Dr. Keefe, Keefe Clinic. Tulsa Chiropractor, pain, natural health care.

It’s really difficult for all of us to see when we are being programmed or manipulated through advertisement/propaganda. But pharmaceutical companies spend billions of dollars on conditioning the population to choose its products over other methods of treatment. And sometimes we’re in an automatic mode when we decide our choice in healthcare. This can be a problem for a number of reasons. The first thing to consider is if you are deciding to utilize a drug as your first option you might not understand the dangers of that approach.

Besides the over 2000 deaths per week due to the side effects of pharmaceutical drugs and the fact that medical care is a number one cause for death in the United States based on CDC statistics, there are other reasons to think twice about drugs being your first approach. Simply put drugs don’t heal, drugs alter your perception of the condition. Let’s take headaches, for example, most headaches are caused by misalignments in the upper neck (muscle tension) other causes could be toxicity problems, allergies, low blood sugar or hormonal problems. Which of these do you think an aspirin fixes? Did you know aspirin causes bleeding in the stomach, Excess Stomach Acid Secretion, Stomach Cramps, Blood coming from Anus, Decreased White Blood Cells? This is just a partial list of potential side effects. Again the aspirin doesn’t treat any of the underlying causes for your condition.

Let’s say your headaches were related to hormonal imbalances because of a developing ovarian cyst. You keep treating the headaches with an aspirin and your ovarian cyst keeps getting worse to the point that it might burst. Wouldn’t it have been nice if the physician you went to wanted to understand the source of your headaches? But a common problem is if you’re a physician and have powerful drugs that can mask symptoms then when a patient presents with certain symptoms you are just gonna write a prescription and consider it appropriate care.

Dr. Keefe, Keefe Clinic. Tulsa Chiropractor, pain, natural health care.

As a chiropractic physician, we don’t mask symptoms with drugs, we have to figure out why the symptom is there. Just to classify a headache is a tension headache or a migraine headache and then give the latest masking drug the pharmaceutical company has recommended, in my opinion, is not proper healthcare. Proper healthcare tries to determine the underlying cause for the condition and correct the cause. I’m not saying that can be done 100% of the time because science does not understand the body fully, I am saying that most the time it can be. The underlying cause of allergies is not an antihistamine deficiency it’s an inappropriate functioning immune system. When you correct the immune system you correct the allergies. Acid reflux is not an antacid deficiency it is an imbalance somewhere within the digestive system. It needs to be found and corrected which might include changing your diet.

Dr. Keefe, Keefe Clinic. Tulsa Chiropractor, pain, natural health care.

Back pain is not a muscle relaxer or anti-inflammatory deficiency disease. When you just treat the symptoms you allow the condition time to get worse. This is one of the reasons that chronic diseases are such a high prevalence in our society. When you chronically just treat symptoms over a lifetime you end up with a basket full of chronic conditions. And this is why many people live their last 10 or 15 years of life in a nursing home or a wheelchair suffering from multiple health problems. If you don’t want to end up there you have to change the choices you make with your body. The fact is most drug therapy is inappropriate. Let me make this clear there is a time for drugs and there is a time for surgeries but they should be the last approach. Unfortunately, when you let certain conditions develop to the point of no return you eliminate a number of your options to get well.

Dr Keefe, Natural Health care, pain, Tulsa chiropractor,

Natural healthcare focuses on health, not disease. Disease care has led to horrible health statistics for countries that focus their attention there. When a type II diabetic is taking one, two or three different medications to try to control their blood sugar they are in fact shortening their lifespan and making chronic disease more likely. The sad thing is the vast majority of type II diabetics can be drug-free and healthy by some simple dietary and nutritional approaches. Lowering your blood sugar with drugs to force the sugar out of the body is not the same as correcting the blood sugar problem. Find the cause, correct the cause. 


It is true that antibiotics can help clear acne in patients who suffer from it but it’s also true that antibiotics will wreck havoc on your digestive tract and weaken your immune system. Is acne an antibiotic deficiency disease? The skin is just the expression of the health of the body. Acne has to do with body ecology, hormonal balance and sometimes food allergies. The chances are the use of antibiotics will make each of these issues worse. And has anybody heard of superbug infections? The overuse of antibiotics is the number one cause of death from superbug infections that have been growing every year for the past 25 years. Is there a place for antibiotics? There is but it’s very rare. There are so many natural immune boosting techniques in natural healthcare that well over 90% of my patients never require any antibiotics in their life as long as they are following the approaches we recommend. Sure there are exceptions to every rule but in our society, the exception is the rule.   

Dr. Keefe, Keefe Clinic. Tulsa Chiropractor, pain, natural health care.                                                                

Do you want to be healthy? Drugs are not going to get you there. Drugs could save your life but the same drugs that saved your life could end your life if you keep taking them. Drugs are toxic, drugs are dangerous. If you want to be healthy then you have to practice a healthy lifestyle. Did you know your nervous system controlled and coordinated everything that happens in your body? That’s why we focus on spinal health to maintain a proper nervous system function. That is one of the five laws of health that we encourage patients to follow. The second law would be the law of diet. Do you really believe you could eat Twinkies all day and stay healthy? Of course not. But just like the big Pharma, big food has programmed you into digging your own grave with your fork. You have to eat a diet that’s consistent with your genetic makeup and actually has real food in it. Eating right is really not that hard with a little direction you can increase your energy levels, strengthen your cardiovascular systems and maintain proper blood sugar levels very easily. The third law is exercise. You don’t have to run marathons, in fact, you can over-exercise to your detriment. Exercise is also related to your genetic makeup. Some people doing the wrong type of exercise can actually hurt themselves. People who have some type of moderate, regular exercise will be healthier than those who don’t. Law four is a positive mental and spiritual attitude. Life can be hard you need to have coping skills in order to be successful. Spiritual disciplines have been shown by research to make us healthier and to allow us to live a longer life. In the fifth law is rest and relaxation.                                                            

None of these laws are really difficult to follow you just need to find yourself in a culture that encourages these. The pharmaceutical approach is not that culture. As nice as it is to have a fire department it’s also a lot better if you never have to call them. And in most circumstances with a little prudence, those disasters can be avoided. One of the best ways to find yourself in the culture of better health is to choose natural healthcare. Making natural healthcare your first choice can prevent a number of disasters in your life and your families health. You still might be referred to a medical specialist from time to time but if your primary care is a physician in the natural healthcare field your outcomes would be greatly improved.

Are you locked in the matrix? Choose natural healthcare and choose a better life.



WEEKLY HEALTH UPDATE Week of: Monday July 16, 2018

Courtesy of:

John H. Keefe III, D.C.

(918) 663-1111


Dr. Keefe, Keefe Clinic. Tulsa Chiropractor, pain, natural health care. 

IN THE NEWS: Kids whose mothers do these 5 things are 75% less likely to be obese The best thing mothers can do to ensure their kids avoid developing obesity may be to take care of themselves. That’s the main takeaway from a study looking at mothers and children published Wednesday in the British Medical Journal. Childhood obesity rates have more than tripled in the US since the 1970s, according to the CDC. Nearly 20% of kids and teens aged 6 to 19 now qualify as obese. Being obese as a child comes with serious long-term health effects, including higher risk for diseases including asthma, bone and joint problems, sleep apnea, type 2 diabetes, depression, and risk factors for heart disease. According to the study, genetics play an important role in obesity, but researchers think lifestyle factors may be behind the increased rate in recent decades. So the study authors decided to analyze lifestyle choices of mothers and children to see how they affected obesity rates. Obesity risk is lowest for children whose mothers make five healthy lifestyle choices. These mothers maintain a healthy weight, exercise at least the recommended 150 minutes per week, and don’t smoke. They eat a high quality diet, determined by high intake of vegetables, fruits, nuts, whole grains, healthy fats, and low consumption of sugary beverages, red and processed meat. Finally, they drink light to moderate amounts, quantified as two small glasses of wine or one standard pint of beer a day.

WELLNESS: Obesity makes breast cancer cells more aggressive We already know that obesity diminishes health in a number of ways. Now the increased spread of breast cancer can be added to that list. Research out of Heidelberg University Hospital and Helmholtz Zentrum München, Technische Universität München (TUM) has yielded some enlightening discoveries. During their research, the European scientists found that obesity causes cytokines to be released into the bloodstream. This in turn impacts the metabolism of breast cancer cells, causing them to become much more aggressive. Losing excess body weight will reduce the risk of breast cancer metastasis: Breast cancer metastasis and recurrence after tumor surgery is the primary cause of deaths from cancer in women. Other studies have linked obesity with aggressive breast cancer forms. Important note: Postmenopausal women are at an even higher risk of developing breast cancer that metastasizes. Naturally, we all understand the importance of maintaining a healthy weight for good health. These research results should give overweight women – at a high risk for breast cancer – even more incentive to lose weight. Take action today: Favor organic (chemical free) fruits and vegetables; eat high-quality protein while avoiding processed foods. Lower mental and emotional stress – especially the repair of toxic personal relationships. Exercise on a regular basis – even if it’s just walking. And, finally, replace those toxic personal care or household cleaning products with safer versions that use natural ingredients like, essential oils. These steps will go a long way to reducing your risk of cancer or any other chronic health problem.

Dr. Keefe, Keefe Clinic. Tulsa Chiropractor, pain, natural health care.

CHIROPRACTIC: KIDS AND TECH NECK Neck problems are becoming way too common with today’s technology. Over the years the development of the proper position of computer monitors and keyboards have become better understood but with today’s smartphones we are back to the starting line. The average head weighs about 10 pounds and it sits on the smallest vertebra in the body. When you lean your head forward just 1 inch you develop up to 16 to 18 pounds of pressure on your spine particularly your low back. This steady head forward posture puts the muscles, discs and joints in the neck under a lot of stress. Over time this can alter the normal curve in the neck leading to degenerative changes. As this process develops headaches, neck tension, eyes and sinus symptoms, shoulder problems, elbow problems, carpal tunnel syndrome are just a few of the issues that can develop. You add the effect of technology on poor sleeping habits you become a neck problem waiting for the point of explosion i.e. symptoms. Unfortunately degenerative changes in the neck don’t always show up symptomatically for a decade or more. When you feel the first symptoms the underlying problem could be very hard to fix. For your kids’ sake you need to discuss keeping the phone out in front of them so they don’t have to bend their head forward and down. Chiropractic adjustments are the most effective treatment for tech neck.

Dr Keefe, Keefe Clinic, Natural Health Care, Tulsa Chiropractor, Diet, Pain,

 FUNNY BONE: Q. Why did the invisible man turn down the job offer? A. Because he just couldn’t see himself doing it.@@ Wife: “In my dream, I saw you in a jewelry store and you bought me a diamond ring.” Husband: “I had the same dream and I saw your dad paying the bill.”@@ I just ended a long-term relationship today. I’m not too bothered, it wasn’t mine.@@ Never lend money to a friend. It’s dangerous. It could damage his memory.@@ Every day I get up and look through the Forbes list of the richest people in America. If I’m not there, I go to work.@@ Money isn’t everything, but it certainly keeps you in touch with your children.@@ You take away the looks, money, intelligence, charm and success and, really, there’s no real difference between me and George Clooney.@@ I saw a sign that said “Watch for children” and I thought, “That sounds like a fair trade”.

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The Study:  The influence of pelvic adjustment on the posture of female university students.     

The Study:
The influence of pelvic adjustment on the posture of female university students.
The Facts:
a. The authors looked at changes in posture in female university students who received pelvic adjustments using the Gonstead Technique.
b. The pelvis positioning “…is the most important element that determines the sagittal alignment and posture of the body and abnormal posture triggers diverse problems, including flat-back syndrome, cervical kyphosis, local organ ailments such as uterine prolapse and gastric herniation.”
c. The subjects were female university students and they were divided into a group that received the adjustments and a control group that did stretching only.
d. A thrust was made for a posterior inferior innominate with the patient prone.
e. The adjustments were made 3 to 5 times by a physical therapist. (emphasis ours)
f. A Back Mapper was used to make the postural measurements.
g. The stretching group showed no significant changes, but the adjustment group showed significant changes in trunk imbalance, pelvic position, pelvic torsion, and position of the scapulae.
Take Home:
Adjustments improved posture.
Reviewer’s Comments:
Global rotation is the sum of all the relative rotations so if you changed one or more relative rotations you would tend to affect the global rotation to some degree. In other words, if you change the alignment of boney structures then you will tend to affect the posture. But why do I say “tend to”? Because, I want you to understand that this subject is more complex than simply improving the alignment of a single segment and then automatically assuming that global alignment will also improve. Likewise, it is possible for patients to demonstrate reasonably healthy global posture and still exhibit small, single segment problems (misalignment, dysfunctional motion, etc). You need both good relative and good global alignment. But then you regularly read Science in Brief so you already had that figured out.
Reviewer:  Roger Coleman DC

WEEKLY HEALTH UPDATE Week of: Monday June 4, 2018


Courtesy of:

John H. Keefe III, D.C.

(918) 663-1111

IN THE NEWS:. STD Prevalence Skyrockets Amid Concerns Over Growing Antibiotic-Resistance Three of the more commonly transmitted diseases have reached record levels in the U.S. Nationwide, there were 1.6 million cases of chlamydia in 2016, 470,000 cases of gonorrhea and 28,000 new cases of syphilis. Mutations of the Neisseria gonorrhoeae bacteria that cause gonorrheal infections have led to a high incidence of antibiotic resistance, making it extremely difficult to treat. Research looking at syphilis samples from the U.S., South America, Europe, Africa and Australasia found both of the two main strains of syphilis have developed antibiotic resistance. STD prevalence in California has increased by 45 percent in the past five years. In 2017, 300,000 cases of chlamydia, gonorrhea and syphilis were reported, 54 percent of cases occurring in those under the age of 25. The number of babies born infected with syphilis quadrupled, and with it, stillbirths spiked as well. Of the 278 congenital syphilis cases on record in California last year, 30 resulted in stillbirth, which is triple the number of syphilis-related stillbirths reported in 2016.

WELLNESS: Mercury poisoning: Ways “silver” dental fillings can destroy your health Many integrative healthcare providers describe chronic exposure to mercury as a “biochemical train wreck” and an “underreported epidemic.” To find the primary source of low-level mercury poisoning, many of us need look no further than our own dental work. “Silver” dental fillings, used on almost half of all dental restorations in the United States, contain 45 to 55 percent mercury – and the simple acts of chewing and drinking hot liquids can cause the release of harmful mercury vapors. Accumulating in the brain, kidneys, liver, lungs and gastrointestinal tract, mercury jeopardizes human health in literally dozens of ways. The symptoms of mercury poisoning listed below range in severity from merely annoying to potentially life threatening. But be advised: as shocking as it seems, this overwhelming litany of harm is just a partial list.  Emotional and psychological symptoms According to the IAOMT, mercury exposure can cause a “baker’s dozen” (more or less) of truly disturbing psychological symptoms – including aggression, suicidal ideation, fits of rage, mood swings and manic depression. Gastrointestinal problems Mercury disrupts the intestinal flora of the gut microbiome, the community of beneficial bacteria that helps to regulate health. This can result in digestive complaints such as diarrhea, constipation, loss of appetite and weight loss. Other GI symptoms from low-level mercury poisoning include nausea, vomiting and heartburn. Respiratory difficulties asthma, allergies, bronchitis, emphysema, chest congestion, shortness of breath and shallow respiration. Reproductive issues Reproductive problems linked to mercury include Infertility, lowered sperm count, premenstrual syndrome, genital discharge and spontaneous abortions. Neurological disorders Tremors, paralysis, neuropathy, epilepsy, headaches, dizziness and vertigo have been reported with mercury poisoning. Impaired immune system According to Dr. McGuire, mercury poisoning can significantly impair the immune system, raising susceptibility to disease and causing autoimmune disorders.

Dr Keefe, Natural Health care, pain Tulsa chiropractor,


CHIROPRACTIC: Chiropractic is a healthcare discipline that emphasizes the inherent recuperative power of the body to heal itself without the use of drugs or surgery. The practice of chiropractic focuses on the relationship between structure (primarily the spine) and function (as coordinated by the nervous system) and how that relationship affects the preservation and restoration of health. In addition, doctors of chiropractic recognize the value and responsibility of working in cooperation with other health care practitioners when in the best interest of the patient. One of the best things about receiving chiropractic adjustments is that they are a completely drug-free path to healing the body naturally. Chiropractic benefits including helping to naturally improve problems such as: Back pain, Headaches, Bowel regularity, Improved mental clarity, Ear infections, Neck pain, Arthritis and joint pain, Scoliosis, Asthma, Blood pressure, Healthy pregnancy, Organ function, Surgery prevention. Despite its popularity, there are still a lot of misconceptions about the field of chiropractic care, including how the practice works and how chiropractors are trained. For example, did you know that many chiropractic programs incorporate an entire year of PhD-level advanced nutrition training? Think chiropractic first, drug second and surgery last.

FUNNY BONE: Thank God I don’t have to hunt for my food, I don’t even know where tacos live…@@That frail moment when you pull your blankets up and punch yourself in the face.@@When people tell me “you’re going to regret that in the morning,” I sleep in until noon because I’m a problem solver.@@It’s okay if you disagree with me, I can’t force you to be right.@@Dear pimples if you’re going to live on my face, I need to see some rent.@@Working in a mirror factory is something I can totally see myself doing.@@Someone stole my Microsoft Office I said, “ they’re gonna pay. You have my Word.”@@I feel bad for the homeless guy, but I feel really bad for the homeless guy’s dog, It must be thinking “man, this is the longest walk ever.”@@Someone stole my mood ring, I don’t know how I feel about that.

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WEEKLY HEALTH UPDATE Week of: Monday May 28, 2018


Courtesy of:

John H. Keefe III, D.C.

(918) 663-1111


DIET: 43 Times More Vitamin C than an Orange, a Weapon Against the Flu Camu camu (Myrciaria dubia) is a small orange-red fruit, similar in size to that of a large cherry, with a tart flavor; the camu camu tree grows primarily in South America. Camu camu contains exceptionally high amounts of vitamin C — anywhere from 1,882 to 2,280 milligrams per 100 grams of fresh fruit. For comparison, acerola cherries typically contain around 1,678 mg of vitamin C per 100 grams. Vitamin C is an important immune booster and helps defend against viral attacks and inflammation. It’s also used by your body for wound healing, repairing and maintaining the health of your bones and teeth. Camu camu also contains a number of other valuable nutrients, including manganese, copper, carotenoids, flavonoids, essential amino acids (including valine, serine and leucine), gallic and ellagic acid, and fiber. Research suggests camu camu can help boost cognitive function and reduce your risk of dementia, facilitate muscle growth, aid digestion, lower your risk of obesity, Type 2 diabetes, cancer, macular degeneration and more.

IN THE NEWS: Untreatable ‘super gonorrhea’ case could be ‘tip of the iceberg’ The medical community is sounding the alarm after a man in the U.K. has become the first patient with a type of gonorrhea infection that is not responding to the antibiotics commonly used to cure it. Doctors are calling it the “worst-ever” case of the sexually transmitted disease, which hits approximately 78 million men and women every year. According to the BBC, the unidentified man had a regular partner but picked up the disease earlier this year after a sexual encounter with a woman in South East Asia. STDS HIT RECORD HIGH IN US, 2M CASES REPORTED IN 2016 “This is the first time a case has displayed such high-level resistance to both of these drugs and to most other commonly used antibiotics,” said Dr. Gwenda Hughes, from Public Health England, to the BBC. If left untreated, gonorrhea can lead to pelvic inflammatory disease, ectopic pregnancy, stillbirths, severe eye infections in babies and infertility in both men and women. In the United States, there are approximately 300,000 reported cases of gonorrhea each year. But because infected people often have no symptoms, the actual number of cases is likely closer to 600,000, according to Reuters.

Dr Keefe, Keefe Clinic, Natural Health Care, Tulsa Chiropractor, Diet, Pain,

CHIROPRACTIC: Breaking the code of disease. One of the greatest rewards that a doctor of any type can have is helping someone recover their health. When we stopped taking care of ourselves like we should, it just a matter of time before we realize our mistake. Sometimes we don’t appreciate our health until we lose it. One of the tools that we have found very effective in “breaking the code of disease” is Vega testing. We have been able to help a multitude of patients recover their health after other methods have failed. One thing that’s important to realize is drugs primarily cover your symptoms. If you don’t fix the underlying cause and allow healing to take place, then you’re just giving disease time to develop into a more serious condition. I see that it has been some time since your last visit and I would like to encourage you to take a proactive stance concerning your health. Health is the best insurance you can have. Besides eating right for your body type, getting some type of regular movement (exercise), chiropractic adjustments and nutritional therapy are some of the most powerful tools in health recovery and maintenance. Are you noticing your performance and energy less than you would desire? Are you ignoring some reoccurring symptoms/pain or having issues with sleep or digestion? Are you having issues with brain fog or memory? Are you just not enjoying life like you use to? You need to call us today and let us unravel the issues affecting your well-being. Both you and your family would appreciate a healthier you. Call us today for an appointment, do something good for yourself.

FUNNY BONE: My dog used to chase people on a bike a lot. It got so bad, finally I had to take his bike away.@@ A woman walks into a library and asked if they had any books about paranoia. The librarian says “They’re right behind you!”@@ Why did the old man fall in the well? Because he couldn’t see that well.@@ I know a lot of jokes about unemployed people but none of them work.@@ My wife accused me of being immature. I told her to get out of my fort.@@ I just wrote a book on reverse psychology. Do *not* read it!@@ I used to think I was indecisive, but now I’m not too sure.





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The case for turmeric

In the West, traditional eastern medicines are not usually recognized until there is scientific evidence to back it up. Well, in the case of turmeric, there is!

Dr. Keefe, Keefe Clinic. Tulsa Chiropractor, pain, natural health care.


(1) Kills 16-times more cancer cells than the leading chemo drug Eloxatin — without harming healthy cells (International Journal of Oncology)

(2) Performs better in memory tests than the drug Aricept (the most widely prescribed Alzheimer’s drug) — Salk Institute for Biological Studies

(3) Lowers cholesterol and triglyceride levels better than the statin drug Lipitor (Journal of Drug Research and Development)

(4) Beats Celebrex for relieving knee arthritis pain (Journal of Alternative and Complementary Medicine)

(5) Relieves rheumatoid arthritis pain better than Ibuprofen (Journal of Phytotherapy Research)

(6) “Therapeutic effects are comparable to pharmaceutical NSAIDs… but with a major difference in that this compound is nontoxic and free of side effects.” – Vanderbilt and University of Pittsburgh researchers (Journal of Surgical Neurology International)

(7) “More effective in stopping the protein fragments from forming than many other drugs being tested to treat Alzheimer’s” – UCLA Alzheimer’s Department and Veterans Affairs researchers (Journal of Biological Chemistry)

(8) “It’s 400-times more potent than the diabetes drug Metformin” — reports Auburn University researchers (Journal of Biochemical and Biophysical Research Communications)

(9) More effectively treats Major Depressive Disorder (MDD) than Prozac — without Prozac’s devastating side effects, according to a randomized, controlled study.

(10) Treats chronic uveitis — a leading cause of blindness — better than corticosteroids… the only available prescription treatment (Journal of Phytotherapy Research)

(11) “Could enhance erectile function with more efficacy and more prolonged duration of action than Viagra” (International Journal of Impotence Research)

(12) Destroys more colon cancer stem cells than FOLFOX (one of the most widely prescribed chemotherapy protocols) – Baylor University researchers



Head_On_Collision, Dr Keefe, Natural Health care, pain, Tulsa chiropractor,


Car accidents are most likely the number one cause for chronic disability and/or pain. The August 1999 issue of American Family Physicians, the article notes that  3.5 million people are injured in motor vehicle accidents in the U.S. each year. Even minor car accidents can cause changes in the spine that can lead to degenerating joint disease and future pain.  Studies indicate that chiropractic care is the best treatment for the vast majority of injuries from a car accident.  The main reason that chiropractic patients have less problems in the future and recover better from their present complaints is because of the focus in chiropractic care.

Dr. Keefe, Natural Health care, pain, Tulsa chiropractor, neck pain, headache,


The injuries to the spine will cause slight misalignments in the joints of the neck and back.  It’s these misalignments that produce the majority of symptoms, not pulled muscles.  Chiropractic care and analysis focuses on the detection and correction of spinal subluxations.  Subluxation is the term for misalignments that develop in the spine.  These misalignments can stay there for years unless they are corrected by chiropractic adjustments.  The average patient after a car accident that visit an emergency room usually are only given pain pills and muscle relaxers.  This of course allows the misalignments to remain.  It’s this focus on just the symptoms of the injury that leave a high percent of car accident victims with ongoing disability, pain and degenerating joint disease.

15-yrs-post-whiplash, Dr. Keefe, Natural Health care, pain, Tulsa chiropractor, neck pain, headache,


One study showed problems five or more years after the accident. Symptomatic recovery occurred in 57 per cent of the 146 patients, while degenerative changes developed after the injury in 39 per cent.  Journal of Bone and Joint Surgery, 1974;56:1675-1682.

headachespine, Dr. Keefe, Natural Health care, pain, Tulsa chiropractor, neck pain, Dr. Keefe, Natural Health care, pain, Tulsa chiropractor, neck pain, headache,,


……several studies have investigated and linked the relationship of altered cervical curve configuration to the presence of chronic headache pain. CBP Structural Rehabilitaion of the Cervical Spine, Deed E. Harrision, DC, Donald D. Harrison, PhD, DC, MSE, Jason W. Haas, DC, 2002 Harrison CBP Seminars, Inc.  pg. 56, “Cervical Lordosis and Headaches”

whiplash, Dr. Keefe, Natural Health care, pain, Tulsa chiropractor, neck pain, headache,


Cerebral symptoms after whiplash injury of the neck: a prospective clinical and neuropsychological study of whiplash injury. Ettlin TM, Kischka U, Reichmann S, Radii EW, Heim S, Wengen D, Benson DF. University Clinics, Basel, Switzerland.

Dr. Keefe, Natural Health care, pain, Tulsa chiropractor, neck pain, headache,


Twenty one unselected patients with an acute whiplash injury of the neck had neurological and neuropsychological assessment, cervical x rays, EEG, BAEP, MRI, and an otoneurological examination within two weeks of the injury. Subjectively, 13 patients reported concentration deficits, 18 reported sleep disturbances, 9 had symptoms of depression, and 7 female patients told of menstrual irregularities.   Scientific Automobile Accident Reconstruction treatise by Barzeley; Published by Mathew Bender 1984; Chapter 46:

”              The simple fact remains: neck injuries do occur as a result of rear-end automobile accidents.  46-2

”              Whiplash injuries may be present as a result of automobile accidents, even though no physical, radiological or other objective evidence of injury can be found. 46-3

”              Usually the onset of symptoms occurs from 12 to 24 hours afterward. Sometimes there may be as much as weeks or even months delay between the automobile accident and the experience of symptoms. 46-5

”              Most people just don’t expect injuries to occur when the impact velocity has been low and damage to the vehicles has not been great. It is common sense to expect that the severity of the injuries should be in proportion to the severity of the collision. However, whiplash injuries most frequently result from relatively minor automobile accidents without major damage done to the vehicles. 46-6

”              Rear-end collisions produce a sudden forceful hyperextension of the neck which is immediately followed by recoil into neck flexion. 46-8

”              Probably most of the injuries result from the sudden traumatic snapping of the neck when the acceleration of the head suddenly shifts directions. 46-10

Dr. Keefe, Natural Health care, pain, Tulsa chiropractor, neck pain, headache,


In most cases you’re better off in the long-term to break a bone than to damage a joint.  When you damage a joint, you primarily damage the connective tissue in the joint which can leave that joint unstable for the rest of your life.  When you break a bone, the bone heals stronger than it was before.  Connective tissue has a history of poor healing.  By bringing that joint back to its proper alignment, you allow the maximum healing to the  soft tissue or connective tissue in that joint.  And by maintaining that alignment over the long-term, you assure maximum results. Out of 50 or so outcome studies which have been published in the past 40 years.  They nearly unanimously presented 30 to 50 percent of whiplash victims are left with some form of residual pain or dysfunction.

Our treatment goals are not only to make you feel better now, but to try to assure that 10 years from now your injuries will not be bothering you.

Dr. Keefe, Natural Health care, pain, Tulsa chiropractor, neck pain, headache,


Dr. Keefe, Natural Health care, pain, Tulsa chiropractor, neck pain, headache,


Cholesterol, the lie has been revealed


Open Access

Nutrients 201810(5), 604; doi:10.3390/nu10050604

Inflammation, not Cholesterol, Is a Cause of Chronic Disease
Alexandros Tsoupras, Ronan Lordan and Ioannis Zabetakis *
Department of Biological Sciences, University of Limerick, V94 T9PX Limerick, Ireland
Correspondence:; Tel.: +353-0-61-234-202
Received: 23 April 2018 / Accepted: 9 May 2018 / Published: 12 May 2018



Since the Seven Countries Study, dietary cholesterol and the levels of serum cholesterol in relation to the development of chronic diseases have been somewhat demonised. However, the principles of the Mediterranean diet and relevant data linked to the examples of people living in the five blue zones demonstrate that the key to longevity and the prevention of chronic disease development is not the reduction of dietary or serum cholesterol but the control of systemic inflammation. In this review, we present all the relevant data that supports the view that it is inflammation induced by several factors, such as platelet-activating factor (PAF), that leads to the onset of cardiovascular diseases (CVD) rather than serum cholesterol. The key to reducing the incidence of CVD is to control the activities of PAF and other inflammatory mediators via diet, exercise, and healthy lifestyle choices. The relevant studies and data supporting these views are discussed in this review.

cardiovascular disease; atherosclerosis; inflammation; platelet-activating factor; oxidised lipoproteins; cholesterol; chronic diseases

1. Introduction

1.1. Biological Significance of Cholesterol—Circulating Blood Cholesterol

Cholesterol, an unsaturated alcohol of the steroid family, is essential for the normal function of all animal cells. It is also a fundamental element for the normal structural makeup and the fluidity of all cell membranes. Cholesterol interacts with phospholipid bilayers in the cell membrane and increases membrane packing. Cholesterol also takes part in signal transduction, intracellular transport, nerve conduction, and signalling pathways through lipid rafts and caveolae. Cholesterol has various other biological functions, i.e., it is a precursor molecule for several biochemical pathways such as the synthesis of vitamin D, steroid hormones (e.g., cortisol, aldosterone, and adrenal androgens), and sex hormones (e.g., testosterone, oestrogens, and progesterone). Cholesterol is also a constituent of bile salts, which are crucial constituents of digestion, as they facilitate the absorption of lipids, fats, and fat-soluble vitamins A, D, E, and K [1].
Since cholesterol is mostly a lipophilic molecule, it does not dissolve well in blood. For this reason, it is packed into lipoproteins that are composed of a lipid core (which can contain cholesterol esters and triglycerides) and a hydrophilic outer membrane comprising phospholipids, apolipoprotein, and free cholesterol. This allows for the transport of the nonpolar lipid molecules such as cholesterol and triglycerides around the body through the blood to cells that require them. Plasma lipoproteins are separated into five major classes: chylomicrons, very-low-density lipoproteins (VLDL), intermediate-density lipoproteins (IDL), low-density lipoproteins (LDL), and high-density lipoproteins (HDL) [1,2].
Cholesterol can enter the blood through the digestion of dietary fat via chylomicrons. However, since cholesterol has an important role in cellular function, it can also be directly synthesised by each cell in the body. Notably, LDL particles are thought to act as a major transporter of cholesterol to the peripheral tissues, as at least two-thirds of circulating cholesterol resides in LDL. Conversely, HDL molecules are thought to do the opposite. They take excess cholesterol and return it to the liver for excretion [1,2].
Recent evidence suggests that dietary intake of cholesterol can influence plasma and serum levels, but not significantly. However, this is still subject to debate and further study [3]. Plasma cholesterol levels along with the levels of LDL cholesterol, HDL cholesterol, and serum triglycerides are currently used as biomarkers of the so-called standard ‘lipid profile’ for each individual. The standard lipid profile has been widely used as a traditional biomarker, not only for cardiovascular health but also for other lipid-related abnormalities and disorders [4].

1.2. Cholesterol Levels: Demonising a Risk Factor but Not the Causative Mechanisms of Chronic Diseases

Several modifiable and non-modifiable risk factors (genetic, environmental, nutrition, and lifestyle, etc.) are thought to influence the balance between health and disease by inducing mechanisms related to disease onset, development, and the manifestations of symptoms. The presence or coexistence of these risk factors seem to trigger underlying molecular and cellular mechanistic pathways that can lead to continuous chronic manifestations and the long-term loss of tissue homoeostasis and tissue dysfunction. These continuous chronic manifestations can develop over time before cellular disturbances manifest and cause tissue disorders, while, if not counterbalanced by our immune system and by specific preventive measures such as a healthy diet and lifestyle, the subsequent symptomatic disease finally appears, and medical treatment may be required to reduce the risk of mortality. Elucidating these molecular and cellular mechanistic pathways and acquiring the mechanistic evidence of the underlying multifactorial causes of a chronic disease can lead to suitable preventive targets against these diseases with fewer side effects, which is an ongoing difficult and demanding task. Such difficulties have misled the scientific and medical community to often and lightly extrapolate the easily acquired observed statistical and epidemiological correlations of traditional risk factors to several chronic diseases, towards matching these risk factors as the causative agents of these diseases.
According to the ‘cholesterol hypothesis’, high blood cholesterol is a major risk factor, while lowering cholesterol levels can reduce risk [5]. Dyslipidaemias (i.e., hypercholesterolaemia or hyperlipidaemia) are abnormalities of lipid metabolism characterised by increased circulating levels of serum total cholesterol, LDL cholesterol, triglycerides, and decreased levels of serum HDL cholesterol. High levels of LDL cholesterol and non-HDL cholesterol have been associated with cardiovascular risk, while other cholesterol-related serum markers, such as the small dense LDL cholesterol, lipoprotein(a), and HDL particle measurements, have been proposed as additional significant biomarkers for CVD risk factors to add to the standard lipid profile [6]. HDL cholesterol has been considered as the atheroprotective ‘good’ cholesterol because of its strong inverse correlation with the progression of CVD [7]; however, it is the functionality of HDL cholesterol, rather than its concentration that is more important for the preventative qualities of HDL cholesterol in CVD. In general, dyslipidaemias have been ranked as significant modifiable risk factors contributing to prevalence and severity of several chronic diseases including aging, hypertension, diabetes, and CVD. High serum levels of these lipids have been associated with an increased risk of developing atherosclerosis [8].
Furthermore, dyslipidaemias have been characterised by several studies not only as a risk factor but as a “well-established and prominent cause” of cardiovascular morbidity and mortality worldwide [9]. Even though such an extrapolation is not adequate, it was, however, not surprising that this was made, because since the term arteriosclerosis was first introduced by pioneering pathologists of the 19th century, it has long been believed that atherosclerosis merely involved the passive accumulation of cholesterol into the arterial walls for the formation of foam cells. This process was considered the hallmark of atherosclerotic lesions and subsequent CVD. Moreover, one-sided interpretations of several epidemiological studies, such as the Seven Countries Study (SCS), have highlighted outcomes that mostly concerned correlations between saturated fat intake, fasting blood cholesterol concentrations, and coronary heart disease mortality [10,11,12,13]. Such epidemiological correlations between dyslipidaemias and atherosclerosis led to the characterisation of atherosclerosis as primarily a lipid disorder, and the “lipid hypothesis” was formed, which would dominate thinking for much of the 20th century.
In the clinical setting, in order to address the lipid hypothesis, the levels of cholesterol related plasma lipoproteins and triglycerides (lipid profile) have been used as traditional biomarkers for cardiovascular risk, but also for dietary and treatment guideline designs [5]. Dietary and medical guidelines have focused on the reduction of cholesterol and lipid levels as the best way to prevent chronic diseases such as CVD [5,9]. Such guidelines suggest the application of statin therapies in order to reduce the levels of cholesterol (through inhibition of cholesterol synthesis by HMG-CoA reductase inhibitors); however, numerous side effects have been reported, including the development of other chronic diseases such as diabetes mellitus [14]. Moreover, specific dietary strategies for reducing cholesterol intake are the mainstay of management in most cases of dyslipidaemia, prior to, or simultaneously with, the initiation of a lipid lowering agent [9]. Dietary fats, cholesterol, and the levels of serum cholesterol in relation to the development of CVD have been somewhat demonised.
On the other hand, since cholesterol is an essential biomolecule for the normal function of all our cells, an emerging question has recently surfaced: “how much do we need to lower the levels of cholesterol”? Furthermore, given the fact that cholesterol plays a crucial role in several of our cellular and tissue mechanisms, it is not surprising that there are several consequences due to the aggressive reduction of cholesterol levels in the body, which has been common practice over the last few decades. In addition, targeting cholesterol and fat intake by introducing diets with low-fat products and by reducing the intake of high-fat foods can lead to less absorption and lower bioavailability of other lipids containing high value nutrients, such as several lipid soluble vitamins (especially vitamin D) and other lipid molecules. Such lipids have exhibited a plethora of beneficial bioactivities, not only related to reducing the risk of chronic diseases but also through a wide range of important bio-functionalities and anti-inflammatory properties [3]. Therefore, lower cholesterol levels do not equate to better health, or to lower risk of chronic diseases such as CVD. Homeostasis must be maintained, even with regard to cholesterol, both HDL and LDL [15].
Moreover, recent systematic reviews and meta-analyses have started to question the validity of the lipid hypothesis, as there is lack of an association or an inverse association between LDL cholesterol and both all-cause and CVD mortality in the elderly [15] and several cancers such as lung, prostate, and breast cancer [16,17,18]. Such studies provide the rationale for more research about the causes (and not only the risk factors) of chronic diseases such as atherosclerosis, CVD, and cancer, but also for a re-evaluation of the guidelines for cardiovascular prevention, in particular because the benefits of statin treatments have been exaggerated [15].
Statistical and epidemiological extrapolations often lack fully clarified biochemical mechanistic evidence, while associations and correlations do not necessarily mean causation. In addition, a follow-up by systematic reviews and meta-analyses often present contradictory outcomes against the initial results that were introduced by early stage epidemiological studies lacking consistency, biological gradient, and coherence. Thus, such extrapolations can lead to one-sided, premature targeting of risk factors accompanied with consequences, often without the desirable outcomes. Targeting a risk factor such as high serum cholesterol may decrease the probabilities for a disease, but usually cannot prevent the causation of chronic diseases.

1.3. Revisiting the Lipid Hypothesis: Outcomes of the Mediterranean Diet against Inflammation

Previous epidemiological and observational studies, such as the SCS in which the lipid hypothesis was mostly based, have been re-evaluated. For example, even though within the SCS the strength of the association between serum cholesterol and cardiovascular mortality were similar in different cultures, the absolute risks differed substantially. Kromhout reported that at a serum cholesterol level of 200 mg/dL, the 25-year cardiovascular mortality rate was five times higher in the Northern European populations of the SCS compared to the Southern Mediterranean populations [19], and thus the relations between diet, serum cholesterol, and cardiovascular mortality are more complex than originally thought. This is because it is not only dietary cholesterol involved, but other lipids and antioxidants may play a role in the onset and prevention of atherosclerosis [19]. Such a low prevalence of cardiovascular mortality in the Mediterranean cohorts of SCS is now attributed to their lifestyle and especially to their dietary habits, namely the traditional Mediterranean diet (Med-diet) [10,20]. A common feature of the diet amongst populations in the Mediterranean is a relatively high dietary intake of vegetables, fruits, legumes, whole grains, monounsaturated fats, and nuts, followed by moderate consumption of fish, dairy products (mainly cheese and yogurt), alcohol, and low consumption of red and processed meats [21].
The major outcomes of the SCS and other similar epidemiological studies (i.e., studies trying to decipher the ‘French Paradox’ [22]) concerning the protective effects of dietary patterns, such as the Med-diet against chronic diseases, were initially either neglected or misinterpreted. CVD and cardiovascular mortality occurred in much relatively lower rates in the Southern European populations (i.e., Italy and Greece) despite a rather high dietary intake of saturated fats and cholesterol [10,20,23]. A recent systematic review and meta-analysis revealed that Med-diet can actually reduce the incidence of cardiovascular events, breast cancer, and type II diabetes mellitus, without any restriction on fat intake [24].
Over the last 2 years there has been a significant number of studies referring to adoption of the Med-diet pattern and its associated beneficial outcomes in a plethora of several chronic diseases that are either directly or indirectly related to inflammation. These studies refer to heart failure, CVD [25], cancer [26,27], obesity [28], metabolic syndrome [29,30,31], diabetes [31,32,33,34], and other subsequent manifestations such as diabetic retinopathy [35], asthma [36], autoimmune diseases such as rheumatoid arthritis [37], incident frailty risk [38], non-alcoholic fatty liver disease [39,40], inflammatory bowel disease [41], cognitive health, the risk of Alzheimer’s disease and dementia [42,43,44], and age-related macular degeneration [45].
In addition, the Med-diet has also been associated with beneficial outcomes, even in secondary CVD prevention [46]. When patients suffering from CVD or diabetes follow the Mediterranean dietary pattern, the incidence of recurrent myocardial infarction and cerebrovascular events is reduced. The protective effect of this dietary pattern can be maintained for up to four years after the first infarction (Lyon Diet Heart Study) [47]. Moreover, in contrast to the contradictions of lipid hypothesis and mortality in elderly people [15], the HALE project has also shown that individuals aged 70 to 90 years following a Med-diet and healthy lifestyle have a 50% lower rate of all-cause and cause-specific mortality [48]. Followers of the Med-diet are also less likely to suffer sudden cardiac death and age-related cognitive decline [49].
The inverse association between Med-diet and all causes of diseases and cardiovascular-mortality has been attributed to several of its pleiotropic protective effects. For instance, the Med-diet can beneficially influence several risk factors such as lowering BMI, blood pressure, reducing insulin resistance, reducing lipid levels (i.e., the ratio of cholesterol/HDL cholesterol), and improving HDL-cholesterol functionality [50,51,52,53,54]. However, the main beneficial impact of Med-diet is on the improvement of endothelial function and the decrease of the inflammatory milieu, inflammation-related mediators, biomarkers such as platelet-activating factor (PAF), and several cytokines. It is also suggested that there is an improvement of oxidative stress, with lower concentrations of oxidised LDL and improved apolipoprotein profiles, and, finally, there is evidence of beneficial effects against platelet aggregation and blood coagulation [3,55,56,57,58].
The overall outcomes and beneficial effects of Med-diet have radically shifted the attention from the lipid-centric model that is characterised by the desired reduction of cholesterol levels to more effective targeting against the factual causative factors of chronic diseases, which are inflammation and its related manifestations. Prevention is key to reducing global mortality due to chronic diseases such as CVD; therefore, it is imperative to separate the underlying causes and processes of the disease from the risk factors and symptoms of disease. The clarification of the key roles and interplay of various cells, inflammatory mediators, and pathways during chronic inflammatory manifestations related to the onset of several chronic diseases is of great importance and may lead to a plethora of novel potential targets for fine-tuning of the inflammatory response during the chronic smouldering of inflammation that characterises these disorders.

2. Re-Discovering Chronic Inflammation as the Cause for Chronic Diseases

Inflammation is a physiological reaction of the innate immune system that maintains a constant internal milieu while being exposed to continuously changing environmental pressures, irrespective of whether the initial causes originate from mechanical, physical, chemical, infectious, immunological, or reactive natural traumatic injury or metabolic dysfunction. The inflammatory response aims to reduce the agent that causes tissue injury and/or minimise these effects, to induce appropriate wound healing and to restore tissue homeostasis. Inflammatory responses are initiated by innate sensing mechanisms that detect the presence of microbial infection, stressed or dying cells, loss of cellular integrity, barrier breach, etc. A cascade of inflammatory pathways and mechanistic effects is supposedly well-orchestrated by the immune system in order to eradicate the causative agent.
Several immune cells can change their number, morphology, and nature depending on the stage and type of inflammation. Biochemically, inflammation is denoted by a local increase of numerous tissue hormones, transmitters, complement components, cytokines, and lipid mediators such as PAF and eicosanoids. Most of these products are autacoids that are synthesised at the site of inflammation in order to resolve the inflammatory process by removing or inhibiting the actions of the triggering agent [8]. Provided that the immune response succeeds in eliminating the infectious agent or to repair the initial tissue injury, the inflammatory process will be terminated in a timely fashion and thus only affects tissue function transiently.
However, in cases where the inflammation fails to resolve due to the persistence of the triggering agent or due to unsuccessful repair of the initial tissue injury or dysfunction, a sustained underlying inflammatory process develops, leading to further tissue dysfunction and detrimental consequences. Several traditional and emerging risk factors are thought to influence our health and, especially, inflammation-related chronic diseases, by their interrelation with underlying molecular and cellular manifestations that result in chronic inflammatory responses leading to the loss of tissue homoeostasis and dysfunction. Apart from dyslipidaemias, other well-established risk factors include hypertension, diabetes, smoking, excessive food intake, previous infections (influenza, oral pathogens) or underlying autoimmune diseases such as lupus or rheumatoid arthritis, pollution, and genetic abnormalities [59]. It is now well established that a common junction of such risk factors is chronic and unresolved inflammatory manifestations. Inflammation that causes endothelial dysfunction seems to be the key causative underlying mechanistic player, at the molecular and cellular level, for the onset and development of subsequent inflammation-related chronic disorders such as atherosclerosis and subsequent CVD, ischemic and renal disorders, cancer metastasis, diabetes, infections, and comorbidities [8,57,58,59,60,61,62].
For example, in cases of dyslipidaemia, increased cholesterol levels are not the causative agent or the underlying biochemical mechanism responsible for endothelial dysfunction and atherosclerosis development. The accumulation of excess plasma LDL cholesterol is addressed by the innate immune system as an undesired event. Therefore, an inflammatory response at the endothelial wall is promoted to reduce the threat by the removal of excess LDL and oxidised-LDL (Ox-LDL) cholesterol from the blood stream to the subendothelium, where they are engulfed by comigrated monocytes for final removal [63,64]. During chronic inflammatory diseases, inflammation and infections can also induce a variety of alterations in lipid metabolism, including decreases in serum HDL cholesterol, increases in triglycerides, lipoprotein(a), and LDL levels. These changes of the lipid levels may initially dampen inflammation or fight infection; however, the sustained inflammation can contribute to the increased risk of atherosclerosis [65]. In addition to affecting serum lipid levels, inflammation also adversely effects lipoprotein function; LDL is more easily oxidised, as the ability of HDL to prevent the oxidation of LDL is diminished, while several steps in the reverse cholesterol transport pathway are also adversely affected during inflammation. The greater the severity of the underlying inflammatory disease, the more consistently these abnormalities in lipids and lipoproteins are observed [65]. Thus, it is not serum cholesterol and lipoproteins that influence the endothelium but the inflammatory response that affects the well integrity and functionality of the endothelium.
Apart from the effects of inflammation on plasma lipids, it is now well established that more important soluble and cellular immune factors associated with chronic inflammation can promote inflammation-related endothelial dysfunction and atherogenesis, either during dyslipidaemia or independently of dyslipidaemia [66]. Even though atherosclerosis and CVD were previously viewed as lipid storage disorders, we now recognise that inflammation drives much of endothelial dysfunction and mechanisms of clinical complications with these diseases and related comorbidities, such as sepsis [67,68], human immunodeficiency virus (HIV) infection [69,70,71,72,73,74], periodontal diseases [75,76,77], kidney disorders [78,79,80,81], healthy ageing, and inflammatory autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis, independently of traditional cardiovascular risk factors such as serum lipid levels [66,82,83].
Inflammation plays a key role in all stages of the formation of vascular lesions maintained and exacerbated by several risk factors such as unhealthy diet and lifestyle, smoking, hyperlipidaemia/hypercholesterolaemia, hypertension, autoimmune diseases, etc. The consequence of chronic inflammation is endothelial dysfunction that sets in, and we can define it as an integrated marker of the damage to arterial walls by classic risk factors. Endothelial dysfunction is usually characterised by an inflammation-related milieu acting on leukocytes and endothelial cells, through an interplay with other immune cells such as T lymphocytes, mast cells, dendritic cells (DC), and platelets [57,58,66,84,85]. The orchestrated overexpression and increased production of pro-inflammatory cytokines occurs, including interleukin-6 (IL-6), tumour necrosis factor (TNF) and its receptor, high-sensitivity C-reactive protein (hsCRP), type I interferons (IFN-α, IFN-β), adhesion molecules, chemokines, and lipid inflammatory mediators such as PAF and eicosanoids. Other linked events include the increased generation of reactive oxygen species (ROS), the increased oxidation of LDL cholesterol, and the reduction of protective nitric oxide levels.
Therefore, the mechanistic pathways and key players implicated in the inflammatory crosstalk taking place throughout the onset, development, and progression of chronic diseases is of great importance, in order to unravel putative preventive and therapeutic targets with less side effects. The inverse effects of the Med-diet with chronic diseases is mostly related to the pleiotropic effects and interplay of its food constituents on all these inflammation-related pathways; following a Mediterranean dietary pattern leads to the reduction of several inflammatory mediators and biomarkers related to the endothelial functionality, such as decreases in hsCRP, IL-6, and intracellular adhesion molecule-1 (ICAM-1) [27].

3. The Role of PAF in Chronic Diseases and the Beneficial Effects of the Mediterranean Diet

3.1. PAF Structure, Activities, and Metabolism: The Role of PAF

3.1.1. PAF Structure and Physiological Roles

PAF is a potent lipid inflammatory mediator with pleiotropic effects that are implicated in several chronic diseases [57]. The classic PAF molecule is characterised by an alkyl ether linkage at the sn-1 position, an acetyl group at the sn-2 position, and a phosphocholine group at the sn-3 position of glycerol backbone (1-O-alkyl-2-sn-acetyl-glycero-3-phosphocholine, [86]) (Figure 1A). These three structural features are all equally important requisites for the optimal biological activity of PAF, mediated by its stereospecific binding to its specific receptor [87,88]. Because of the ether linkage at the sn-1 position, the classic molecule of PAF is an unusual lipid, as such moieties are not common in animals, nor is it common to find the acetic acid esterified directly to glycerol at the sn-2 position. Thus, it seems that PAF was chosen by evolution to participate in specific functions in several of our cells, tissues, organs, and throughout the body. PAF was the first intact phospholipid known to have messenger functions by binding to a specific receptor on the cell membrane, and not simply via physicochemical effects on the plasma membrane of the target cell [79].
Figure 1. (A) Typical structure of classic platelet-activating factor (PAF) molecule [86]. (B) Representative structures of bioactive polar lipids (PL) towards the PAF inflammatory pathways (B), which have been identified in several foods of the Mediterranean diet [56].
Lately, the term ‘PAF family’ has been proposed to include every other phospholipid molecule called PAF-like molecules, which have similar structures to those of the classic PAF molecule, and they exhibit similar bioactivities [89]. However, such PAF-like moieties are usually less potent than PAF by several orders of magnitude, i.e., increasing the chain length beyond 3 carbons at the sn-2 position decreases its biological potency; likewise, altering the polar group at sn-3 position decreases the potency of the molecule. The molecular composition of PAF varies depending on different species and cell types. Related PAF-like lipids include, for example, the acyl-phosphatidylcholine-PAFs (with a short chain acyl group at the sn-2 position), ethanolamine-PAFs, inositol-PAFs, oxidised alkyl-acyl phosphatidyl glycerophosphocholines [90,91], and hydroxyl-alkyl acyl phospholipids [76,77].
PAF, in general, play a vital role in various physiological processes such as mediation of normal inflammatory responses, regulation of blood circulation and pressure, regulation of coagulation responses, glycogen degradation, brain function, reproduction, foetal implantation, lung maturation, initiation of parturition, and exocrine gland functions [92]. However, PAF can be regarded as both a friend, since it is presumed to have evolved as part of a protective mechanism in the innate host defence system, but also as a foe, because of its involvement in uncontrolled inflammation-related pathological conditions [93]. When present in excess, PAF has been implicated in the pathogenesis of several inflammation-related chronic disorders [57]; thus, its synthesis, distribution, and degradation are all strictly controlled, as would be predictable for such a potent molecule with a wide range of diverse actions.

3.1.2. The PAF/PAF-Receptor Signalling Pathways

PAF and PAF-like molecules act through their binding to a unique G-protein coupled seven transmembrane receptors, called the PAF-receptor (PAF-R) [87,88]. Species identity, differentiated by heterogeneity in linkage, degree of unsaturation, and carbon chain length of the alkyl or acyl chains at the sn-1 and sn-2 position, partially dictates signalling specificity by eliciting various signal transduction pathways following PAF-R activation [94,95]. The PAF-R is constitutively present on platelets, leukocytes, and endothelial cells, and further expression may be induced by appropriate stimuli. PAF-R is highly expressed by cells within the innate immune and cardiovascular systems [96], pointing to a role for PAF and PAF-like molecules as pleiotropic communicators in plasma [97].
Ligand binding (PAF and/or PAF-like molecules) to the PAF-R subsequently triggers multiple intracellular signalling pathways and gene-expressions, depending on the target cell and PAF levels (concentration) in blood or tissue [87,88,89,98] (Figure 2 (A1–A3)). For example, activation of the PAF-R signalling initiates (through a Gq-linked mechanism) PLCβ-mediated hydrolysis of PIP2 to produce IP3 and DAG, leading to transient elevation of cytosolic Ca2+ released from intracellular stores and activation of PKC. The rise in Ca2+ also activates cPLA2α, leading to the release of arachidonic acid (AA) and lysophosphatides, which can serve as substrates for further synthesis of eicosanoids and PAF, respectively. In addition, signalling through Gi-linked PAF-R inhibits the conversion of ATP to cAMP by adenylate cyclase, thus preventing the activation of PKA and related signalling events.
Figure 2. Role of PAF, PAF-R, and its related pathways in the inflammatory cascades and in the pathogenesis of inflammation-related chronic disorders; increased PAF levels by pro-inflammatory stimuli and binding of PAF on its receptor, PAF-R, on the membranes of several cell types can lead to intracellular cascades and a PAF cycle-related amplification of the initial stimuli (A) and in numerous cell responses according to each cell type (B), which can lead to endothelial dysfunction and the onset and progression of inflammation-related chronic diseases. A1. Several risk factors and related upstream pro-inflammatory stimuli trigger formation of PAF and PAF-like molecules (i.e., oxidised phospholipids) and expression of PAF-R. A2. Binding of PAF/PAF-like molecules on PAF-R promote several inflammation-related intracellular pathways; activation of the PAF-R signalling initiates (through a Gq-linked mechanism) PLCβ-mediated hydrolysis of PIP2 to produce IP3 and DAG, leading to transient elevation of cytosolic Ca2+ released from intracellular stores and activation of PKC. The rise in Ca2+ also activates cPLA, leading to the release of AA and lysophosphatides, which can serve as substrates for further synthesis of eicosanoids and PAF, respectively. Signalling through Gi-linked PAF-R inhibits the conversion of ATP to cAMP by adenylate cyclase, in this way preventing the activation of PKA and related anti-inflammatory signalling events. A3. Activation of the PAF/PAF-R intracellular pathways leads to the activation of cPLA2 and PAF biosynthetic enzymes (LPCAT) for further formation of PAF and other lipid second messengers, thus creating a PAF cycle and further amplification of the initial inflammatory stimuli, while expression of genes involved in inflammatory manifestations (such as genes of several cytokines, integrins, selectins, metalloproteinase, several enzymes for eicosanoids, and ROS, etc.) is also induced. The pathways inducing the PAF-CPT-related synthesis of PAF are not fully elucidated. B. Increased PAF levels at the site of inflammation and ligand binding (PAF and/or oxidised phospholipids binding) on PAF-R can promote a broad spectrum of PAF effects depending on the cell type and tissue, which is achieved through the production and release of various downstream mediators, such as PAF itself and several other mediators of inflammation such as eicosanoids, cytokines (i.e., TNF-α, IL-1α, IL-6, IL-8, INF-γ, etc.), growth factors (i.e., VEGF, IGF, TGF), ROS, and RNS, but also through the expression of selectins and integrins (i.e., ICAM, VCAM, P-Selectin, E-Selectin) in the membranes of activated cells. Thus, increased downstream mediators, PAF levels, and the subsequent further activation of the PAF/PAF-R pathways promotes the activation and aggregation of platelets and leukocytes, activation of endothelial cells, leukocyte adherence, motility, chemotaxis, invasion, migration, and subsequent endothelial dysfunction, thus stimulating the onset and development of inflammation-related chronic diseases and disorders. C. Microconstituents of several foods of the Mediterranean diet have been found to beneficially inhibit the PAF/PAF-R pathways and PAF synthesis towards homeostatic re-equilibration of PAF levels and activities [57]. PAF: platelet-activating factor; PAF-R: G-protein-coupled PAF-receptor; AC: adenylate cyclase; NF-kB: nuclear factor-kappa light-chain-enhancer of activated B cells; MAPK: mitogen activated protein kinase; ERK: extracellular signal-regulated kinases; Akt: protein kinase B; PI3K: phosphatidylinositol 3-kinase; mTOR: mechanistic target of rapamycin; DAG: diacylglycerol; AA: arachidonic acid; cPLA2: cytosolic phospholipase A2; PKC: protein kinase C; PKA: protein kinase A; LPCAT: acetyl-CoA: lyso-PAF acetyltransferases; PAF-CPT: dithiothreitol l-insensitive CDP-choline: 1-alkyl-2-acetyl-sn-glycerol cholinephosphotransferase; ATP: adenosine triphosphoric acid; cAMP: cyclic adenosine monophosphate; PLC: phospholipase C; MMP: metalloproteinase; COX: cyclooxygenase; iNOS: nitric oxide synthase; eNOS: endothelial nitric oxide synthase; ROS: reactive oxygen species; RNS: reactive nitrogen species; NADPO: nicotinamide-adenine dinucleotide phosphate oxidase; XO: xanthine oxidase; IL-6: interleukin-6; IL-1: interleukin-1; TNFα: tumour necrosis factor-α; ACS: acute coronary syndrome; VEGF: vascular endothelial growth factor; PL: phospholipids; CVD: cardiovascular diseases; CNS: central nervous system.
Signalling through other pathways is also amplified by the PAF/PAF-R pathway activation, since inhibition of PAF synthesis or PAF-R blockade significantly attenuates signalling through apparently unrelated pathways, suggesting a critical role for PAF/PAF-R action as a co-stimulatory signal. For example, many VEGF-directed effects on vascular endothelium require PAF synthesis [57]. Nevertheless, the activation of the PAF/PAF-R pathway further triggers the activation and aggregation of platelets and leukocytes and promotes leukocyte and platelet adherence, motility, chemotaxis, invasion, migration, ROS generation, and further PAF formation (Figure 2) [89,98].

3.1.3. PAF Levels Result from Enzymatic Biosynthesis, Non-Enzymatic Oxidative Synthesis, and Enzymatic Catabolism

Under normal circumstances, homeostatic levels of PAF present in plasma and biological tissue seem to be regulated by a balance of its biosynthetic and catabolic enzymatic pathways [57]. PAF is synthesised throughout the body by the specific stimulation of various cell types such as platelets, macrophages, monocytes, eosinophils, basophils, and endothelial cells. PAF is mostly produced in the blood, lungs, kidney, myocardium, brain, liver, skin, saliva, retina, uterus, and embryo [56,99,100]. Two enzymatic pathways by which PAF is biosynthesised in the body are the ‘remodelling’ and the ‘de novo’ pathways (Figure 3(A1)).
Figure 3. PAF levels result from enzymatic biosynthesis, non-enzymatic oxidative synthesis, and enzymatic catabolism, while bioactive microconstituents of the Med-diet beneficially affect these pathways. (A1) The enzymatic biosynthesis of PAF contributes to basal PAF levels or a periodic increase of PAF levels during normal inflammatory responses, while during unresolved and chronic inflammatory manifestations, the enzymatic biosynthesis of PAF is responsible for pathologically increased PAF levels through a continuous induction of the PAF cycle; (A2) Non-enzymatic synthesis of PAF occurs during oxidative stress, increasing ROS and RNS and inducing the synthesis of PAF and PAF-like molecules. When Ox-LDL is produced, PAF-like molecules mimic the activities of PAF. These pathways are not regulated enzymatically; (B) Catabolism of PAF is enzymatically regulated by PAF-AH. PAF catabolism is activated during both acute and chronic inflammatory manifestations and inactivates both PAF and PAF-like molecules; (C) Bioactive microconstituents present in foods of the Med-diet (i.e., polar lipids) have demonstrated beneficial outcomes by inducing homeostatic equilibration of PAF levels and activities through the Inhibition of the PAF/PAF-R pathways and modulation of the PAF anabolic and catabolic enzymes. PAF: platelet-activating factor; PAF-R: G-protein coupled PAF-receptor; PAF-CPT: dithiothreitol l-insensitive CDP-choline: 1-alkyl-2-acetyl-sn-glycerol cholinephosphotransferase; Lyso-PAF-ATs (LPCAT1, LPCAT2): acetyl-CoA: lyso-PAF acetyltransferases; cPLA2: cytoplasmic phospholipase A2; PAF-AH: PAF-acetylhydrolase; PC: Phosphatidylcholine; ROS: reactive oxygen species; RNS: reactive nitrogen species; LDL: low-density lipoprotein; Ox-LDL: oxidised-LDL; Med-diet: Mediterranean diet.
The remodelling enzymatic pathway of PAF biosynthesis involves remodelling of a membrane lipid constituent (a long-chain fatty acyl residue in sn-2 is replaced with an acetyl residue), and it has been proposed that this pathway is periodically involved in the acute pro-inflammatory production of PAF under activation of several cells during inflammation [101]. More specifically, the action of cytoplasmic phospholipase A2(PLA2) yields a precursor of PAF called lyso-PAF (1-O-alkyl-sn-glyceryl-3-phosphorylcholine), which is then acetylated by at least two isoforms of acetyl-CoA: lyso-PAF acetyltransferases, namely, LPCAT1 and LPCAT2 (lyso-PAF AT), leading to the formation of PAF [102]. LPCAT2 is highly expressed in inflammatory cells, and, depending upon the inflammatory stimulus used to activate the cells, PAF is produced within seconds, minutes, or hours following stimulation. In addition, PAF itself can act as an inflammatory signal, and the binding of PAF to its receptor on inflammatory cells can promote the very rapid (within 30 s) production of PAF; PAF-induced, protein kinase, Cα-mediated phosphorylation of LPCAT2 enhances enzymatic activity, leading to the vary rapid production of PAF. Thus, a PAF cycle can consistently induce increased PAF levels and subsequent inflammatory cascades (Figure 2 and Figure 3)
The de novo enzymatic pathway of PAF biosynthesis is similar but distinct to the biosynthesis of phosphatidylcholine, since a phosphocholine function is transferred to alkyl acetyl glycerol. This pathway has been initially reported as the pathway responsible for the constitutive production of PAF basal levels. A key step in this route is the conversion of 1-O-alkyl-2-sn-acetyl-glycerol to PAF by a specific dithiothreitol l-insensitive CDP-choline: 1-alkyl-2-acetyl-sn-glycerol cholinephosphotransferase (PAF-CPT) [57,81]. Interestingly, apart from the remodelling pathway, which is always activated in both acute and chronic inflammation, the key enzyme of the ‘de novo pathway, PAF-CPT, seems to be more active during chronic inflammatory manifestations, thus contributing to an increase of basal levels of PAF that seem to be related to the continuous activation of inflammatory cascades in the long-term during the development of inflammation-related chronic disorders [57,70,81]. Thus, the regulation of the biosynthetic pathways of PAF seems to be more complicated than was initially thought, while both PAF biosynthetic routes are correlated with well-established inflammatory and immunological biomarkers (i.e., several cytokines, viral load, CD-40L, etc.) in several cases [57,69,70,79,81,103,104].
Apart from its enzymatic biosynthetic pathways, PAF and PAF-like lipids can also be produced through non-enzymatic synthesis by oxidation of other lipids during oxidative stress [105,106]. The production of PAF and such PAF-like oxidised lipids usually occurs during inflammation and oxidative stress (Figure 3(A2)). Vice versa, PAF and PAF-like lipids can also stimulate the production of ROS and nitrogenous species such as reactive nitrogen species (RNS) during oxidative and nitrosative stress in inflammation-induced endothelial dysfunction and atherosclerosis [89].
The main catabolic enzyme that reduces PAF levels is PAF acetylhydrolase (PAF-AH), delicate phospholipase A2 that removes the acetate group from the PAF molecule and thus transforms PAF to its inactive form of lyso-PAF (Figure 3B) [107]. These enzymes, PAF-AH, are produced largely by hepatocytes and macrophages, and are widely distributed in human plasma, blood cells, and a variety of tissues. Subsequent research revealed that the PAF-AH family includes intracellular forms called PAF-AH I and PAF-AH II, as well as an extracellular third isoform [108]. PAF-AH, an extracellular isoform in plasma, is a member of the PLA2 superfamily of enzymes that is also known as lipoprotein-associated phospholipase A2 (Lp-PLA2), since it circulates in blood in association with plasma lipoprotein particles such as LDL and HDL, or the PLA2 group 7 (PLA2G7) [107,108,109,110]. Intracellular PAF-AH type I exists in the cytoplasm of many (probably all) types of mammalian cells and tissues [111]. Interestingly, the intracellular PAF-AH Type II that has no homology with PAF-AH I, but shares sequence similarity to plasma PAF-AH, was reported to act as a cellular Phospholipase A2 that hydrolyses oxidatively modulated or truncated phospholipids (with short length or oxidatively modified sn-2 acyl chains). It is thus suggested that PAF-AH (II) functions as an antioxidant phospholipase that plays a protective role also against oxidative stress [108,112].

3.2. The PAF Pathway and Metabolism in Chronic Diseases

Under normal conditions, plasma and tissue levels of PAF are tightly regulated by its metabolic pathways. However, production of PAF and PAF-like molecules can become elevated and/or dysregulated during extended periods of immune activation and chronic inflammation-related disorders by amplification of its synthesis, either through cascades activating its biosynthetic enzymes or through oxidative production of PAF, or usually by both [57,69,70,79,81,103,104,113]. PAF plays a major role in the physiopathology of inflammatory reactions and is produced and released in large quantities by inflammatory cells in response to specific stimuli, such as upstream regulators (IL-1, IL-6, TNF-α, Endothelin, oxidative stress, and PAF itself; Figure 2A) [57,78,89,114].
Increased PAF levels at the site of inflammation can activate several cell types through its receptor. This leads to the initiation of a broad spectrum of PAF effects depending on the cell type and tissue, which is achieved through the production and release of various downstream mediators, such as PAF itself and several other mediators of inflammation such as eicosanoids, cytokines (i.e., TNF-α, IL-1α, IL-6, IL-8, INF-γ, etc.), growth factors (i.e., VEGF, IGF, TGF), ROS, and RNS, but also through the expression of selectins and integrins (i.e., ICAM, VCAM, P-Selectin, E-Selectin) in the membranes of activated cells (Figure 2B) [57,58,78,89,113,114].
The interconnected crosstalk between PAF, pro-inflammatory upstream mediators that induce PAF production, and PAF-induced downstream mediators seems to be interrelated during inflammatory manifestations and inflammation-related chronic diseases. These pathways serve as one of the main junctions between many inflammatory cascades that ultimately lead to endothelium dysfunction and inflammation-related disorders such as atherosclerosis, CVD, renal disorders, cerebrovascular, central nervous system (CNS) disorders, metastatic angiogenesis during cancer, sepsis, and several other chronic disorders (Figure 2B) [57,58,78,89,113].

3.2.1. PAF in Atherosclerosis and CVD

Cardiovascular diseases (CVD) are the leading cause of death worldwide. It is estimated that 49 million people are now living with the disease in the European Union alone [115]. Atherosclerosis is a slow progressive disease in which lesions or plaques form in large and medium-sized arteries, consisting of necrotic cores, calcified regions, accumulated modified lipids, migrated smooth muscle cells (SMC), foam cells, endothelial cells, and several leukocyte subtypes. Monocytes, circulating blood precursors of tissue macrophages, and myeloid-derived DC influence plaque development following recruitment into the intima and differentiation to foam cells.
In contrast to the previous notions concerning the passive accumulation of lipids in macrophages during the formation of foam cells, it is now clear that there are more complex inflammatory mechanisms acting on monocytes, macrophages, platelets, several other leucocyte subtypes, and endothelial cells that seem to promote atherosclerosis via pro-inflammatory foam cell formation [66]. Persistent and unresolved inflammation at the vascular wall gives rise to inappropriate platelet and leukocyte recruitment at the endothelium. The inflammatory interplay and crosstalk between these cells and endothelial cells, facilitated by several inflammatory mediators, initiates the cascades that induce chronic inflammatory manifestations at the vascular wall, which counteracts the homeostatic inflammatory response, leading to endothelial dysfunction and initiation of proatherogenic events that lead to atherogenesis and atherosclerosis [116]. PAF is one of the main junctions between several inflammatory pathways (cytokines, oxidative stress, eicosanoids, etc.) and their interplay with cells participating in inflammation-related atherosclerosis. Therefore, PAF is implicated in all stages of atherosclerosis, from the initiation of atherogenesis all the way through to plaque formation, development, instability, and rupture [58,89,105,117].

The Pro-Inflammatory Crosstalk between PAF with Several Cells and the Endothelium Induces Early Pro-Atherogenic Phases of Endothelial Dysfunction

At early pro-atherogenic conditions, PAF is produced in several cells, such as platelets, leukocytes, and endothelial cells under pro-inflammatory stimuli and/or by the oxidation of lipoproteins. Thus, PAF can further propagate oxidative stress, through the oxidation of LDL and the reduction of NO bioavailability, but mostly by acting as a potent chemotactic factor for other human cells that exhibit its receptor on their membranes, such as monocytic and granulocytic leukocytes of the innate and adaptive immune system, endothelial cells, etc. Following these activations, a number of mediators are released by these activated cells (e.g., PAF itself, several cytokines, eicosanoids, ROS, RNS, and several enzymes), while adhesive molecules are expressed in their cell membranes (i.e., chemokines, selectins, and integrins, such as E-selectin, P-selectin, MCP1, ICAM-1, VCAM-1, etc.) that facilitate platelet-platelet, platelet-leukocyte, and platelet-leukocyte-endothelium aggregates and interplay [58,89]. The PAF pathway downstream products can further contribute to the propagation of atherosclerosis.
Molecules of the selectin family mediate interactions between platelets and leukocytes, with the endothelium allowing leukocytes and platelets to roll along the vascular endothelium wall. Platelet binding of the endothelium seems to precede the appearance of leukocytes in plaques and induces bidirectional expression of adhesion molecules and the production of monocyte attracting chemokines, such as PAF that plays a central role in cytokine-induced monocyte adherence to endothelium [58,89,117,118]. Activated platelets that adhere to the inflamed endothelium may enhance leukocyte recruitment, activation, and transmigration, thereby enhancing the inflammatory processes underlying atherosclerosis [119]. PAF and Leukotriene B4 (LTB4), derived by activated platelets, leukocytes or endothelium, but also thrombin (through PAF and LTB4 pathways), can propagate the activation of platelets and the subsequent activation and adhesion of leucocytes through the interplay of chemokines and their receptors [117]. An important aspect of this platelet-leucocyte interplay is the diversity of leukocytes recruited by vessel wall adherent platelets, such as the platelet-mediated recruitment of neutrophils, monocytes, DC, T-lymphocytes, B-lymphocytes, and NK-cells to endothelium [117].
In addition, platelets regulate neutrophil activation through the generation of PAF as a chemoattractant pro-inflammatory lipid [120]. Activated endothelial cells and platelets generate considerable amounts of PAF, which act cooperatively with other extracellular stimuli to induce full integrin activation and leukocyte arrest [58,89,120]. However, whether PAF mostly originates from activated platelets, endothelial cells or leukocytes are not well defined yet [120]. Independently of its origin, the presence of PAF activates through its PAF/PAF-R pathways expression of integrin molecules at cell membranes to promote firm adhesion between leukocytes, platelets, and vascular endothelium [117].
PAF, other vasoactive compounds, angiogenic compounds, and pro-inflammatory mediators, such as arachidonic acid metabolites, histamine, cytokines, chemokines, and proteolytic enzymes, can also be released by mast cells that accumulate in the human arterial intima and adventitia during atherosclerotic plaque progression, and thus aggravate atherogenesis [8]. Cytokines produced by mast cells may be activated by pro-inflammatory stimuli, including cytokines, hypercholesterolemia, and hyperglycaemia, and trigger the endothelial expression of adhesion molecules such as P-selectin, VCAM-1, and chemokines such as PAF that mediate the recruitment and adhesion of leukocytes [8].
Similar to other chemoattractants, PAF has been detected in circulation; however, this molecule is mostly cell membrane-associated and operates in a paracrine manner on the G-protein coupled receptors of neighbouring cells [58,89,120]. Thus, PAF is also a main player in juxtacrine signalling and adhesion of leukocytes to other cells, and has also been shown to regulate firm neutrophil adhesion on the surface of immobilised spread platelets [119,121]. The level of platelet stimulation impacts directly on neutrophil adhesion to platelets monolayer, upon which neutrophil activity is spatially regulated by PAF generation [58,89,120]. Platelets and activated neutrophils act jointly to induce expression of adhesion molecules, permeability changes, and limit the bioavailability of nitric oxide, altogether aggravating endothelial dysfunction and facilitating subsequent monocyte plaque recruitment [122].

The Inflammatory Crosstalk Between PAF and Several Cells at the Intima and Subintima Leads to the Induction of Plaque Development and Increased Plaque Growth and Expansion

In the aortic lumen, endothelial cells have been activated by the aforementioned PAF-implicated downstream manifestations, leading to increased endothelium permeability and endothelial dysfunction. Subsequent abnormal recruitment, migration, and infiltration of monocytes then take place in the intima and subintima. Within the intima, monocytes secrete lipoprotein-binding proteoglycans, resulting in increased accumulation of modified LDL, which sustains inflammation. In addition, once in the intima, differentiation factors such as the macrophage colony-stimulating factor (M-CSF) differentiate pro-inflammatory monocytes into inflammatory type macrophages that ingest modified lipoprotein to become foam cells [59,123].
Emerging evidence suggests that the role of monocytes and macrophages in atherosclerosis is not simply that of a passive acceptor of lipids [66]. Apart from their phagocytic roles, macrophages can also instruct or be instructed by other immune cells by producing various immune effector molecules and by acting as antigen-presenting cells (APC). Plaque-related macrophages can have many phenotypes and functions depending on the stage of the disease; several monocyte subtypes exist, and subsequently several pro-inflammatory and anti-inflammatory macrophage subtypes also exist, while macrophages can rapidly adapt their phenotype and consequently their function in response to changes of the microenvironment and intracellular signalling pathways [122]. After appropriate activation, macrophages can exhibit a pro-inflammatory phenotype that can further activate endothelial cells, which in turn triggers further blood monocyte recruitment [122,124]. Thus, upon activation, the pro-inflammatory subtype of macrophages and foam cells produce inflammatory cytokines and chemokines that enhance inflammation and further regulate monocyte and T cell infiltration [59,124].
Macrophages express a myriad of receptors including G-protein coupled receptors such as PAF-R, through which they scan their environment for activation or polarisation signals, e.g., cytokines, growth factors, oxidised phospholipids, etc., [59,124,125,126], while, when in the atherosclerotic plaque, macrophages are capable of releasing a large repertoire of pro-inflammatory cytokines according to their phenotype and depending on the plaque microenvironment, including IL-1, IL-6, IL-12, IL-15, IL-18, TNF family members, and PAF, as well as anti-inflammatory cytokines like IL-10 and TGF-β family members (TGF-β1, BMPs, GDFs) [58,59,124].
Several autacoid molecules of the microenvironment, such as PAF and its receptor, play a significant role in the pro-inflammatory activation of macrophages by oxidative stress and in the uptake of Ox-LDL by macrophages [125], since Ox-LDL contains inflammatory PAF-like oxidised phospholipids that mimic PAF and interact with these cells [105]. In addition, autacoids such as PAF and PAF-like molecules in Ox-LDL also play a significant role in the cytoskeletal reorganisation of these cells during differentiations [127], as macrophages engulf and retain large molecules such as Ox-LDL, oxidised phospholipids, and blood cells, which have also migrated into the intima and sub-intima. The macrophages become lipid-loaded foam cells through phagocytosis, scavenger-receptor mediated uptake, and pinocytosis; the macrophages become lipid-loaded foam cells [58]. The term ‘foam cells’ both reflects the microscopic appearance of these lipid-laden macrophages and denotes early fatty streak lesions [122]. This process is outlined in Figure 4.
Figure 4. A schematic of the key role of PAF in the onset, progression, and expansion of atherosclerotic plaques and their subsequent cardiovascular disorders. Atherosclerotic events take place in four discrete stages (IIaIV) as follows: (I) Under normal conditions, blood cells roll within the blood stream during physiological blood circulation. Leukocytes scavenge the endothelium by weak adhesion on it and after rolling, return to the blood stream. (IIa) Upstream pro-inflammatory stimuli (cytokines, PAF, etc.) induce PAF synthesis and expression of the PAF-R on the membranes of endothelial and blood cells. (IIb) Binding of PAF to its receptor on the membranes of these cells further induces the PAF cycle-related amplification of the initial inflammatory stimuli, which is achieved through the expression of inflammation-related genes and the subsequent production and release of various downstream mediators, such as PAF itself and several other mediators of inflammation including eicosanoids, cytokines, growth factors, further oxidative stress (ROS, RNS, Ox-LDL, and Ox-PL), and selectins and integrins in the membranes of activated endothelial cells and leukocytes. (III) If unresolved, the PAF cycle-related inflammatory activation of endothelial cells leads to tight adhesion of leukocytes on the activated endothelium and subsequent migration of these leukocytes and Ox-LDL to the subendothelium. There, the crosstalk of key-junction inflammatory mediators such as PAF within the developing plaque microenvironment, with a panel of inflammatory cells of both the innate and adaptive immune system, favours inflammatory phenotypes in these cells and perpetuates a continuous inflammatory milieu, leading to the differentiation of monocytes to macrophages, which engulf Ox-LDL and further transform to foam cells; thus, facilitating the onset, increase, and expansion of atherosclerotic plaque. (IV) Although plaques can grow to a sufficiently large size to compromise blood flow, most of their clinical complications are attributable to arterial occlusion due to plaque erosion or rupture. Vulnerable plaques are typically large, with a necrotic core covered by a thin fibrous cap, and they contain high levels of inflammatory immune cells. Gradually accumulating foam cells die in the intima due to inflammation-induced apoptosis, and when not promptly disposed of, become necrotic, progressively leading to the formation of a thrombogenic and pro-inflammatory necrotic core with cholesterol crystals. In addition, the thin layer of the fibrous cap easily ruptures due to PAF-related inflammatory and atherothrombotic stimuli. Thus, as the plaque continues to develop, it can become unstable and rupture, leading to major cardiovascular event. PAF: platelet-activating factor; PAF-R: G-protein coupled PAF-receptor; ROS: reactive oxygen species; RNS: reactive nitrogen species; Ox-LDL: oxidised LDL; Ox-PL: oxidised phospholipids; IL-6: interleukin-6; IL-1: interleukin-1; TNFα: tumor necrosis factor-α; VEGF: vascular endothelial growth factor.
The interplay of PAF with other APC such as DC is also implicated in several stages of atherosclerosis. Under atherosclerotic conditions, the role of DC is to take up atherosclerosis-specific antigens, which become locally activated, and migrate out of the plaque towards either local draining or distant lymph nodes, where they induce protective anti-inflammatory T cell activation and proliferation. However, apart from their role in directing different T and B cell subsets, not all their functions have been fully elucidated or understood. Nevertheless, impaired migration of DC to lymph nodes results from inhibitory signals generated by PAF or Ox-LDL that act as a PAF mimetic, thus suppressing immunologic priming. In contrast, normal DC migration and priming can be restored by HDL or HDL-associated PAF acetylhydrolase (PAF-AH), which mediates inactivation of PAF and oxidised LDL. In this context, HDL and PAF-AH maintain a normally functional DC compartment [128]. In addition, DC produce PAF that engage the PAF-R in DC membranes during maturation, and thus the capacity of DC to present antigens to lymphocytes is downregulated, due to the induction of IL-10 and the sustained and increased PGE2 synthesis mediated by the PAF-R. In contrast, PAF-R antagonists, by disrupting this suppressor pathway, increase DC function and could therefore be useful in increasing efficiency of vaccines and/or treatment [129]. The above PAF effects on DC perpetuate local inflammation, decrease the activation of anti-inflammatory T-lymphocytes, and thus further increase plaque growth.
Lymphocytes, particularly T-lymphocytes, are also recruited to the vessel wall by mechanisms such as monocyte recruitment; thus, they are present in atherosclerotic lesions in parallel with macrophages, but in lower amounts. CD4+ T cells (also called Th1 cells) express pro-atherogenic roles, whereas prominent Th2 (CD8+ T cells) and Treg responses seem to exhibit unclear and still controversial anti-inflammatory effects, resulting in a reduction of atherosclerosis and/or a more favourable plaque morphology in atherogenesis. PAF and other platelet-related inflammatory mediators, such as thromboxane A2, serotonin, and histamine, also display Th1 cell-regulatory effects towards the Th1 response that promotes the progression of atherosclerosis and diverse effects on Th2 response [130]. Activated platelets produce a significant amount of TxA2, which inhibits Th1 proliferation and cytokine production [131], while they also express PAF-R, and PAF can enhance Th1 cytokine production [130,132].
PAF can also promote differentiation of Th17 cells that are present in atherosclerotic lesions, which can induce cytokine production by these cells. Activated platelets and platelet thrombi create a unique microenvironment with counteracting mediators for Th17 polarisation by secreting substantial amount of PAF, TGFβ, and IL-1β [130]. However, the role of Th17 also remains controversial, as both atherogenic, as well as atheroprotective, effects have been reported [59]. Nevertheless, both PAF and Ox-LDL that mimic PAF and the PAF-R have the capacity to induce atherogenesis due to activation of T-cells and monocytes/macrophages [133]. These events lead to an expansion of atherosclerotic plaque burden and perpetuation of the pathogenic T-cell response.
Overall, there is intricate interplay and crosstalk between a panel of inflammatory cells of both the innate and adaptive immune system. When key-junction inflammatory mediators within the developing plaque microenvironment are increased, there is favour towards inflammatory phenotypes in these cells, which perpetuates a continuous inflammatory milieu, leading to further increase and expansion of the atherosclerotic plaque. Subsequently, the intimal thickness increases, and blood flow is eventually impaired. Gradually accumulating foam cells die in the intima through inflammation induced apoptosis. When these cells are not promptly disposed of they become necrotic, progressively leading to the formation of a thrombogenic and pro-inflammatory necrotic core containing cholesterol crystals [58].

The Overgrowth and Instability of Plaques and Subsequent Acute Cardiovascular Events

During plaque growth and expansion, SMC migrate from the media to the intima and proliferate, forming a fibrous cap from extracellular matrix deposition, where activated lymphocytes and calcium deposits are found. Although plaques can grow to a sufficiently large size to compromise blood flow, most of their clinical complications are attributable to arterial occlusion due to plaque erosion or rupture. Vulnerable plaques are typically large with a necrotic core covered by a thin fibrous cap and contain high levels of inflammatory immune cells [122]. The thin fibrous cap easily ruptures, as there are areas of the plaque where few SMC are present, and macrophages exist in abundance. This is because inflammatory cells cause the death of SMC, which are the main source of collagen that produce and maintain the fibrous cap. PAF is also implicated in the release of several proteases from leukocytes, such as elastase, that degrade the vessel’s extracellular matrix components of the intima, which may lead to plaque rupture [58]. As the plaque continues to develop it can become unstable and rupture, leading to a major cardiovascular event such as myocardial infarction, stroke, or congestive heart failure, depending on the location of the rupture.
Platelets are critical effectors in the development, progression, and resolution of the final stages of atherosclerosis, and plaque rupture, which is responsible for acute coronary disorders and stroke, not only due to their direct effects on the endothelium but also by acting as a ‘bridge’ for other cells within the vascular system [119,121]. Plaque rupture occurs under inflammatory cascades and atherothrombosis through an interplay of platelet-leukocyte aggregates. Upon vessel injury (i.e., plaque rupture), platelets readily adhere to damaged endothelium, and this binding event facilitates further activation and discharge of activating factors stored in platelet granules. Such platelet secretory components include membrane ligands and several chemokines such as PAF that play a role in further recruitment of leukocytes, additional platelets, or other blood cells to the vessel wall [121]. Platelet adhesion under conditions of high shear stress, which occurs in stenotic atherosclerotic arteries, is central to the development of arterial thrombosis. Therefore, precise control of platelet adhesion must occur to maintain blood fluidity and to prevent thrombotic complications [119].

Concluding Remarks on PAF in Atherosclerosis and CVD

The potent pro-inflammatory mediator, PAF, and its related PAF/PAF-R pathways are key-junctions of the inflammatory milieu during all stages of atherosclerosis and subsequent CVD. Some biochemical mechanisms involved include the pro-inflammatory induction of endothelial dysfunction, oxidative and nitrosative stress, increased platelet reactivity, recruitment/tight-adhesion, and trans-endothelial cell migration of inflammatory cells from the circulation, differentiation of pro-inflammatory monocytes to inflammatory macrophages, induction of macrophage uptake of Ox-LDL, foam cell formation, induction of plaque growth, plaque instability that leads to eventual plaque rupture, and subsequent cardiovascular events. Outcomes from multiple animal model experiments and several clinical studies have also outlined the crucial role of PAF in atherosclerosis due to its elevated levels and its inflammatory interplay and crosstalk with several cells in the pathogenesis of cardiovascular disorders. Clinical studies that have evaluated the role of PAF as a predictor of CVD have also been reviewed [89].
PAF-R antagonists have been tested with promising results [134,135,136,137,138,139,140], however the most prominent beneficial outcomes against atherosclerosis development and CVD were found when food-derived PAF inhibitors such as those present in the foods of the Med-diet. These molecules beneficially inhibit PAF activities and modulate its metabolism towards homeostatic PAF levels [103,140,141,142,143,144,145]. Many of these components are present in olive oil, wine, fish, and dairy products (Table 1). Interestingly, the administration of polar lipid extracts from fish or olive oil to hypercholesterolemic rabbits lead to the regression of atherosclerotic plaques [103,142,143,144,145]. These results clearly outline that targeting inflammation and its key-junctions such as the PAF/PAF-R pathways and PAF metabolism provide beneficial outcomes against atherosclerosis and CVD, even without targeting hypercholesterolaemia. Thus, by targeting inflammation, the cause of these disorders through non-toxic approaches such as the Med-diet and by not targeting single risk factors (such as hypercholesterolaemia) seems to provide preventive and protective beneficial results against atherosclerosis and CVD.
Table 1. Studies on the beneficial impact of microconstituents from foods of the Mediterranean diet, such as polar lipids and vitamins, towards inflammation-related disorders, through their effects on the PAF pathways and metabolism.

3.2.2. The Role of PAF in Cancer and Metastatic Angiogenesis

Cancer is the second leading cause of death in developed countries. New blood vessel formation penetrating solid tumours seems to be required for their growth and metastasis. Production of PAF and overexpression of PAF-R are implicated in the tumour-endothelium interplay during cancer growth, invasion, and metastasis in several types of cancer [57,114,169,170,171]. PAF and PAF-R are also involved in tumour growth that is associated with immunosuppression [172,173,174], while the crosstalk between PAF/PAF-R pathways and growth factors receptors pathways suggests a potentially important signalling link between inflammatory and growth factor signalling in cancer [173,174,175].
It is not yet fully understood whether the initial levels of PAF in the tumour microenvironment originate from migrated inflammatory circulating cells as a response, or by activated endothelial cells in the vessels neighbouring tumours, or by the tumour cells themselves. However, there is correlation between the malignancy of cancer cells and PAF production and PAF-R expression. It seems that the production and accumulation of PAF in the tumour microenvironment originates from the coexistence of two or of all these procedures and/or by the inactivation of PAF-AH. For example, the PAF basic biosynthetic enzymes such as LPCAT1 (an isoform of lyso-PAF-AT) are overexpressed in several cancer cells and correlated with cellular invasiveness and migration. Therefore, LPCAT1 seems to contribute to tumour growth and metastasis in these types of cancer [176,177]. Moreover, endothelial cell PAF production results in enhanced inflammatory cell recruitment, while endothelial accumulation of PAF by PAF production and inactivation of PAF-AH plays also a role in cancer cell migration to distal locations [178]. In addition cigarette smoking, a classic risk factor for several cancers, contributes to metastatic disease via production of PAF and PAF-like molecules in lung tumours [174], while smoking related inhibition of breast cancer cell PAF-AH results in PAF accumulation and a subsequent increase in cell motility, tumour growth, and metastasis [178,179].
Independently of the origin, the presence of PAF in the microenvironment of tumours activates cancer cells and endothelial cells to further amplify the production of both PAF, angiogenic factors, and increased expression of their receptors on cell-membranes, including the PAF-receptor, leading to a PAF cycle and further induction of several PAF/PAF-R related cascades. These cascades, in coordination with angiogenic cytokines and growth factors, enhance the initial signal and induce morphological alterations and cellular activities such as growth proliferation and motility, expression of adhesion molecules, extracellular matrix breakdown, migration, and endothelium reorder that leads to the formation of distinct neoplastic vessels in the tumour microenvironment [57]. All of the above result in the onset and development of tumour-induced angiogenesis and metastasis [57]. For example, in pancreatic cancer, PAF overexpression leads to cell proliferation and tumourigenesis through the PAF/PAF-R related MAPK signalling pathway, causing neoplasia [170]. In addition, PAF and PAF-like molecules are in part transported by tumour-derived extracellular vesicles, which play an important role in intercellular communication through PAF-R expressed by a variety of microenvironmental cells and endothelial cells, favouring metastasis [172]. Apart from its crucial role in cancer metastasis, which has been extensively reviewed [57], recent outcomes have demonstrated that PAF is also implicated in immunosuppression-related cancer induced by UV-irradiation, in which UV-induced production of PAF and PAF-like molecules and the expression of PAF-R activates systemic immune suppression and delays DNA repair [93].
On the other hand, PAF and its receptor have been beneficially associated with cell survival during radiotherapy or chemotherapy, by proliferative signals on the surviving cells that are induced by apoptotic cells. These signals take place through mechanisms dependent on the activation of PAF-R related pathways of NF-kB, such as up-regulation of anti-apoptotic factors and decrease of the cytotoxic effect of chemotherapeutic agents, thereby contributing to cell survival [172]. However, recent studies have demonstrated that during cancer therapies (i.e., irradiation of carcinoma cells or chemotherapy), PAF-R ligands can be generated that further aggravate immune suppression and, when bound on the PAF-R of cancer cells, induce anti-apoptotic factors that protect the tumor cells from death induced by these treatments, while the combination of radiotherapy with PAF-R antagonists could be a promising strategy for cancer treatment [173,180].
In several cancer types, PAF through the NF-kB pathway controls the expression of genes that take part in processes that lead to metastatic angiogenesis on one hand, while on the other hand it results in apoptosis of cancer cells, during the immune response and haematopoiesis during chemotherapies and radiotherapies [57]. It seems that PAF is a unique growth regulator with apparently diverse functions; PAF, like NF-kB, seems to promote distinct biological processes, and these dual actions of PAF may relate to the point of action in the cell cycle [57]. The timing, space, and quantity of its production play a significant role in the malignant or beneficial direction of its effects. Understanding how conditions and factors that control timing, location of activity, and the quantity of PAF levels and how these relate to the metabolic enzymes of PAF is of great importance.
PAF-R antagonists have exhibited promising results in vitro and in vivo as anti-angiogenic molecules in several cancer cells and tumours, but also by reducing persistent pain during cancers [57,114,181,182]. In addition, the combination of chemotherapy and classic PAF-R antagonists seems to reduce the tumour volume and cause higher tumour regression when compared to each treatment alone [172,180]. Recently, synthetic glycosylated alkyl-phospholipids that act as PAF agonists and antagonists have exhibited promising antiproliferative outcomes and are now regarded as and can be new class of anti-tumour drugs [183]. However, apart from using synthetic or classic PAF antagonists, a dietary profile rich in bioactive molecules and food-derived PAF inhibitors such as those present in foods of the Mediterranean diet seems to provide beneficial preventive and protective effects against development, growth, and metastatic manifestations of cancer cells by inhibiting PAF activities and/or modulating its metabolism towards homeostatic PAF levels [57,137] (Table 1).

3.2.3. The Role of PAF in Glomerulosclerosis and Renal Disorders

PAF has been characterised as one of the main inflammatory mediators implicated in renal pathophysiology [184]. Production of PAF in the kidney can potentially be attributed to infiltrating inflammatory cells, but mostly to resident renal cells such as the mesangial cells of glomeruli [81,185]. Once synthesised, PAF does not accumulate in renal cells, but it is secreted and thus affects mesangial cells, neighbouring podocytes, and other infiltrating cells by binding to its receptor and inducing PAF/PAF-R pathways. In the kidney, PAF-R mRNA is ubiquitously expressed, and a gradient of its expression levels seems to exist; it is higher in the renal cortex, lesser in the outer medulla, and much lesser in the inner medulla, while within the nephron, the glomerulus demonstrates the highest PAF-R expression [78]. PAF infusion affects renal hemodynamics and glomerular permeability, resulting in changes in filtration rate and proteinuria [78].
Apart from the physiological effects of PAF, its increased levels and overexpression of PAF-R in kidney are involved in the pathogenesis and progression of renal damage and acute renal failure [78,184,186,187]. Thus, PAF is implicated in antibody- and complement-mediated glomerular injury, in antithymocyte antibody-induced glomerular damage and other experimental models of immune renal damage, and in patients with lupus nephritis and IgA nephropathy [78]. PAF participates in the development of kidney graft dysfunction, namely, transplant rejection chronic transplant nephropathy and immunosuppressive drug-mediated nephrotoxicity [78]. PAF is also implicated in drug-related renal damage of different causes, such as cyclosporin A, glycerol, gentamicin, and cisplatin [78].
However, the most important role of PAF in renal dysfunction is its implication in the onset and progression of glomerulosclerosis, a renal disorder that shares common features with atherosclerosis and can lead to organ failure. Crosstalk between several renal cells of the glomeruli, such as the mesangial cells and podocytes, takes place during this disorder and the PAF/PAF-R pathways form key junctions during all steps. It has been proposed that PAF might be one of the chemokines released by mesangial cells that mediate their communication with podocytes. PAF enhances its own receptor expression [188], through which it stimulates multiple downstream inflammatory signalling pathways, mostly in mesangial cells, leading to the release of AA metabolites and subsequent prostanoid and thromboxane generation, leukocyte recruitment, mesangial cell contraction, intracellular lipid accumulation, and transforming growth factor (TGF)-β mediated upregulation of extracellular matrix production. All of these molecular events potentially culminate in the development of glomerulosclerosis and fibrosis, which are key feature of progressive renal disease, regardless of the primary cause [78,188,189]. In addition, PAF promotes inflammatory infiltration of the glomerulus, since it functions as a chemoattractant, and it increases adhesion of polymorphonuclear leukocytes and monocytes to mesangial cells through integrins [78]. PAF increases the expression of the LDL-receptor and scavenger receptors in mesangial cells, and thus causes an increased uptake of lipids and their accumulation in mesangial cells, leading to the formation of foam cells, which is an important stage of glomerulosclerosis and a key factor that participates in the initiation and progression of lipid-mediated renal injury [78,188].
Several PAF-R antagonists have been used in several of the aforementioned renal disorders with promising results [78,137]. However, apart from using classic PAF antagonists, recent results have highlighted the protective role of a dietary profile rich in bioactive molecules, antioxidants, and food-derived PAF inhibitors such as those present in the Mediterranean diet through beneficially inhibiting PAF activities and/or modulating its metabolism towards homeostatic PAF levels [80,81] (Table 1). In addition, the use of vitamin D or vitamin-D analogues as treatment in haemodialysis patients has also exhibited similar beneficial effects, since such a treatment strongly inhibits PAF and thrombin activities, affects PAF metabolism towards equilibrating PAF levels, and reduces circulating levels of IL-8, IL-1β, and TNF-α [79]. As reducing dietary cholesterol levels may be ineffective, such outcomes have further supported the notion of using full-fat products such as dairy products and non-low-fat products, since the full-fat dairy products exhibit higher bioavailability of high-value nutrients such as bioactive polar lipids and vitamin D, which both possess strong anti-inflammatory and protective properties [3].

3.2.4. The Role of PAF in Cerebrovascular and Central Nervous System Disorders

PAF and the PAF/PAF-R pathways are also present in the CNS, where they exhibit a number of diverse physiological and pathological functions. PAF is synthesised in neuronal cells throughout the CNS, while these cells also express the PAF-R [190,191]. When present at normal concentrations, PAF is a modulator of many CNS processes, ranging from long-term potentiation to neuronal differentiation [113,191]. Excessive levels of PAF appear to play an important role in neuronal cell injury and in various inflammation-related CNS pathological conditions, such as neuroinflammatory cascades implicated in depression and neurodegeneration, Alzheimer’s disease, stroke, ischemia-reperfusion injury, spinal cord injury, multiple sclerosis, Parkinson’s disease, neuropathic pain, epilepsy, central malaria, meningitis, depression, cognitive deficits, and HIV-induced neurotoxicity [190,191,192]. Increased PAF synthesis through the PAF/PAF-R pathways can cause a severe inflammatory response, reduction of biological membrane integrity, ROS and RNS formation, expression and release of cytokines, alterations in blood–brain barrier permeability and the permeability of blood vessel walls, activation and recruitment of inflammatory and immune cells, secretion of cell-specific proteins, induction of cell apoptosis through specific signalling pathways, and other pathological responses [113,190,191,192,193]. PAF accumulation in CNS diseases exacerbates the inflammatory response and pathological consequences, while application of PAF inhibitors or PAF-R antagonists significantly reduces inflammation, protects cells, and improves the recovery of neural functions by blocking the PAF pathway [191,192,194]. Several PAF inhibitors of natural origin have also exhibited beneficial outcomes in CNS disorders, especially ginkgolides that are derived from Ginkgo biloba [137,195]. However, further studies are required to establish the mechanisms surrounding how a healthy diet can improve systemic inflammation associated with the PAF pathway and CNS disorders.

3.2.5. The Role of PAF in Allergies and Asthma

Anaphylaxis is defined as a severe, life-threatening, systemic or general, immediate reaction of hypersensitivity, with repeatable symptoms caused by a dose of stimulus that is well tolerated by healthy persons [196,197]. Recently, PAF and PAF-AH have been reported as clinically valuable biomarkers of anaphylaxis [196], since PAF produced and released by mast cells, basophils, neutrophils, eosinophils, fibroblasts, platelets, endothelial cells, and even cardiac muscle cells plays an important role in anaphylaxis and several other allergic reactions, from allergic rhinitis to asthmatic complications [67,196,197,198,199,200,201,202]. Eosinophils, mast cells, and basophils are implicated in allergies, and they have the capacity to influence each other’s functions through a crosstalk, where other mediators such as PAF are also implicated [198,199,200,203]. PAF increases the production of eicosanoids, ROS, cytokines, growth factors, platelet-derived growth factor (PDGF), RANTES, and degranulation of eosinophils, while it also acts as a chemoattractant for these cells, and, via integrins, it increases their adhesion to vascular endothelium. Mast cells not only produce PAF, but they can also be activated by it through the PAF/PAF-R pathways. Thus, exposure of mast cells to PAF leads to the induction of specific functions in these cells such as degranulation of their granules via neuropeptides and PAF-dependent release of histamine. In fact, the greater the levels of PAF in mast cells microenvironment, the more enhanced the release of histamine. At the same time, PAF-activated myocardial mast cells locally release factors responsible for cardiac dysfunction and hypotension that occur in severe anaphylactic reactions [197,200].
Increased levels of PAF correlate with the severity of allergic systemic reactions. Thus, PAF has been found to be involved in several allergic and anaphylactic reactions and shock, in inflammation of bronchi and bronchial asthma and in asthmatic patients’ bronchoconstriction, in mucus hypersecretion, in allergic rhinitis, and in urticaria pathogenesis [200]. Several studies have shown that PAF can enhance obstructive changes of bronchi by stimulation of allergic inflammation of the respiratory tract epithelium, while PAF can also increase the permeability of skin’s capillaries and induces the development of wheals, flare, and inflammatory reactions in the skin through its interactions and crosstalk of the aforementioned inflammatory cells involved in these pathological conditions [200].
The protective role of PAF-AH in reducing PAF levels is usually highly diminished through allergic reactions [196,200], while administration of recombinant PAF-AH in animal models exhibited protective results and reduced mortality due to anaphylactic reactions [196], implying that modulation of PAF metabolism towards homeostatic PAF levels can also provide beneficial outcomes in these disorders too. In addition, specific PAF-R inhibitors have been used in several allergy-related disorders [137], and even specific anti-allergic drugs were designed and are currently used according to their anti-PAF effects [204,205], while combination of PAF inhibitors with other therapies such as antihistamines provided better outcomes [137,198,199,201]. However, further studies are required to establish the potential of a healthy diet to improve systemic inflammation associated with the PAF pathway and allergic complications.

3.2.6. The Role of PAF in Chronic Infections and Inflammation-Associated Comorbidities

Inflammatory and immune responses are central to protecting against most infectious agents. However, the pathogenesis and tissue damage after infection are not usually related to the direct action microorganisms and of their replication, but instead to altered immune and inflammatory responses triggered following contact with the pathogen. Many diseases develop as an adverse consequence of an imbalanced inflammatory response; thus, chronic and unresolved infections are usually accompanied by chronic and unresolved inflammatory manifestations and comorbidities [206]. PAF and PAF-like molecules are implicated in inflammatory manifestations occurring in several infections [206,207], such as HIV [69,70,71,72,73,74,85], leishmaniosis [208], periodontitis [75,76,77], or even in sepsis [67,209]. The relationship between increased PAF levels, overexpression of PAF-R, and the PAF/PAF-R pathways with several other mediators such as cytokines and inflammatory cells leads to the progression of such diseases and their related comorbidities.
The most common coexistent diseases associated with chronic infections are CVD, CNS disorders, and tumour malignancies, which are usually promoted by increased levels of PAF and PAF-related continuous and unresolved inflammation [57,67,68,69,70,71,72,73,74,75,76,77,85,208]. In addition, PAF seems to act in synergy with infectious agents to initiate and propagate the disease process, i.e., viral load in HIV-infected patients was positively correlated with PAF synthesis and levels, while viral products such as Tat-protein induce PAF synthesis and PAF-related HIV-induced non-AIDS comorbidities, such as CVD, Kaposi sarcoma, neurodegeneration, and dementia [69,70,71,72,73,74].
Several PAF inhibitors have been used in infectious diseases with promising results, mostly in relation to their deterioration of the PAF-related chronic inflammatory manifestations [67,71,74,85,137,207,209,210,211]. However, in the case of severe sepsis, clinical trials using recombinant human PAF-AH or PAF-R antagonists failed to reduce the mortality of severe septic patients, although a substantial reduction in organ dysfunction was achieved [206]. Drugs administrated in such infectious pathologies have also been thoroughly screened for potential dual actions against both the infectious agent and PAF activities and synthesis. Several antiretrovirals and their combinations in highly active antiretroviral therapy have been found to exhibit beneficial outcomes in HIV infected patients through their capabilities to inhibit PAF activities and to influence PAF metabolism towards reduction of PAF levels in vitro and in vivo, while similar outcomes have also been found for several antibiotics [68,69,71,73]. Nevertheless, inhibition of PAF activities and modulation of PAF metabolism towards homeostatic PAF levels seem to be useful therapeutic targets with which to interfere with inflammatory damage that follows an infection, and thus they may reduce the risk of several comorbidities in infectious disorders. Although there are several studies published on the importance of a healthy diet for infection prevention, further studies are required to establish the potential role of healthy eating to improve systemic inflammation associated with the PAF pathway and related complications during chronic infections.

3.2.7. The Role of PAF in Various Inflammation-Related Chronic Diseases

PAF has also played a role in several other inflammation-related chronic diseases and their related comorbidities, including types I and type II diabetes mellitus [212,213,214], acute pancreatitis [215,216], liver injury [217], inflammation-related intestine tissue dysfunction such as necrotising enterocolitis [218,219], inflammatory ocular diseases [220], vascular dysfunction during acute lung injury [221], and autoimmune disorders, such as rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease, and Crohn’s disease [222,223,224].
Several PAF inhibitors have been used in these inflammation-related diseases with promising results [137,216,217,222,225,226]. These effects were mostly due to the deterioration of PAF-related chronic inflammatory manifestations present in these disorders. However, apart from using synthetic or classic PAF antagonists, a dietary profile rich in bioactive molecules, antioxidants, and food-derived PAF inhibitors such as those present in foods of the Mediterranean diet may provide beneficial preventive and protective effects against these diseases too, through beneficially inhibiting PAF activities and/or modulating its metabolism towards homeostatic PAF levels. For example, the consumption of components of the Med-diet or a traditional Greek Mediterranean diet can reduce PAF-related inflammatory outcomes such as platelet activity in patients suffering from type II diabetes mellitus and metabolic syndrome, but also in healthy subjects. This has been attributed to the presence of PAF inhibitors among other possible effects, and these effects can occur over a short period of time [227,228,229]. In addition, the use of probiotics has exhibited beneficial effects against necrotising enterocolitis [218]; this is unsurprising, as fermented dairy products, which are also components of the Med-diet, are rich in PAF inhibitors and have also exhibited beneficial outcomes in several inflammation-related intestine dysfunctions [3].

3.3. Targeting the PAF Pathways and Metabolism – Beneficial Outcomes of the Mediterranean Diet

Common junctions in the mechanistic crosstalk of inflammatory mediators, signalling pathways, and cellular interactions that occur during chronic and unresolved inflammatory manifestations seem to be promising therapeutic targets for the prevention and treatment of inflammation-related chronic diseases. Drug-based therapeutic interventions targeting inflammatory mediators such as cytokines (i.e., by using specific antibodies against pro-inflammatory cytokines and their receptors) and eicosanoids (i.e., by using specific inhibitors of COX-1 and COX-2) have also been proposed, and relative trials such as CANTOS are still in progress. However, such approaches can sometimes provide undesirable effects and may leave the individual immunocompromised and at a greater risk of infections, since disruption of the physiological balance seems to be a risky strategy [230,231], which is clearly behind the multifaceted effects of such mediators.
On the other hand, since PAF and its related inflammatory cascades belong to the most vital joint mechanistic pathways of inflammation-related chronic disorders, the exploration of possible therapeutic approaches targeting PAF and its related pathways may provide better outcomes. Focus initially was given to the PAF/PAF-R interaction, thus inhibiting the exacerbation of the complex PAF inflammatory pathways [89,134,135,136,137]. There are several agonists of synthetic and natural origin [57,89,134,135,136,137,140,232], which can competitively or noncompetitively displace PAF from its binding sites on PAF-R and thus directly inhibit the PAF/PAF-R related pathways and PAF activities. Furthermore, other similar molecules can indirectly affect the PAF/PAF-R pathways by affecting the up-stream and/or downstream microenvironment of PAF-R, lipid, rafts, and other related cellular receptors.
Even though such specific PAF antagonists for the PAF/PAF-R pathway have exhibited promising results, the most prominent beneficial effects have been derived from polar lipids and polar lipid extracts derived from several foods, particularly from foods in the Med-diet (Figure 1B and Table 1) [56,57,80,81,103,142,146,147,148,149,150,151,152,153,154,155,156,157,158,159,162,163,164,165,233,234]. These Med-diet polar lipids exhibit in vitro and in vivo anti-inflammatory activities through either directly or indirectly inhibiting the PAF/PAF-R pathways and thus PAF activities, but also by downregulating its levels through modulating the activities of key metabolic enzymes of PAF by either upregulation of the PAF catabolic enzymes and/or the downregulation of the basic PAF biosynthetic enzymes (Figure 2C and Figure 3C, and Table 1) [57,80,81,103,146,148].
Notably, the uptake of such dietary polar lipids seems to beneficially affect the functionality of HDL lipoproteins, especially in atherosclerotic conditions. HDL has been characterised as the ‘good’ cholesterol, since not only does it remove excess cholesterol from the blood stream and from atherosclerotic plaques, but it has also exhibited anti-inflammatory and antioxidative properties through a plethora of cardioprotective enzymes bonded in HDL, including the aforementioned PAF-AH enzyme activity, which is the main catabolic enzyme of PAF [110]. These HDL-associated activities contribute to the maintenance of endothelial cell homeostasis, which protects the cardiovascular system [235]. Plasma PAF-AH is also found in atherosclerotic lesions, since it comigrates there along with the lipoproteins (i.e., LDL), where it is incorporated. Plasma PAF-AH (Lp-PLA2) mainly plays an anti-inflammatory role in leukocyte/platelet/endothelium activation and seems to suppress atherogenic changes in plasma lipoproteins (such as LDL) by promoting the catabolism of PAF and by removing oxidised phospholipids present in Ox-LDL, including oxidised phospholipids that mimic PAF, which are generated by oxidative modifications of lipoproteins such as LDL during pro-atherogenic and atherosclerotic events [107,109,110]. Thus, during inflammatory cascades that cause increased PAF levels, this isoform of PAF-AH (LpPLA2) seems to be activated as a homeostatic mechanism to downregulate these events by downregulating the levels of PAF and oxidised phospholipids as a terminator signal [236]. However, during persistent and prolonged inflammatory cascades and persistent oxidation of plasma lipoproteins, plasma PAF-AH is progressively inactivated (plasma PAF-AH is incorporated mainly in LDL) and loses its capacity to protect against the pro-inflammatory actions of PAF and PAF-like lipids [98]. Because of that, but also because of the activities of the oxidised sub products of PAF-AH actions in LDL oxidised phospholipids, the use of plasma PAF-AH as an atherogenic biomarker and therapeutic target has been debated [109,236].
Nevertheless, HDL and its enzymes, including PAF-AH, seem to protect against these manifestations. The focus has been placed on increasing HDL levels as one of the main goals of dietary interventions and drug administration for cardioprotection [110]. Dietary intake of bioactive polar lipids, particularly those baring ω-3 PUFAs, increase HDL levels and the incorporation of such anti-inflammatory and antioxidant dietary polar lipids to HDL, thus providing an additional protective mechanism by increasing plasma PAF-AH activity and protecting the HDL enzymes (such as PAF-AH) from oxidation-related inactivation. This is in agreement with the beneficial in vitro and in vivo effects of several dietary polar lipids, especially on PAF metabolism and HDL biofunctionality [56].
PAF can generate ROS, and oxidative stress is a key feature of the atherothrombotic processes in the pathology of CVD. Therefore, it is important to recognise that foods of the Med-diet such as fruit and vegetables are high in chemical constituents, many of which are regarded as powerful antioxidants, such as vitamins A, C, and E [237]. Despite positive findings from in vitro studies, clinical trials have consistently failed to show a benefit for the use of antioxidants, as associations between plasma concentrations of antioxidant vitamins and protection against CVD have proved elusive, and large interventional trials have failed to conclusively show any benefit of their administration [238,239,240,241]. Despite this, the European prospective investigation into cancer and nutrition (EPIC) Norfolk study found that increased plasma concentrations of vitamin C were inversely associated with CVD-related mortality and all-cause mortality. The study found that this increase was due to increased intake of fruit and vegetables, which led to an approximate 20% decrease in CVD mortality [242]. However, a meta-analysis has shown that vitamin C supplementation did not reduce cardiovascular events; thus, the antioxidant effects of vitamin C were not responsible for the beneficial effects of increased consumption of fruit and vegetables [243]. A large-scale, 20-year study found that diets rich in vitamin C were associated with a lower incidence of stroke, but no coronary heart disease in the elderly [244]. Considering these findings, it may be the case that vitamin C may not be the active agent that induced the effects witnessed in the Norfolk study, but although eating fruit and vegetables will increase plasma vitamin C levels, the effects observed may be through other fruit- and vegetable-derived nutrients [241], or synergism between multiple nutrients that affect different mechanisms including inflammation through the mechanisms of the PAF pathways [245].
The bioavailability of vitamins, phenolic compounds, and other antioxidants is often cited as the main reason that in vitro and ex vivo studies do not seem to agree [237]. For instance, some antioxidants such as phenolic compounds are effectively screened out by the gut of rapidly metabolised and excreted [246]. Plasma concentrations of phenolic compounds are typically in the nanomolar range—too low to have a direct impact on antioxidant capacity [241]. However, many of these antioxidant molecules do seem to possess beneficial effects upon consumption, including the idea that they induce indirect antioxidant activity by acting as a mild toxin to stimulate a general xenobiotic and/or an antioxidant response [237]. Further research is required to elucidate the effects of certain biomolecules against ROS and inflammatory pathways.
Overall, the protective outcomes of the adoption of Med-diet towards chronic diseases seem to be associated with the pleiotropic beneficial effects of its bioactive microconstituents that are not only limited to increasing plasma-HDL levels, functionality, and providing better stability against oxidation, but mainly on their effects on the levels, activities, and metabolism of key-inflammatory mediators such as PAF [56,57]. However, more in vivo results are needed in several chronic disorders and their inflammation-related manifestations in order to further support these findings. In particular, clinical trials implementing dietary patterns such as the Med-diet that are rich in bioactive polar lipids interacting with the PAF/PAF-R pathways and metabolism are required to gain further insight into the role of PAF in chronic diseases.

4. Conclusions

In this review, we clarify the roles of risk factors, such as plasma cholesterol and the importance of causative agents for chronic diseases, namely chronic and unresolved inflammation and its manifestations. Instead of cholesterol, targeting and treatment of inflammation will lead to lower side effects in chronic disorders. The overall outcomes and the extensive paradigms of the beneficial effects of the Mediterranean diet against the inflammatory milieu, without any reported side effects so far, have radically shifted attention away from the lipid-centric hypotheses and the subsequent trends for targeting cholesterol towards more effective approaches against inflammation, which is the causative factors of chronic diseases.
Therefore, the causative role of inflammation in the onset and progression of several chronic disorders is summarised with respect to the role of PAF and its related inflammatory cascades, which seem to serve as common junctions of the inflammatory milieu. The coexistence of several risk factors seems to upstream pro-inflammatory stimuli (i.e., cytokines, oxidative stress, PAF itself, etc.), leading to increased levels of PAF that, through the PAF/PAF-R pathways, attenuate the initial signal, while downstream inflammatory cascades, in combination with inactivation of homeostatic mechanisms such as PAF catabolism, can result in chronic and unresolved inflammatory manifestations and related chronic disorders.
Common junctions, such as PAF and its related inflammatory pathways, seem to be promising therapeutic targets for the prevention and treatment of the onset and progression of inflammation-related chronic diseases, particularly CVD. Implementation of healthy lifestyle choices based on appropriate dietary interventions and exercise have exhibited beneficial outcomes and health benefits, without noticeable side effects. Adoption of dietary patterns such as the Med-diet provides bioactive food microconstituents with pleiotropic beneficial effects that are not limited to decreasing co-absorption of cholesterol and increasing plasma HDL levels and functionality, but mainly by providing better stability against oxidation and inflammation. Therefore, microconstituents such as polar lipids and vitamins present in foods of the Med-diet beneficially affect the levels, activities, and metabolism of key inflammatory mediators implicated in chronic diseases, including the PAF pathway, towards reducing inflammation and acquiring homeostasis, which can lead to reduced risk of inflammation-related chronic disorders.
Nature has provided us with a wide range of dietary weapons, which, if appropriately combined in dietary patterns such as the Med-diet, can beneficially contribute to improving our quality of life, health, and life expectancy by equilibrating the inflammatory milieu to normal levels and thus preventively reducing the risk of inflammation-related chronic disorders. Let us not forget the words of Hippocrates of Kos (460-377 BC), who is universally recognised as the father of modern medicine: “Let food be thy medicine and medicine be thy food”.

Author Contributions

A.T, R.L., and I.Z. contributed equally to the drafting of the manuscript.


The authors acknowledge the financial support of Enterprise Ireland (study grant references: IP-2016-0488Y; IP-2017-0596-Y; and IP-2017-0508-Y), the Department of Biological Sciences, and the Faculty of Science and Engineering at the University of Limerick, Ireland.

Conflicts of Interest

The authors declare no conflict of interest.


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WEEKLY HEALTH UPDATE Week of: Monday May 14, 2018


Courtesy of:

John H. Keefe III, D.C.

(918) 663-1111


IN THE NEWS: Why Most People Need Vitamin B12 Supplementation According to the U.S. Department of Agriculture, nearly 40 percent of the U.S. population have marginal vitamin B12 status and 9 percent are deficient. Vitamin B12 insufficiency and deficiency increase your risk of serious health problems, many of which mimic more serious neurological diseases and can easily lead to misdiagnosis and improper treatment. B12 is required for many vital biological functions, including production of adrenal hormones, metabolizing fat, carbs and folate, formation of red blood cells, iron absorption, nervous system function, cognitive health and much more. B12 deficiency can even affect a woman’s Pap test, which screens for cervical cancer. Low B12 can affect the appearance of cervical cells, which can result in a false positive. Animal foods have become a questionable source of B12 thanks to modern farming practices, and many experts now believe most people really need to take a B12 supplement to ensure healthy B12 status.

Dr. Keefe, Keefe Clinic. Tulsa Chiropractor, pain, natural health care.

WELLNESS: Natural Ways To Ease Nasal Allergies 1. Use A Natural Nasal Spray A growing number of studies suggest that xlear/xylitol nasal spray may be more effective at treating and preventing allergy symptoms than standard nasal sprays. 2. Essential Oils Many essential oils have anti-inflammatory properties, which can help reduce irritation and inflammation in your nasal passages. Favorite way to get these benefits is by diffusing a couple drops each of lemon, lavender, and peppermint essential oils to a diffuser. 3. Change Your Air Filter Your HVAC system has a filter that helps to trap dust, dirt, pollen, pet dander, and other allergens. Call Keefe Clinic and order a filter through us, it lasts a lifetime with proper cleaning. 4. Wear Sunglasses When you do go outside during the springtime (or whenever you’re suffering from seasonal allergies), wear sunglasses. Your shades can provide a barrier that may help keep pollen and other allergens out of your eyes, which can help reduce your symptoms. 5. Exercise Indoors Exercising is important, but doing it outside when you’re suffering from seasonal allergies is only going to make things worse. 6. Eat Probiotics Probiotic foods are packed with good bacteria, and those good bacteria can be very beneficial. Not only do they aid in digestion, but recent studies suggest they may even help reduce allergy symptoms too. This link is still being studied, but increasing your consumption of probiotic foods like yogurt, sauerkraut, and kimchi certainly can’t hurt!  7. Keep Pets Off Beds As much as you may love to snuggle with your pets, this can do more harm than good where seasonal allergies are concerned. If your pets go outside during the day, they can get pollen trapped in their fur. If they transfer that pollen into your bed, it will likely turn you into an itchy, sneezy mess while you sleep. So fight the urge to snuggle in bed with your pets, at least until your seasonal allergies have subsided for the year! 8. Eat Local Honey Another natural remedy that may be worth trying is eating a small amount of local honey (meaning honey produced locally in your area) every day. Some people believe that because local honey contains local pollen, that eating the honey will help your body develop an immunity to it. At Keefe Clinic we have an allergy mix that contains the pollens for this area. Very effective.

 CHIROPRACTIC: Carpal tunnel syndrome Symptoms of carpal tunnel syndrome may include: Numbness, tingling, burning, and pain—primarily in the thumb and index, middle, and ring fingers, Occasional shock-like sensations that radiate to the thumb and index, middle, and ring fingers, Pain or tingling that may travel up the forearm toward the shoulder, Weakness and clumsiness in the hand—this may make it difficult to perform fine movements such as buttoning your clothes, Dropping things—due to weakness, numbness, or a loss of proprioception (awareness of where your hand is in space). In most cases, the symptoms of carpal tunnel syndrome begin gradually—without a specific injury. There is a connective tissue tunnel within the wrist that nerves pass through to get to the fingers sometimes this area can swell and sometimes there is damage to the connective tissue itself. This is a fairly good success rate with chiropractic care which saves the need for surgery that might just trigger other surgeries because of the surgical trauma to the area. The nerves that pass through the carpal tunnel come from the neck and go through the shoulder and elbow on the way to the fingers. Misalignments in any of these areas can set you up for carpal tunnel syndrome. If you or someone you know has symptoms like these we can help. Call for an appointment today.

 FUNNY BONE: Light travels faster than sound. This is why some people appear bright until you hear them speak.@@Never argue with stupid people, they will drag you down to their level and then beat you with experience. Mark Twain@@The difference between stupidity and genius is that genius has its limits. Albert Einstein@@Have you ever noticed that someone driving slower than you is an idiot, and someone going faster than you is a maniac? George Carlin@@ I was having dinner with Garry Kasporov (world chess champion) and there was a check tablecloth. It took him two hours to pass me the salt.@@A minister who was very fond of pure, hot horseradish always kept a bottle of it on his dining room table. Once, at dinner, he offered some to a guest, who took a big spoonful. The guest let out a huge gasp. When he was finally able to speak, he choked out, “I’ve heard many ministers preach hellfire, but you are the first one I’ve met who passes out a sample of it.”

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The truth about soy and cancer




A High Intake of Soy Is Directly Related To A Low Incidence of Breast Cancer

The relationship between soy intake and cancer incidence is referred to as an inverse correlation. An inverse correlation means when one factor is high (soy intake) the other factor is low (breast cancer incidence). These patterns have been observed when researchers examine soy intake and breast cancer incidence in various countries around the world.

For example, in Asia, soy intake is very high, and the breast cancer incidence is very low. In contrast, in North American and Europe, soy intake is very low and breast cancer incidence is high. This inverse correlation between soy intake and breast cancer has been ruled out as a genetic one because when Asian women relocate to the U.S. their daughters and granddaughters acquire the same cancer incidence as other Americans.

What Are The Health Benefits Of Soy Foods?

These are some of the proposed health benefits of soy, which Dr. Hilakivi-Clarke outlined. All of which, she points out, remain controversial:

  • Prevention of breast cancer and recurrence
  • Promotion of cardiovascular health
  • Prevention of osteoporosis
  • Prevention of menopausal symptoms
  • Cognitive benefits

Why Is There Fear That Soy Increases Breast Cancer?

As I mentioned, genistein is one of the phytoestrogens (isoflavones) found in soy foods. The chemical structure of genistein is similar to ovarian estradiol that women produce naturally. Studies with human breast cancer cells (in culture or in nude mice) show that as concentrations of genistein are increased, the growth of human breast cancer cells also increase. This is why for years cancer patients and survivors (and the general population) were told to avoid soy foods. There was a fear that soy would increase breast cancer, despite studies showing low rates of breast cancer in Asian women who eat large amounts of soy. The good news is that in recent years, soy is no longer feared and studies have shown that it could actually be a benefit for those concerned about cancer. (The moral of the story is if you are a research mouse that has been injected with human breast cancer cells don’t eat soy, but if you’re human soy will protect you. With that said some people are allergic to soy.)

Dr. Keefe, Keefe Clinic. Tulsa Chiropractor, pain, natural health care.

High Intake In America is Very Low Intake in Asia

Observational human studies have been done to better understand soy. An observational study observes what happens when women eat their usual diets. This is different from intervention studies in which women would be randomly assigned to either a high soy or low soy diet (studies like this have not been done). The observational human studies have shown that soy intake reduces the risk of breast cancer by about 30%. In the Asian observational studies, a high intake of soy was over 20 mg per day (low intake is 5 mg per day). In Western woman, high intake of soy is only 0.8 mg per day or more (and low intake is less than 0.5 mg per day). Not surprisingly, there is no effect of ‘high’ soy intake in American women…and you can see why! American women have very low soy intake (only 0.8 mg per day, which well below the ‘low’ intake in Asian women of 5 mg per day).

Soy Consumed Throughout Life

As we see in the studies described above, the amount of soy consumed can help to explain the difference in breast cancer incidence between Asian women and American women. The other variable to consider is the time in life when soy is consumed. In Asian cuisine, soy is introduced to the diet of young children and they continue to consume soy throughout their lives. In contrast to this, women in the western world tend to introduce soy into their diet only late in life—usually when they are trying to treat their menopausal symptoms with food.

Soy Intake, Breast Cancer Patients and Survival

The observational studies give us information about incidence of breast cancer, but what about survival from breast cancer? After I looked at several studies that examined this relationship, the overall finding is that soy food intake after breast cancer diagnosis does not have a significant effect on survival. Although, one of the studies did show a reduced mortality with high intake of soy foods. The studies did agree though that there is no negative effect, in other words, there was not a reduction in survival when the patient consumed soy.

Breast Cancer Recurrence and Soy Food Intake

What about recurrence of breast cancer, does soy intake make a difference?

In this case, there is a benefit. The higher the intake of soy after a breast cancer diagnosis, the lower the risk of recurrence. This relationship was true for both Asian and Western women. However, it was pointed out by Dr. Hilakivi-Clarke the women were consuming soy before they got breast cancer.

If I Didn’t Consume Soy Before My Breast Cancer Diagnosis, Should I Start Now?

This is a common question of many western woman confronted with a breast cancer diagnosis. This question has not been investigated, so it isn’t known what the effect would be.

Dr Keefe, Keefe Clinic, Natural Health Care, Tulsa Chiropractor, Diet, Pain,

How Does Soy Impact My Immune System?

Genistein, one of the isoflavones in soy, has been shown to have a positive impact on the immune system. It can enhance both cytotoxic T cells and Natural Killer cells. Cytotoxic T cells and Natural Killer cells are immune cells that can attack cancer. Genistein has been shown to inhibit IL-6 and TNF alpha, which are known to promote cancer cell growth. Genistein is also anti-inflammatory. Its anti-inflammatory property is protective against cancer as inflammation can drive the cancer process.

Soy During Cancer Treatment

Chemotherapy and radiation can create inflammation. This inflammation can have negative effects by impairing the effect of the treatment. The genistein in soy foods can prevent therapy-induced inflammation and stimulate anti-tumor activity. The overall effect of genistein can be an improved response to the cancer therapy.

Genistein Needs A Functioning Immune System To Fight Cancer

In order for genistein to have beneficial effects, an immune system is required. This can explain why studies that use only human breast cancer cells (in culture or in nude mice) showed that soy increased the cancer cell growth. A nude mouse doesn’t have a functioning immune system, neither do the isolated cancer cell cultures. So, genistein is not directly helping to fight cancer cells. The benefit from soy (genistein) comes from how it supports our immune systems.

What Should I Do as a Cancer Thriver?

Based on the information in the NCI presentation, I would recommend that you continue to include whole traditional soy foods in your diet. This would include edamame, soybeans, tofu, soymilk (made from whole soy beans) miso and tempeh among others.

How Much Soy Should I Eat?

Dr. Hilakivi-Clarke recommends 2-3 servings per day of soy foods. No studies have been done yet to shown whether fermented or non-fermented is better. Also no information on the benefit of beginning soy foods after a breast cancer diagnosis have been published. But based on the many benefits of genistein on the immune system, I would suggest that even if soy wasn’t part of your diet before your cancer, it could be a benefit. But until further research is done, this will remain an educated recommendation on my part.

Examples of Healthy Servings of Soy Foods

  1. 3 oz of tempeh—tempeh is fermented tofu and it is popular in Indonesian cuisine. If you aren’t familiar with it, I encourage you to buy a block and slice it, marinate it in an Asian dressing and grill it on your sandwich grill. It’s great in sandwiches and salads!
  2. Organic Tofu Cutlets—extra firm tofu can be sliced about ¼ inch thick and prepared like a cutlet of meat. It can be dipped in scrambled egg, then a bread crumb/ground flax seed herb mixture and pan-fried.
  3. Soy Beverage—this can be used in place of dairy. I suggest that you read the label closely to make sure you are getting an unsweetened version made from whole soy beans and not soy protein concentrate.



WEEKLY HEALTH UPDATE Week of: Monday April 30, 2018


Courtesy of:

John H. Keefe III, D.C.

(918) 663-1111


IN THE NEWS: YALE SCIENTISTS IDENTIFY CAUSE OF AUTOIMMUNE DISEASES AND HOW TO SUPPRESS THEM Autoimmune diseases, such as lupus, may be caused by bacteria in the small intestines that travel to other parts of the body, a new study from Yale has revealed. The study also found that these diseases can be suppressed or even prevented with an antibiotic or vaccine specifically designed to destroy these bacteria. Researchers analyzed Enterococcus gallinarum, a type of bacteria that typically lives in the gut but has also been found in other areas of the body. Using mice, the team observed how the presence of E. gallinarum in organs outside the gut led to inflammation and antibody production. The team then repeated this on human models by taking tissue samples from the livers of healthy volunteers and contaminating them with E. gallinarum. The same autoimmune response was observed. At the time, the researchers couldn’t confirm how the bacteria travel from the gut to other organs in patients with autoimmune diseases, but they suspect an impaired gut barrier may be to blame. Dr. Martin Kriegel, the senior study author, suspects that the bacteria may travel from the gut to other parts of the body, such as the lymph nodes, after entering the bloodstream via this impaired barrier. “We found signs of an impaired gut barrier in patients and detected DNA of the same bacterium as found in mice within the liver tissue of these autoimmune patients,” Kriegel, an adjunct assistant professor at the Yale School of Medicine at the time of this study, told Newsweek. NOTE: Dysbiosis is a condition where abnormal organisms live in the gut. Probiotics help control this. Leaky gut can be corrected through nutritional therapy.

 WELLNESS: WHAT ARE PROBIOTICS? Probiotics are live bacteria and yeasts that are good for your health, especially your digestive system. We usually think of these as germs that cause diseases. But your body is full of bacteria, both good and bad. Probiotics are often called “good” or “helpful” bacteria because they help keep your gut healthy. You can find probiotics in supplements and some foods, like yogurt. Doctors often suggest them to help with digestive problems. Your good gut bacteria is also responsible for: Producing vitamin B12, butyrate and vitamin K2-Crowding out bad microbes-Creating enzymes that destroy harmful bacteria-Stimulating secretion of IgA and regulatory T-cells, which support immune function. Probiotics have been in our systems from the moment we were born. When a newborn is in the birth canal of the mother during delivery, the baby is exposed to the bacteria of his or her mother for the first time. This event starts a chain of events inside the baby’s GI tract, and the infant’s GI tract starts to produce good bacteria. NOTE: antibiotics, certain chemicals in processed foods and drink can disrupt the healthy bacteria in your gut. Be extremely cautious about the use of antibiotics they are not as safe as you been led to believe. Cultured/fermented foods help keep your friendly bacteria healthy, eat wisely.

CHIROPRACTIC: CHIROPRACTIC ENHANCES IMMUNITY-Chiropractic patients for over a hundred years have indicated when they get chiropractic care they have less illness including colds and flu’s etc. several years ago a researcher studying chiropractic patients said that there immune function was 200% more effective than the average person on the street. There are a growing number of research papers that indicate just that. Chiropractic is a smart choice for your families health.—Chiropractic and the Neuroimmune ConnectionAri Cohn, DC. Journal of Vertebral Subluxation Research ~ September 30, 2008 ~ Pages 1-5. Enhanced Phagocytic Cell Respiratory Burst Induced by Spinal Manipulation: Potential Role of Substance P Brennan PC, Kokjohn K, Kaltinger CJ, Lohr GE, Glendening C, Hondras MA, McGregor M, Triano JJ    J Manipulative Physiol Ther 1991;   14 (7) Sep:   399-408 Enhanced Neutrophil Respiratory Burst as a Biological Marker for Manipulation Forces: Duration of the Effect and Association with Substance P and Tumor Necrosis Factor Brennan PC, Triano JJ, McGregor M, Kokjohn K, Hondras MA, Brennan DC   J Manipulative Physiol Ther 1992;   15 (2) Feb:   83-89 Spinal Manipulative Therapy Reduces Inflammatory Cytokines but Not Substance P Production in Normal Subjects This work was originally funded by the Consortial Center of Chiropractic Research (CCCR) J Manipulative Physiol Ther 2006 (Jan);   29 (1):   14–21 Changes in Health Measures in HIV+ Chiropractic Patients Lisa A. Caputo, DC   This work is in progress under a grant from the Consortial Center for Chiropractic Research and the National Institutes of Health (NIH) National Center for Complementary and Alternative Medicine (NCCAM)

 FUNNY BONE: I’m really good friends with 25 letters of the alphabet… I don’t know Y@@Why don’t ants get sick? Because they have little anty-bodies.@@ My name is Fin, which means it’s very hard for me to end emails without sounding pretentious.@@I was watching the London Marathon and saw one runner dressed as a chicken and another runner dressed as an egg. I thought: ‘This could be interesting’.@@ You can’t lose a homing pigeon. If your homing pigeon doesn’t come back, then what you’ve lost is a pigeon.@@ I could tell my parents hated me, my bath toys were a toaster and a radio. Rodney Dangerfield


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WEEKLY HEALTH UPDATE Week of: Monday April 23, 2018


Courtesy of:

John H. Keefe III, D.C.

(918) 663-1111

Dr. Keefe, Keefe Clinic. Tulsa Chiropractor, pain, natural health care.


IN THE NEWS: Rare Gene That Confers Drug Resistance Between Bacteria Now Found in 27 States At present, 23,000 Americans die each year from drug-resistant infections; estimates suggest that by 2050 the global death toll from antibiotic-resistant disease will reach 10 million per year. One significant driver of antibiotic-resistant bacteria is the routine use of antibiotics in agriculture. Another major contributor to and source of drug-resistant infections is hospitals. One particularly troublesome multidrug-resistant bacteria that is gaining ground is carbapenem-resistant enterobacteriaceae (CRE), which produces an enzyme that breaks down antibiotics. Tests conducted on nearly 5,780 antibiotic-resistant bacterial samples collected from hospitals and nursing homes found 1 in 4 contained genes known to confer drug resistance, and 221 contained a particularly rare drug-resistance gene that confers a very high level of resistance. The 221 samples came from 27 different states, which shows this new drug-resistance gene has already spread far and wide. The gene was found in samples of pneumonia, bloodstream infections and urinary tract infections. NOTE: There are multiple safe and effective natural treatments for infections, try a natural approach first then consider a drug like antibiotics only if necessary.

WELLNESS: Pantothenic Acid: A Crucial Vitamin for Optimal Health What Is Pantothenic Acid? The popularity of pantothenic acid or vitamin B5 pales in comparison to that of the other B vitamins, probably because it’s easily obtained from a well-balanced diet, so a deficiency of it is quite rare. Being a lesser-known vitamin does not take away from its worth, though. Pantothenic acid is still essential for your health, as it helps perform a number of functions that sustain life itself, including: Breaking down fats and carbohydrates for energy-Producing red blood cells-Manufacturing sex and stress-related hormones-Synthesizing cholesterol. As with other forms of vitamin B, pantothenic acid is not stored in the body because it’s water-soluble. The excess pantothenic acid that your body did not use will be flushed out through your urine, which means that you have to obtain it from your food every day. While a deficiency in vitamin B5 rarely occurs, it’s still entirely possible, especially if you have dietary restrictions that may keep you from eating foods rich in this nutrient. Pantothenic acid is sensitive to heat and humidity, so consuming processed foods that have been subjected to high-temperature manufacturing methods may not be enough to replenish your body’s level of this vitamin. Pantothenic acid performs vital functions that may help keep your overall well-being in optimal condition. One of these functions is its ability to support the synthesis of hormones in the adrenal glands, which may help you cope with stressful situations, hence why it’s also known as the “anti-stress” vitamin.

Dr Keefe, Natural Health care, pain, Tulsa chiropractor,

CONDITION OF THE WEEK: SLEEP DISORDER-Myth 1: Getting just one hour less sleep per night won’t affect your daytime functioning.You may not be noticeably sleepy during the day, but losing even one hour of sleep can affect your ability to think properly and respond quickly. It also compromises your cardiovascular health, energy balance, and ability to fight infections. Myth 2: Your body adjusts quickly to different sleep schedules. Most people can reset their biological clock, but only by appropriately timed cues—and even then, by one or two hours per day at best. Consequently, it can take more than a week to adjust after traveling across several time zones or switching to the night shift. Myth 3: Extra sleep at night can cure you of problems with excessive daytime fatigue. The quantity of sleep you get is important, sure, but it’s the quality of your sleep that you really have to pay attention to. Some people sleep eight or nine hours a night but don’t feel well rested when they wake up because the quality of their sleep is poor. Myth 4: You can make up for lost sleep during the week by sleeping more on the weekends. Although this sleeping pattern will help relieve part of a sleep debt, it will not completely make up for the lack of sleep. Furthermore, sleeping later on the weekends can affect your sleep-wake cycle so that it is much harder to go to sleep at the right time on Sunday nights and get up early on Monday mornings. You may be sleep deprived if you…Need an alarm clock in order to wake up on time-Rely on the snooze button-Have a hard time getting out of bed in the morning-Feel sluggish in the afternoon-Get sleepy in meetings, lectures, or warm rooms-Get drowsy after heavy meals or when driving-Need to nap to get through the day-Fall asleep while watching TV or relaxing in the evening-Feel the need to sleep in on weekends-Fall asleep within five minutes of going to bed. NOTE: Chiropractic and nutritional therapy are extremely effective for sleep problems, ask about it on your next appointment.

FUNNY BONES: Father: “Son, you were adopted.” Son: “What?! I knew it! I want to meet my biological parents!” Father: “We are your biological parents. Now pack up, the new ones will pick you up in 20 minutes.”@@In a bakery: Man to the shop assistant: “I’ll have that thing there, please.” Shop assistant: “Cupcake?” Man: “OK, Cupcake, I’ll have that thing there, please.”@@ “Hey dad how was your weekend?” – “Light, dark, light, dark, Monday.”@@ A jellyfish has existed as a species for 500 million years, surviving just fine without a brain. That gives hope to quite a few people.

WEEKLY HEALTH UPDATE Week of: Monday April 16, 2018


Courtesy of:

John H. Keefe III, D.C.

(918) 663-1111


IN THE NEWS:  TOXINS HIDDEN IN YOUR HOUSE Did you know that the regular use of cleaning products can have as much impact on your lungs as smoking a pack of cigarettes a day? The American Thoracic Society’s American Journal of Respiratory and Critical Care Medicine recently reported that scientists at Norway’s University of Bergen tracked 6,000 people, with an average age of 34 at the time of enrollment in the study, who used cleaning products over a period of twenty years. They found that lung function decline in women, who regularly used cleaning products, was equivalent over the period to those with a 20-cigarette daily smoking habit. That’s a pack a day. And these cleaning substances have the added threat of fueling the most prevalent type of Alzheimer’s, Inhalational Alzheimer’s. NOTE: the health food store has several safe alternatives to help clean your house, clothes and yourself. Buyer beware.

 WELLNESS:  HERBS FOR STRESS AND WELLNESS Your adrenal glands secrete more than 50 hormones, including aldosterone (which helps regulate your blood pressure), cortisol and adrenaline, the latter two of which can become overactivated by stress. Exposure to chronic inflammation or long-term illness can result in hypothalamic-pituitary-adrenal (HPA) axis dysfunction, triggering symptoms associated with “adrenal fatigue”. Adaptogenic herbs can be useful if you’re struggling with persistent stress. Four of the most well-recognized adaptogens for adrenal support are ashwagandha, rhodiola, ginseng (Asian and Siberian) and tulsi. Ashwagandha helps your body adapt to stress by balancing your immune system, metabolism and hormonal systems. The root contains the highest concentration of active ingredients that modulate hormones, including thyroid hormone, estrogen, progesterone and testosterone. Rhodiola has been shown to be particularly beneficial for your nervous system. It has antidepressant and antianxiety benefits, and has been shown to reduce symptoms of burnout associated with work stress.

Dr. Keefe, Keefe Clinic. Tulsa Chiropractor, pain, natural health care.

CHIROPRACTIC: CHIROPRACTIC AND DNA REPAIR Can regular Chiropractic care affect you on a genetic level? The answer is yes. But how? DNA is the molecule of life. It contains our genes which make us what we are. DNA makes up our chromosomes which are held in the nucleus of our cells. DNA is very fragile and susceptible to damage from environmental stresses. It is estimated that our cells experience anywhere from 1,000 to 1,000,000 incidences of DNA damage PER DAY. If this DNA damage is left and not repaired, our DNA sequences cannot be read or will not be read properly. This will result in abnormal cell function or expression. Three things can the occur; senescence, which means the cells stop dividing, cell death and/or tumor growth. All three are not good things as they lead to poor health and premature aging. Going through life, we experience physical, chemical, and emotional dis-stress. These stresses affect the function of the nervous system. The investigators hypothesized that these disturbances in nerve function could affect oxidative stress and DNA repair on a cellular level. Oxidative stress, metabolically generating free radicals, is now a broadly accepted theory of how we age and develop disease. Oxidative stress results in DNA damage, and inhibits DNA repair. The good news is that our cells are equipped with numerous enzymes (too many to list) whose job it is to continually repair this DNA damage. This DNA repair can be measured through blood tests that measure serum Thiol levels. The serum Thiol level is an indicator of the level of DNA repair. The higher serum Thiol, the more DNA repair and the better your health and aging. In a landmark study published in the Journal of Vertebral Subluxation Research, chiropractors collaborating with researchers at the University of Lund found that chiropractic care could influence basic physiological processes affecting oxidative stress and DNA repair.  These findings offer a scientific explanation for the positive health benefits reported by patients receiving chiropractic care. The researchers measured serum thiol levels in 25 patients under short term chiropractic care, and 21 patients under long term chiropractic care. The results were compared to those of a non-chiropractic control group of 30 subjects.  Long-term chiropractic care of two or more years was shown to re-establish a normal physiological state independent of age, sex, or nutritional supplements. Symptom-free or primary wellness subjects under chiropractic care demonstrated higher mean serum thiol levels than patients with active disease, and produced some values that were higher than normal wellness values in non-chiropractic subjects. Serum thiols are primary antioxidants, and serve as a measure of human health status . The test provides a surrogate estimate of DNA repair enzyme activity, which has been shown to correlate with lifespan and aging. After you have completed corrective Chiropractic care you need Wellness care to maximize your health potentials.  Ask about Wellness care.


FUNNY BONE: If people say they just love the smell of books, I always want to pull them aside and ask, To be clear, do you know how reading works?@@ Been reading up on the thesaurus lately because a mind is a terrible thing to garbage.@@ “Poor Old fool,” thought the well-dressed gentleman as he watched an old man fish in a puddle outside a pub. So he invited the old man inside for a drink. As they sipped their whiskeys, the gentleman thought he’d humor the old man and asked, “So how many have you caught today?”The old man replied, “You’re the eighth.”@@ I think it’s pretty cool how the Chinese made a language entirely out of tattoos.@@ Just before the final exam in my college finance class, a less-than-stellar student approached me. “Can you tell me what grade I would need to get on the exam to pass the course?” he asked. I gave him the bad news. “The exam is worth 100 points. You would need 113 points to earn a D.” “OK,” he said. “And how many points would I need to get a C?”


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WEEKLY HEALTH UPDATE Week of: Monday April 9, 2018


Courtesy of:

John H. Keefe III, D.C.

(918) 663-1111

IN THE NEWS: ‘Wi-Fried’ — Is Wireless Technology Dooming a Generation to Ill Health? According to many experts, chronic, heavy exposure to wireless radiation is likely having severe repercussions for our health, especially that of children, who are now being exposed even before birth. While a number of different devices contribute to the overall radiation burden, those kept closest to your body on a regular basis, such as your cellphone, are of greatest concern. Your body has natural electromagnetic fields (EMFs), as many of your bodily processes involve the transmission of electric signals, and external interference can disrupt those signals. Inside every cell in your body are mitochondria, the power plants of your cell, and they are adversely impacted by EMFs, resulting in mitochondrial and cellular dysfunction. Two organs most vulnerable to outside RF interference are your heart and brain. Both also have the highest density of voltage gated calcium channels, which are inappropriately activated by EMFs, thereby causing most of the damage associated with EMF exposure. NOTE: Certain cell phone covers can help block some of this radiation.

WELLNESS: Increasing negative ions in the air through crystal salt lamps. Since the beginning of recorded history, the beneficial properties of salt have been well known and documented. Early civilizations greatly valued salt, and used it as a trading currency as well as a preservative for food. For years, many European countries have used salt mines and hot salt springs to promote a sense of rejuvenation. People rest and rejuvenate in salt mines and caves (in spa-like ambiance in many cases), for periods of time to help aid their mood and overall sense of calm. Why are the salt mines so beneficial? Quite simply… the very dry, fresh environment of a salt mine is key. The solution involves pure Himalayan crystal salt… the same type of salt I offer in my office… the same type of salt Himalayan miners go deep into the earth to uncover. Ever breathe and experience the air around a thunderous waterfall… on a serene mountain top… at a pulsating seashore… or after a wild thunderstorm? I’m sure you have. Remember how fresh the air felt and how easy it was for you to breathe? Well, what you experienced was likely the result of negative ions. The rush of negative ions helps neutralize and balance the positive ions. Many published articles and scientific studies report how negative ions in the air can have positive effects. One demonstration of that is how they potentially increase the growth rate of certain plants. In most of these studies, sophisticated negative ion generators were used in controlled group environments – not something you can readily recreate in your own home. Something else you can do to help offset excessive frequency vibrations while you’re actually using an electronic device is to use beautiful decorative lamps, called crystal salt lamps.

CONDITION OF THE WEEK: ALLERGIES AND CHIROPRACTIC– We are entering allergy season and for those of you who have allergies this can be a tough time of the year. Though just remember some people suffer from allergies year round. Allergies really are not caused by pollens they are caused by an inappropriate response to pollens by your immune system. Sometimes adjustments alone can reestablish normal immune function and eliminate allergies. For others we need to work at desensitizing the person from the pollens. Air filtration systems along with negative ion generation can give you a safe place in your house. We offer a filter to put in your return air vent that takes out 97% of what’s floating in the air including pollens. So this allergy filter along with an air purification system with negative ions can greatly reduce your exposure to pollens in your house. Most people understand the concept of allergy shots where you introduce a diluted form of the pollen over time to develop immunity. We have used oral drops over the past 30+ years and found them superior to allergy shots. Recently American allergists have started moving to the oral drops as well. With the regular use of these drops you desensitize your body’s response to the pollen and in time you can be allergy free. There is also electronic device called the Elmag that can electronically balance your immune system while you’re wearing it and many people become symptom-free. Lately it’s been difficult to access the elmag but it can be ordered through the Internet from a European country. The allergy drops that we offer are safe for all ages and the dosage is 10 drops under the tongue three times a day, for a stronger effect five drops six times a day can be more effective. Sometimes adrenal support, vitamin C or other nutrients are important for the immune system to respond. If you suffer from allergies don’t suppress your immune system with antihistamines seek a natural approach that’s both safe and effective.

FUNNY BONE: Here are some Stephen Wright quotes:  Someone sent me a postcard picture of the earth. On the back it said, “Wish you were here.@” Last night I played a blank tape at full blast. The mime next door went nuts. @If a person with multiple personalities threatens suicide, is that considered a hostage situation?@ Just think how much deeper the ocean would be if sponges didn’t live there. @If a cow laughed, would milk come out her nose? @Whatever happened to preparations A through G? @Why do they sterilize needles for lethal injections? @Why don’t they just make mouse-flavored cat food?@ If it’s tourist season, why can’t we shoot them? @So, what’s the speed of dark?@ Isn’t Disney World a people trap operated by a mouse? @How come abbreviated is such a long word? @If olive oil comes from olives, where does baby oil come from? @I went for a walk last night and my kids asked me how long I’d be gone. I said, “The whole time.” @How come you don’t ever hear about gruntled employees? And who has been dis-ing them anyhow? @After eating, do amphibians need to wait an hour before getting OUT of the water? @If you’re sending someone some Styrofoam, what do you pack it in? @I just got skylights put in my place. The people who live above me are furious.



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WEEKLY HEALTH UPDATE Week of: Monday April 2, 2018


Courtesy of:

John H. Keefe III, D.C.

(918) 663-1111


IN THE NEWS:. WHEN THE STATE CONTROLS WHAT YOU EAT In Canada, it’s illegal to sell or give away raw milk, a law that’s enforced in many provinces. In Ontario, distributing raw milk was long considered to be a regulatory offense punishable by fines, but as of January 2018 an order issued by Ontario’s Superior Court calls for anyone who distributes or sells raw milk in the area to face years in prison. Members of one area food co-op believe the Ontario injunction violates their constitutional right to access raw milk, and they’ve filed a motion to have the injunction stayed. In the meantime, the co-op has been forced to stop distributing the milk in order to avoid criminal charges, feeding it to pigs and chickens instead of handing it out to co-op members. Raw dairy farmers have been put out of business for mere suspicion of contamination. Even in the absence of a complaint of contamination, farmers and consumers are often harassed over the buying and selling of raw milk. In contrast, Blue Bell Creamery — the third-largest ice cream maker in the U.S. whose ice cream sickened 10 people with listeria, three of whom died as a result, in 2015, was fined just $175,000 for the incident. Ultimately, the choice of what to eat should belong to the individual consumer, not the state or federal government. If the FDA and other government agencies are allowed to impose their view of “safe food” on consumers, raw milk won’t be the only thing lost — one day virtually all food could be pasteurized, irradiated and/or genetically engineered.

WELLNESS: SUPERFOOD OF THE WEEK: CHERRIES. Famed for their anti-inflammatory superpowers, cherries are the hottest stone fruit on the block. … They’re also packed with anthocyanins, a powerful phytonutrient that jump-starts your immune system and gives cherries that gorgeous red hue. Cherries are a favorite summer treat with a number of valuable health benefits, thanks to their antioxidants and powerful anti-inflammatory compounds. Both sweet and tart cherries are easy to grow. Cherry trees will grow about 1 foot per year, start producing fruit in two to four years and can produce anywhere from 150 to 300 pounds of cherries per tree per year once fully mature. Tart cherry trees are self-pollinating and can be grown in USDA plant hardiness zones 4, 5 and 6. They require about 1,000 chill hours below 45 degrees F during winter months. Tart cherries contain two powerful compounds, anthocyanins and bioflavonoids, which help prevent and relieve arthritis and gout. Sweet cherries such as Bing are also useful against gout, as they lower both uric acid and C-reactive protein levels. Sweet cherry is suitable for USDA zones 5 through 9, and need about 150 to 300 chill hours during winter months. Northwest Oklahoma is a 6 where the middle of the state including Tulsa is a 7 and the southern East tip of Oklahoma is an 8 hardiness zone. Self-pollinating cultivars include Stella, Black Gold and North Star. Others may need companion trees to ensure successful pollination. To keep birds from flying away with your harvest, cover the tree with netting as the fruit starts to form. Planting mulberry trees nearby can also help lure birds away from your cherry trees, but won’t prevent them from eating your cherries as well.

CHIROPRACTIC: Disease care vs. healthcare–Healthcare has undergone a change in the past 100+ years. Diet and herbal therapy along with other more natural treatments were a form of healthcare practice by most doctors. With the advent of antibiotics and the ability to convert herbs into powerful drugs healthcare made a major switch. This idea that we could control disease through drugs gained acceptance. There is no question within crisis care that drug therapy really shines. If your heart stops on the operating table a shot of adrenaline could save your life. Unfortunately this has led to a major change in healthcare. Instead of diet, exercise, vitamins or herbal treatment the idea that you could control all diseases through drugs took over healthcare. Unfortunately we have found that this is not the case in most instances. It’s true that an antibiotic used to be able to wipe out infections that otherwise killed people in the past. Unfortunately that’s becoming less and less of a miracle and turning into more of a nightmare. The problem is the overutilization of antibiotics has led to bacterial resistance diseases where the patient dies even with IVs of antibiotics pumping into their bloodstream. Antibiotics weaken the immune system not strengthening it. Herbs were very powerful back in the day but when chemist found that they could isolate the active ingredient in herbs and make it synthetically it produced stronger effects. But because all the synergistic properties of the herb were left on the table side effects became a growing problem. When you took the herb it would produce health benefits but when you took the synthetic active ingredient those benefits were increased along with side effects. Today over 2000 people a week die from side effects from the prescriptions they get from their medical doctors. And the other problem is drugs don’t heal. Insulin doesn’t heal diabetes, heart drugs don’t heal the heart they just modify the symptoms, antidepressants don’t heal the mind they just alter your perceptions. With the advancement in natural healthcare not only can these issues be treated they can be corrected in time because of the use of nutrients that fix the underlying problem. Find the problem, fix the problem is the approach in natural healthcare whereas find the symptom, suppress the symptom is the approach in drug therapy. Choose your healthcare wisely.

Dr Keefe, Keefe Clinic, Natural Health Care, Tulsa Chiropractor, Diet, Pain,

FUNNY BONE: A boy asks his father, “Dad, are bugs good to eat?” “That’s disgusting. Don’t talk about things like that over dinner,” the dad replies. After dinner the father asks, “Now, son, what did you want to ask me?” “Oh, nothing,” the boy says. “There was a bug in your soup, but now it’s gone.”@@ Q. How much room is needed for fungi to grow? A. As mushroom as possible@@ Three contractors are bidding to fix a broken fence at the White House. One is from Chicago, another is from Tennessee, and the third is from Minnesota. All three go with a White House official to examine the fence. The Minnesota contractor takes out a tape measure and does some measuring, then works some figures with a pencil. “Well,” he says, “I figure the job will run about $900. $400 for materials, $400 for my crew, and $100 profit for me.” The Tennessee contractor also does some measuring and figuring, then says, “I can do this job for $700. $300 for materials, $300 for my crew, and $100 profit for me.” The Chicago contractor doesn’t measure or figure, but leans over to the White House official and whispers, “$2,700.” The official, incredulous, says, “You didn’t even measure like the other guys! How did you come up with such a high figure?” The Chicago contractor whispers back, “$1000 for me, $1000 for you, and we hire the guy from Tennessee to fix the fence.” “Done!” replies the government official. And that, my friends, is how the new stimulus plan will work. 

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WEEKLY HEALTH UPDATE Week of: Monday March 19, 2018


Courtesy of:

John H. Keefe III, D.C.

(918) 663-1111

Dr. Keefe, Keefe Clinic. Tulsa Chiropractor, pain, natural health care.

IN THE NEWS: The Nitric Oxide Dump Do you have three or four minutes, one to three times a day, to devote to your health? By using that time to engage in one of the best high-intensity exercises out there — the Nitric Oxide Dump — you can improve your mitochondrial health, slowing down age-related muscle decline. The fact is, if you live in the U.S. and work full time, you sit an average of 13 hours a day, then sleep for an average of eight.1 This means you’re sedentary 21 hours of the day! The Nitric Oxide Dump workout stimulates your body’s release of nitric oxide (NO), improving your mitochondrial health, slowing down age-related muscle decline and boosting heart health. It involves just four movements — squats, alternating arm raises, non-jumping jacks and shoulder presses — which are done in repetitions of 10, with four sets each. The workout takes just three or four minutes and should be repeated three times a day, with a minimum of two hours between sessions. Squats (10) Begin by standing with your feet hip-width apart, feet parallel, toes pointing forward and the weight of your body distributed evenly between your heels and the ball of your foot. Perform 10 squats in rapid sequence, keeping your quadriceps engaged. Your butt should move back as though you’re going to sit in a chair while your arms move forward for balance. You can do a shallower squat if you have knee or back pain. Alternating Arm Raises (10) Alternate swinging your arms at a 90-degree angle. Keep your form tight and your muscles controlled, avoiding swinging your arms too high or too low This will work a number of muscles in your deltoids, which are the rounded, triangular-shaped muscles on the uppermost part of your arm and the top of your shoulder. Non-Jumping Jacks (10) Begin standing straight with your arms down, fists touching in front of your pelvis. Use a broad rotation, circle your arms upward on each side to touch your fists over your head. Circle back down to hit your fists at the bottom and repeat 10 times. If you have shoulder problems with your rotator cuffs, try this variation instead: Start with your hands at a prayer position in front of your chest. Keep your hands pressed together lightly as you extend them above your head. Circle your arms out to the sides to release before bringing them back to the prayer position. Repeat 10 times. Shoulder Presses (10) Bring fists above your shoulders on either side of your head, elbows bent. Extend your arms straight above your head. Return to position with fists just over your shoulders and repeat 10 times. When you’re done, you should feel your fingertips tingling, and this is a great sign because it means nitric oxide is freely flowing through your body.

Dr. Keefe, Keefe Clinic. Tulsa Chiropractor, pain, natural health care.

WELLNESS: HEALTH BENEFITS OF GRAPE SEED EXTRACT Grape seed extract is a derivative of grape seeds (usually wine grapes), and is mostly made up of proanthocyanidins/procyanidins, vitamin Eflavonoids, and polyphenols . Proanthocyanidin is one of the compounds that make up Green Tea extract, and the benefits of green tea may be somewhat replicated by grape seed extract alone.  Proanthocyanidins come from many different fruits, nuts, and plants and have a wide range of effects on the body. 1) Grape Seed Extract Reduces Blood pressure and Promotes Blood Flow 2) Grape Seed Extract Possesses Nootropic and Anti-Stress Activity 3) Grape Seed Extract Protects Cognitive Function 4) Grape Seed Extract May Protect Stomach and Ameliorate IBS 5) Grape Seed Extract Lowers Inflammation 6) Grape Seed Extract May Improve Osteo and Rheumatoid Arthritis Symptoms 7) Grape Seed Extract Can Ameliorate Asthma, Lung Inflammation and Possesses Anti-Allergenic activity 8) Grape Seed Extract May Protect Against Cancer 9) Grape Seed Extract and Metabolic Syndrome 10) Grape Seed Extract is Anti-Bacterial 11) Grape Seed Extract Increases Antioxidant Activity 12) Grape Seed Extract Protects Male Reproductive Health 13) Grape Seed Extract Protects Skin 14) Grape Seed Extract May Reduce Estrogen and Increase Testostosterone Levels 15) Grape Seed Extract Reduces Swelling 16) Grape Seed Extract May Help Diabetic Symptoms 17) Grape Seed Extract May Reduce Food Intake 18) Grape Seed Extract is Cardio-Protective 19) Grape Seed Extract Interacts With Cytochrome P450 20) Grape Seed Extract Has Kidney Protective Effects 21) Grape Seed Extract Builds Bone Density 23) Grape Seed Extract May Help With Oral Health ASK about grape seed extract on your next visit.

Dr Keefe, Natural Health care, pain Tulsa chiropractor,

CHIROPRACTIC: ONE OF THE FUNDAMENTALS FOR HEALTH To stay healthy diet, exercise, rest and relaxation are some of the components that are important. To be healthy means your body is functioning properly. Function depends on the nervous system, it’s the nervous system that tell glands to secrete their hormones or enzymes, it’s the nervous system that regulates your immune system, it’s the nervous system that performs the miracle of upright posture and walking. You nervous system can slowly become compromised by misalignments and other structural stresses that you could be completely unaware of as they develop. That’s why most health problems come on slowly over a period of time. When you get adjusted you release the intelligence within the body to better regulate and control. If you are needing more hormones the nervous system will accomplish that or if you needing more enzymes to digest your foods the nervous system regulates that as well. Patients who get regular chiropractic care become stronger and healthier over time. Once the pain is gone or maybe some other symptom doesn’t mean your body doesn’t need to continue chiropractic adjustments. Your spine is stressed from daily activities from improper lifting to improper sitting posture or even sleep posture. When you’re under stress muscles tighten up which put your spine under even more stress. When you nervous system can properly regulate and control your body then you stay in a lot better health. Stay regular with care it pays big dividends.

Dr Keefe, Keefe Clinic, Natural Health Care, Tulsa Chiropractor, Diet, Pain,


On my way home from work, I stopped at Taco Bell for a quick bite to eat. In my billfold are a $50 bill and a $2 bill. I figure that with a $2 bill, I can get something to eat and not have to worry about anyone getting irritated at me for trying to break a $50 bill.

Me: “Hi, I’d like one seven-layer burrito please, to go.”
Server: “That’ll be $1.04. Eat in?”
Me: “No, it’s to go.” At this point, I open my billfold and hand him the $2 bill. He looks at it kind of funny.

Server: “Uh, hang on a sec, I’ll be right back.”He goes to talk to his manager, who is still within my earshot. The following conversation occurs between the two of them:

Server: “Hey, you ever see a $2 bill?”
Manager: “No. A what?”
Server: “A $2 bill. This guy just gave it to me.”
Manager: “Ask for something else. There’s no such thing as a $2 bill.”
Server: “Yeah, thought so.”
He comes back to me and says, “We don’t take these. Do you have anything else?”
Me: “Just this fifty. You don’t take $2 bills? Why?”
Server: “I don’t know.”
Me: “See here where it says legal tender?”
Server: “Yeah.”
Me: “So, why won’t you take it?”
Server: “Well, hang on a sec.”

He goes back to his manager, who has been watching me like I’m a shoplifter, and says to him, “He says I have to take it.”

Manager: “Doesn’t he have anything else?”
Server: “Yeah, a fifty. I’ll get it and you can open the safe and get change.”
Manager: “I’m not opening the safe with him in here.
“Server: “What should I do?”
Manager: “Tell him to come back later when he has real money.”
Server: “I can’t tell him that! You tell him.”
Manager: “Just tell him.”
Server: “No way! This is weird. I’m going in back.”
The manager approaches me and says, “I’m sorry, but we don’t take big bills this time of night.”
Me: “It’s only seven o’clock! Well then, here’s a two dollar bill.”
Manager: “We don’t take those, either.”
Me: “Why not?”
Manager: “I think you know why.”
Me: “No really… tell me why.”
Manager: “Please leave before I call mall security.”
Me: “Excuse me?”
Manager: “Please leave before I call mall security.”
Me: “What on earth for?”
Manager: “Please, sir.”
Me: “Uh, go ahead, call them.”
Manager: “Would you please just leave?”
Me: “No.”
Manager: “Fine — have it your way then.”
Me: “Hey, that’s Burger King, isn’t it?”

At this point, he backs away from me and calls mall security on the phone around the corner. I have two people staring at me from the dining area, and I begin laughing out loud, just for effect. A few minutes later this 45-year-oldish guy comes in.

Guard: “Yeah, Mike, what’s up?”
Manager (whispering): “This guy is trying to give me some (pause) funny money.”
Guard: “No kidding! What?”
Manager: “Get this… a two dollar bill.”
Guard (incredulous): “Why would a guy fake a two dollar bill?”
Manager: “I don’t know. He’s kinda weird. He says the only other thing he has is a fifty.”
Guard: “Oh, so the fifty’s fake!”
Manager: “No, the two dollar bill is.”
Guard: “Why would he fake a two dollar bill?”
Manager: “I don’t know! Can you talk to him, and get him out of here?”
Guard: “Yeah.”
Security Guard walks over to me and…
Guard: “Mike here tells me you have some fake bills you’re trying to use.”
Me: “Uh, no.”
Guard: “Lemme see ’em.”
Me: “Why?”
Guard: “Do you want me to get the cops in here?”

At this point I am ready to say, “Sure, please!” but I want to eat, so I say, “I’m just trying to buy a burrito and pay for it with this two dollar bill.”

I put the bill up near his face, and he flinches like I’m taking a swing at him. He takes the bill, turns it over a few times in his hands, and says, “Hey, Mike, what’s wrong with this bill?”

Manager: “It’s fake.”
Guard: “It doesn’t look fake to me.”
Manager: “But it’s a two dollar bill.”
Guard: “Yeah… ?”
Manager: “Well, there’s no such thing, is there?”

The security guard and I both look at him like he’s an idiot, and it dawns on the guy that he has no clue.

So, it turns out that my burrito was free, and he threw in a small drink and some of those cinnamon thingies, too.

This all made me want to get a whole stack of two dollar bills just to see what happens when I try to buy stuff. If I got the right group of people, I could probably end up in jail. You get free food there, too!











WEEKLY HEALTH UPDATE Week of: Monday March 12, 2018


Courtesy of:

John H. Keefe III, D.C.

(918) 663-1111


IN THE NEWS: Help Preserve Your Eyesight With B Vitamins A study published in the July 2013 issue of the American Journal of Clinical Nutrition adds to the evidence suggesting certain B vitamins may be important in the prevention of age-related macular degeneration (AMD), which is the leading cause of vision loss in people over 55 years of age in the U.S. and Canada. Previous studies have shown that taking certain antioxidant vitamins and minerals as supplements (vitamin E, vitamin C, beta-carotene, selenium and zinc), at specific dosages, can slow the progression of AMD. What the Latest Study Says In the latest study, known as the Blue Mountain Eye Study, serum folate (B-vitamin folic acid), vitamin B12 and homocysteine status were determined from blood samples drawn in 1997-1999 from cohort members ages 55 and older. AMD was assessed in 1,760 survivors from retinal photographs taken in 2002-2004 and 2007-2009. Results showed that higher blood levels of homocysteine were associated with a significant increased risk of developing AMD, whereas higher levels of vitamin B12 were strongly associated with decreased risk of developing AMD. Homocysteine is a toxic end-product of metabolism known to damage blood vessels and increase the risk of cardiovascular disease. How You Can Prevent AMD It is thought that AMD is a highly preventable disease, thus requiring attention to various lifestyle behaviors. Extrapolating from what we know from experimental, observational and clinical studies, the following practices appear to be the best proactive strategies to prevent the development of AMD:Don’t smoke-Protect your eyes from UV light-Prevent the onset of type 2 diabetes by maintaining your ideal weight, performing endurance and strength-training exercises regularly, and keeping your blood sugar levels within an ideal range (talk to your doctor to for more info)-Eat a diet rich in brightly colored vegetables and fruit (dark green, yellow, orange, blue, purple, red).-Take dosages of antioxidants and B vitamins:Vitamin C: 1,000 mg-Vitamin E: 400 IU-Selenium: 200 mcg-Zinc: Vit A 25,000 IU -Lutein powder: 6 mg-B-50 complex, including 400 mcg folic acid, 50 mcg vitamin B12 and 50 mg vitamin B6(which also lowers homocysteine) If you’re already suffering from advanced macular degeneration, higher dosages of certain vitamins, minerals and phytonutrients are required to slow the progression of the disease.

WELLNESS: Poor Sleep Is Bad for Your Waistline If you think you’re getting a good night’s sleep on a regular basis, you’re either fooling yourself or in an extremely small minority. That’s because increasingly, people are tossing and turning, waking up repeatedly, going to bed late and waking up early, or just plain waking up feeling tired, unrefreshed and unready to take on the next day because of a poor night’s sleep. There are short- and long-term consequences of poor sleep, ranging from irritability and concentration lapses (short term) to cardiovascular disease (long term), but your weight and waistline also may suffer, according to research published in PLoS One, the peer-reviewed journal of the Public Library of Science. In a recent study, adults were divided into three groups based on their average sleep duration: Less than six hours nightly (5.88 hours), more than seven hours (7.26 hours), and more than eight hours (8.44 hours). If you got the most average sleep per night, your body-mass index (BMI) was about two points lower than if you got the least average sleep per night. Getting the most sleep, compared to the least, also corresponded with 1.6 inch smaller waistline, on average, compared to getting the least sleep. NOTE: We have several natural products that can help your sleep. Ask about it on your next visit. Also visit and type sleep in the search bar.

CHIROPRACTIC: Knee Osteoarthritis: Steroid Injections Aren’t the Answer Knee osteoarthritis can be painful and limit your activities, but corticosteroid injections aren’t the answer, according to new research published in the May 16, 2017 issue of the Journal of the American Medical Association. In the study, quarterly steroid injections actually increased cartilage loss over a two-year period without providing any benefit. That’s a loss-loss situation if you ask us. Patients suffering from knee osteoarthritis with synovitis were divided into two groups, with one group receiving the corticosteroid injections every 12 weeks for two years and a second group receiving a placebo (saline injections) at the same frequency and over the same time frame. Patients in the steroid group lost an average of 0.21 mm in cartilage thickness over the two-year period compared with only 0.10 mm, on average, in patients not receiving corticosteroids. What’s more, patients receiving steroid injections scored only 1.2 points lower on a 0-20 pain scale (0 = no pain, 20 = extreme pain), while patients not receiving steroid treatment scored 1.9 points lower following the intervention period. In other words, patients who received no steroids reported less pain at three-month follow-ups than patients who received steroids! Osteoarthritis is the most common form of arthritis in the world, which makes finding effective treatment options paramount. Unfortunately (and as we’ve said repeatedly with other scenarios), drugs – in this case, injections – may not be the answer. If you suffer from osteoarthritis, talk to your doctor about nondrug alternatives to manage your pain and reduce other symptoms. NOTE: Steps to prevent and correct knee problems: arch supports, anti-inflammatory diet including fish oils, supplements that build Cartledge, keeping your knees in proper alignment.

Dr Keefe, Keefe Clinic, Natural Health Care, Tulsa Chiropractor, Diet, Pain,

 FUNNY BONE: When I went to the ER to have a painful ingrown toenail removed, I was sobbing, gagging, petrified … the works. But my doctor knew how to calm me down. “Don’t worry about a thing,” he assured me. “I just looked up how to perform this operation on YouTube.”@@ Had a woman who was in active labor, despite insisting she couldn’t be pregnant. She said her last period was “like ten months ago” so she’d gone through menopause. She was 25.@@ While in dental school my friend pulled out several bombed out (technical term) teeth on a adult male. After the procedure was finished and post-op instructions we given, the man asked, “So when should I expect my new teeth to grow in?” He was serious.@@ I gave my patient the results of her sleep study: “It looks like you stopped breathing in your sleep over 65 times per hour.”  Her response: “Did I start back?”@@ Call it … carma! A car belonging to a pregnant patient was broken into. The only thing that was stolen was a wine bottle in a brown paper bag. It turns out, that’s where she was keeping her urine sample, which she’d brought in to be tested Visit our web sites: &

WEEKLY HEALTH UPDATE Week of: Monday Feb. 19, 2018


Courtesy of:

John H. Keefe III, D.C.

(918) 663-1111

IN THE NEWS: Depressed and Anxious Patients Receive More Than Half of All Opioid Prescriptions  In 2014, 1.2 million Americans ended up in the emergency room with an opioid-related side effect; in 2015, 33,000 died from an opioid-associated drug overdose. Adults with depression and anxiety receive 51 percent of all opioid prescriptions in the U.S.; 19 percent of the 38.6 million Americans diagnosed with a mental health disorder use opioids, compared to 5 percent of the general population. Women are being prescribed opioids during pregnancy and after delivery, creating drug dependent mothers and infants; 23 percent of 1.1 million pregnant women enrolled in Medicaid filled a prescription for an opioid in 2007. Well over 65,000 die from opioid abuse last year compare that to 58,000 that died in the Vietnam War. When it comes to pain control our healthcare system is broken. Chiropractic care along with electrotherapy, acupuncture and even nutritional therapy can help resolve the underlying condition that causes the pain. Seek a natural approach for all of your healthcare issues including pain.

WELLNESS: Apple Cider Vinegar As you may know, apples, and especially apple juice, are high in sugar and are not something I recommend eating regularly as it will typically shift you out of fat-burning if frequently eaten. However, when you ferment apple juice or cider, the sugars are digested as a result of the fermentation process. Apple cider vinegar contains very little sugar and carbohydrate, making it a very attractive food from a dietary standpoint. Apple cider vinegar offers many potential health benefits: Apple cider vinegar contains a number of important components, such as organic acids: acetic, citric, formic, lactic, malic, and succinic acids. It also contains acid, catechins, epicatechin, chlorogenic acid, caffeic acid, and p-coumaric acid. Plus, it’s a source of manganese and potassium. Research suggests acetic acid may be the most significant of these components for health, and is found in high levels in apple cider vinegar. In various studies, researchers have found that acetic acid and the other constituents may help with a variety of healthy body functions: Healthy oxidation and cholesterol support, Normal cardiovascular support, Healthy cognitive function, Normal lymphatic drainage and normal detoxification processes, Athletic recovery. According to new research, healthy vinegar with acetic acid may support nutritional ketosis, and in turn, your mitochondrial health.

CONDITION OF THE WEEK: B VITAMINS  Hardly anyone talks about B vitamins these days. I believe that’s about to change. With our deteriorating food quality, rising assaults on gut health, and a living environment that becomes more toxic by the day, it’s clear that we need this complex of brain and body nutrients more than ever. Most people are eager to remain mentally sharp, energetic and independent into their later years. As you’ll soon see, researchers are discovering potential benefits of the family of B vitamins that are much greater than we ever imagined.Because of this, the day we give B vitamins the attention they deserve has finally arrived…Keep in mind, you don’t need to have a flat-out deficiency in any of these vitaminsSurprisingly, many of the subjects in the studies you’re going to hear about didn’t. They just had lower levels. Increasing their intake of these vitamins made all the difference for these study subjects. Going from low or even routinely recommended minimal levels to optimal levels allowed them to benefit in significant ways! Low levels of B vitamins can affect your body in many different ways because of the vitamins’ far-reaching and interrelated effects. A B vitamin complex deficiency can show up in multiple ways. Any one of these common symptoms could be a result of low levels of one or more B vitamins: Inability to sleep well..Fatigue and apathy..Mental “fog,” confusion, and forgetfulness..Mood swings and irritability..Gastrointestinal symptoms..Joint or muscle discomfort..Muscle weakness..Loss of muscle mass.. Numbness or tingling in fingers and toes..Frequent bruising.. eadaches.. Irritability..Dry, cracking skin. Because the vitamin B complex is a group of eight major B vitamins that work together, you can impact their synergy just by running low on one. For example, many of the B complex vitamins are needed for healthy skin. If you’re low in one or two, that can affect the actions of the others. Your nervous system requires B vitamins to respond properly to adjustments.

FUNNY BONES: Patience: what you have when there are too many witnesses.@@Hold your wife’s hand in the mall because if you let go, she’ll start shopping. It looks romantic. But it’s actually economic.@@The IRS returned my tax return to me this year after I apparently answered one of the questions incorrectly… In response to the question, “do you have anyone dependent on you?” I wrote, “9.5 million illegal immigrants, 1.1 million crackheads, 3.4 million unemployable scoundrels, 80,000 criminals in over 85 prisons plus 650 idiots in Washington.” The IRS stated the answer I gave was “unacceptable!” I then wrote back “Who did I leave out??”@@Wi-Fi went down for five minutes, so I had to talk to my family. They seem like nice people.



WEEKLY HEALTH UPDATE Week of: Monday Feb. 13, 2018


Courtesy of:

John H. Keefe III, D.C.

(918) 663-1111


IN THE NEWS: Researchers Uncover Link Between Immune Function And Osteoarthritic Pain And Progression The immune system plays a pivotal role in the amount of pain and disease progression experienced by patients with osteoarthritis (OA), McMaster University researchers have found. This discovery could lead to new strategies for improving joint pain management and immune function in older adults with arthritis. The study, published in the medical journal Osteoarthritis and Cartilage, found that monocytes, the white blood cells necessary to regulate immune responses, were more activated and pro-inflammatory in women with osteoarthritis, and that elevated inflammation and body mass index were associated with this increased activation. When compared with a control group, this combination created a perfect storm – one that was found to increase the pain and progression of knee osteoarthritis. The study involved 22 women with OA, and 22 women of the same age without OA.NOTE: Monocytes are usually elevated in response to bacteria and parasites. Recently study show that rheumatoid arthritis can be triggered in some cases by a bacteria in milk. Nutritional formulas that enhance immune function allow for the body to eliminate these microorganisms and begin the healing process. Detoxification, anti-inflammatory diet are just some of the things that can be helpful in health recovery.

WELLNESS: Chuck Norris Focuses Attention on Heavy Metal Risks After Enhanced MRI Magnetic resonance imaging (MRI) is a study allowing your physician to see detailed images of your organs and tissues using a large magnet and radio waves. Gadolinium-based contrast agents (GBCAs) may be prescribed to enhance the image but the heavy metal gadolinium is known to deposit in your brain, bone and organs. The FDA acknowledges the metal may be found in your tissues for years but claims there is no known effect, despite the rising number of people suffering from kidney damage, cognitive dysfunction and muscle wasting. Strategies you may consider if an enhanced MRI is absolutely necessary include optimizing your gut and nutrition, eating fermented foods and using a sauna to aid detoxification. After undergoing three MRIs with GBCAs to evaluate her rheumatoid arthritis, Gena O’Kelley, the wife of American film icon Chuck Norris, began experiencing severe physical symptoms that began with a burning sensation in her skin. She described it as if there was acid burning her skin, slowly covering her body.  She reports that she visited the emergency room five or six nights in a row, while doctors ran multiple tests for ALS, MS, cancer and Parkinson’s disease. However, it was O’Kelley who made the connection between her burning skin, contracted arm and cognitive issues and the multiple MRIs she had undergone. She told Full Measure: “When we got to the hospital in Houston this last time, and I’m so bad and I said, listen, I am sober enough in my thinking right now, because I had such brain issues going on, I said I’m only going to be able to tell you this one time and I need you to listen to me very closely. I have been poisoned with gadolinium or by gadolinium and we don’t have much time to figure out how to get this out of my body or I am going to die.” After five months of treatment in China and then in a clinic in Nevada, O’Kelley was able to return home to her seven children for continued treatment by a physician in Houston. Norris shared their tax return records documenting $2 million over three years in uninsured medical expenses to help O’Kelley return to health. Now Norris is suing 11 medical companies for the part they played in not warning the couple and others of the dangers of using a GBCA for MRI contrast.

Dr Keefe, Natural Health care, pain, Tulsa chiropractor,

CHIROPRACTIC: IMMUNE FUNCTION studies of chiropractic patients have shown interesting differences with those patients that have ongoing chiropractic care and just the average person off the street. One of those differences we have discussed in a past newsletter about DNA repair. Those who have gotten regular chiropractic adjustments have a higher level of a chemical that’s involved in repair of DNA. Our DNA is traumatized hundreds if not thousands of times during the day and repair of DNA is essential in longevity and health in general. Many years ago an immunologist studying chiropractic patients who receive regular care were found to have an immune system operating 400% better than the average person on the street. The nervous system regulates and controls every system in your body and misalignments depress function including immune function. When you receive an adjustment you improve nervous system control and coordination over your immune system. Keeping a healthy immune system requires a clean diet, plenty of fluids, exercise, proper rest and a healthy nervous system. Increase your immune function through regular chiropractic care.

FUNNY BONE: When my three-year-old was told to pee in a cup at the doctor’s office, he unexpectedly got nervous. With a shaking voice, he asked, “Do I have to drink it?”@@ Probably the worst thing you can hear when you’re wearing a bikini is “Good for you!”@@ A couple years ago my therapist told me I had problems letting go of the past.@@ “Doctor, there’s a patient on line 1 that says he’s invisible” “Well, tell him I can’t see him right now.”@@ Dr.’s are saying not to worry about the bird flu because it’s tweetable.@@ When an employment application asks who is to be notified in case of emergency, I always write, “A very good doctor”.@@ I grew a beard thinking it would say “Distinguished Gentleman.” Instead, turns out it says, “Senior Discount, Please!”

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