September 2009 Issue | Gan Siok Ngoh, BDS, MSc Orchard Scotts Denta

 


 

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Welcome to the September 2009 issue of Functional Medicine Update . Those of you who have been listening over the last several months know there is a theme for 2009, and that theme is really connecting environmental factors that modulate and influence the neuroendocrine immune system and ultimately signal to the body either immunological stability or immunological vigilance and activation. We started off in June and July with some extraordinary discussion concerning gluten as one family of molecules that modulate immune function and ultimately inflammatory signaling. We used that as an example to demonstrate that food and its constituents contain information responded to by the body in a very unique way (a personalized way) based upon the unique sensitivities locked into that person’s signaling processes connected to their genes and their epigenome in ways that make their environmental response different than that of others. From there, we went into the August issue and an extraordinary discussion with Professor Delzenne and Dr. Cani related to the modulating effects of the gut microbiome and how it influences the translation of the signals from the environment into intercellular signal transduction processes that can have far-reaching, distant effects upon function, including that of neurologic function and cardiovascular function. Even things related to obesity can be tied to alterations in the gut microbiome, as was mentioned in that issue.

In this issue-September-we have the privilege of speaking with another remarkable clinician, in this case a periodontist from Singapore who is of high repute and background (academic and clinical). She will be talking to us about another locus in the body for immunological dysregulation, and that is infection in the oral cavity and the relationship that has to systemic health.

As a clinician, when you are starting to really evaluate, from a functional medicine perspective, the antecedents, triggers, and mediators that give rise to the signs and symptoms of disease, you start looking where the triggers may reside. We’ve talked about dietary triggers, environmental triggers, gut microbial triggers, and now we are going to talk about infection in the oral cavity and in the sinuses-other resident places in the body where a smoldering activation of the immune system can occur that alters the functional status of the neuroendocrine immune system that then spreads itself through unique susceptibilities or sensitivities into differing diseases in differing individuals.

I’d like to state that this is a unique model to functional medicine, but, as you probably know, it is not. It’s a model from Hans Selye, who adapted a term from physics into physiology (stress), and that appropriated term talked about agents that would modulate immune function and endocrine function in such a way as to have diverse effects on the appearance of diseases that cut across many different diagnostic codes (or ICD-9 codes) and different subspecialties of medicine. A stress factor could be seen in one individual as peptic ulcers, and in another it could be seen as a heart attack, and in a third it could be seen as osteoporosis, and in a fourth it could be seen as diabetes. This construct that a factor in the environment could spread itself through different susceptibilities or sensitivities into different expressed diseases in differing individuals is a very different model than that of, for instance, bacterially induced disease, where we say a specific bacterium, such as a pneumococcus bacterium, produces a specific disease called pneumonia, for which a specific molecule is there to treat it (that would be, say, an antibiotic like penicillin).

That model, which is a very simple linear reductionistic model for the origin of disease certainly has merit and value, but it is only one of multiple etiologies that are associated with the origin of disease. In chronic disease, it would appear as if the “bug” (in the previous example, the bacteria), is related to its environment, which is related to the susceptibilities or sensitivities of the individual, and ultimately, then, it spreads itself into a myriad of potential diseases, not just one disease. That is certainly going to be the theme that you’ll hear about in this month’s Functional Medicine Update

To peak your interest, let me give you an interesting quote that just recently was published by the American Academy of Periodontology. This was from their most recent contribution to the American College of Cardiology. It may seem that these are strange bedfellows and that we have cut across wide swaths of differing disciplines within the health and medical sciences, going from dentistry and periodontology to looking at cardiology and heart-related dysfunction. How does this all work? To me this is a classic example of what we have been trying to develop over the last 20 years as we’ve defined functional medicine. It is not just psychosomatic medicine, and not just geriatric disability medicine, but medicine that is related to a web of interaction, a hologram of physiology, a matrix of interacting variables.

What does this press release say? This is a summer 2009 press release and it states, “Cardiovascular disease, the leading killer of men and women in the United States, is a major public health issue contributing to 2400 deaths each day. Periodontal disease, a chronic inflammatory disease that destroys bone and gum tissues that support teeth affects nearly 75 percent of Americans and is the major cause of adult tooth loss. And while the prevalence rates of these disease states seems grim, research suggests that managing one disease may reduce the risk for the other.”1 Does this sound at all familiar to the theme that we have been describing in functional medicine for two decades, plus?

The press release goes on to say, “A consensus paper on the relationship between heart disease and gum disease was recently published concurrently in two leading publications, the American Journal of Cardiology (AJC), a publication circulated to 30,000 cardiologists, and the Journal of Periodontology (JOP), the official publication of the American Academy of Periodontology (AAP). Developed in concert by cardiologists, the physicians specialized in treating diseases of the heart, and periodontists, the dentists with advanced training in the treatment and prevention of periodontal disease, the paper contains clinical recommendations for both medical and dental professionals to use in managing patients living with, or who are at risk for, either disease. As a result of the paper, cardiologists may now examine a patient’s mouth, and periodontists may begin asking questions about heart health and family history of heart disease.”

The line is blurry. The disciplines look a little bit more fuzzy. Going on, the press release says, “The clinical recommendations were developed at a meeting held earlier this year of top opinion-leaders in both cardiology and periodontology. In addition to the clinical recommendations, the consensus paper summarizes the scientific evidence that links periodontal disease and cardiovascular disease and explains the underlying biologic and inflammatory mechanisms that may be the basis for this connection.”

“According to Dr. Kenneth Kornman…Editor of the Journal of Periodontology [and an expert, I might add, in inflammatory disorders]…the cooperation between the cardiology and periodontology communities is an important first step in helping patients reduce the risk of these associated diseases.” Dr. Kornman is quoted as saying, “Inflammation is a major risk factor for heart disease, and periodontal disease may increase the inflammation level throughout the body. Since several studies have shown that patients with periodontal disease have increased risk [of] cardiovascular disease, we felt it was important to develop clinical recommendations for our respective specialties. Therefore, you will now see cardiologists and periodontists joining forces to help [their] patients.”

“For patients this may mean receiving some unconventional advice from their periodontist or cardiologist. The clinical recommendations outlined in the consensus paper advise that periodontists not only inform their patients of the increased risk of cardiovascular disease associated with periodontal disease, but also assess their risk for future cardiovascular disease and guide them to be evaluated for the major risk factors. The paper also recommends that physicians managing patients with cardiovascular disease evaluate the mouth for the basic signs of periodontal disease [including such signs] as significant tooth loss, visual signs of oral inflammation, and receding gums.”

“While additional research will help identify the precise relationships [among] periodontal disease and cardiovascular disease, recent emphasis has been placed on the role of inflammation-the body’s reaction to fight off infection….”

“Both periodontal disease and cardiovascular disease are inflammatory diseases, and inflammation is the common mechanism that connects them,” says Dr. David Cochran, President of the American Association of Periodontology and the Chair of Periodontics at the University of Texas Health Science Center at San Antonio. “The clinical recommendations included in the consensus paper will help periodontists and cardiologists control the inflammatory burden in the body as a result of gum disease or heart disease, thereby helping to reduce further disease progression, and ultimately improve our patients’ overall health.”

I think you can kind of get the drift, can’t you? It is a time of change. Disciplinary boundaries are being broken down. The walls are coming down, to use a metaphor. The age of interconnectedness has started to emerge. We don’t just call these comorbidities-periodontal disease and cardiovascular disease. What we would rather call them are disorders coming from a single inflammatory burden-a single trigger that triggers mediators that are shared among different tissues that give rise to diseases of different name. It clearly indicates that clinicians need to be very mindful of looking for sites of focal inflammation in the body–places where resident bacteria and viruses continue to elicit an immune response that causes an inflamed response.

What are the most significant singular advances that have occurred through medical technology that have improved health outcome in large populations? At the head of that list has to be something that medicine had probably very little (directly) to do with, but had remarkable impacts upon reducing the burden of infectious disease and the attendant effects it has on inflammatory response. I’m speaking about hygiene, sanitation, and nutrition. These principal factors (which are taught very little in traditional primary therapies and may be relegated to the sidebar of public health) represent extraordinarily important contributions to the overall reduction and burden of disease in populations over the last 150 years.

Revisiting the Writings of Ivan Illich
Ivan Illich wrote a book that I consider absolutely to be a classic read for everyone in the field; the book was called Medical Nemesis. That book really describes, very factually, how important the introduction of sanitation, hygiene, and nutrition was coming into the 19th and early 20th centuries on improving life expectancy and reducing disease, morbidities, and premature mortalities. There is a nice article that was published that goes back, retrospectively, and looks at the important contribution that Medical Nemesis, as a book, and even Ivan Illich, as an author, made to our understanding of medicine.2 The article appeared in the journal Medicine, Health Care, and Philosophy in 2003. Ivan Illich has subsequently passed away. Medical Nemesis, which I used back in my professorial years in the 70s as one of my textbooks for required reading for students, is now kind of a forgotten book, but I think it has a very powerful implication even today.

Ivan Illich was known as a philosopher, historian, priest, and social commentator. He died in Bremen, Germany in December of 2002. He was noted originally for his critique of the church, education, and medicine, but his concepts really dealt with very fundamental issues. These issues related to the relationship of humans to their environment and how their ideas about this relationship shaped their outcome, both as individuals and as populations, and what this all means in terms of medicine, and in particular the role of health care in contemporary society. If you ever get a chance to get hold of a copy of Medical Nemesis at your library I urge you to pick it up and read it. It is a fairly short read, but it is a profoundly dense book, relative to ideas, because it helps us to recognize the important role that certain things that we take for granted (proper sanitation, hygiene, and nutrition) have on overall burden of disease, and that those things make pale, in comparison, all other medical therapies that have been developed since, even antibiotics. These three things are the principal drivers for the improvement in human life expectancy over the past 150 years, and yet often we relegate these to second tier importance because we now take them for granted.

This concept of “Is it the bugs or the environment that produced the disease?” is still as much a debate today as it was back in the day of Pasteur at the end of the 19th century/beginning of the 20th century. We know that the “la terraine,” the environment in which the bugs live, is very important for determining their pathogenesis, but we also know the presence of the bug can be important as well. It is a combination of both factors. If you have immunologically compromised patients you have more potential for the growth of organisms, and the growth of more organisms produces more toxic byproducts that activate and alter the immune system function. Which does what? Dysregulate the body’s defense system and allow for more bugs to grow. Now we are in a tight cycle of self-replication-a positive feedback cycle, so to speak. You have to break the link. How do you break the link? You can kill the bugs, but as we know, you also have to change the terrain. You have to improve the functional status of the organism so that they can resist the growth of these bugs (these opportunistic organisms that may always be out there).

That has been the longstanding challenge, hasn’t it? To balance, in medical therapy, those two factors: reduction of the appearance of the bug that is the offending agent (for which we have done a culture or a swab and we recognize that we have a certain sensitivity to a certain medication for that bug), and then to enhance the integrity of the soil of that individual (meaning their environment, so as to result in an environment that is less likely to support the growth and the survival of those opportunistic, infectious organisms). In periodontal disease, oral hygiene, proper sanitation, and proper nutrition are important. The bugs will always be there because the mouth is a very fertile ground for growing bugs. You have to combine together the Illich-like concepts of sanitation, hygiene, and nutrition in order to manage, preventively, the potential for triggering immunological activation and inflammation. You don’t want a person to be on antibiotics their whole life; what you want is their body to modulate their function (la terraine).

These concepts are very interesting because they contract right back to the cellular level. Now we are developing cellular cytology and ways of looking, individually, within the macromolecules of cells and seeing how environmental factors like chronic inflammation that comes with infection can actually alter cellular function and imprint the genes of those cells with epigenomic tags that may set that cell into a certain phenotype of alarm and perpetuate this alarm over time. We recognize that these processes that are associated with constant exposure to inflammatory response from an activated immune system also ultimately erode the actual book of life by contributing to the shortening of the ends of our chromosomes (the telomeres), which can influence the stability of our genome (we talked about this in a previous issue with Dr. Michael Fenech). Genomic instability comes with inflammation and oxidative stress, and ultimately reduces the patency of the message in our book of life that gets translated into the integrity of our cellular function.

All of this maybe sounds a little bit theoretical, broad brush, and not clinically relevant to when you are sitting in the exam room with that patient. You may say, “That’s really great on a theoretical level-I like the story-but it really doesn’t relate much to what I’m seeing in my patients.” I want to cite a new paper that may help you to understand how it does relate to your patients.

How Telomere Length Relates to Your Patients
How do you improve the quality of the immune system through nutrition? That is a topic that we have been discussing for the last several months in Functional Medicine Update. We might say it another way: Does the proper intake of simple things like multivitamins have any influence on the signaling that ultimately regulates telomere length and genomic stability? That is an interesting question. An answer partially emerged when, in a recent issue of the American Journal of Clinical Nutrition, a paper titled “Multivitamin Use and Telomere Length in Women” was published.3 The authors of this paper are from the National Institutes for Environmental Health Sciences in the National Institutes of Health Research Triangle in North Carolina, as well as the University of Utah, Department of Human Genetics. They evaluated (in women) the influence that a multivitamin supplement had on telomere length. These were women 35–74 years, who took a multivitamin and had their diets evaluated through a nutrient intake questionnaire (a 146-item food questionnaire). White blood cell (leukocyte) DNA was analyzed to look at telomere length. This is similar to one study I described in an earlier issue of Functional Medicine Update that was done at the University of California, San Francisco, in men with prostate cancer who were put on a lifestyle therapy (this was in collaboration with Dr. Dean Ornish), in which researchers showed (and reported in The Lancet magazine in 2008) that the lifestyle therapy with diet, stress reduction, and exercise resulted in improved telomerase activity in the men that placed on lifestyle therapy versus controls.4

Telomeres are the TTAGGG tandem repeat sequence at the end of chromosomes that relate to the prevention of detrimental recombination and degradation of our book of life (our chromosomes). In somatic cells, the length of telomeres decreases with each cell division, and this is related to the Hayflick Number (which I also discussed in a previous issue). Leonard Hayflick, who was a cell biologist at Stanford many years ago, found that cells could (in culture) go about 50 cell doublings before they could no longer replicate, and this had something to do with the continued loss of the length of their telomeres, until they eventually were unable to maintain proper genomic stability and the message of their book of life was unable to be adequately translated into the next generation of cells. As a result of this research, telomere length has been proposed as a marker for biological aging.

Consistent with this hypothesis, preliminary epidemiological studies have related shorter telomeres to higher mortality and higher risk of certain age-related chronic diseases, including heart disease and cancer. Experimental evidence suggests that oxidative stress and chronic inflammation contribute to the attrition of telomeres and their loss of cellular replication. Now there is increasing evidence to at least suggest that several micronutrients (including antioxidants, vitamins, and minerals) can help modulate states of oxidative stress in chronic inflammation. We could postulate, therefore, that these micronutrients could affect the rate of degradation or attrition of telomeres. Based on articles Dr. Bruce Ames and others have published over the years, multivitamin supplements (in an orthomolecular manner) can influence the relative protection against oxidative injury and the processes that may relate to the loss of these telomeres.

Going back to the study on women published in the American Journal of Clinical Nutrition, the investigators recruited these women and put them on a vitamin supplement (versus those who were not supplemented). This was a fairly, what we would consider to be “run-of-the-mill”-type nutritional supplement. These were not megavitamin doses nor extraordinary formulations, but just kind of your standard vitamin/mineral protection supplements. The researchers then looked, over time, at the average telomere length in these women. This study differed from the Ornish study that looked at telomerase activity and showed an increase in activity of the telomere repair enzyme (telomerase). In this study, the actual lengths of telomeres (in white cells) were evaluated, and it was found that there was a statistically significant increase in average telomere length in those individuals taking the vitamin supplement.

High-Potency Antioxidants Appear to Have Greater Influence on Protecting Telomeres
Nutrient formulations that had high potency antioxidants appeared to have greater influence on protecting telomeres. Those supplements that were what you might consider to be just B vitamins alone didn’t have nearly the effect of those that were multi-nutrient with high antioxidant formulations that were taken at least 4 to 6 days a week. In those particular examples there was much higher uptake and there appeared to be a dose-response relationship: the more frequently the person took it corresponded to the highest response in improving the length of their telomeres. Data from this study certainly suggests strongly that enhanced vitamin/mineral intake and increasing antioxidant level intake has a positive impact on maintenance of telomere length. If you believe (as the basis of science, now, is seeming to believe) that maintenance of telomere length is one of the principles associated with reduced biological aging and age-related chronic disease risk, then we would say this cell marker would track to a positive health outcome in these individuals who are taking the higher doses of vitamins containing antioxidants.

There is a very interesting editorial that follows this paper that appeared in the American Journal of Clinical Nutrition, and the editorial goes on to say some very interesting things.5The author of the editorial says that leukocyte telomere length (LTL) is associated with age-related disorders (as was measured in this particular study), particularly atherosclerotic risk. Conflicting results have been published on whether the leukocyte telomere length forecasts survival in the elderly, but recent research using a same-sex twin model clearly showed that co-twins with a shorter leukocyte telomere length were more likely to die first. These observations support the hypothesis (or the proposition) that leukocyte telomere length is a biomarker of human aging. Telomeres are known as the “mitotic clock” in cultured human somatic cells, and it appears, in this issue, that this telomere length is generally used as a marker, therefore biological aging based upon this biological clock mechanism.

I think that if you look at the influence that we are talking about, it looks as if the increase in telomere length with multinutrient supplementation tracks back to protection of functional characteristics that are very important for the maintenance of high-functioning life, in this case in humans (not in rodents and not in single cells, but in humans). How does that track back to the other side of the equation, which are those things that would increase inflammatory burden, oxidative injury, and the relative pressure on enhancing the rate of loss of telomeres? That answer has to do with things like focal infection and its relationship to proinflammatory initiation.

In past issues of Functional Medicine Update, we’ve talked about the gut as being a site of potential focal inflammation, and in this issue we are going to move into talking about the oral cavity. One could think of the sinuses or other sites in the body where focal infection is associated with proinflammatory initiation, increased oxidative injury, shortening of telomeres, and lowered biological function. You could say, “Well, there must be a variety of antioxidants that influence these processes. What would we put at the head of the list?” I don’t think we can put anything at the “head” of the list because they all work together in a cooperative manner to create an envelope of function to help to protect against oxidative injury and inflammatory excesses. We should really think of this as a team rather than as the “antioxidant-of-the-month”-type of club.

Coenzyme Q10 Supplementation Used in a Study Involving Infertile Men
There are, however, cases of selective supplementation with individual antioxidants have been demonstrated to have clinical benefit. A recent report that I think is very interesting appears in the Journal of Urology that talks about the efficacy of a single antioxidant supplement at high dose, and this would be coenzyme Q10, or ubiquinone.6 Coenzyme Q10, in this case, was administered to a total of 212 infertile men with idiopathic difficulties and low sperm count. These were randomly assigned to receive either 300 milligrams of coenzyme Q10 daily, or a similar placebo regime. They were placed on a treatment phase. Semen analyses were then done to look at anti-sperm antibodies and various hormonal levels in these men and the motility and vitality of sperm. By the way, you might ask, “Why would they choose to use coenzyme Q10 in this particular condition?” As you probably know, sperm are really just an inclusion body with a huge amount of mitochondria. Sperm have to have a lot of energy in order to swim, and their tail is powered by mitochondria (oxidative phosphorylation), and when the tail falls off, so fall off the mitochondria. The sperm are driven by this biochemical reactor called the mitochondria (the energy powerhouse of that cell), and therefore defects in mitochondrial oxidative phosphorylation have been identified to be associated with sperm-related problems and infertility. That is one of the reasons they chose coenzyme Q10 for this study-because it is one of the antioxidants that has been clearly identified to be very important in the electron transport chain for protecting mitochondrial bioenergetics.

What were the results of this study that was published in the Journal of Urology in 2009? What the researchers found was a very significant, statistically important improvement in semen parameters in the 300 mg coenzyme Q10 daily supplementation group versus the placebo group. They suggest that further studies are needed to draw a final conclusion, but the results do seem to implicate coenzyme Q10 supplementation as being very valuable in improving sperm quality; now what is needed is a more prolonged study to look at pregnancy (in situations where men were infertile and attempting to impregnate their partner and lead to term birth). I think this is a very interesting and encouraging story that talks about the role that a single antioxidant can have on a functional characteristic (in this case, coenzyme Q10 on sperm function in males).

What we are really talking about is modulating various gene-response influences. If inappropriately modulated, these end up being translated or becoming a disease that we eventually can put a name on. Going back to Dr. Dean Ornish’s work that he did in prostate cancer, I think it is very interesting to hear what happened in males with prostate cancer following two years of lifestyle intervention. There is a very nice paper that was published in the journal Urology in 2008 authored by Dr. Ornish and his colleagues from the University of San Francisco School of Medicine.7 As a result of this study, what they report is that patients with early-stage prostate cancer choosing active surveillance might be able to avoid or delay conventional treatment at least two years (the study length of this study) by changing their lifestyle diet components. In this case not only did telomerase activities increase, but the progression of cancer (as measured by PSA and other examinations) was retarded as well versus a group that didn’t engage in lifestyle intervention, which involved using a minimally processed fundamental diet along with stress reduction and exercise. So lifestyle intervention in prostate cancer patients was demonstrated to have a very significant influence on improving status at two years. This is a clinical example, not just a cell example.

Management of Inflammatory Signaling Can Have an Influence on Cognition
What about things like neurodegenerative diseases? Probably at the head of this list is Alzheimer’s disease. There is a very powerful body of literature that is now emerging around Alzheimer’s disease prevention and even early management through metabolic management of inflammatory signaling through diet and lifestyle intervention. I found an article that appeared recently in 2009 titled “The Alzheimer’s Disease–Diabetes Angle: Inevitable Fate of Aging or Metabolic Imbalances Limiting Successful Aging” to be a very important paper.8 This article appeared in the Journal of Alzheimer’s Disease in 2009. In this short article, the authors suggest that Alzheimer’s disease is not an inevitable consequence of aging, but rather it is an inevitable consequence of aging processes associated with altered signaling and increased inflammation connected to dietary signals that enhance immune activation and inflammatory response through hyperinsulinemia and uncoupling mitochondrial oxidative phosphorylation and free radical oxidative stress. Diet and lifestyle intervention in this condition can modulate, epigenetically, the phenotype (in other words, the expression of what we later call Alzheimer’s disease).

There is also a magnificent review article on this topic that appeared in Behavioural BrainResearch in 2008 titled “Epigenetic Codes in Cognition and Behaviour.”9 This is such a dramatically powerful article because it really gets us away from the feeling that these neurological diseases are genetically hardwired and are inevitable. Rather there are many modifying factors that relate to diet and lifestyle that signal (through these kinase signaling processes) either a friendly response to our environment, or an alarm state that puts the neurological system at war with itself by altering epigenetic tags, changing histone acetylation/deacetylation/methylation patterns in promoter regions of genes, upregulating expression of proinflammatory genes, and inducing what later becomes known as neurofibrillary tangles, or oxidative injury in the nigrostriatal regions of the brain that we associate with Parkinson’s disease. I think these epigenetic codes in cognition and behavior and environmental influences on it are extraordinarily important.

How much of this equation is related to nutrition? Are nutrients major players in this or are they just minor bit players? There is a marvelous review paper on this subject titled “Brain Foods: The Effects of Nutrients on Brain Function.”10 This article appeared in the July 2008 issue of Nature Reviews Neuroscience and the author talks about how epigenetic regulation through diet and exercise and reduction of environmental exposure to toxins can modulate, epigenetically, the expression of factors that ultimately might initiate problems in cognition and problems in neurochemical function that, at later stage, we diagnose as a disease such as Parkinson’s or Alzheimer’s. This regulation includes things like omega-3 fatty acids, but also things like phytochemicals that come from garlic, and grapes and peanut skins, and cruciferous vegetables. This complex diet-with an array of these phytochemicals-plays a role in modulating insulin signaling, oxidative stress, telomerase shortening, and epigenetic signaling. Even vitamin D may play a very important role in cognitive performance in middle age and older individuals. And if you don’t understand this, the Journal of Neurology, Neurosurgery, and Psychiatry published a very powerful paper in 2009 that demonstrated that people with low 25-hydroxyvitamin D levels had declined cognitive performance in middle age versus those that had higher 25-hydroxyvitamin D levels.11 All of this is part of how our environment signals to our cells and creates an outcome called our phenotype.

With that in mind, let’s move to our extraordinary discussion with our clinician/researcher of the month, who is going to tell us a little bit about the periodontal connection to inflammatory signaling and diseases beyond that of diseases of the oral cavity.


INTERVIEW TRANSCRIPT

Clinician/Researcher of the Month
Gan Siok Ngoh, BDS, MSc
Orchard Scotts Dental
501 Orchard Road
#05-08 Wheeelock Place
Singapore 23 8880

One of the great privileges of the life that I have been fortunate enough to lead over the years is travel and meeting some extraordinary people, internationally, who are doing really pace-setting work. In this issue you are going to have the benefit of traveling internationally with me (at least telephonically) to visit with Dr. Gan Siok Ngoh, who is in periodontology, and who I had the privilege of meeting at an international conference in Singapore a couple of years ago. I am absolutely impressed by the scholarship and the clinical acumen that she has brought to her work that relates to the oral-systemic link to health and disease. After hearing her talk, I asked her whether she would be willing to share the information she had provided to the audience with listeners of Functional Medicine Update and she said yes. Now we have been able to finally arrange the time. Let me tell you a little bit about her.

Dr. Gan has a degree in dental surgery from Singapore and was in government dental practice for two years, then went into private general practice. She moved from that into a hospital-based general dental practice. In 1991, through the UK, she attained her Masters in Science in periodontology. Dr. Gan obviously has a very interesting research base as well as a clinical base. She has been in solo practice, in a hospital-based dental practice with a focus on periodontology and full-mouth dentistry, and from 1992–2008 had also been looking at the relationship to chronic degenerative and immune-compromised diseases. During that time she also became very skilled in a variety of complementary (and what we might call functional) medicine integrated strategies and techniques that she now brings into her practice. So she has a very wide-ranging background, from very solid dentistry into the science and research model, and then into the integrative model as well. We couldn’t find a more well-schooled nor more clinically experienced person to cover this important topic than Dr. Gan.

Let me welcome you, Dr. Gan, to Functional Medicine Update. It is a very great privilege and honor to be able to talk with you today.

GSN: Thank you very much for the invitation. I am more than happy to share with you my experiences and my knowledge.

JB: Let me ask the question that probably everyone would want to know first: How did you come to extend your traditional periodontal practice and background into these other areas that we’ll be discussing as it relates to systemic health? There must have been some things that you observed or something that affected you to want to broaden your perspective.

GSN: When I started working in a hospital-based practice, I was seeing a lot of immuno-compromised patients-patients with chronic degenerative diseases. And I was very upset that with all the formal knowledge we had, we were not able to actually help the patients fully. That got me into searching, and searching, and searching, and that led me to Switzerland, to Canada, to Austria, to Germany, Hungary…to find out about other therapies that could help augment the healing processes of an individual. I began to notice, also, from my studies in traditional Chinese medicine, Ayurvedic medicine, and hormone toxicology, that the mouth and oral tissues are able to express certain other symptoms if we look closely enough. And because my interest is periodontology (the science of the gums), that led me into understanding the tissues and how they behave and what they are telling us.

JB: That’s a fantastic segue into my next question. A lot of the clinicians that are listening are not experts in the oral health area. Maybe it would be helpful for you to give us some primer information on plaque, gingivitis, the periodontium, and the microbiology of the mouth to set the context so we are all understanding the language.

The Microbiology of the Mouth
GSN: When you stop brushing your teeth, bacteria in the mouth adhere to the oral sulcus with highly specific mechanisms. After the attachment, the aggregate organize themselves around teeth structures to produce dental plaque or what you call dental biofilm. This is a sticky, gelatinous polysacchariade mass that harbors physically structured microbial communities. Over time or upon removal, it can harbor pathogenic disease-causing species in large numbers. This is demonstrated and it causes inflammation or gingivitis. Gum disease is the most common disease, even for the health conscious. This local inflammation tries to protect the body against the onslaught of the bacterial infection resulting in the vessels being more permeable, bleeding, and activation of complement clotting and kinin systems. Without removal of these bacteria, you have invasion of these bacteria into the tissues, causing a lot of systemic effects. Unknown to many people, we actually have immune cells (our polymorphonuclear neutrophils) coming out from the gingival sulcus to fight against the bacteria every day in normal individuals. This is something that most physicians-and most people-don’t realize. The neutrophils are actually attracted there by the bacteria and the antigens. They would go there to phagocyte hosts that digest and clear away the bacteria. However, if they are not able to clear away the bacteria, the inflammation becomes even more enlarged. The proinflammatory cytokines produced in the tissues by the fibroblasts, which are the predominant cells of the gums, would elaborate prostaglandins, interleukin-1beta, interleukin-6, interleukin-8, tumor necrosis factor alpha, and interferon gamma, which are mediators that modulate inflammation, both locally and systemically. The systemic endocrine effect evidence is supported by the findings of increased hepatic production of C-reactive proteins and fibrinogen among patients with periodontal disease. In fact, we also see it in production of specific antibodies to the oral organisms in the peripheral blood. This is the systemic relationship and we can give you evidence the periodontitis, although it can be a local inflammation, has a big systemic link.

JB: This is absolutely remarkable. When we are talking about chronic inflammation, I think many of us forget the importance of the oral cavity as a reservoir or as an incubator for inflammatory triggers. This reminds me slightly of the work of Barry Marshall with H. pylori and peptic ulcer disease. Dr. Marshall, who subsequently won the Nobel Prize in medicine and physiology for his discovery, tried to get people to understand that the infection of the organism mobilized the body’s immune defense and produced this tissue destruction that was really a result of the body’s own response the stealth organism (the H. pylori). It sounds like organisms in the mouth may be producing a similar type of effect to that which he observed in the H. pylori. So it sounds like there is some similarity here about the relationship between environment, organisms, and systemic inflammation.

GSN: Definitely. And the presence of these oral organisms in the host tissue (the gingival tissue) can cause it to become ulcerated when it is diseased. When you are eating or chewing or talking, you are actually pushing all of these bacteria and their products into the sub-epithelial components to exert systemic inflammatory response. That would activate, also, the monocyte/macrophage access and upregulate catabolic cytokines and inflammatory mediators. We know that with the upregulation of all these proinflammatory mediators and cytokines there is also a change in the serum lipid metabolism, causing a lot of changes, like the upregulation of C-reactive protein and the fibrinogen, and that induces atherosclerosis through the ICAM-1 expression and clot formation. That brings us to the co-relationship with heart disease.

JB: Before we take that step, can I just stop [you there]? For some of our individuals who are not dental practitioners, they may forget or not be mindful of some of the early clinical science–things like shrinkage of gums, or bleeding gums upon brushing, or some of the things that maybe they haven’t correlated in their minds as being really markers of soft and hard tissue inflammatory processes. Can you help us understand, from your expertise, what the mouth looks like when we start to see these processes occurring? What kind of warning signs does the patient present with?

Warning Signs to Look For in the Mouth
GSN: In the very initial stage, you will have reddening of the gums and there will be bleeding, and the patient might complain of pain or discomfort. If it is looked at more closely and probed, then you would be able to elicit some bleeding in the gums, or when you use a brush to get into the gingival sulcus and that draws blood, that is really an indication that there is already inflammation going on at the base of gingival sulci.

JB: Does shrinkage of the gums (which a lot of patients complain about-that their gums seem to be receding), is that related to this process?

GSN: Yes. Definitely. When there is a shrinkage of the gums, which can occur in younger patients, older patients, or at any age, it is also a result of the disease that has already destroyed the periodontal tissues causing loss of the gingival tissues, because healing would oscillate between destruction and tissue regeneration and repair. As the destruction of the gums carries on during the inflammation, the tissues will be lost and then the tissues will shrink, and so the patients will present with longer teeth. Sometimes patients who present with increased tooth mobility or who tell the dentist that their teeth have changed may have recurrent gum infections. Those are telltale signs that they actually have a deeper chronic inflammatory disease going on.

JB: I have heard it said that the principal risk factor for periodontal disease is poor oral hygiene (lack of proper oral hygiene-brushing and flossing), but it seems, from the way you are describing it, there may be also some systemic risk factors beyond that of the regional bacterial factor. So it may be a combination-is that what I am hearing? There may be extended risk factors to periodontal disease beyond that just of oral hygiene issues?

GSN: Definitely it is more than just oral hygiene, although the bacteria is the etiological factor in the process of this periodontal disease. It is the host response that is very much affected, so as we said earlier, the polymorphonuclear neutrophils are the first line of defense. If there are any defects in the PMN leukocytes, then there would be also a defect in the host response resulting in more structural destruction, as is seen in patients who are diabetics and patients who have autoimmune diseases like rheumatoid arthritis. Systemic conditions are also a very important part.

JB: It sounds like what you are describing is that the oral cavity is a laboratory (or an early-warning place) in the body that we should really pay attention to because it allows us to see, visually, aspects of the body’s immune system, nutritional status, and local host effects that may be not easily as seen if it is occurring inside the body, like in the vasculature. This is like a telltale, almost, for us, it appears.

Clues About Systemic Health Can Be Found in the Mouth
GSN: Exactly right, and that is why, as a periodontist, I find a lot of interesting things going on inside the oral cavity and how the tissues present themselves. The type of bleeding, even, can tell me that the liver is in a very distressed state. The way the tissues are keratinized and the way the tissues behave when the patient brushes, and the way the tongue…the accumulations of the bacteria/plaque on the tongue…give me an indication of the gastrointestinal dysfunction as well, and this is where I use nutritional products (nutrigenomics) to help modulate the host response. I feel this is a very innovative way of treating periodontitis–a very nutritional and environmental/lifestyle way of helping the patient to get their health back by boosting up their immunity because 80{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of our immune cells come from the gut.

JB: I think what you just said is extraordinarily important for those who are listening because what you are really emphasizing is that the oral cavity is a biomarker for the functional status of the immune, neurologic, and endocrine systems and that what we are really looking at, therefore, is this network of physiological function, of which the oral cavity is one of the important barometers. So this is very consistent with the functional medicine model and needs to be brought much more into the examination and evaluation of the patient, it would seem, from what you just said.

GSN: Exactly right. Over the years I have learned more about functional medicine and I have incorporated it into my practice. I am able to see more results-better results-without having to use drugs and antibiotics in the treatment of periodontitis/gingivitis, and I am helping patients to get back to that balance of health. Of course, lifestyle factors like smoking, inadequate sleep, and chronic stress (the three most important lifestyle factors affecting the progression of periodonditis) have to be addressed, and this is something that I would also have to address with patients during periodontitis treatment.

JB: With that in mind, let’s now shift back to where you were going: let’s look at the systemic diseases that are linked with periodontal infections. Maybe you can help us to understand the breadth of those conditions, which have been demonstrated in the literature to have a connection.

Systemic Conditions Research Shows to be Associated with Periodontal Disease
GSN: Cardiovascular disease, preterm/low-birth-weight babies, diabetes, rheumatoid arthritis, and adrenal and respiratory diseases have been linked with periodontal infections and there are many papers and research that have been supporting these findings. Recently some of these papers indicate that periodontal disease causes changes in the systemic physiology. A recent paper in The Lancet suggested that there is a close association with a predisposition for certain kinds of cancers, like pancreatic and kidney cancers.12 To understand the cellular molecular mechanisms responsible for the cyclical association, I think one must identify the common physiological changes that produce the synergy when periodontal disease and systemic conditions coexist.

Let’s look at the cardiovascular system. In the infection theories, the dental infections are risk factors for atherosclerotic disease because the streptococcus protein is associated with platelet aggregation. Porphymonas gingivalis activate and have been known to multiply in endothelial cells and contribute to acute thromboembolic events. A distant injury by the circulating oral microbiotoxins promotes cardiovascular pathologies, like the Gram-negative polysaccharides, which would induce the adipose production of interleukin-6 and that would upregulate the C-reactive proteins. So this distant inflammation from the locally produced cytokines would exert systemic effects, causing changes in the serum lipid levels and increasing the serum C-reactive proteins. You know that with an increase in C-reactive proteins of rapid origin, there is an induction of the ICAM-1 expression and the clot formation, and contribution to atherogenesis.

JB: So when we look at this extraordinary mechanism that correlates or connects periodontitis to systemic disease, I think one of the questions I’ve heard people ask (who are not nearly as familiar with this topic as you) is, “Do we think periodontitis causes this, or is it just an associative risk factor?” In other words, is it an effect or is it a cause that really relates to the linkage to cardiovascular disease or type 2 diabetes? An analogy would be cholesterol: we know that cholesterol is very highly correlated (when it is elevated) with the increasing risk to heart disease, but the question is, does it cause it or is it just an associative factor? What is your opinion? Do you believe that the infection in the periodontium in the oral cavity is the causative agent or is it the effect of other things that are leading to this immunological disturbance?
GSN: I think there are cyclical events surrounding when these two conditions coexist, such that one would augment the other. And there is also a possibility that oral inflammation, with an increase of the serum proinflammatory cytokines and the change in the immune response (where the antibodies to the bacteria are not effective against the microorganisms in the biofilm), forms immune complexes and cross reacts with the host tissues, further causing damage. A constant bacteremia is induced when the person eats and chews (you are actually pushing bacteria into your circulation system). That, in itself, upregulates and sets the stage and can even predispose the patient to the onset of diabetes and coronary heart disease because of the upregulation of the inflammatory markers, the bacteremia, and the change in the immune response (the upregulation of the proinflammatory cytokines and probably a reduction of the cofactors). It is a cyclical association.

JB: Yes. That’s a wonderful explanation, and that fits so nicely into the functional medicine matrix network model. In your presentation I recall you cited a very interesting study on carotid intimal medial thickness, which I think was Desvarieaux’s work from 2005, correlating periodontal bacterial burden with CIMT.13 Can you remind our listeners of that study? That sounds very, very interesting.

GSN: In this study, which was an epidemiological study of 1000 patients where they had no history of myocardial infarct or stroke, using DNA techniques and B-mode ultrasound, they were able to find that the intima medial thickness was closely related with antibody levels, and stroke and coronary heart disease were more influenced by the periodontal microorganisms than the antibody titer levels that were high. The elevated antibodies appeared to be associated with periodontal disease and chronic systemic conditions (that is, the coronary heart disease and diabetes). That is why dentists and physicians both have to be on the alert for this. I show in my presentation that I picked up, through orthopantomography (OPG), a thickening (or rather a calcification) of a carotid erythema. I quickly referred the patient to the cardiologist for intervention and possibly saved him (I hope) from myocardial infarct or a stroke. I have had patients who have also reported that prior to their stroke they had actually recurring dental infections (oral infections) and they felt that that contributed to the onset of their stroke. This is a real-life scenario that we have to be paying attention to as well, before the evidence comes out, to show the direct correlation.

JB: This is one of those kinds of “goosebump” discussions for me that is so interesting and has so many implications. Last month we had the privilege of interviewing Professor Delzenne and Dr. Cani from Louvain Catholic University, who are working on the obesity/enteric bacteria connection. They have demonstrated that obesity in animals is related to the kinds of bacteria that live in their gut, and they can actually cause obesity to be treated by just changing bacterial flora in the gut. Now we are talking about the oral cavity with bacterial burden of different potential pathogens and inflammatory response. I wonder if there is any connection among obesity, periodontal disease, and, say, diabetes or heart disease. Is a connection starting to be seen there?

Obesity and Periodontal Disease
GSN: Yes, definitely. The recent data is that obesity is considered as one of the risk factors for periodontal disease because obesity, itself, alters the metabolic and endocrine function of the adipose tissue, resulting in increased production of fatty acids, hormones, cytokines, and acute phase reactants. So the obesity constitutes the low-grade chronic inflammatory state. Increase in the body mass index is associated with increase in number and size of adipose sites, which are highly active metabolically, producing large amounts of TNF alpha and interleukin-6; one-third of circulating interleukin-6 is produced in adipose tissue. TNF alpha also produces insulin resistance at the receptor level. So similarly, periodontal disease is associated with increased cytokine levels of tumor necrosis factor alpha, interleukin-6, predisposing the patient to insulin resistance. It is also clinically experienced that patients who are obese also have a more inflamed state of their periodontia.

JB: How about the connection to metabolic syndrome or insulin resistance/hyperinsulinemia (which is often one of the risk factors-increased waist-to-hip ratio and central adiposity)? Do you see any connection in insulin resistance with that of periodontal disease or has that not been demonstrated?

GSN: There is a model where insulin resistance, which is induced by the TNF alpha production, and which is exacerbated by obesity, would cause (also) an increase in hyperinsulinemia and hyperglycemia (worsening the glycemic index), priming the patient for worsening of the diabetes and priming that patient for periodontal disease. In periodontal disease patients we also find that they have an increase of serum lipid level changes, like the LDP cholesterol and triglycerides, and this also upregulates the C-reactive proteins in the liver and primes the patient also for heart disease. Definitely there is an inter-relationship of diabetes and cardiovascular disease with periodontal disease.

JB: That is really fascinating (the way you are describing it). Again, it sounds like it is almost like what we would call a dog chasing its tail: the infection can increase inflammation, inflammation can then blunt insulin sensitivity, blunted insulin sensitivity results in hyperinsulinemia, which then adversely affects the immune system to increase more inflammation. So it sounds like what we are talking about is a cycle of amplified potential pathology, as you get a patient into that situation where they have the periodontal infection, and then away they go with inflammation and insulin resistance. One makes the other worse, it sounds like to me.

GSN: Yes, exactly right. In fact, you can have infections (non-periodontal infections) and that could also produce worsening of the insulin resistance and aggravate a glycemic control. Once the infection is controlled, the insulin resistance can persist for weeks or months after the clinical recovery from the infection. Although periodontal treatment can reduce the Gram-negative infections and inflammation and restore the insulin sensitivity over time, it can still result in improved metabolic control.

JB: That is a nice segue or transition into probably what a lot of our listeners are thinking now, and that is, “What are the therapeutic options, then, for patients that have periodontal disease in these systemic inflammatory conditions? How do you approach this?” Maybe you could tell us a little bit about (from a dental practitioner’s perspective and from a systemic integrative practitioner’s perspective) how one approaches this?

Therapeutic Options for Periodontal Disease
GSN: The key role is played by the presence of bacteria, so of course for a dentist, our main focus and target would be the removal of these bacteria as a requirement for periodontal disease treatment. That would include professional methods of removal with repeated scaling and good cleaning, whether surgically or non-surgically; the use of antibiotics, systemically and locally; and administered, where needed, the use of antiseptics. One new approach is actually reduction of the serum lipid levels, which seems promising, and the introduction, also, of omega-3 fatty acids to help with the resolution of the healing phase of the inflammation after the periodontal treatment, because it has been found that the omega-3 fatty acids are able to promote the resolution of the inflammation. And, of course, teeth brushing on a regular basis is very important because microbiofilm is a tenacious physical barrier. It protects the bacterial colonies from the effects of antibiotics, antiseptics, and host defense mechanisms. I feel that the most effective is still tooth brushing. It is a very humbling experience, but it is actually preventing the growth of the bacteria into very complex microbiofilms, where we need very strong germicides or biocides to kill these biofilms and cause a lot of other damage along the way. They even disrupt the bacteria within the gut. My main tool is actually the toothbrush and teaching the patient how to brush. It goes back to basics: brushing with water is good enough, and brushing correctly and precisely and at regular intervals.

JB: That is really important information. That is the “news-to-use” that is very powerful. I think your concept of destroying biofilms systemically by giving drugs versus regionally by doing it mechanically, that is a very important point for everybody to keep in mind-that these biofilms can be very tough to get rid of, and when you try to treat them systemically you are treating a lot of things that you probably don’t want to have an effect on, so the regional mechanical disruption using brushing sounds really wise. Because more and more people are moving away from hand brushing to mechanized brushing using various types of devices that are electrically driven, do you find the same benefit from the kinds of electromechanical brushing devices that you do with a hand brush?

Brushing: Is Low Tech Best?
GSN: Manual tooth brushing allows you to feel things very closely and it lets you experience it correctly. If you have a motorized brush it can be too fast for you to feel. I think that we have a lot of sensation in our gums, and it is there for a purpose-for us to feel it and to know whether we are brushing correctly. The design of the brush, where you have fine bristle ends to get into the healthy gingival sulcus, is very important to prevent further build up of the biofilm in the gingival sulci. Whether you use mechanical or whether you use manual is really up to you, but the method and precision of doing it on a regular basis is very important. I fully embrace technology where you can use it to help you and take out the tedium of tooth brushing. Of course, some people are oral enthusiasts and they brush away their gums. It has to be closely monitored and supervised. Each person has to be taught exactly how to brush their teeth because the gingival biotype and the gingival morphology around all of the teeth are different. I believe that this can be done by everybody. If you are not so dexterous you may need a motorized toothbrush to help you, but I have taught brushing to blind patients and they can be very good at it. It is a very kinesthetic kind of technique and I think many people-once they get it and they feel it and they experience it-are able to take it home. This would even help them to prevent any cardiovascular events, even.

Website Recommended for More Information
JB: Very, very powerful information. I want you to say a few words in close, if you would, about the magnificent website: www.thesystemiclink.com. Can you tell us a little bit about that? I think it is really very important.

GSN: They did a lot of studies in oral hygiene and how oral hygiene strategies can be instituted to prevent cardiovascular events. Of course this web link can be shared with everybody.

JB: For anybody that wants kind of the bibliography, they can really find tremendous referential support for what you’ve been talking about. You are an amazing person. You are not only obviously a very attentive dentist and one who is bringing the skill of your craft to your patients, but you are also expanding this sphere of influence to people around the world. What an important topic as we move into this age of more and more opportunistic infection and its relationship to chronic disease.

GSN: I feel that periodontal disease, with dental care, is highly preventable, and it can be very simple. It starts with just a toothbrush and water and awareness. You can prevent a lot of other systemic problems that can result from the build-up of biofilm, so why not make it freely available information to people and make it part of a routine in life and normalcy? People should not be afraid of brushing their teeth-of feeling their mouth-because that feeling/feedback that they get is a big indication to them as to how their immune system is doing and how the inflammation state is through the presence of bacteria and pathogens in the mouth. If people can really grasp this, they can really help themselves a lot and prevent diseases. I think everybody wants to go into old age happily and healthily without having to incur more hospital visits and hospital costs. I think if oral care can be instituted as simply as possible (without fear), we would be helping patients a lot, eventually physicians as well.

JB: Dr. Gan, I want to thank you so much. This has been a very illuminating visit with you. It is not only that you have contextualized this in a wonderfully supportive way, but you have given us some real news-to-use to take away from this. Oftentimes people might come away from these discussions saying, “That was very interesting, but I’m not sure what I should really do.” In this case it is very clear, from your directive, what should be done. I think coming to the website, www.thesystemiclink.com, can provide them with the next step. Thank you and we wish you the very, very best in your continued work and look forward to sharing with you at another time.

GSN: Thank you very much again.

I’m not sure if this issue of Functional Medicine Update has hit you as it has hit me, but this has been a very kind of profound “a-ha” issue for me. The story that we have been telling for (now) 27 (going on 28) years in Functional Medicine Update is really starting to become rich, deep, mature, and powerful. It is incorporating discoveries across many, many disciplines, and it is demonstrating the convergence of those discoveries around a theme: that the way we have been approaching medicine over the previous 100 years, to look for the cause of a disease and treat it with a drug or a specific surgery, is only part of the story. That if we really want to understand “the” story of the rising tide of the burden of chronic disease, we have to broaden the lens of understanding into these areas of contributing factors that modulate genomic and epigenomic expression patterns and ultimately regulate how cells, tissues, organs, organ systems and whole bodies respond to the world in which they find themselves.

The Sacred Law of Salads
I came across a recent paper, whose title I think probably sounds very esoteric, but it is a really interesting paper that really ties much of this together. The title is “Giacomo’s Castelvetro’s Salads. Anti-HER2 Oncogene Nutraceuticals Since the 17th Century?”14 Now, does that get your interest at all? What does that all mean “Giacomo Castelvetro’s Salads, Anti-HER2 Oncogene Nutraceuticals Since the 17th Century”? It goes something like this (just to show you why this issue of Functional Medicine Update has been so profound for me): “We are accumulating evidence to suggest that 17th century Renaissance foodways–largely based on old “Mediterranean dietary traditions”– may provide new nutraceutical management strategies against HER2-positive breast cancer disease in the 21st century. Epidemiological and experimental studies begin to support the notion that “The Sacred Law of Salads” (i.e., raw vegetables, plenty of generous olive oil)–originally proposed in 1614 by Giacomo Castelvetro in his book The Fruit, Herbs & Vegetables of Italy–might be considered the first ( unintended) example of customized diets for the management of chronic disease, including breast cancer prevention, based upon individual genetic make-up… First, the so-called salad vegetable dietary patterns (i.e., a high consumption of raw vegetables and olive oil) appears to exert a protective effect confined to the HER2-positive breast cancer subtype with no significant influence on the occurrence of HER2-negative breast cancers. Second, all the main olive oil constituents (i.e., the omega-9 monounsaturated fatty acid and polyphenolic compounds such as the secoiridoid glycoside oleuropein or the lignin acetoxypinoresinol dramatically reduce HER2 expression and specifically induce apoptotic cell death in cultured HER-2-positive breast cancer cells, with marginal effects against HER2-negative cells. Third, an olive oil-rich diet negatively influences experimental mammary tumorigenesis in rats, likewise decreasing HER2 expression.” If early 1600s Castelvetro’s salads can be used as dietary protocols capable of protecting women against biologically aggressive HER2 –positive breast cancer subtypes, then what else might we see-what spreading effect might this have-on reduction of the burden of chronic disease? Who are those that are most susceptible to positive influence and how can you reduce the triggers that ultimately weave their way into the phenotype of complex disease? That is the theme I think that we are taking away from the last several months of Functional Medicine Update. I would say it is the dawn of “back to the future”-reappropriating old knowledge in new ways. Thanks for being with us.


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