foundation, Marblehead, MA www.inflammationresearchfoundation.org

"A Silent Killer in Our Midst" Dr. Barry Sears, Zone Health.com www.zoneliving.com (2005)



Insulin

Insulin is the storage hormone that drives nutrients into cells. It is vital for your survival since it allows cells to either store nutrients or immediately use them for energy. Without adequate levels of insulin, your cells would literally starve to death. And this is exactly what happens in type 1 (childhood-onset) diabetes, in which the patient is producing no insulin. (In fact, only a small percentage of diabetics have this type of diabetes.) Without injections of insulin, death is the inevitable outcome. But most of us are much more likely to have the opposite problem: we make way too much insulin. This is bad news, since it is excess insulin that makes you fat and keeps you fat.

Excess insulin's link to silent inflammation stems from the fact that it increases the production of arachidonic acid (AA), the building block for all pro-inflammatory eicosanoids. And if that isn't bad enough, recent research shows that insulin induces inflammation by increasing the production of interleukin-6 (IL-6), a pro-inflammatory cytokine that causes the formation of C-reactive protein, another marker for silent inflammation. The bottom line: controlling insulin is essential if you want to reverse silent inflammation and move toward a state of wellness.


"A Silent Killer in Our Midst" Dr. Barry Sears, Zone Health.com www.zoneliving.com (2005)


Cortisol (hydrocortisone)

A steroid hormone, or glucocorticoid, produced by the adrenal gland. It is released in response to stress and a low level of blood glucocorticoids. Its primary functions are to increase blood sugar through gluconeogenesis; suppress the immune system; and aid in fat, protein and carbohydrate metabolism.

When your body is in a constant state of silent inflammation, it reacts to it by having your adrenal glands pump out high amounts of cortisol, the primary anti-inflammatory hormone used to decrease excess inflammation. We tend to think of cortisol as a stress hormone, but in reality it is an anti-stress hormone. At the cellular levels all stress creates an inflammatory state caused by an over-production of pro-inflammatory eicosanoids. Cortisol is sent out to lower the levels of these eicosanoids, which is fine over the short run when stress is temporary. But having a high level of constant silent inflammation means you are going to have high levels of cortisol on a permanent basis, causing a number of nasty consequences such as increasing insulin resistance (which makes you fatter), killing nerve cells (which makes you dumber), and depressing your entire immune system (which makes you sicker). This is the collateral damage that comes from increased silent inflammation.


"Cortisol" Wikipedia, en.wikipedia.org/wiki/Cortisol

"First Aid USMLE Step 1" Tao Le et al. (2009)

"A Silent Killer in Our Midst" Dr. Barry Sears, Zone Health.com www.zoneliving.com (2005)



Arachidonic Acid (AA)

This is the 20-carbon length long-chain omega-6 fatty acid that is the immediate precursor of many eicosanoids that increase inflammation. Egg yolks, fatty red meat, and organ meats are rich sources of arachidonic acid.


"Anti-Inflammatory Medicine: Dietary Modulation of Eicosanoids" Inflammation Research Foundation, Marblehead, MA www.inflammationresearchfoundation.org


Eicosapentaenoic Acid (EPA)

This is the 20-carbon length long-chain omega-3 fatty acid that that inhibits the formation of arachidonic acid (AA). Fish oils are the richest source of EPA.


"Anti-Inflammatory Medicine: Dietary Modulation of Eicosanoids" Inflammation Research Foundation, Marblehead, MA www.inflammationresearchfoundation.org

















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