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Through the years, I have spoken with many individuals, usually, women, who have now been diagnosed with fibromyalgia.  Fibromyalgia is a condition in which individuals suffer from chronic pain, and have tenderness in about a dozen different spots in the body, and have “brain fog”.   They suffer from unremitting fatigue, bowel problems, difficulty in sleeping through the night, and waking up unrefreshed.  As would be expected, they are depressed and anxious as well.

 There are some physicians, even now, that think fibromyalgia “is all in the minds” of their patients.  Some studies have shown, that compared to the general population, individuals with fibromyalgia have significantly higher levels of depression and anxiety.  [Now why someone who is in pain and tired much of the time, would be depressed is beyond me.]

 I once spoke to a male physician who said that he always thought that fibromyalgia was “just” a psychological problem, having nothing to do with biology.  I asked him why he used the past tense, and he said to me, “because I got it!”. 

 Now that the pharmaceutical industry has come out with at least three FDA-approved medications for fibromyalgia, it evidently means that fibromyalgia can now be classified as a disease, and many clinicians treat it as such.  

Many patients have differing success when using these prescription medications.  The three pharmaceuticals reduced pain symptoms by only 30%.  Some of the medications made a difference in fatigue, but not in sleep patterns.  Many of these medications result in side effects ranging from insomnia (which they were trying to combat in the beginning!), nausea, and diarrhea.  Unfortunately for individuals suffering with fibromyalgia, many patients find that if the medication does work for them, too often it is for only a short-period of time, for as little as six months total.

Most clinicians state that the cause of fibromyalgia is unknown, but that “painful tissues” are not associated with inflammation. 

I respectfully suggest that inflammatory responses are major contributors to the pain and discomfort those individuals with fibromyalgia experience.  Indeed, I cannot imagine that a person can feel pain, in the absence of inflammation.

Increasingly, the literature suggests that fibromyalgia, and other neuromuscular conditions are characterized by low-grade inflammation.  Inflammatory cytokines such as tumor necrosis factor-alpha and IL-1, and other immunological factors, have been found to be at higher levels than “normals” and may be resulting in the fatigue and flu-like illness experienced by individuals with fibromyalgia.

Controlling run-away inflammation by returning to immune homeostasis, immune balance, has, in my experience, resulted in dramatic differences in the quality of life of individuals suffering with fibromyalgia.  These individuals have tried other approaches with only limited success, so why not support balanced immune responses?

Medscape Family Medicine 2012 WebMD, LLC
www.actabiomedica.it/data/2007/2_2007/fietta.pdf
www.medicinenet.com/fibromyalgia/article.htm
www.ncbi.nlm.nih.gov/pubmed/21975140
www.ncbi.nlm.nih.gov/pubmed/19957871

 

Obstructive sleep apnea syndrome  (OSAS) occurs when an individual repeatedly stops breathing, sometimes as many as 1-2 times a minute during their sleep.  It is most frequently associated with heavy snoring, broad swings in heart rate, and, as one would expect, extreme daytime sleepiness.  Those that suffer with sleep apnea are prone to accidents; they are twice as likely to be involved in car crashes as compared to individuals without the condition.

 The relationship between inflammation and sleep apnea is complicated, with not only inflammation of the airways, but  body-wide inflammation as well.

 As with other inflammatory conditions, obstructive sleep apnea is associated with cardiovascular disease, diabetes, and obesity.  Visceral fat, belly fat, is a major predictor of having obstructive sleep apnea syndrome, since fat cells produce large amounts of immune modulating molecules, that trigger inflammation.

 People suffering with sleep apnea have complex imbalances of immune factors, cytokines.  Their levels of immune modulating cytokines, such as tumor necrosis factor and interleukin (IL)-6, are markedly high, as are levels of other inflammatory proteins, including  C-reactive protein (hsCRP). [CRP is a blood protein typically associated with the presence and amount of inflammation in the body.]  Additionally,  hormones that regulate insulin and hunger levels are higher than levels found in those without sleep apnea.

 There is conflicting data about the affect of CPAPs, continuous positive airway pressure breathing devices,  on inflammation. Some studies suggest that the devices help lower the number of inflammatory molecules circulating in the body, other studies suggest that using a CPAP increases inflammation.

 Successfully battling disease, and healing , is determined by inflammatory immune cells and the types and ratios of cytokines they generate.  Restoring balance, immune homeostasis, to the body, helps the body stay healthy, and recover rapidly when in ill health.

emedicine.medscape.com/article/295807-overview
www.sciencedaily.com/releases/2008/02/080218214401.htm
www.ncbi.nlm.nih.gov/pubmed/22515302
www.chestjournal.chestpubs.org/content/127/3/1074.full
www.chestjournal.chestpubs.org/content/126/1/1.long
www.mayoclinic.com/health/sleep-apnea/DS00148
www.ncbi.nlm.nih.gov/pubmed/22408197

The concept of epigenetics was first introduced in the 1940s, and its implications on how we modulate inflammation through its processes are intriguing and exciting.

For most of my scientific career, we were taught that biological processes of the body were pre-determined by genes. It was said that DNA’s message was set-in-stone, and except through mutations which might result in cancer, or mutations and recombinations of genetic material that were handed down from one generation to another, the message encoded by DNA was unchanging.

Accumulating evidence suggests that altering our diet, life style, and environment, significantly influences gene expression; the way that the body translates the DNA message. We can change the affect our genes have on our physiological and emotional well-being.

It never ceases to amaze me that the medical profession writes off conditions such as arthritis, heart disease, cancer, strokes, Alzheimer’s etc. as being the result of “aging”; basically, saying to their patient, “you have to live with it because you are getting old”.

Instead, health practitioners might better focus on the fact that imbalances of inflammatory and anti-inflammatory responses contribute to health issues. Directing the emphasis on life style changes would enable individuals to take steps towards breaking the inflammation cycle, literally affecting the DNA message, and the resulting quality of their lives.

There are simple approaches that help maintain immune balance, immune homeostasis. Two such changes are: limiting the size of fat cells, and exercise. Fat cells, especially around our abdominal area, produce large amounts of pro-inflammatory cytokines, that trigger inappropriate levels of inflammation.

Exercise is a way to neutralize these molecules since contracting our muscles releases potent anti-inflammatory cytokines.

Additionally, the daily consumption of two or more servings of hyperimmune egg can go a long way toward supporting the body’s natural immune-rebalancing attempts.

In the controversy of genes vs. nurture, we now know that it is a combination of both that makes the difference. We can help regulate what our genes “say” by how we choose to live our lives.

www.sciencemag.org/site/feature/plus/sfg/resources/res_epigenetics.xhtml

www.ncbi.nlm.nih.gov/pubmed/22004920.1

target=”_blank”>articles.mercola.com/sites/articles/archive/2012/04/11/epigenetic-vs-determinism.aspx

www.ncbi.nlm.nih.gov/pubmed/22428854

www.ncbi.nlm.nih.gov/pubmed/20388091

 

(Please see prior posting)

ACHIEVING INFLAMMATORY HOMEOSTASIS, IMMUNE BALANCE, NATURALLY

CONTROL INFLAMMATION

Restoring immune inflammatory balance, homeostasis, may reduce diabetic symptoms, help guard against infections, and contribute to overall health by letting the body heal itself. Lifestyle changes, rather than medication, are the best ways to regain immune balance, inflammatory homeostasis.

BECOME PHYSICALLY ACTIVE.

Muscles release anti-inflammatory molecules every time they contract. To help balance the levels of inflammation in the body, try to be physically active at least 150 minutes a week. Walk to the bus at a brisk pace. Stand, instead of sitting. Work faster when in the garden. Exercise while watching TV. Just get moving!

This week’s pre-publication article from the journal, Diabetes Care, reports that diabetics that participated in aerobic and resistance training twice a week were more fit than controls, even when they personally did not have any weight loss. Moreover, another publication this week in the journal, Endocrine, reports that even without weight reductions, exercise by itself helps control blood sugar levels.

GET TO YOUR IDEAL WEIGHT.

Obese individuals are at greater risk of getting diabetes. Fat cells release pro-inflammatory cytokines, messages that result in inflammation. Many diabetic symptoms are reduced, even with minimal weight loss.

Make smarter beverage and food choices. The most recent discussions about foods is to ignore the amount of fat you take in, and instead, concentrate on decreasing your total carbohydrate intake.

 Limit your intake of:

  • Liquid carbohydrates such as sodas, either regular or “diet”, fruit juices, “energy” drinks, beer.
  • Fried foods.
  • Starches, such as corn, white rice, chips, nachos, French fries.
  • White flour such as found in breads, pasta, cakes, desserts.

 Fill half your plate with vegetables and colorful fruit. The following foods are reportedly helpful to diabetics: Brewer’s yeast, broccoli, buckwheat, liver, okra, peas, and spinach.

VITAMIN D MAY PLAY A ROLE IN BALANCING INFLAMMATORY RESPONSES. Recent studies suggest that vitamin D, actually a hormone-like biochemical, is involved in cell growth and immunity. Studies suggest that vitamin D suppresses proinflammatory cytokines and increases anti-inflammatory cytokines. Organ systems such as liver, skin, thymus, small intestines, and pancreas have cells that bind a form of vitamin D. Certain groups of diabetics have low levels of vitamin D.

The body produces its own vitamin D when sun exposure is appropriate. Moderate sun exposure during the summer months, stimulates the production of its vitamin D. In temperate climes, supplementation may be prudent.

 OMEGA-3 FATTY ACIDS. There are suggestions in the scientific literature that diabetics may benefit from consuming omega-3 fish oils. Consume 2-3 servings of fish/week or take supplements.

MODERATE COFFEE CONSUMPTION. Certain compounds in coffee may help decrease inflammation. Moderate consumption of coffee may be helpful to diabetics.

HYPERIMMUNE EGG. Immunologists have shown that consumption of multiple servings/day of hyperimmune egg is a natural way to help the body regain its immune homeostasis.

IN SUMMARY

Important steps that a diabetic can take are to become physically active, control their diet and weight, and are other steps to reduce inappropriate inflammation.


www.ncbi.nlm.nih.gov/pubmed/22399699

www.ncbi.nlm.nih.gov/pubmed/22407494

www.ncbi.nlm.nih.gov/pubmed/20181814

www.ncbi.nlm.nih.gov/pubmed/22404117

www.ncbi.nlm.nih.gov/pubmed/22397028

www.ncbi.nlm.nih.gov/pubmed/19957870

www.ncbi.nlm.nih.gov/pubmed/21593500

www.ncbi.nlm.nih.gov/pubmed/22375372

 

 

The body’s cells, especially brain and red blood cells, obtain their energy needs from the glucose (sugar) that circulates in the bloodstream.  There is an optimum amount of glucose that our body needs.  Too high a level of glucose, is just as bad as too little. The body uses insulin, a hormone, to support healthy levels of blood sugar.  Individuals with diabetes cannot properly control their blood glucose levels, and are therefore at risk of cardiovascular disease, stroke, eye, kidney, skin, and nervous system complications.

 The probability of getting diabetes is especially high in obese individuals.  Fat cells, especially those found around one’s waist, release pro-inflammatory cytokines.  The production of these immune factors result in inflammatory responses that destroy insulin-producing cells, making it difficult for the person to control their blood glucose.

 Dr. Umut Ozcan of Children’s Hospital Boston, has stated that “For 20 years, inflammation has been seen as detrimental, whereas it is actually beneficial.”  Research demonstrates that obese individuals have difficulty in maintaining healthy blood sugar levels due to imbalances of inflammatory molecules. Some proteins triggered by inflammation help the body control glucose levels, whereas other types of inflammatory molecules are detrimental to maintaining healthy glucose levels. 

 Dr. Ozcan continues,  “It may be that inflammatory pathways are not working optimally and there could be a resistance to the cytokines that mediate the inflammation.”.

 Restoring immune homeostasis, balance,  by helping the body control excessive inflammation may reduce the symptoms of diabetes or the risk of getting the condition in the first place.    Lifestyle changes, rather than medication, are the best way to regain immune balance.

 Please look for our next posting that will describe ways that one can help correct imbalances between pro-inflammatory (molecules that lead to inflammatory responses) and anti-inflammatory cytokines (cell messages).

 

www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0031225

www.cdc.gov/obesity/causes/health.html

www.nature.com/nm/journal/v17/n10/abs/nm.2449.html

vectorblog.org/2011/09/in-diabetes-inflammation-may-be-part-of-the-solution-not-the-problem/

http://cat.inist.fr/?aModele=afficheN&cpsidt=20604914

 

Many patients that undergo chemotherapy report lingering effects of the disease, or from treatment protocols. Some individuals report that experience problems with cognition, clear thinking, memory, focus, concentration, and staying organized which they call “brain fog” or “chemo brain.”

The relationship between inflammation and cancer is still under intense study. Immune inflammation plays a major role during different stages of tumor development, from recognition of the cancer cells, to metastasis, to resolution of the disease. There are proven complex interactions between immune and cancer cells during which there appears to be “cross-talk.”

Chemotherapeutic medications are, of necessity, cytotoxic. The medications cause the death of cells (apoptosis) by programming their death or by interfering with certain biochemical processes within the cell.

The relationship of inflammatory immune cells and dead cells is a complex one. Whenever a cell dies because of infection or injury, inflammatory immune cells release inflammatory cytokines, messages that activate immune cells to clean up debris, and start the healing process.

Chemotherapy, in which both healthy and cancerous cells are killed, can have unintended effects. The medications can damage immune cells and their DNA; the very cells that the body needs to stop cancer cells from multiplying, to clean up the dead cells, and heal the body after cytotoxic challenge.

An example of such a possible problem is tumor lysis syndrome. When large numbers of cells are killed by chemotherapeutic agents, the dying cells release vast amounts of inflammatory-triggering compounds. The body is simply overwhelmed by these factors, resulting in significant immunological and chemical disruptions throughout the body.

A limited number of studies, still to be replicated, suggest that long after treatment has ended, healthy brain cells continue to die off. And at least one study has shown altered brain structure in individuals that had undergone chemotherapy a year previously. These results however, were not seen in patients that had received chemotherapy three years previously.

The relationship between inflammation, cancer, and cancer therapy, is not understood. However, the available science suggests that limiting excessive inflammatory responses by the immune system, may help minimize the adverse effects of chemotherapy, especially as it relates to the brain.

 

http://www.mayoclinic.com/health/chemo-brain/DS01109


www.ncbi.nlm.nih.gov/pubmed/20303878


www.ncbi.nlm.nih.gov/pubmed/21545608

www.nature.com/cdd/journal/v15/n1/full/4402255a.html

www.ncbi.nlm.nih.gov/pubmed/22294874

www.nature.com/nrclinonc/journal/v3/n8/full/ncponc0581.html

jbiol.com/content/7/4/11

 

For years, physicians told their (overwhelmingly female) patients, that patient complaints of skeletal and muscle pains, sleep disorders, overwhelming fatigue not improved by bed rest, brain “fog”, and lack of stamina, were “all in their mind”.

However once pharmaceutical medications were introduced into the market place to help decrease some of these symptoms, health practitioners started diagnosing these conditions as chronic fatigue syndrome, CFS or ME, myalgic encephalomyelitis.

Viral Involvement Controversial

In 2009, an article in the prestigious journal Science reported that 95% of subjects with chronic fatigue syndrome were infected with a specific virus and/or had antibodies to that virus. The investigational team emphasized that these findings did not prove that there was a link between this virus and chronic fatigue, but that the virus might be “a contributing factor”.

Late this past year, the editors of Science retracted the controversial article due to the poor quality controls, and omissions in the description of certain figures. Additionally, other laboratories have been unable to replicate the results.

This specific virus may not have been responsible for ME, but the concept is sound since other studies have suggested that bacterial and viral infections can trigger inflammatory immune diseases such as heart valve damage, arthritis, multiple sclerosis, diabetes, and systemic lupus erythematosus (SLE).

Autoimmune Inflammatory Conditions

Inflammatory diseases are often manifestations of an autoimmune inflammatory response. Autoimmune disease occurs when the immune system “over-reacts” to a stimulus and attacks its own cells with excessive inflammatory responses.

Digestive Tract-A Large Immune Organ

The lining of the digestive tract is heavily populated by immune cells and is considered a major immune organ. Many CFS patients complain of gut dysfunction, and have been diagnosed with irritable bowel syndrome (IBS) and with proinflammatory cytokine production.

Increase in Inflammatory Markers

Immunologically, individuals with chronic fatigue have increased blood levels of inflammatory compounds, such as C-reactive protein (CRP), and exhibit immunological abnormalities, including increased numbers of activated immune cells, and high levels of inflammatory cytokines, indicative of inflammation.

“… [T]he simplest way to think about … findings [such as these-HCG] is that people with increased inflammation–from whatever source–are more likely than others to develop a range of symptoms that frequently lead to a diagnosis of a condition such as CFS …” says William C. Reeves, MD, Chief of the Chronic Viral Diseases Branch, the Centers for Disease Control and Prevention (CDC). “

Role of Immune Inflammation

Immune inflammation helps defend the body from infection and heals the body after injury. However, when immune inflammation is in “overdrive”, autoimmune and other autoinflammatory conditions result.

Making certain lifestyle changes will contribute to lowering the amount of inflammation in the body. These are: a) becoming physically active so that muscle contractions generate naturally-occuring anti-inflammatory molecules and b) controlling one’s weight to reduce the levels of inflammatory compounds being released by fat cells.

Other steps to consider are moderate exposure to sunlight (or taking vitamin D3 supplements), consuming omega-3, and adding hyperimmune egg to one’s diet.

Immune Balance

Good health is determined by the balance between the pro-inflammatory and anti-inflammatory cytokines produced by our immune cells; maintaining these immune factors in their appropriate amounts, is essential.

www.sciencemag.org/content/326/5952/585
www.sciencemag.org/content/334/6063/1636.1
www.sciencedirect.com/science/article/pii/S0889159108004261
www.nutritionandmetabolism.com/content/7/1/79
www.ncbi.nlm.nih.gov/pubmed/19758205
cmr.asm.org/content/9/4/532.abstract
www.ncbi.nlm.nih.gov/pubmed/16380690
www.ncbi.nlm.nih.gov/pubmed/18801465

For some, the holidays, and especially the morning of January 1, is pure misery, since they suffer with nasty hangovers. Alcohol hangovers occur when blood alcohol concentrations (BAC) return to zero. The event is characterized by pounding headache, sensitivity to lights and loud noises, dizziness, drowsiness, nausea, vomiting, dry mouth, sweating, concentration problems, hyper-excitability, and anxiety and/or depression.

The biology of hangovers is complex and surprisingly, has not been well- researched. Dehydration and sleep deprivation may be contributors to the state of being hung over, but biological changes during suggest that, as with a majority of disease, imbalances of immune factors, especially excessive production of inflammatory cytokines, may be the culprit.

Hangovers are reminiscent of “sickness behavior”, the feelings that sick individuals have during the course of fighting an infection. “Feeling poorly” is the effect of increased levels of proinflammatory cytokines, that increase inflammation in the brain.

During inflammation, a great deal of cross-talk, mediated by cytokines, goes on between the immune system, the brain, and the intestines, which stimulates a wide range of physical, hormonal, nervous , gastrointestinal, and emotional responses.

Increased levels of inflammatory cytokines, such as IL-12 and interferon-gamma (IFN-gamma) are found in individuals suffering from hangovers. Additionally IL-10 , which suppresses inflammatory cytokines, is also found at higher levels in hangover subjects.

C-reactive proteins (CRP) are found in the blood and are considered an excellent marker for inflammation in the body. High levels of C-reactive protein are strongly associated with the severity of hangover events. The response may be related to inflammation induced by excessive ingestion of certain alcohol components such as congeners, or alcohol metabolites.

Numerous anecdotal reports suggest that when the body is in immune inflammatory balance, that hangovers will not occur at all, or, will be severely limited in their scope.


http://alcalc.oxfordjournals.org/content/43/2/124.full
http://www.ncbi.nlm.nih.gov/pubmed/15226168
http://www.ncbi.nlm.nih.gov/pubmed/14693266
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC508465/pdf/1002641.pdf
http://www.ncbi.nlm.nih.gov/pubmed/20712594
http://www.ncbi.nlm.nih.gov/pubmed/11259077

 

 Role of Balancing Inflammatory and Anti-inflammatory Immune Factors (e.g., Cytokines):

An injury requires enough inflammation to start the healing process, but not so much that it starts a cascade of immune inflammation that causes damage to by-stander tissues. Cytokines are immune factors generated by white cells that initiate pro-inflammatory (inflammatory) responses and anti-inflammatory responses in response to infection or injury. A healthy person produces appropriate levels of these factors depending on the challenge it encounters. A body in immune homeostasis will either up-regulate, increase immune inflammation, or down-regulate, limit its inflammatory responses, depending on the body’s needs.

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) Doctors often suggest non-steroidal anti-inflammatory drugs (NSAIDs), including aspirin when a patient complains of a sprain or other work- or sport-related injury.. These pharmaceutical compounds inhibit the production of immune inflammatory molecules such as cytokines. Limit the amount of inflammation and its resulting pain and stiffness are decreased.

The problem is that many of these medications put people at risk of significant digestive, cardiovascular, kidney, and muscular/skeletal problems. For example, according to the American College of Gastroenterology, the regular use of non-steroidal anti-inflammatory drugs is the major cause of potentially life-threatening ulcers and stomach bleeding.

Also, some practitioners question whether the use of NSAIDs may be the cause of increases in osteoarthritis and the high level of knee and hip replacements.

Because of concerns about health risks, some health practitioners physicians suggest complementary, more natural methods, to decrease pain and inflammation, and perhaps even prevent damage from muscle injury.

Complementary Approaches:

Glucosamine: Glucosamine is a natural substance produced by the body that encourages cartilage regeneration and the production of synovial fluid that helps “lubricate” the joints. There is evidence that glucosamine has anti-inflammatory properties.

 Omega-3 Fish Oil:  Omega-3 fish oils have been shown to have anti-inflammatory properties and help the body control pro-inflammatory cytokines and the pain that results from up regulating, increasing, inflammation.

 Vitamin D3:Vitamin D appears to affect immunological function such as inflammation. Vitamin D supplementation has been found to provide therapeutic relief.

Hyperimmune Egg: Hyperimmune egg, an all natural, food-based ingredient, is another approach to helping the body return to immune inflammatory homeostasis. In a study conducted at a major hospital in NYC, individuals on hyperimmune egg for 30 days reported higher levels of joint comfort.

When certain types of glucosamine are added in combination with hyperimmune egg, joints appear to heal more rapidly and individuals report changes in their quality of life.

 Summary:

When experiencing sprains, strains, or other injuries due to work, sports, or accidents, one might wish to consider the use of complementary ingredients prior to starting on prescription medications.

 

http://www.ncbi.nlm.nih.gov/pubmed/20424410
http://www.ncbi.nlm.nih.gov/pubmed/17112189
www.ncbi.nlm.nih.gov/pubmed?term=Family%20Practice.%202005%3B22%3A118-125
http://www.ncbi.nlm.nih.gov/pubmed/20726384
http://www.ncbi.nlm.nih.gov/pubmed/20737476
http://newsblog.mayoclinic.org/2009/03/20/mayo-clinic-researchers-link-vitamin-d-and-chronic-pain-relief/
http://www.ncbi.nlm.nih.gov/pubmed/22143284
http://www.umm.edu/altmed/articles/omega-3-000316.htm
http://www.ncbi.nlm.nih.gov/pubmed/21067953
http://HyperimmuneEgg.org
www.google.com/patents/about/6706267_Glucosamine_and_egg_for_reducing.html?id=SAwRAAAAEBAJ

Exercise is essential for workers such as firefighters and paramedics that have physically-and emotionally-demanding jobs, and is mandated by most departments.

According to a study by the University of Arizona, Tucson, AZ and the Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, 30% of the strains and sprains that firefighters and paramedics experienced, happened as they were working out. Seventeen percent of injuries, and almost half of time off work for injuries, were caused by strains and sprains resulting from workers carrying individuals.

Pain and inflammation “feed one another”. Pain triggers more inflammation and inflammation  leads to more pain. It is not clear how the body senses pain, nor biochemically, the exact events that lead to the sensation of pain. We know however, that pain signals from our back or limbs travel along nerve cells to the spinal cord and up to the brain, and that inflammation in the spinal cord and brain is either the direct cause of pain, or a major contributor to pain sensations that we experience.

When muscles and tissues are injured, immune cells respond by entering the area and releasing cellular factors (e.g., cytokines) that will up-regulate inflammation as a way to help the body heal.

However, it is as important for the body to decrease its inflammatory responses after a challenge is met, as it is to increase the response in the first place. Decreases in inflammatory responses, down-regulation, result from the production of different amounts of anti-inflammatory cytokines and their ratio to pro-inflammatory cytokines that cause inflammation. It all about the appropriate balance of immune responses, immune homeostasis.

(Please watch for the next posting discussing natural methods of helping the body achieve immune homeostasis, and recover, and heal faster.)

injuryprevention.bmj.com/content/early/2011/11/03/injuryprev-2011
www.nature.com/nrneurol/journal/v7/n3/full/nrneurol.2011.4.html
www.ncbi.nlm.nih.gov/pubmed/19096368
www.ncbi.nlm.nih.gov/pubmed/22119349
www.gluegrant.org/inflammation101.htm
http://www.ncbi.nlm.nih.gov/pubmed?term=Curr%20Drug%20Targets%20Immune%20Endocr%20Metabol%20Disord%202005%205%3A413

The immune system is responsible for helping the body heal itself after illness or injury, and to defend the body against attack from pathogens such as viruses, bacteria, and molds, and cancer cells that multiply too rapidly.

In some overly sensitive people however, the immune system may mistakenly view harmless substances, allergens (e.g., peanuts, pollen, dust mites, pet dander), as putting the body at risk of infection.

In response to an attack, the immune system produces large immune molecules called antibodies, immunoglobulins, along with smaller immune co-factors to help in the fight.

Individuals with allergies tend to have higher levels of immunoglobulin E (IgE), a class of antibody. IgE attaches tightly to special immune cells called mast cells. They are found in the skin and linings of the intestine, eyes, and nasal passages. Mast cells play a pivotal role in host defense, inflammation, and tissue repair.

Mast cells are pre-loaded with inflammatory factors. At the body’s next exposure to the allergen, the allergen binds to the IgE, like a key going into a lock, and triggers the release of mast cell biochemicals such as histamine, and small immune factors such as cytokines.

A number of studies suggest that men and women with allergies are at a lower risk of developing glioma, a brain cancer. Gliomas are among the most common and most rapidly growing brain tumors. Men and women with moderately higher levels of IgE, compared to clinically normal individuals, had statistically significant lower probabilities of developing gliomas.

However, as is usually the case in biology, more is not always better. Individuals with significantly elevated levels of IgE were not at a lower risk for developing malignant gliomas.

Look for future postings on the role of inflammation and cancer. Any search will reveal that inflammatory responses play major roles at different stages of tumor development. Since the relationship of inflammation, cancer, and immunological responses are under study, it is best to let the body do what it does best, and that is protect us from illnesses.

To optimize health, immune homeostasis, immune balance, is essential.


www.ncbi.nlm.nih.gov/pubmed/21726235
www.jnci.oxfordjournals.org/content/early/2011/10/17/jnci.djr361.abstract
www.nature.com/nri/journal/v4/n10/fig_tab/nri1460_F1.html
www.ncbi.nlm.nih.gov/pubmed/21978688

A properly functioning immune system protects the body against infections by bacteria, viruses, fungi and other pathogens, and helps it heal. When our bodies detect a threat, or a stimulus that is “perceived” to be a threat, it orchestrates a delicate but highly aggressive immune inflammatory response to meet that threat.

There are two initial phases of immune responses:

  • Innate/early phase — a “built-in” or “automatic” response that is prepared at all times to defend the body against infection and cell mutations, such as those seen in cancers, and
  • Acquired– a more “educated” immune response that takes time to evolve in response to a specific trigger.

Inflammation is a complex event during which immune cells migrate into an area in response to various immune factors. These messages, such as cytokines, are used to to communicate and coordinate an organize attack against pathogens, or to help the healing process. After the threat has been resolved, other immune cells come in to carry away dead organisms and cells, and start the repair process.

A well-balanced immune system, a system in immune homeostasis, will mount enough of an inflammatory response to eliminate the threat, and then go on to repair damaged tissues. However, problems may arise if the immune system continues to generate an inflammatory responses after a challenge has been met —when inflammatory responses do not lower in intensity.

In such cases, the immune system is “over-responsive”; it is unbalanced, out of homeostasis. An over-active immune system leads to conditions where the body starts to destroy its own healthy tissue (e.g. diabetes, thyroid, lupus, multiple sclerosis, fibromyalgia, etc.) or it may lead to allergies and chemical sensitivities, or poor healing.

Many people have the mistaken impression that “boosting” immune function at all times is useful. This is simplistic. People with autoimmune conditions, such as those mentioned above, are already “over responding”. The last thing they need is to further “boost” their immune response, increase their autoimmune responsiveness.

Another example of “boosting” immune response is artificially increasing the level of natural killer (NK) cells within the body. NK cells often make up part of the body’s “early response”. “Boosting” numbers of certain white cells is unnatural and may cause other difficulties due to excessive numbers of these cells.

Increased levels of NK cells, as well as autoimmunity, have been associated with women who have difficulty conceiving. Women who have experienced spontaneous abortions and miscarriages, have higher than normal levels of NK cells.

Additionally, other types of specific immune cells, for example those that play a role in protecting the body from infection, may promote miscarriage and premature births, when they are at higher than normal levels.

The lesson here is that all of our immune cells and their components have to be balanced, or in a state of homeostasis, for our body to naturally heal and protect itself.

There are a number of simple steps that one can take to return the body to homeostasis, including using recovery proteins, exercise, smarter food choices, and maintenance of healthier weights.

http://www.ncbi.nlm.nih.gov/pubmed/20237962
http://www.ncbi.nlm.nih.gov/pubmed/20528832
http://www.ncbi.nlm.nih.gov/pubmed/21162648
 

Taking an aspirin a day may lower cancer risk.

Individuals took a minimum of 75mg a day of aspirin for 6 years. Twenty years later, these individuals had a 24% lower risk of developing colon cancer in the first place, and a 35% lower risk of death from colon cancer as compared to placebo.

This was especially important because the some of the cancers studied are found in a part of the colon that is not easily seen with current screening tests.

The populations studied were males at cardiovascular risk. Forty percent of the patients were smokers and most were males. Therefore, the effectiveness of aspirin for non-smokers or females is not known.

 “Cross-talk” between cancer and immune cells.

We have long known that there is “cross-talk” between cancer and immune cells. Immune cells affect the growth of cancer cells and cancer cells affect immune cell inflammatory responses.

Inflammation and Cancer.

Studies have shown that patients with inflammatory bowel diseases, such as ulcerative colitis, or Crohn’s disease, are more likely to develop gastrointestinal cancers than the general population.

Inflammation of the gut occurs with the release of inflammatory cytokines and other immune molecules. They have been shown to contribute to the development and growth of gastrointestinal cancers.

Aspirin regulating immune balance.

Thus aspirin may be helping to regulate the body’s inflammatory responses, and helping to keep the body in immune balance, immune homeostasis.

 
www.thelancet.com/journals/lancet/article/PIIS0140-6736(10)62110-1/abstract

www.ncbi.nlm.nih.gov/pmc/articles/PMC2866629/

www.ncbi.nlm.nih.gov/pubmed/18473765

 

The Centers for Disease Control is investigating at least 100 reports of food poisoning, and 18 deaths, due to contaminated cantaloupes. DNA isolated from infected individuals has determined that Listeria is the responsible bacteria. Ninety-eight percent of 93 individuals contacted by monitoring agencies were hospitalized due to their infections. Because of lag times between consumption of these cantaloupes, illness, diagnosis, and laboratory confirmation, more cases are expected to occur.

Five percent of the human population has Listeria in its stool. It is also found in stools of non-human mammals, and birds. This may explain the fact that Listeria is found in water, soil, and animal feed.

Newborns, pregnant women, and individuals with immune disorders such as kidney disease, cancer, diabetes, and HIV/AIDS are at increased risk of becoming ill when infected with Listeria. In 89 % of cases, Listeria pass through the intestinal wall and enter the blood stream. From there, they are carried throughout the body and can end up in the brain, spinal cord, heart, eyes, liver, spleen, lungs, bones, and joints.

Instead of being attacked by immune cells, initially, Listeria hides in immune cells, multiplies, and infects other white blood cells. To stop the infection and return to immune balance, immune homeostasis, the body defends itself by releasing inflammatory and anti-inflammatory cytokines, cell messages, and antibodies, large proteins that mark the bacteria for destruction by inflammatory immune cells.

About half of adults with Listeria infection will be diagnosed with meningitis, an inflammatory condition of the brain and spinal cord. Endocarditis, inflammation of the inner lining of the heart, results in deaths of about 50% of patients.

So, ultimately, excessive inflammation kills infected individuals.

 

www.faqs.org/health/topics/74/Listeriosis.html#ixzz1ZgKQS5E5
www.cdc.gov/listeria/outbreaks/cantaloupes-jensen-farms/100411/index.html#introduction
www.ncbi.nlm.nih.gov/pubmed/21830209
www.ncbi.nlm.nih.gov/pubmed/8251578
www.experts.scival.com/mskcc/grantDetail.asp?t=ep1&id=373762&o_id=3&

Today, three immunologists, Drs. Ralph Steinman*, Jules Hoffman, and Bruce Beutler, won the Nobel Prize in Medicine/Physiology for adding to our scant knowledge of immune system responses to pathogenic microorganisms and cancer cells. Their studies should also provide a better understanding as to how excessive inflammation leads to autoimmunity, attacks on the body’s own healthy tissues.

Two decades ago Dr. Ralph Steinman and his colleague, Dr. Zanvil Alexander Cohn at the Center for Immunology and Immune Diseases, Rockefeller University in New York City, described dendritic cells, specialized immune cells that interact with other immune cells to define how the body will respond to underlying infection and disease.

Dendritic cells are essential to the body’s ability to control immune inflammatory homeostasis. Immune homeostasis is the delicate balance of all immune responses, especially inflammatory and anti-inflammatory responses, that that the body uses to fight disease. Too little inflammation may result in uncontrolled growth of pathogens or cancer cells, whereas too much inflammation, may result in autoimmune conditions such as diabetes, arthritis, lupus, multiple sclerosis, Crohn’s disease, etc.

Part of the role of immune homeostasis is to determine “what comes next” in meeting immune challenges. Dr. Steinman and his colleagues described an important phase of the immune response, “maturation”, which helps the body determine inflammatory and other responses to infection.

Dendritic cells are also important in helping the body maintain immunological “memory”. This assures a more rapid and thorough immune response if is attacked by the same pathogen another time. [Successful immunization depends on immunological memory.]

Dr. Jules Hoffman and his team, described how the immune system first recognizes invading pathogens and then helps trigger the immune system to go into its protective mode.

Dr. Beutler discovered the inflammatory cytokine, tumor necrosis factor, TNF, and a marker on certain bacterial cells that helps the body recognize that it has been infected, so that it can mount an appropriate inflammatory attack.

www.nobelprize.org/nobel_prizes/medicine/laureates/2011/press.pdf

www.rockefeller.edu/labheads/steinman/pdfs/2003-APMI.pdf

www.ncbi.nlm.nih.gov/pubmed/21960036

www.wrvo.fm/post/nobelists-showed-how-immune-defenses-work-and-go-awry

*The Nobel Committee has expressed “deep sadness and regret” at the news that Dr.
Steinman died a few days before its announcement.   Typically, the Nobel Prize is not awarded posthumously, but the Committee has decided to proceed with bestowing the award on Dr. Steinman.

According to the World Health Organization smoking is the second largest preventable cause of disease and premature death. Globally, tobacco products are responsible for 5 million deaths annually. A person dies every 6 seconds from smoking-related diseases including chronic diseases and cancer.

Among its many effects, smoking triggers an immunologic response in arteries and veins which is associated with increased levels of inflammatory markers, such as C-reactive protein and increases in white blood cells. C-reactive protein is strongly associated with lifetime smoking exposure as measured by pack-years. Several studies have shown that such markers predict future cardiovascular events including atherosclerosis.

However, once smokers quit, their risk of future cardiac events and death gradually declines, and within 5 years, smoking-associated inflammatory responses start to return to normal.

Cigarette smoking has also been linked to increased risk of autoimmune diseases, including lupus, rheumatoid arthritis, multiple sclerosis, thyroid, and liver. Autoimmune diseases are immune disorders where the body attacks itself resulting in excessive inflammation and tissue damage.

Considering that cigarette smoke contains over 7000 chemicals, the likelihood that smoking triggers autoimmune and other excessive inflammatory immunological responses makes sense. An example of smoke-induced illness is chronic obstructive pulmonary disease (COPD) in which a person has difficulty in getting enough air.

The lungs, in response to cigarette smoke, activate cells lining the lungs and immune cells, resulting in inflammatory responses. If an individual is infected with a bacterial or viral infection in addition to the smoke assault, it results in a vicious cycle of more difficulties in breathing and greater inflammation. Studies have indeed shown that patients with COPD have autoantibodies and inflammatory responses against lung cells.

Researchers have reported that in female smokers, physical activity, known to help reduce inflammation, reduced their relative risk of developing lung cancer by more than 65 percent.

Thus, it might be expected that if smokers were better able to control their inflammatory responses and return to immune homeostasis, that they might be less likely to develop chronic diseases.

 

www.ncbi.nlm.nih.gov/pmc/articles/PMC1160597/

www.plosmedicine.org/article/info%3Adoi%2F10.1371%2Fjournal.pmed.0020160

www.ncbi.nlm.nih.gov/pubmed/21907865

www.ncbi.nlm.nih.gov/pubmed/17975205

www.medicalnewstoday.com/releases/58661.php

 

Bernard Lown, MD The Lost Art of Healing Boston New York Houghton Mifflin Company 1996

Medicine in the United States is widely regarded as the best in the world*. Hardly a day passes without a major scientific breakthrough. Many formerly fatal diseases are now curable. People are healthier and live longer than ever. Still, patient dissatisfaction with doctors has rarely been more acute. Although physicians are increasingly able to cure disease and prolong life, the American public is suspicious, distrustful of, even antagonistic to, the profession. Doctors, uneasy, astonished, resentful, and angry, universally acknowledge a crisis in health care. With the focus on colossal medical expenditures, amounting to a trillion dollars annually, most of the numerous solutions involve containing runaway costs….

Medicine’s profound crisis, I believe, is only partially elated to ballooning costs, for the problem is far deeper than economics. In my view, the basic reason is that medicine has lost its way, if not its soul.

* And yet, depending on the Agency that sponsored the study on longevity, America ranks either 27 or 30th , in the world in terms of mortality. Countries like Malta and South Korea have longer life expectancies than individuals in the U.S.

Next week the United Nations will hold a unique Summit, the first one focusing on the worldwide chronic diseases such as diabetes, cancer, heart, and lung disease. These are also the major diseases that challenge Americans.

And it has become increasingly obvious that uncontrolled immune inflammatory responses are major contributors to disease. Inflammation results in illnesses of many types, and vice versa. For example in the case of cancer and inflammation, there is “cross talk” between immune and tumor cells with inflammatory responses playing major roles during different stages of tumor development.

The key to health is immune balance, immune homeostasis. Immune homeostasis is a state where the level of inflammatory cytokines, is inhibited by anti-inflammatory cytokines and other immune factors. The right ratio of these cell messages restores the body’s delicate immune balance, and lessens the likelihood that one will become ill. Controlling inflammation is a primary approach to decreasing chronic disease.

 

http://hdr.undp.org/en/statistics/

www.jci.org/articles/view/25102

www.ncbi.nlm.nih.gov/pmc/articles/PMC2866629/

 

An article this week from Shirley Wang, a Wall Street Journal reporter, brought the public’s attention back to the fact that there is no cure for the usually fatal disorder, amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease. Amyotrophic lateral sclerosis (ALS) is a paralytic disease caused by the gradual degeneration of nerve cells in the brain and spinal cord. The breakdown of neruons interrupts the ability of muscles of the body to send messages to the brain. ALS results in difficulties in talking, swallowing, moving, and paralysis, and eventually, the loss of the ability to breathe.

An international group of scientists recently reported in the journal Nature, that the lack of a certain protein might be the common underlying cause of neurodegenerative diseases such as ALS, dementia, Parkinson’s, and Alzheimer’s. The task of this specialized protein is to remove the debris of damaged nerve cells and help in their repair. When this function no longer occurs, normal transmission of signals from muscles to brain is blocked.

One individual commented on Ms Wang’s article. “It seems outrageous to me that in 2011 a quickly fatal disease that was brought to our national attention in 1939 continues to steal our best and brightest without any treatment and with few clues as to the cause. We must do better….”

I agree. Instead of treating a condition after damage has occurred, why not prevent excessive inflammatory responses from causing damage in the first place? The ALS Association does an excellent job explaining that, “The glia cells that usually support and nourish their neighboring neurons in the nervous system can become over active in certain diseases”. And that leads to over production of cytokines, immune signals, that are mediators of inflammation,and damage to the nerve cells.

Inflammation protects the body from infection and repairs tissue damage. But uncontrolled levels of inflammation damages healthy by-stander cells, and tissues. When it comes to the repair protein mentioned above, perhaps individuals with ALS, or other neurodegenerative diseases, are attacking this protein, and decreasing the quantities needed for clean-up and repair.

A body in immune homeostasis, immune balance, is unlikely to attack itself. Instead one approach that research should take is finding ways to help the body modulate inappropriate levels of inflammation.

 

www.ninds.nih.gov/disorders/amyotrophiclateralsclerosis/detail_ALS.htm

www.chicagotribune.com/health/ct-met-northwestern-als-breakthrough-20110822,0,4185292.story

www.nature.com/nature/journal/v477/n7363/full/nature10353.html

http://www.alsa.org/research/about-als-research/inflammation.html

 

This is the second part of a two day posting. Please see yesterday’s posting for the introduction to this posting. Thank you.

Cancer Risks

Responders are 19% more likely to develop cancer than their non-exposed colleagues, with skin, prostate, thyroid, and non-Hodgkin’s lymphoma, being the most common of the cancers. Many of the airborne toxins to which individuals were exposed, benzene, volatile organics, metals, polycyclic aromatic hydrocarbons, pulverized building materials, glass fibers, asbestos, lead, hydrochloric acid, polychlorinated biphenyls, organochlorine pesticides, and polychlorinated dioxins and furans are linked to causing cancer.

Cancer is an illness that may take years to develop and detect. Dr. Ware Kuschner, Stanford School of Medicine, CA says, “Carcinogenic effects, if any, will not be observed for a very long period of time.” [As an aside, according to the University of Pennsylvania School of Veterinary Medicine, eight search and rescue dogs have died from cancer since their exposure to rubble from the Sept. 11 terrorist attack.]

 

Pulmonary Function Declines

We do not have sufficient data from the general population residing and working in lower Manhattan, nor detailed health information of individuals that returned to their home states or countries after their contributions to rescue efforts. However, of the rescue, recovery, and clean-up personnel that were monitored, 42% have respiratory problems.

Steep declines in pulmonary function were first detected after 9/11 and they have largely persisted. Over the last nine years, 28% of those monitored have had asthma and 42% sinusitis (inflammation of sinuses). They also suffer from upper airway cough syndrome (UACS) and sarcoidosis. Sarcoidosis is an inflammatory autoimmune disorder in which the body’s own immune system attacks and destroys the tissues of the body. There has been a 36-fold increase in the number of individuals with this disease that can affect the lungs, lymph nodes, eyes, skin, heart, liver, and brain. The hallmarks of the disease are clusters of inflammatory cells throughout the body and often, significant, life-altering declines in breathing and other bodily functions.

 Inflamamtion: The Body’s Defense Against Perceived Threats

The immune system mounts an immune, inflammatory response when the body is exposed to pathogens, pollutants, or toxins. The inflammatory cells release immune factors, such as cytokines, cellular messages, that are involved in cell-to-cell communication with the “purpose” of recruiting more inflammatory cells into an area to help eliminate a perceived threat.

Pollutants and chemicals can trigger airway inflammation and increase mucous production. Other immune molecules cause narrowing of airways resulting in the contraction of the muscles lining the airways. The combination of inflammation and increased mucous makes it difficult for air to enter or leave the lungs and can result in breathing issues.

Additionally, lungs that do not function properly, areideal for the multiplication of molds, bacteria, and viruses. The lungs continue their struggle to eliminate pollutants and pathogens, resulting in a chronic, persistent, dry cough and worsened lung function.

 Immune Homeostasis, Immune Balance

A healthy person produces the right amount of inflammation in response to environmental and biological challenges. If WTC responders and others involved in rescue and clean-up of the 9/11 destruction, were able to control the amount of inflammation in their bodies , the body could finally start its healing process. Returning the body to inflammatory homeostasis, to inflammatory balance, would result in significant differences in the quality of their lives.

 

A Personal Note

It has been my conviction for years that a compromised immune system is at the root of the majority of health issues of World Trade Center responders, recovery and clean-up workers.

As a former New Yorker, I, as most Americans and overseas friends, took the attacks on America’s premier city personally and we still feel-grief and compassion, especially around this time of the year.

But what has really gnawed at me all these years is that surviving workers,–individuals who thought only of others and risked their lives to help despite terrible odds, are still suffering emotionally and physically.

I have been frustrated by my inability to reach the right people to share my decades long experience suggesting a different approach to helping individuals regain their health.

Based on decades of working with individuals having immune issues, I am confident that World Trade Centers workers would experience major quality of life changes if they were able to help their body regain its delicate balance—return to its optimum immune homeostasis.

These brave souls have visited physician after physician, clinic after clinic without a solution to what ails them. Ten years of searching for answers is long enough. It is now time for these individuals to take control of their own health by helping their bodies return to inflammatory homeostasis, balance.

I am not a health practitioner, but I am a scientist who can provide the facts to you. You will know within a short period of time whether or not my suggestions work for you.

I encourage you to contact me so we can start on the journey.

Resources:

www.guardian.co.uk/world/2011/sep/02/world-trade-centre-rescuers-health-risk

www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)60989-6/abstract

www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)61180-X/abstract

www.thelancet.com/journals/lanonc/article/PIIS1470-2045(01)00543-5/fulltext

www.home2.nyc.gov/html/doh/wtc/html/know/mental.shtml

 

It is ten years since the horrific 9/11/01 attacks on the World Trade Center in New York City, The Pentagon in Washington, DC, and Flight 93 in Pennsylvania. On that day at the World Trade Center alone, there were approximately 3,000 murders.

These events have not only left the families, friends, and citizen survivors distraught and at great emotional and financial risk, but the heroic responders, the rescuers, recovery, and clean-up personnel, and civilians that lived and worked in the area, continue to pay a significant price in terms of their health.

There will never be a true accounting of how many individuals were exposed to smoke, thick-coatings of dust, combustion materials, asbestos, polychlorinated biphenyls (PCBs), dioxin, asbestos, and metals. Fire fighters, police, military members, paramedics, construction and iron workers, municipal employees, security workers, residents and workers in the area, and those that came from afar to help, were exposed to these toxic chemicals for days, weeks, and months. Fires burned for 69 days and even eight months after the destruction, workers were still searching for body fragments (1).

For some, the years may be receding from memory, but there are many individuals, and rescue and recovery dogs, that have, or are, still, paying a significant price for their heroic sacrifices. If they are still alive, their emotional and physical health has declined significantly, and no one seems to be able to help them.

Only limited funding has been available to study and monitor individuals that were at Ground Zeroand its surrounding environs. When researching information for this article I was surprised at the relatively few, peer-reviewed publications on this topic, and there is even less information on the effects of this trauma on children and adolescents.

Multiple Health Issues

A primary investigation now led by Dr Juan Wisnivesky, Mount Sinai School of Medicine in New York, has said, “Our findings show a substantial burden of persistent physical and mental disorders in rescue and recovery workers who rushed to the site of the WTC and labored there for weeks and months. Many of these individuals now suffer from multiple health problems (2), since World Trade Center-related mental and physical health conditions often co-exist (3).

Mental Health Issues Persist

One year after 9/11, it was estimated that more than 420,000 people New Yorkers were suffering from post traumatic stress disorders (PTSD) as a result of the attacks (1). This month, the prestigious British journal, Lancet, reports that 32% of tested personnel experienced post traumatic stress disorders and 28% per cent experienced depression at some time after 9/11. The incidence of most of the disorders was highest in workers with greatest World Trade Center exposure (3,4). Other emotional problems such as recurring nightmares, flashbacks, self-medication with alcohol, etc. have also been persistent issues.

Tomorrow: 9/11 Responders: Cancer Risks, Pulmonary Function, Immune Homeostasis, Balance.

1) www.guardian.co.uk/world/2002/aug/18/usa.terrorism

2) www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)61180-X/abstract

3) www.guardian.co.uk/world/2011/sep/02/world-trade-centre-rescuers-health-risk

4) www.thelancet.com/journals/lanonc/article/PIIS1470-2045(01)00543-5/fulltext

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